Anti-plasma kallikrein antibody dosing regimen for treating plasma kallikrein-associated disorders

Abstract

The present invention describes methods, eg, dosing regimens, for administering anti-plasma kallikrein antibodies to treat plasma kallikrein-associated disorders, including hereditary angioedema (HAE).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 387,187, filed December 13, 2022; U.S. Provisional Patent Application No. 63 / 482,674, filed February 1, 2023; U.S. Provisional Patent Application No. 63 / 446,299, filed February 16, 2023; U.S. Provisional Patent Application No. 63 / 491,335, filed March 21, 2023; U.S. Provisional Patent Application No. 63 / 498,163, filed April 25, 2023; U.S. Provisional Patent Application No. 63 / 518,023, filed August 7, 2023; and U.S. Provisional Patent Application No. 63 / 597,115, filed November 8, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION

[0002] The present invention relates to the field of plasma kallikrein and plasma kallikrein-related disorders, including hereditary angioedema (HAE), as well as to therapeutic antibodies, particularly anti-plasma kallikrein (pKal) antibodies, and methods for treating plasma kallikrein-related disorders, including HAE, more particularly dosing regimens for treating plasma kallikrein-related disorders by administering anti-pKal antibodies. [Background technology]

[0003] background

[0003] Plasma kallikrein (pKal) is a serine protease and a potential drug target for various inflammatory, cardiovascular, infectious (sepsis), and oncological diseases (Sainz IM et al., Thromb Haemost 98, 77-83, 2007). Activation of pKal amplifies intrinsic coagulation via feedback activation of factor XII and potentiates inflammation via production of the pro-inflammatory nonapeptide bradykinin. As the primary kininogenase in the circulation, plasma kallikrein is primarily responsible for the production of bradykinin in the vascular system.

[0004] Hereditary angioedema (HAE) is caused by a rare autosomal dominant disorder that results in a deficiency of functional C1 esterase inhibitor (C1-INH), a serpin family protein that blocks the activity of plasma kallikrein (pKal). Insufficient inhibition of pKal results in acute, painful, and unpredictable attacks of angioedema (swelling under the skin) and excessive production of bradykinin, a vasoactive inflammatory mediator that causes swelling (edema) of the face, limbs, abdomen, and airways (Zuraw BLet et al., N Engl J Med 359, 1027-1036, 2008). Such attacks, often triggered by unknown triggers, can have potentially life-threatening consequences.

[0005] The majority of HAE cases (types I and II) are caused by mutations in the SERPING1 gene, which result in a reduction in the amount (type I, approximately 85% of patients) or function (type II, approximately 15% of patients) of the C1-esterase inhibitor protein (C1-INH) encoded by this gene (Busse et al., 2021, J Allergy Clin Immunol Pract., 9:132-150 e133; Zuraw, 2008, N Engl J Med, 359:1027-1036). Fully functional C1-INH inhibits the activity of two key enzymes in the contact activation system, factor XIIa (FXIIa) and pKal; a deficiency in the amount or function of C1-INH leads to uncontrolled activity of these enzymes (Craig et al., 2012, Allergy Asthma Proc, 22, 354-361). Uninhibited contact pathway activity in types I and II HAE leads to widespread, uncontrolled proliferation of bradykinin production by plasma kallikrein, resulting in excessive and pathological edema and pain (Zeerleder et al., 2016, Ann Med. 48(4):256-267).

[0006] The estimated prevalence of types I and II HAE ranges from 1 in 10,000 to 1 in 50,000, with an estimated fewer than 8,000 patients in the United States and fewer than 15,000 in Europe (Busse et al., 2021, J Allergy Clin Immunol Pract., 9:132-150 e133; Lumry et al., 2018, Front Med (Lausanne), 5:22; Nzeako et al., Arch Intern Med., 151:2417-2429. Patients with HAE are typically diagnosed by the age of 20, with the average age of disease onset being approximately 11 years (Christiansen et al., Clinical Pediatrics, 2016, 55(10):935-942). Patients typically present to the emergency room or primary care physician with limited disease awareness and, although improving, often fail to refer to an allergist, immunologist, or HAE specialist for diagnosis. Clinical suspicion of type I and type II HAE can be confirmed by available blood tests. In addition to abnormalities in C1-INH levels and function, plasma C4 levels are always significantly reduced in the blood of most patients. The most common comorbidities associated with HAE include anxiety, depression, cardiovascular disease, hypertension, and hyperlipidemia (Banerji et al., 2017, N. Engl J Med, 376:717-728), as well as autoimmune diseases, particularly systemic lupus erythematosus and thyroid disease (Sundler Bjorkman et al., 2022, Clin Transl Allergy, 12(3):e12135). Psychiatric symptoms are not uncommon but are generally thought to be caused by the burden of the disease (Banerji et al., 2017, N. Engl J Med, 376:717-728; Lumry et al., 2018, Front Med (Lausanne), 5:22).

[0007]

[0007] Generally, there are two treatment approaches for managing the unpredictable, recurrent edema attacks typically experienced by patients with HAE: (1) an on-demand approach, in which acute treatment is administered at the onset of an attack to reduce the severity and duration of the attack, and (2) a preventative or prophylactic approach, in which treatment is administered chronically or before a predictable event to reduce the frequency and severity of future attacks. In the United States, the Food and Drug Administration has approved several on-demand and preventative therapies for the treatment of HAE, but despite the existence of these therapies, many treatment strategies fail to completely prevent HAE attacks. This is primarily due to the variability in patient response to approved medications, resulting in unpredictable and incomplete attack prevention and cumbersome treatment regimens requiring frequent administration.

[0008] For example, the dosing regimens of existing therapeutics for treating plasma kallikrein-related disorders such as HAE can be challenging for patients, whether administered orally or parenterally. TAKHZYRO® (lanadelumab-flyo), a monoclonal anti-plasma kallikrein antibody, was approved by the U.S. Food and Drug Administration in 2018 as a prophylactic medication to prevent HAE attacks, but 300 mg of the antibody must be administered every two weeks, and some patients may only be suitable for dosing up to four weeks. CINRYZE® (C1-esterase inhibitor (human)) is a purified C1 inhibitor protein (C1-INH) isolated from human blood and must be administered intravenously every three to four days. ORLADEYO® (berotralstat), a small molecule inhibitor of plasma kallikrein, must be taken orally daily. Summary of the Invention [Problem to be solved by the invention]

[0009]

[0009] Therapeutic antibodies against pKal can prevent attacks, allowing HAE patients to live more normal lives without the fear that a given activity will cause severe and potentially fatal attacks. Maintaining efficacy by suppressing the frequency and severity of attacks, coupled with reduced dosing frequency, would significantly improve the lives of people with HAE. Therefore, there is a need for a dosing strategy for HAE treatment that reduces dosing frequency to improve both patient compliance, ease of administration, and quality of life. [Means for solving the problem]

[0010] Summary of the Invention

[0010] The present invention is based in part on the discovery that antibodies that bind to plasma kallikrein, e.g., human plasma kallikrein, can be used to treat plasma kallikrein-dependent disorders such as HAE, and that treatment of these disorders with these antibodies disclosed herein can be achieved using dosing regimens that allow for less frequent dosing compared to the dosing regimens required by commercially available pKal antibodies and other therapies.

[0011]

[0011] The methods disclosed herein achieve therapeutically effective levels of pKal inhibition over long intervals of three months or more, allowing subjects with HAE to receive doses of antibody at less frequent intervals, improving the patient's quality of life and reducing the risk of severe and potentially fatal HAE attacks for several months at a time from just a single dose of antibody.

[0012]

[0012] The methods disclosed herein are designed to provide a safe and effective preventative treatment that is administered infrequently to reduce the disease burden and treatment burden in people with plasma kallikrein-associated disorders, such as HAE.

[0013] The present invention provides a method for treating a human subject with a plasma kallikrein-associated disorder, such as HAE, by administering a loading dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody to the subject; and, beginning at least about two months after administration of the loading dose, administering a maintenance dose of 150 to 1,500 mg of the anti-plasma kallikrein antibody to the subject at least about every two months thereafter. For example, the maintenance dose is administered about every three months thereafter. For example, the maintenance dose is administered about every three, four, five, six, seven, eight, nine, ten, eleven, or twelve months thereafter. The loading dose can be 600 mg, followed by a maintenance dose of 300 mg administered every three months. The loading dose can be 1,200 mg, followed by a maintenance dose of 900 mg administered every six months thereafter.

[0014] The present invention also provides a method for treating a human subject with a plasma kallikrein-associated disorder, such as HAE, by administering a loading dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody to the subject; administering a first maintenance dose of 150 to 1,500 mg of the anti-plasma kallikrein antibody to the subject about 1 to 8 weeks, e.g., 1 to 2 weeks, after the loading dose; and administering a second maintenance dose of 150 to 1,500 mg 2 to 9 months after the first maintenance dose, with subsequent maintenance doses administered every 2 to 9 months, e.g., every 3 months or every 6 months, after the second maintenance dose. The first maintenance dose, second maintenance dose, and any subsequent maintenance doses are the same dose. For example, the loading dose is in the range of 300 to 900 mg, and the maintenance dose is also in the range of 150 to 450 mg. For example, the loading dose is 600 mg and the maintenance dose is 300 mg. For example, the loading dose is 600 and the maintenance doses are all 400 mg or all 450 mg. The maintenance dose may be half the loading dose.

[0015] The present invention also provides a method for achieving circulating blood levels of anti-plasma kallikrein antibody greater than 10 μg / mL for at least two months in a subject with a plasma kallikrein-associated disorder, e.g., hereditary angioedema (HAE), by administering a loading dose followed by a maintenance dose of an anti-plasma kallikrein antibody to the subject, e.g., blood levels greater than 10 μg / mL for about three months.

[0016] The present invention also provides a method for treating a human subject with a plasma kallikrein disorder by administering to the subject a first dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody, followed by a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody at a first time period following administration of the first dose, and then administering one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody to the subject at intervals equal to the first time period. The first dose, the second dose, and any subsequent doses are the same amount. The first time period can be 3 to 9 months, e.g., 3 months, or 6 months or 9 months. The first time period can be 12 months. The dose can be 500 to 1,500 mg or 600 to 1,200 mg, e.g., 600 mg, e.g., 800 mg, e.g., 900 mg, or e.g., 1,200 mg.

[0017] The present invention also provides a method for treating a human subject with a plasma kallikrein disorder by administering to the subject a first dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody, followed by administering to the subject a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody a first time period following administration of the first dose; and administering to the subject a third dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody a second time period equal to the first time period, followed by administering to the subject one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody at intervals equal to a third time period longer than the first and second time periods. The first dose, the second dose, and any subsequent doses are the same amount. The dose can be 500 to 1,500 mg or 600 to 1,200 mg, e.g., 600 mg or 1,200 mg. The dose can be 300 to 900 mg. The first period may be 2 to 6 months, for example, 3 months, and the third period may be 4 to 9 months, for example, 6 months. The first period may be about 3 to 6 months, for example, 3 months, and the third period may be about 6 to 12 months, for example, 9 months, or for example, 12 months. The first period may be 1 to 4 weeks, for example, 1 week or 2 weeks, and the second period may be 3 to 6 months, for example, 3 months or 6 months.

[0018] The present invention further provides a method of treating a human subject having a plasma kallikrein disorder by administering to the subject a first dose of 300 to 2,000 mg, e.g., 300 to 900 mg, of an anti-plasma kallikrein antibody, and administering to the subject a second dose of 300 to 2,000 mg, e.g., 300 to 900 mg, of the anti-plasma kallikrein antibody after a first period of time following administration of the first dose, and administering to the subject a third dose of 300 to 2,000 mg, e.g., 300 to 900 mg, of the anti-plasma kallikrein antibody after a second period of time longer than the first period of time, and administering to the subject one or more subsequent doses of 300 to 2,000 mg, e.g., 300 to 900 mg, of the anti-plasma kallikrein antibody at intervals equal to the second period of time. The first dose, second dose, third dose, and any subsequent doses are the same amount. The first period can be 1 to 8 weeks, for example, 1 to 2 weeks, and the second period can be 3 to 6 months. For example, the first period can be 1 week and the second period can be 3 months, or the first period can be 1 week and the second period can be 6 months. The first period can be 2 to 6 months, for example, 3 months, and the second period can be 4 to 9 months, for example, 6 months. The first period can be 2 to 6 weeks, for example, 4 weeks ± 2 weeks, for example, 2 weeks, for example, 4 weeks, for example, 6 weeks; the second period can be 3 to 9 months, for example, 6 months. The second period can also be 5 months. The dosage can be 500 to 1,500 mg or 600 to 1,200 mg, for example, 600 mg or 1,200 mg. The dosage can be 300 to 450 mg. The dosage can be 600 mg. The dosage can be 700 mg. The dosage can be 800 mg. The dose may be 900 mg. The dose may be 1,200 mg. The second dose may be administered approximately 3 months after the first dose, the third dose may be administered approximately 12 months after the second dose, and subsequent doses may be administered at 12-month intervals after the third dose, such that the subject receives a dose of antibody approximately every 12 months after the second dose. The dose may be 1,200 to 1,500 mg, for example, 1,200 mg, for example, 1,300 mg, for example, 1,400 mg, or for example, 1,500 mg. The dose may be 1,200 mg.

[0019]

[0019] The present invention further provides a method for treating a human subject with a plasma kallikrein disorder by administering to the subject a first dose of 300-2,000 mg of an anti-plasma kallikrein antibody, followed by one or more treatment cycles consisting of a first subsequent dose of 300-2,000 mg of the antibody, followed by a second subsequent dose of 300-2,000 mg of the antibody. In a treatment cycle, the first subsequent dose is administered a first period of time after the first dose or a third period of time after the second subsequent dose of the previous treatment cycle, the third period of time being equal to the first period of time; and the second subsequent dose is administered a second period of time after the first subsequent dose. In this embodiment, the first period of time is shorter than the second period of time; and the first dose, first subsequent dose, and second subsequent dose are of the same amount. The first period can be 2 to 6 weeks, e.g., 4 weeks ± 2 weeks, e.g., 2 weeks, e.g., 4 weeks, e.g., 6 weeks; the second period can be 3 to 9 months, e.g., 6 months. The second period can be 5 months. For example, a first dose is administered, followed by a treatment cycle consisting of (a) a first subsequent dose administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and (b) a second subsequent dose administered 6 months after the first subsequent dose. The dose can be, for example, 500 to 1,500 mg, e.g., 600 to 1,200 mg, e.g., 600 mg. For example, a first dose may be administered, followed by a treatment cycle consisting of (a) a first subsequent dose administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and (b) a second subsequent dose administered 5 months after the first subsequent dose. The dose may be, for example, 500 to 1,500 mg, e.g., 600 to 1,200 mg, e.g., 600 mg. The dose may be administered subcutaneously. The plasma kallikrein disorder may be HAE. The first period may be 1 to 2 weeks, and the second period may be 3 to 6 months, e.g., 3 or 6 months. The dose may be 300 to 900 mg.

[0020] The present invention further provides a method for treating a human subject with a plasma kallikrein disorder, such as HAE, by administering a treatment cycle of an anti-plasma kallikrein antibody to the subject. The treatment cycle comprises administering a first dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody to the subject, followed by administering a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody to the subject a first period of time after the administration of the first dose, and then repeating the treatment cycle one or more times after a second period of time from the second dose, wherein the second period is longer than the first period and the first and second doses are the same. For example, the first period can be 4 weeks ± 2 weeks, and the second period can be 5 weeks ± 2 weeks or 6 weeks ± 2 weeks. The dose can be 600 to 1,200 mg, e.g., 600 mg. The treatment cycle can be, for example, about 6 months, with the first period plus the second period being about 6 months. The treatment cycle may be, for example, about 7 months, such that the first period plus the second period is about 7 months. The first period may be 1 to 2 weeks, and the second period may be 3 to 6 months, e.g., 3 months or 6 months. The dose may be 300 to 900 mg.

[0021] According to these methods, any loading dose, or any first dose, second dose, optional third dose, or any subsequent dose can be in a range selected from 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, or 450 to 500 mg. The loading dose, or any first dose, optional second dose, optional third dose, or any subsequent dose can be in a range of 500 to 2,000 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose may be 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 850-900 mg, 900-50 mg, 950-1,000 mg, 1,000-1,050 mg, 1,050-1,100 mg, 1,100-1,150 mg, 1,150-1,200 mg, 1,200-1,250 mg, or 1,300-1,400 mg. The dose may be within a range selected from 50 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg, 1,350 to 1,400 mg, 1,400 to 1,450 mg, 1,450 to 1,500 mg, 1,500 to 1,550 mg, 1,550 to 1,600 mg, 1,600 to 1,650 mg, 1,650 to 1,700 mg, 1,700 to 1,750 mg, 1,750 to 1,800 mg, 1,800 to 1,850 mg, 1,850 to 1,900 mg, 1,900 to 1,950 mg, or 1,950 to 2,000 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 600 to 900 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 300 to 900 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 300 to 450 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 450 to 600 mg.The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 600 to 750 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 750 to 900 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be within a range selected from 900 to 1,200 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose may be 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1 ,175mg, 1,200mg, 1,225mg, 1,250mg, 1,275mg, 1,300mg, 1,325mg, 1,350mg, 1,375mg, 1,400mg, 1,425mg, 1,450mg, 1,475mg, 1,500mg, 1,525mg, 1,550mg, 1,575mg, 1,600mg, 1,625mg, 1,650mg, 1,675mg, 1,700mg, 1,725mg, 1,750mg, 1,775mg, 1,800mg, 1,825mg, 1,850mg, 1,875mg, 1,900mg, 1,925mg, 1,950mg, 1,975mg, or 2,000mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, may be 300 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose may be 400-450 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose may be 600 mg.The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose, can be 900 mg. The loading dose, or any first dose, any second dose, any third dose, or any subsequent dose can be 1,200 mg.

[0022] According to these methods, the maintenance dose (including any first maintenance dose, second maintenance dose, or subsequent maintenance dose) can be in the range of 250 to 1,500 mg. For example, the maintenance dose can be 250 to 300 mg, 300 to 350 mg, 350 to 400 mg, 450 to 500 mg, 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, ... The maintenance dose may be within the range of 1,050 mg, 1,050-1,100 mg, 1,100-1,150 mg, 1,150-1,200 mg, 1,200-1,250 mg, 1,250-1,300 mg, 1,300-1,350 mg, 1,350-1,400 mg, 1,400-1,450 mg, or 1,450-1,500 mg. For example, the maintenance dose may be within the range of 300-450 mg. The maintenance dose may also be within the range of 150-250 mg, or may be 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg. For example, maintenance doses are 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, and 950 mg The maintenance dose is selected from the group consisting of 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, and 1,500 mg. In one particular embodiment, the maintenance dose is 300 mg, while in another embodiment, it is 450 mg. In one embodiment, the maintenance dose is within the range of 150 to 500 mg. The maintenance dose may be half the amount of the loading dose.

[0023]

[0023] Any of the above loading doses can be used together with the above maintenance doses. For example, the loading dose can be 600 mg and the maintenance dose can be 450 mg. Alternatively, the loading dose can be 600 mg and the maintenance dose can be 300 mg. For example, the loading dose can be 300 to 900 mg, and the maintenance dose can be half the loading dose.

[0024]

[0024] According to the method of the present invention, the loading dose and the maintenance dose can be administered subcutaneously to the subject. Alternatively, the loading dose and the maintenance dose are administered intravenously to the subject. Furthermore, optionally, the subcutaneous dose is administered from a pre-filled syringe, an automatic injection device, or via an on-body or wearable injection device. When administered intravenously, the dose is administered as a bolus injection or by infusion.

[0025] According to the method of the present invention, the anti-plasma kallikrein antibody is administered to a subject at a concentration of 100 to 200 mg / mL, for example, 100 to 150 mg / mL or 150 to 200 mg / mL. For example, the concentration can be 100 mg / mL, 150 mg / mL, or 200 mg / mL.

[0026] According to the methods of the invention, the loading dose maintains a blood concentration, e.g., serum concentration or plasma concentration, of the antibody above about 10 μg / mL for about two months, e.g., above about 12 μg / mL for about three months. Similarly, the maintenance dose may maintain a blood concentration, e.g., serum concentration or plasma concentration, of the antibody above about 10 μg / mL for about two months, e.g., above about 12 μg / mL for about three months.

[0027] A subject administered an anti-plasma kallikrein antibody according to these aforementioned methods may experience a reduction in the number of HAE attacks per month, compared to the subject's baseline number of attacks per month before treatment began; for example, the reduction from baseline may be about 75-90% or about 75-100%. The subject may also experience a reduction in the severity of HAE attacks, compared to the subject's baseline attack severity before treatment with the methods disclosed herein began. The methods disclosed herein may also reduce the subject's Angioedema Quality of Life Score (AEQoL) by at least 6 points, at least 10 points, at least 15 points, or at least 20 points, compared to the subject's AEQoL score before treatment with the methods disclosed herein began. The methods disclosed herein may also reduce the subject's level of activated plasma kallikrein, compared to the subject's baseline before treatment began, optionally with the plasma kallikrein level measured about monthly.

[0028]

[0028] In certain embodiments, the anti-plasma kallikrein antibody is formulated into a pharmaceutical composition comprising a pharmaceutically acceptable excipient. For example, the pharmaceutical composition comprises an anti-plasma kallikrein antibody, such as STAR-0215, and histidine, L-methionine, sorbitol, glycine, and polysorbate 80. More specifically, the pharmaceutical composition comprises an anti-plasma kallikrein antibody, such as STAR-0215, and 10 mM histidine-HCl, 75 mM glycine, 10 mM L-methionine, 150 mM sorbitol, and 0.05% w / v polysorbate 80 at pH 5.8.

[0029]

[0029] According to these methods, the anti-plasma kallikrein antibody may have a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region containing M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

[0030]

[0030] In some embodiments, the anti-plasma kallikrein antibody may have an immunoglobulin heavy chain variable region comprising CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3; and an immunoglobulin light chain variable region comprising CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 5, and CDRL3 having the amino acid sequence of SEQ ID NO: 6; the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

[0031]

[0031] In other embodiments, the anti-plasma kallikrein antibody may have an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

[0032] In certain embodiments, the anti-plasma kallikrein antibody can have an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. The antibody can have an IgG1 constant domain. For example, the antibody can be STAR-0215.

[0033] In some embodiments, the subject treated according to the disclosed methods is a human subject. [Brief explanation of the drawings]

[0034] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0034] Figure 1 is a schematic diagram of the biochemical and cellular processes leading to hereditary angioedema caused by deficiencies in the amount or function of C1-INH. Abbreviations: B1R GPCR = G protein-coupled receptor bradykinin receptor 1; B2R GPCR = G protein-coupled receptor bradykinin receptor 2; C1-INH = C1 esterase inhibitor; des-R9-BK = des-Arg(9)-bradykinin; FXII = factor XII; FXIIa = factor XIIa; HMWK = high molecular weight kininogen. [Figure 2A]

[0035] Figure 2A shows that STAR-0215 ​​inhibits plasma kallikrein-mediated cleavage of HMWK in cynomolgus monkeys. Figure 2A is a Western blot showing intact HMWK and cleaved HMWK (endogenous pKal substrate). Control HQC, MQC, and LQC, with approximately 99, 67, and 18% cHMWK, are shown to the right of each blot. Figure 2A shows Western blots of intact HMWK and cHMWK from control animals and animals administered 10, 30, and 100 mg / kg of STAR-0215 ​​up to 43 days. [Figure 2B] Figure 2B shows that STAR-0215 ​​inhibits plasma kallikrein-mediated cleavage of HMWK in cynomolgus monkeys. Figure 2B is a line graph showing data from Western blot analysis, showing percentage (%) cHMWK ± SD (n=3) over the study period. [Figure 2C]

[0035] STAR-0215 ​​inhibits plasma kallikrein-mediated cleavage of HMWK in cynomolgus monkeys. Figure 2C is a Western blot showing intact HMWK and cleaved HMWK (endogenous pKal substrate). Control HQC, MQC, and LQC with approximately 99, 67, and 18% cHMWK are shown to the right of each blot. Figure 2C shows Western blots from control and animals treated with STAR-0215 ​​(100 mg / kg) for up to 127 days. [Figure 3]

[0036] 1 is a graph of the results of a pharmacokinetic model predicting the target concentration of STAR-0215 ​​required to produce long-term inhibition of pKal. The graph shows the predicted serum concentration of STAR-0215 ​​(μg / mL) over time. The shaded area indicates the level of plasma kallikrein in patients during an HAE attack and is the target concentration expected to completely inhibit plasma kallikrein in patients during an HAE attack. The highest line on the graph is the 600 mg dose, the middle line is 300 mg, and the lowest line is 100 mg. The modeling results indicate that the target concentration of STAR-0215 ​​can be achieved with a single dose of 100 mg or greater. The target concentration expected to completely inhibit pKal in patients during an HAE attack (shown in green). [Figure 4]

[0037] FIG. 1 is a schematic outlining the Phase 1a study design to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of STAR-0215 ​​in healthy adult subjects. [Figure 5]

[0038]

[0023] Figure 1 is a series of bar graphs showing the level of pKal activation and inhibition by STAR-0215, as determined by the level of cleaved high molecular weight kininogen (cHMWK) as a percentage of cHMWK + intact HMWK over time in plasma samples from study cohorts following ex vivo activation of plasma with Factor XIIa. Data are presented from left to right for placebo, the 100 mg cohort, the 300 mg cohort, and the 600 mg cohort, providing the level of cleaved high molecular weight kininogen (cHMWK) as a percentage of cHMWK + intact HMWK over time from Day 1 to Day 84 for each cohort. Data are expressed as mean + SD % cHMWK; n = 6 subjects for each time point in each dose group unless otherwise noted. 100 mg, n = 7 at all time points; 600 mg, Days 56 and 84, n = 5. The shaded area at the bottom of each graph indicates the average level of cHMWK in non-activated plasma samples (12%). [Figure 6]

[0039]

[0023] Figure 1 is a series of bar graphs showing the level of pKal activation, as determined by the level of cleaved high molecular weight protein (cHMWK) in plasma samples taken from the study cohorts pre-dose and on days 2 and 6 after STAR-0215 ​​administration, when activated ex vivo by Factor XIIa. The shaded area at the bottom of the graph indicates the level of cHMWK in the non-activated plasma samples. Data are expressed as mean + SD. Pre = pre-dose. Statistics are calculated by one-way ANOVA versus pre-dose for each dose level. * = p<0.05; ** = p<0.005; *** = p<0.0005 [Figure 7A]

[0040] Figure 7A is a graph showing the level of pKal activation as determined by high molecular weight cleavage levels (cHMWK) in plasma samples collected from the test cohorts. Figure 7B is a bar graph showing the level of pKal activation from pre-dose to day 84 for the 300 mg and 600 mg cohorts after STAR-0215 ​​administration, as activated ex vivo by factor XIIa. Data presented as mean + SD; STAR-0215 ​​statistics calculated by a mixed-effects model with Dunnett's correction for multiple comparisons versus pre-dose of STAR-0215; *=p<0.05; **=p<0.01; ***=p<0.0002. The shaded area at the bottom of each graph indicates the level of cHMWK in the non-activated plasma sample. A comparison with similar parameters for the anti-pKal antibody lanadelumab, as reported in Chyung et al. (Ann Allergy Asthma Immunol, 2014, 113:460-466), is provided in the right panel. [Figure 7B]

[0040] Figure 7B is a graph showing the level of pKal activation as determined by high molecular weight cleavage levels (cHMWK) in plasma samples collected from the test cohorts. Figure 7B is a line graph showing the level of pKal activation from days 1 to 224 after administration in the 300 mg SC and 600 mg SC STAR-0215 ​​cohorts and up to day 84 in the 1,200 mg SC STAR-0215 ​​cohort, when activated ex vivo by factor XIIa, as determined by Western blot. Data are mean + / - SD, p<0.05 using t-test. [Figure 8]

[0041] 1 is a line graph showing serum levels of STAR-0215 ​​in cohorts of healthy study subjects who received a single 100 mg, 300 mg, or 600 mg bolus subcutaneous injection of STAR-0215. Serum levels from days 1 to 84 for each cohort are provided. The dotted horizontal line indicates the concentration threshold of 12 μg / mL (80 nM) associated with clinical benefit. The mean (SD) concentrations of STAR-0215 ​​over time are shown. [Figure 9A]

[0042] Figure 9A shows line graphs depicting serum levels of STAR-0215 ​​in cohorts of healthy study subjects receiving 300 mg (■) and 600 mg (▲) bolus subcutaneous injections of STAR-0215. Figure 9A shows levels from Day 1 and through Day 84 for the 300 mg cohort, and from Day 1 through Day 56 for the 600 mg cohort (as data was only available through Day 56). Levels in each graph are compared to lanadelumab (◆) as reported by Chyung et al. (Ann Allergy Asthma Immunol, 2014, 113:460-466). PK comparisons of t, T, C, and CL are shown in the figure table. T = half-life; T = time to maximum concentration; C = maximum concentration; CL = clearance. [Figure 9B]

[0042] Figure 9B is a line graph showing serum levels of STAR-0215 ​​in cohorts of healthy study subjects who received 300 mg (■) and 600 mg (▲) bolus subcutaneous injections of STAR-0215. Figure 9B provides the levels for the 300 mg cohort shown in Figure 9A, but also includes levels for the 600 mg cohort through Day 84. The levels in each graph are compared to lanadelumab (◆) as reported by Chyung et al. (Ann Allergy Asthma Immunol, 2014, 113:460-466). PK comparisons of t, T, C, and CL are shown in the figure table; CL was not available for the 600 mg cohort, as shown in Figure 9B, because none of the cohort members met the calculation criteria (*). In the 300 mg cohort, only one subject met the CL calculation criteria and had a reportable CL (**), as shown in Figure 9B. T1 / 2 = half-life; Tmax = time to maximum concentration; Cmax = maximum concentration; CL = clearance [Figure 10]

[0043] 1 is a graph of the results of a pharmacokinetic model predicting the target concentration of STAR-0215 ​​required to produce long-term inhibition of pKal. The graph shows the predicted serum concentrations of STAR-0215 ​​in μg / mL over time for doses of 300 mg, 450 mg, 600 mg, and 900 mg. The dashed horizontal line indicates the target level of 12 μg / mL (80 nM) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. Modeling results indicate that concentrations of STAR-0215 ​​greater than 12 μg / mL can be maintained for 84 days (3 months) with single doses of 450 mg or greater. [Figure 11A]

[0044] 11A and 11B are graphs showing simulated human PK profiles based on various dosing regimens of STAR-0215. Figure 11A shows the simulated human PK profile based on a 600 mg loading dose on day 0 with 300 mg maintenance doses delivered at 84-day (3-month) intervals after the initial loading dose. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. As shown in Figure 11A, the model-simulated dosing regimen maintains a steady-state concentration of STAR-0215 ​​above 80 nM (12 μg / mL), which is 27 μg / mL. The results suggest that STAR-0215 ​​may provide clinical benefit with less frequent dosing, for example, every 3 months or even every 6 months. [Figure 11B] 11B shows simulated human PK profiles based on various dosing regimens of STAR-0215. Figure 11B shows simulated human PK profiles based on a 600 mg dose on day 1, again on day 28, and every six months thereafter. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. In Figure 11B, the model-simulated dosing regimen maintains a steady-state concentration of STAR-0215 ​​above 80 nM (12 μg / mL), which is 16 μg / mL. The results suggest that STAR-0215 ​​may provide clinical benefit with less frequent dosing, such as every three months or even every six months. [Figure 12]

[0045] Schematic diagram outlining the Phase 1b / 2 study design to evaluate the safety, tolerability, clinical activity, pharmacokinetics, pharmacodynamics, and immunogenicity of STAR-0215 ​​in participants with hereditary angioedema (HAE). The study will enroll three cohorts. Cohort 1 will receive a single dose of STAR-0215 ​​on Day 1, Cohort 2 will receive doses of STAR-0215 ​​on Days 1 and 84, and Cohort 3 will receive doses of STAR-0215 ​​on Days 1 and 28. [Figure 13]

[0046] Western blot images of intact and cleaved HMWK from representative subjects in the 100 mg, 300 mg, and 600 mg cohorts when activated ex vivo by Factor XIIa from pre-dose to day 84 post-dose are shown. The images demonstrate that STAR-0215 ​​inhibits ex vivo Factor XIIa-induced cleavage of plasma HMWK after a single subcutaneous dose, demonstrating reduced levels of pKal activation compared to placebo. [Figure 14]

[0047] Graphs showing the percent change in cHMWK from pre-dose levels in FXIIa-activated samples for all members of each cohort. Significant inhibition of cHMWK at all post-dose time points was observed for the 300 mg and 600 mg cohorts. N=6 for all cohorts. Data are mean ± SD, *=p<0.05 from pre-dose at the indicated doses and time points; not significantly different from placebo at all time points (ns). Statistical testing was two-way ANOVA with Dunnett's test for multiple comparisons. [Figure 15]

[0048] Figure 1 shows the % inhibition of plasma kallikrein activity based on an orthogonal chromogenic reporter substrate (PFR-pNA) assay, confirming dose-responsive, robust, and long-lasting inhibition of plasma kallikrein activity after a single dose of STAR-0215. N=6 for all cohorts. Data are mean ± SD, *=p<0.05 from pre-dose at the indicated doses and time points; not significantly different (ns) from placebo at all time points. Statistical testing was two-way ANOVA with Dunnett's test for multiple comparisons. [Figure 16]

[0049] Two graphs are shown generated by a population PK model predicting the pharmacokinetic duration over time of a 600 mg dose of STAR-0215 ​​administered again on Days 1 and 28 (left graph) or on Days 1 and 14 (right graph). The graphs show that predicted serum levels of STAR-0215 ​​are below the target Cmin of 12 μg / mL around 7 months (lower dotted horizontal line), while predicted serum levels of STAR-0215 ​​are below the target Cmin of 25 μg / mL around 5 months (upper dotted horizontal line). Day 1 / Day 14 dosing results in an increased Cmax compared to Day 1 / Day 28 dosing. [Figure 17A]

[0050] 17A and 17B are graphs generated by a population PK model predicting the pharmacokinetic duration of various dosing regimens administered to cohorts in the Phase 1b / 2 clinical trial described in Example 5. Figure 17A shows the simulated human PK profile for study cohort 1 based on 450 mg on Day 1. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the threshold will be maintained for at least 3 months for cohort 1. [Figure 17B] 17A and 17B are graphs generated by a population PK model predicting the pharmacokinetic duration of various dosing regimens administered to cohorts in the Phase 1b / 2 clinical trial described in Example 5. Figure 17B shows the simulated human PK profile for study cohort 2 based on a 600 mg dose on day 1 and a 300 mg dose on day 84. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that for cohort 2, the threshold is maintained for at least 6 months after the first dose or for at least 3 months after each dose. [Figure 17C]

[0050] Figure 17C is a graph generated by a population PK model predicting the pharmacokinetic duration of various dosing regimens administered to cohorts in the Phase 1b / 2 clinical trial described in Example 5. Figure 17C shows the simulated human PK profile for study cohort 3 based on a 600 mg dose administered on days 1 and again on day 28. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that for cohort 3, the threshold is maintained for at least 6 months after the first dose. [Figure 18]

[0051] FIG. 1 is a schematic diagram of the quantitative systems pharmacology (QSP) model described in Example 3, showing the interaction of STAR-0215 ​​with the plasma kallikrein-kininogen pathway. [Figure 19]

[0052] 1 shows the results of the QSP model simulation described in Example 3, showing the monthly HAE attack frequency predicted by the model for hypothetical cohorts. The top bar graph shows the results of a QSP model simulation, where Cohort 1 (n=500) received a single subcutaneous loading dose of 600 mg of STAR-0215 ​​on day 1, followed by a subcutaneous maintenance dose of 300 mg of STAR-0215 ​​every 3 months (84 days) thereafter, according to the QSP model's simulation of a single dosing regimen. The bottom bar graph shows the results of a QSP model simulation, where Cohort 2 (n=500) received a dosing regimen of 600 mg subcutaneous doses of STAR-0215 ​​on day 1, again on day 28, and every 6 months (every 168 days) thereafter. The results of each simulation are extended through 24 months from the first dose and are shown as the number of acute HAE attacks per month. [Figure 20A]

[0053] 20A and 20B are graphs showing the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. FIG. 20A shows simulated STAR-0215 ​​blood concentrations (μg / mL) over time based on administration of a 600 mg loading dose followed by 300 mg maintenance doses at 3-month intervals thereafter. The dotted horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the dosing regimen shown in FIG. 20A has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 20B]

[0053] Figures 20A and 20B show the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. Figure 20B shows simulated STAR-0215 ​​blood concentrations (μg / mL) over time (336 days) based on a 600 mg dose administered on day 1, followed by a 600 mg dose on day 28 (i.e., one month after the first dose), and then subsequent doses every six months (i.e., 600 mg every six months starting one month after the 600 mg loading dose), where Ctrough is 25.1 μg / mL, which is the concentration of STAR-0215 ​​at the end of the dosing interval. The dotted horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the dosing regimen shown in Figure 20B has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 20C]20A-20C are graphs showing the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. FIG. 20C shows simulated STAR-0215 ​​blood concentrations (μg / mL) over time based on administering a 1,200 mg dose at 6-month intervals. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the dosing regimen shown in FIG. 20C has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 20D]

[0053] Figures 20A and 20B show the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. Figure 20D shows the simulated blood concentrations of STAR-0215 ​​(μg / mL) over time based on the administration of a 1,200 mg dose followed by 900 mg every six months thereafter. The dotted horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. We predict that the dosing regimen shown in Figure 20D has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 20E]

[0053] Figures 20A and 20B show the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. Figure 20E shows the simulated blood concentrations (μg / mL) of STAR-0215 ​​over time based on administering a dose of 1,200 mg, followed by 1,200 mg three months later, followed by 1,200 mg every 12 months thereafter. The dotted horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the dosing regimen shown in Figure 20E has the potential to maintain the necessary threshold of pKal inhibition to prevent HAE attacks in HAE patients. [Figure 20F]

[0053] Figures 20A-20D are graphs showing the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. Figure 20F shows the results of Figures 20A-D overlaid on top of each other. The dashed horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that each of the dosing regimens shown in Figure 20F has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 20G]

[0053] Figures 20A and 20B are graphs showing the results of a simulation using the pharmacokinetic model described in Example 2. Various dosing regimens for STAR-0215 ​​were modeled; median blood concentrations are provided. Figure 20G shows the results of the simulation of Figure 20B, but extended to 24 months, when Ctrough is 27.0 μg / mL, the concentration of STAR-0215 ​​at the end of the dosing interval. The dotted horizontal line represents the threshold concentration of 80 nM (12 μg / mL) believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The population pK model predicts that the dosing regimen shown in Figure 20G has the potential to maintain the necessary threshold of pKal inhibition required to prevent HAE attacks in HAE patients. [Figure 21]

[0054] 1 is a graph showing mean concentrations of STAR-0215 ​​blood levels in study cohorts from the Phase 1a clinical trial cohort described in Example 4 at various time points. At day 84 post-dose, the mean blood level for the 1,200 mg cohort was 72.7 μg / mL, and at day 28 post-dose, the mean blood level for the 600 mg iv cohort was 75.4 μg / mL. [Figure 22]

[0055] Figure 1 shows the STAR-0215 ​​concentrations (μg / mL) through Day 224 in each of the 100 mg, 300 mg, and 600 mg cohorts administered STAR-0215 ​​subcutaneously, the STAR-0215 ​​concentrations (μg / mL) through Day 84 for the 600 mg cohort administered STAR-0215 ​​intravenously, and the STAR-0215 ​​concentrations (μg / mL) through Day 112 for the 1,200 mg cohort administered STAR-0215 ​​subcutaneously. The dotted horizontal line indicates the concentration threshold of 12 μg / mL (80 nM) associated with potential clinical benefit. For the 100 mg cohort, n=7, except from Day 140 onwards, where n=6. For the 600 mg cohort, n=6, except from Day 56 onwards, where n=5. For the 1,200 mg cohort, n=6, except at the 12-hour time point, where n=5. [Figure 23]

[0056] Figure 1 shows the percent inhibition of plasma kallikrein activity based on an orthogonal chromogenic reporter substrate (PFR-pNA) assay for the 300 mg subcutaneous (SC), 600 mg SC, and 1,200 mg SC cohorts through Day 224. Percent inhibition was determined relative to the pre-dose time point. Statistically significant inhibition of ex vivo FXIIa-activated plasma kallikrein activity was observed through Day 84 after single doses of 300 mg and 600 mg, and through Day 224 after a single dose of 1,200 mg SC. N = 6 for all cohorts, except for the 600 mg SC cohort, where N = 5 from Day 56 onwards. Data are mean ± SD, * = p < 0.005 from pre-dose at the indicated doses and time points; not significantly different (ns) from placebo at all time points. Statistical testing was a t-test of the change from baseline equal to 0 at each time point without multiplicity adjustment. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description of the Invention

[0057] The present invention provides methods and compositions for treating plasma kallikrein-associated disorders, such as hereditary angioedema (HAE). The present invention is based, in part, on the discovery that antibodies that bind to plasma kallikrein, e.g., human plasma kallikrein, can be used to treat plasma kallikrein-dependent disorders, such as HAE, and that treatment of these disorders with the antibodies disclosed herein can be achieved using dosing regimens that allow for less frequent dosing compared to dosing regimens required by commercially available pKal antibodies and other therapies.

[0036]

[0058] The methods disclosed herein achieve therapeutically effective levels of pKal inhibition over intervals as long as three months or more, allowing subjects with HAE to receive doses of antibody at less frequent intervals, improving the patient's quality of life, while reducing the likelihood of severe and potentially fatal HAE attacks for several months at a time from just a single dose of antibody.

[0037]

[0059] As shown in Figure 1, HAE cases (Types I and II) can be caused by a deficiency of C1-INH, resulting in the uncontrolled activation of plasma kallikrein, which leads to the overproduction of bradykinin, a key mediator of the vasodilation, angioedema, and swelling of the face, limbs, abdomen, and airways that characterize HAE attacks (Zuraw et al., 2008, Expert Opin Investig Drugs, 17:697-706). Inhibition of plasma kallikrein with the anti-plasma kallikrein antibodies disclosed herein reduces the cleavage of high-molecular-weight kininogen (HMWK) and the formation of bradykinin, thereby preventing the characteristic angioedema seen in HAE patients.

[0038]

[0060] The methods of the present invention are designed to provide a safe and effective preventative treatment that is administered infrequently to reduce the disease burden and treatment burden in people with plasma kallikrein-associated disorders, such as HAE.

[0039] 1.Definition

[0061] To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0040]

[0062] As used herein, the term "antibody," e.g., anti-plasma kallikrein antibody, refers to a full-length or intact antibody containing two immunoglobulin heavy chains, each associated with an immunoglobulin light chain. Although the antibody is bivalent, each binding site binds to the same target, e.g., plasma kallikrein.

[0041]

[0063] As used herein, the term "chronic administration" refers to continuous, regular, long-term administration of a drug, e.g., a plasma kallikrein antibody, e.g., STAR-0215, without substantial interruption, i.e., regular administration. For example, to treat a plasma kallikrein-associated disorder such as HAE, chronic administration of a drug can be daily, twice weekly, once weekly, every two weeks, monthly, every two months, every three months, every four months, every five months, every six months, or more, or combinations thereof, over a period of several months or years to achieve long-term disease control in a subject.

[0042]

[0064] As used herein, the term "complementarity-determining region" or "CDR" refers to an immunoglobulin hypervariable domain that determines specific antibody binding. CDRs are located within four framework regions (FRs). CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. Generally, from the N-terminus to the C-terminus, both light chain variable domains and heavy chain variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As used herein, "HCDR1," "HCDR2," and "HCDR3" refer to CDR1, 2, or 3, respectively, of the heavy chain variable region, and "LCDR1," "LCDR2," and "LCDR3" refer to CDR1, 2, or 3, respectively, of the light chain variable region.

[0043]

[0065] The assignment of amino acids to each CDR is generally based on the Kabat definition (e.g., Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 thed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem., 32:1-75; Kabat, et al., (1977) J. Biol. Chem., 252:6609-6616) or Chothia's definition (see, e.g., Chothia, et al., (1987) J. Mol. Biol., 196:901-917 or Chothia, et al., (1989) Nature, 342:878-883), but not according to the IMGT (see, e.g., Lefranc (2005), Nucl. Acids Res., 33, D593-D597; Lefranc et al., (2003), Dev. Comp. Immunol., 27, 55-77; Lefranc et al. al., (2005), Dev. Comp. Immunol., 29, 185-203 (2005); Lefranc et al., (2005), Dev. Comp. Immunol., 2005, 29, 917-938) or AbM (see, e.g., Martin, et al., (1989) Proc. Natl. Acad. Sci. USA, 86, 9268-9272; Pedersen et al., (1992), Immunomethods, 1, 126; Rees et al., (1996) In Sternberg MJE (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172). In addition to the Chothia and Kabat numbering scheme described above, CDRs can be determined using other approaches known in the art, including, for example, the Martin numbering scheme, the Gelfand numbering scheme, the IMGT numbering scheme, the Honneger numbering scheme, and the ABM numbering scheme (see, e.g., Dondelinger et al. (October 2018) Frontiers Immunol. 8, 2278, 1-15).

[0044]

[0066] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness."

[0045]

[0067] As used herein, the term "hereditary angioedema" or "HAE" refers to a disease or disorder caused by a genetic deficiency or dysfunction of a C1 inhibitor protein, such as human C1 inhibitor protein (C1-INH). HAE is generally characterized by excessive pKal activation and bradykinin release. Both type I and type II HAE are caused by genetic mutations in the SERPING1 gene, which encodes C1-IHN; however, type I results in a deficiency of C1-INH, whereas type II results in dysfunctional C1-INH. "HAE" as used herein also includes type III HAE, in which C1-INH levels and function are normal but patients experience similar bouts of painful edema associated with pregnancy or estrogen intake (e.g., via oral contraceptives). Type III HAE can involve mutations in factor XII, but not in all cases. In all types of HAE, an unknown trigger causes painful edema (swelling) of the skin and / or mucous membranes, such as the face, larynx, hands, feet, gastrointestinal tract, and / or genitals. In some embodiments, HAE refers only to Type I and Type II HAE.

[0046]

[0068] As used herein, the term "human plasma kallikrein" or "human pKal" refers to residues 391-638, shown in bold below, of the human prekallikrein protein (Unipot P03952, KLKB1) having the following amino acid sequence: [ka] The mature form of human prekallikrein contains a signal peptide sequence of amino acid residues 1-19 that can be cleaved during its post-translational processing. Thus, the mature form of human prekallikrein comprises residues 20-638 of SEQ ID NO: 24. Factor XIIa cleaves human pre-kallikrein at R390 / I391 to produce human plasma kallikrein (pKal).

[0047]

[0069] As used herein, the term "loading dose" refers to an initial, higher dose or dosing regimen of a drug, e.g., an anti-plasma kallikrein antibody, administered to a subject at the beginning of a treatment course. A loading dose can achieve the blood concentration of the drug required for the drug's therapeutic effect more quickly than a lower dose. A loading dose can also allow the steady-state concentration of the drug, e.g., an anti-plasma kallikrein antibody disclosed herein, to be achieved more quickly after administration of a maintenance dose. For example, a loading dose can be used to achieve a certain blood concentration (e.g., as measured in serum or plasma) of the drug, e.g., an anti-plasma kallikrein antibody, required for the drug's therapeutic efficacy, e.g., the blood concentration required to inhibit plasma kallikrein in a subject suffering from a plasma kallikrein-dependent disorder, e.g., HAE.

[0048]

[0070] As used herein, the term "maintenance dose" refers to a dose of a drug, e.g., an anti-plasma kallikrein antibody, that is typically lower than the loading dose of the drug and is administered subsequently. A maintenance dose can be administered to a subject to maintain the steady-state concentration of the drug and maintain the therapeutic effect of the drug achieved by the loading dose. For example, a maintenance dose can be administered to maintain a desired blood concentration (e.g., as measured in serum or plasma) of the drug initially achieved by the loading dose over a period of time. For example, a maintenance dose is administered to maintain the blood concentration (e.g., as measured in serum or plasma) of a drug, e.g., an anti-plasma kallikrein antibody, in a subject over a period of time to inhibit plasma kallikrein in a subject suffering from a plasma kallikrein-dependent disorder, e.g., HAE. A maintenance dose can be administered periodically at regular intervals after the loading dose.

[0049]

[0071] As used herein, the term "month" refers to a period of at least 28 days, e.g., 28 days or 4 weeks. In certain embodiments, one month is 28 days. Thus, for example, three months is 84 days or 12 weeks, and six months is 168 days or 24 weeks. The term "about" with respect to months refers to a variation of ±10%. Thus, for example, the term "about one month" means 28 days ±10%, i.e., 28 days ±2.8 days, including 28 days ±2 days, and the term "about three months" means a period of 84 days ±10%, i.e., ±8.4 days, including 84 days (12 weeks) ±1 week.

[0050]

[0072] As used herein, "regular administration" or "administered regularly" refers to administration with intervals between doses. For example, regular administration includes administration at regular intervals that may recur (e.g., weekly, monthly, every two months, every three months, etc.).

[0051]

[0073] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent, e.g., an antibody, such as an anti-plasma kallikrein antibody described herein, with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic applications.

[0052]

[0074] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" refers to a molecular entity, compound, composition, material, and / or dosage form that does not produce adverse allergic or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by relevant regulatory authorities, e.g., USFDA Office of Biologics specifications. "Pharmaceutically acceptable" and "pharmacologically acceptable" can mean approved or capable of being approved by a federal or state regulatory agency or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, more particularly humans.

[0053]

[0075] The term "pharmaceutically acceptable carrier" includes any and all solvents, excipients, fillers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are involved in the transport or transfer of a pharmaceutical agent from one organ or part of the body to another. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0054]

[0076] As used herein, a "pharmaceutically acceptable excipient" refers to a substance that aids in the administration to and / or absorption by a subject of an active agent, such as an anti-plasma kallikrein antibody disclosed herein, without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, such as phosphate buffered saline, emulsions (such as oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, dextrose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, as required, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not deleteriously react with the compositions disclosed herein. For examples of excipients, see Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0055]

[0077] As used herein, "plasma kallikrein-associated disorders" refers to conditions caused by the function or abnormal expression of plasma kallikrein. These conditions include, but are not limited to, hereditary angioedema (including type I, type II, or type III), bradykinin-dependent edema, diabetic macular edema, retinal edema, factor XII-associated cold autoinflammatory syndrome (FACAS), rheumatoid arthritis, gout, intestinal bowel disease, oral mucositis, neuropathic pain, inflammatory pain, spinal stenosis degenerative spinal disease, arterial or venous thrombosis, postoperative ileal, aortic aneurysm, osteoarthritis, vasculitis, edema, cerebral edema, pulmonary embolism, stroke, ventricular assist device or stent-induced coagulation, head trauma or peritumoral cerebral edema, sepsis, acute middle cerebral artery (MCA) ischemic event (stroke), restenosis (e.g., after angioplasty), systemic lupus erythematosus nephritis, Alzheimer's disease, and burns.

[0056]

[0078] As used herein, the term "STAR-0215" or "STAR-215" refers to an anti-plasma kallikrein antibody having two heavy chains and two light chains. Each heavy chain has the amino acid sequence of SEQ ID NO: 9, and each light chain has the amino acid sequence of SEQ ID NO: 10. STAR-0215 ​​is a humanized IgG1 kappa light chain monoclonal antibody.

[0057]

[0079] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods and compositions of the present invention. Such an organism is preferably a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, and rhesus monkey). More preferably, the subject or patient is a human. A subject "in need thereof" refers to a subject who has been identified as needing treatment for a condition to be treated, e.g., a plasma kallikrein-dependent disorder such as HAE, and who is being treated with the specific intent to treat such a condition. In some embodiments, the subject is an adult subject, i.e., 18 years of age or older. In some embodiments, the subject is a pediatric human subject, i.e., 0-17 years of age. In some embodiments, the pediatric human subject is 6-17 years of age or 12-17 years of age. In some embodiments, the pediatric human subject is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 years of age or older, or 17 years of age.

[0058]

[0080] As used herein, the terms "therapeutically effective amount," "therapeutically effective dose," and "effective amount" refer to an amount of a pharmaceutically active agent, e.g., an anti-plasma kallikrein antibody, that, when administered alone (or in combination with an additional therapeutic agent) to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition, or the progression of such a disease or condition, e.g., hereditary angioedema (HAE) or another plasma kallikrein-dependent disorder. A "therapeutically effective dose" also refers to an amount of antibody sufficient to result in at least partial improvement of a symptom, e.g., treatment, cure, prevention, or amelioration of an associated medical condition, e.g., HAE or another plasma kallikrein-dependent disorder, or an increase in the rate of treatment, cure, prevention, or amelioration of such a condition. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to the combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially, or simultaneously. An effective amount of a therapeutic agent may result in at least a 10%, 20%, 30%, 40%, or 50% improvement in a diagnostic measure or parameter. An effective amount may also result in an improvement in a subjective measure when a subjective measure is used to assess disease severity. In some embodiments, an amount is therapeutically effective if it is an amount that can be used to treat or prevent a symptom of a plasma kallikrein-dependent disorder, e.g., swelling / edema. For example, a therapeutically effective amount of an anti-plasma kallikrein antibody disclosed herein may reduce edema caused by a plasma kallikrein-dependent disorder in a subject, or the frequency of HAE attacks, and / or reduce the severity and / or duration of HAE attacks in a subject, e.g., the level and / or duration of edema experienced by the subject during an attack.

[0059]

[0081] As used herein, "therapeutically effective inhibition of plasma kallikrein" refers to a level of inhibition of pKal in a subject that is effective to treat a plasma kallikrein-dependent disorder, such as hereditary angioedema. For example, "therapeutically effective inhibition of plasma kallikrein" results from the administration of a therapeutically effective amount of an anti-plasma kallikrein antibody disclosed herein.

[0060]

[0082] As used herein, the term "threshold blood concentration (or level)" or "threshold circulating concentration (or level)" refers to the concentration of a drug, i.e., the circulating concentration, that must be achieved in the blood for the drug, e.g., an anti-plasma kallikrein antibody, to have a desired therapeutic effect, e.g., inhibition of plasma kallikrein at a level sufficient to treat a plasma kallikrein-dependent disorder, e.g., to reduce the frequency and / or severity and / or duration of HAE attacks or edema caused by the plasma kallikrein-dependent disorder. As used herein, "blood concentration (or level)" refers to the circulating blood level of a drug, e.g., an anti-plasma kallikrein antibody. In some embodiments, blood concentrations or levels (including threshold blood concentrations or levels) are measured as serum concentrations. In other embodiments, blood concentrations or levels (including threshold blood concentrations) are measured as plasma concentrations.

[0061]

[0083] As used herein, the term "treat" or "treatment" includes inhibiting, preventing, or postponing symptoms associated with a disorder or preventing their occurrence, and / or reducing the severity and / or duration of symptoms of such disorders, such as a plasma kallikrein-dependent disorder, e.g., HAE. The term further includes ameliorating existing uncontrolled or undesirable symptoms, preventing further symptoms, and ameliorating or preventing the underlying cause of such symptoms, e.g., plasma kallikrein activation that causes the symptoms of a plasma kallikrein-dependent disorder, e.g., HAE. For example, "treating" a plasma kallikrein-dependent disorder, e.g., HAE, can include inhibiting, preventing, or reducing the frequency of attacks in a subject and / or reducing the severity of attacks and / or achieving therapeutically effective inhibition of plasma kallikrein. In the context of HAE, treatment includes prophylactic measures taken to prevent HAE attacks and reduce the frequency and / or severity and / or duration of HAE attacks in a subject.

[0062] 2. Anti-plasma kallikrein antibodies

[0084] Anti-plasma kallikrein antibodies useful for treating plasma kallikrein-dependent disorders, such as hereditary angioedema (HAE), according to the present invention potently and specifically inhibit pKal activity and have long serum half-lives. For example, these antibodies specifically inhibit pKal activity (e.g., K D These antibodies possess characteristics useful for treating such disorders, including a pH-dependent FcRn binding affinity of 1.0 nM (1.0 nM), a lower affinity for prekallikrein (e.g., >1,000-fold lower affinity), and no measurable inhibitory activity against other serine proteases. Anti-plasma kallikrein antibodies useful according to the present invention contain a YTE-modified Fc domain (corresponding to M252Y, S254T, and T256E according to EU numbering) that enhances pH-dependent FcRn binding and confers extended serum half-life (e.g., 2-3 months or longer). Antibodies useful for treating plasma kallikrein-dependent disorders, including HAE, are described in International Patent Application Publication No. WO 2022 / 165130, the contents of which are incorporated herein by reference for all purposes.

[0063]

[0085] Anti-plasma kallikrein antibodies useful for treating plasma kallikrein-dependent disorders, such as HAE, according to the present invention can be defined by their CDR sequences as disclosed in Tables 1 and 2 below, using the Kabat, Chothia, IMGT, and ABM numbering schemes. It is contemplated that CDR sequences can be identified using other numbering schemes known in the art (see, e.g., Dondelinger et al. (October 2018) Frontiers Immunol. 8, 2278, 1-15).

[0064] [Table 1]

[0065] [Table 2]

[0066]

[0086] In one embodiment, the anti-plasma kallikrein antibody has a heavy chain (or heavy chain variable region) having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, 11, 17, or 22; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, 12, 18, or 23; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3, 13, or 19.

[0067]

[0087] In one embodiment, the anti-plasma kallikrein antibody has a light chain (or light chain variable region) having CDRL1 comprising the amino acid sequence of SEQ ID NO: 4, 14, or 20; CDRL2 comprising the amino acid sequence of SEQ ID NO: 5 or 15; and CDRL3 comprising the amino acid sequence of SEQ ID NO: 6, 16, or 21.

[0068]

[0088] In another embodiment, the anti-plasma kallikrein antibody has a heavy chain (or heavy chain variable region) having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, 11, 17, or 22; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, 12, 18, or 23; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3, 13, or 19; and a light chain (or light chain variable region) having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 4, 14, or 20; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 5 or 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 6, 16, or 21.

[0069]

[0089] In another embodiment, the anti-plasma kallikrein antibody has a heavy chain (or heavy chain variable region) having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain (or light chain variable region) having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 4; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 5; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 6.

[0070]

[0090] The CDRs of anti-plasma kallikrein antibodies may be defined according to the Kabat definition, where the antibody comprises the heavy chain CDRs and light chain CDRs defined by Kabat in Tables 1 and 2 above. The CDRs of anti-plasma kallikrein antibodies may be defined according to the Chothia definition, where the antibody comprises the heavy chain CDRs and light chain CDRs defined by Chothia in Tables 1 and 2 above. The CDRs of anti-plasma kallikrein antibodies may be defined according to the IMGT definition, where the antibody comprises the heavy chain CDRs and light chain CDRs defined by IMGT in Tables 1 and 2 above. The CDRs of anti-plasma kallikrein antibodies may be defined according to the ABM definition, where the antibody comprises the heavy chain CDRs and light chain CDRs defined by ABM in Tables 1 and 2 above.

[0071]

[0091] Antibodies defined by their CDRs according to the foregoing embodiments may contain in their heavy chain an IgG1 constant region comprising the M252Y, S254T, and T256E mutations, numbered according to the EU numbering index. This set of mutations, also known as "YTE" mutations, is believed to enhance pH-dependent FcRn binding and extend the serum half-life of the antibody.

[0072]

[0092] For example, in one embodiment, an anti-plasma kallikrein antibody useful according to the invention for treating a plasma kallikrein-dependent disorder, such as HAE, has a heavy chain having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 6. The heavy chain also has an IgG1 constant region with the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index.

[0073]

[0093] In some embodiments, anti-plasma kallikrein antibodies are defined by their heavy and / or light chain variable region sequences as shown in Table 3 below.

[0074] [Table 3]

[0075]

[0094] The antibody may comprise a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8. Additionally, the heavy chain of the antibody comprises an IgG1 constant region having the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index.

[0076]

[0095] In one embodiment, the anti-plasma kallikrein antibody has a heavy chain variable region sequence having the amino acid sequence of SEQ ID NO: 7. In another embodiment, the anti-plasma kallikrein antibody has a light chain variable region sequence having the amino acid sequence of SEQ ID NO: 8.

[0077]

[0096] For example, in one embodiment, an anti-plasma kallikrein antibody has a heavy chain variable region having the amino acid sequence of SEQ ID NO:7 and a light chain variable region having the amino acid sequence of SEQ ID NO:8.

[0078]

[0097] In another embodiment, the anti-plasma kallikrein antibody has a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8, and the heavy chain has an IgG1 constant region with the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index.

[0079]

[0098] In some embodiments, anti-plasma kallikrein antibodies are defined by their full-length heavy and / or light chain sequences as shown in Table 4 below.

[0080] [Table 4]

[0081]

[0099] For example, in one embodiment, the anti-plasma kallikrein antibody has a heavy chain having the amino acid sequence of SEQ ID NO: 9, which comprises an IgG1 constant region with the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; the mutated residues are underlined in Table 4 above. In another embodiment, the anti-plasma kallikrein antibody has a light chain having the amino acid sequence of SEQ ID NO: 10.

[0082]

[0100] In a further embodiment, the anti-plasma kallikrein antibody has a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10, wherein the heavy chain sequence has an IgG1 constant region with the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; the mutated residues are underlined in Table 4 above. For example, the antibody is STAR-0215.

[0083] 3. Medication and Administration

[0101] The present invention provides methods for treating a plasma kallikrein-dependent disorder, such as hereditary angioedema (HAE), in a subject diagnosed with and / or suffering from such a disorder by administering an anti-plasma kallikrein antibody disclosed herein. In particular, the methods disclosed herein treat a plasma kallikrein-dependent disorder, such as HAE, by infrequent dosing of an anti-plasma kallikrein antibody disclosed herein, for example, about monthly, about every 2 months, about every 3 months, about every 4 months, about every 5 months, about every 6 months, about every 9 months, or about every 12 months or more. Compared to other available treatments for HAE, reduced dosing frequency can result in, for example, improved patient compliance and quality of life, and better disease management.

[0084]

[0102] The methods of administering anti-plasma kallikrein antibodies disclosed herein achieve, maintain, or exceed a desired threshold blood concentration, e.g., serum or plasma concentration, of anti-plasma kallikrein antibody, ensuring therapeutically effective levels of pKal inhibition for an extended period of time, e.g., about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or even longer, e.g., about 9 months or about 12 months.

[0085]

[0103] Thus, disclosed herein are dosing regimens that maintain blood concentrations of antibodies (e.g., as measured in plasma or serum) above the threshold blood concentration required for therapeutically effective levels of pKal inhibition. The dosing regimens disclosed herein can include the following general strategies: (i) Repeated administration of fixed doses (each dose being the same) at equal or varying time intervals; (ii) Administration of doses in repeated "treatment cycles", e.g., fixed doses, where the cycles involve administration of specific doses at specific time intervals. (iii) Administration of one or more loading doses (e.g., one or more initial high doses) followed by maintenance doses (e.g., lower doses) administered at equal or varying time intervals.

[0086]

[0104] A long duration of action can be achieved by administering a single dose of an anti-plasma kallikrein antibody. For example, a single dose of an anti-plasma kallikrein antibody can be sufficient to maintain the blood concentration required for therapeutically effective levels of pKal inhibition for a period of time, such as about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or even longer, such as about 9 months or about 12 months. The duration of action of a single dose can be extended by repeated administration of the antibody according to the methods disclosed herein.

[0087]

[0105] The antibodies disclosed herein can be administered periodically, for example, about every 2, 3, 4, 5, 6, 9, or 12 months or more, to maintain blood levels of the antibody (e.g., as measured in plasma or serum) above the threshold blood level required for therapeutically effective levels of pKal inhibition. The periodically administered doses can be fixed doses of the same amount or can be different amounts, for example, a first dose that is a loading dose followed by subsequent lower maintenance doses administered periodically. For example, administration of a single dose of an anti-plasma kallikrein antibody may be sufficient to achieve, maintain, or exceed a threshold blood concentration of the antibody (e.g., as measured in serum or plasma) resulting in a therapeutically effective level of pKal inhibition for, e.g., 3 months, thereby treating a plasma kallikrein-dependent disorder, e.g., HAE, in a subject for a period of time, e.g., about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or even longer, e.g., about 9 months, or even 12 months. As the antibody is cleared from the circulation over time, another dose of the antibody is administered to the subject to bring the blood concentration of the antibody back above the threshold blood concentration for at least 2 months, at least 3 months, or more. This "another dose" may be the same amount as the first dose, or may be a different dose, e.g., a lower "maintenance dose." Dosing of the antibody can continue periodically, for example, every 2 months, 3 months, 4 months, 5 months, 6 months, or longer, for example, every 9 months or 12 months, and can be administered chronically (e.g., for several years) to treat the disorder over the patient's lifetime. In some embodiments, dosing is every 3 months. In other embodiments, dosing is every 6 months.

[0088]

[0106] In one embodiment, the anti-pKal antibody administered in accordance with the methods disclosed herein is at a concentration of about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 11 μg / mL, 12 μg / mL, 13 μg / mL, 14 μg / mL, 15 μg / mL, 16 μg / mL, 17 μg / mL, 18 μg / mL, 19 μg / mL, 20 μg / mL, 21 μg / mL, 22 μg / mL, 23 μg / mL, 24 μg / mL, 25μg / mL, 26μg / mL, 27μg / mL, 28μg / mL, 29μg / mL, 30μg / mL, 31μg / mL, 32μg / mL, 33μg / mL, 34μg / mL, 35μg / mL, 36μg / mL, 37μg / mL, 38μg / mL , 39μg / mL, 40μg / mL, 41μg / mL, 42μg / mL, 43μg / mL, 44μg / mL, 45μg / mL, 46μg / mL, 47μg / mL, 48μg / mL, 49μg / mL, 50μg / mL, 51μg / mL, 52μg / m L, 53μg / mL, 54μg / mL, 55μg / mL, 56μg / mL, 57μg / mL, 58μg / mL, 59μg / mL, 60μg / mL, 61μg / mL, 62μg / mL, 63μg / mL, 64μg / mL, 65μg / mL, 66μg / mL mL, 67μg / mL, 68μg / mL, 69μg / mL, 70μg / mL, 71μg / mL, 72μg / mL, 73μg / mL, 74μg / mL, 75μg / mL, 76μg / mL, 77μg / mL, 78μg / mL, 79μg / mL, 80μg The subject achieves a blood concentration (e.g., as measured in plasma or serum) of the antibody of, or greater than about 8 μg / mL, 81 μg / mL, 82 μg / mL, 83 μg / mL, 84 μg / mL, 85 μg / mL, 86 μg / mL, 87 μg / mL, 88 μg / mL, 89 μg / mL, 90 μg / mL, 91 μg / mL, 92 μg / mL, 93 μg / mL, 94 μg / mL, 95 μg / mL, 96 μg / mL, 97 μg / mL, 98 μg / mL, 99 μg / mL, or 100 μg / mL. In a specific embodiment, the blood, e.g., serum, concentration of anti-plasma kallikrein antibody is greater than about 8 μg / mL or about 10 μg / mL. For example, the antibody is administered to achieve a blood concentration, e.g., a serum or plasma concentration of the antibody, of greater than about 12 μg / mL.For example, the antibody is administered to provide a blood, eg, serum, concentration of the antibody of 25 μg / mL or greater.

[0089]

[0107] In one embodiment, the anti-plasma kallikrein antibody is administered according to the methods disclosed herein to a subject to increase their blood concentration (e.g., as measured in plasma or serum) to 8-20 μg / mL, 10-20 μg / mL, 12-20 μg / mL, 8-30 μg / mL, 10-30 μg / mL, 12-30 μg / mL, 8-40 μg / mL, 10-40 μg / mL, 12-40 μg / mL, 8-50 μg / mL, 10-50 μg / mL, 12- The antibody is administered to maintain blood concentrations at 50 μg / mL, 8-60 μg / mL, 10-60 μg / mL, 12-60 μg / mL, 8-70 μg / mL, 10-70 μg / mL, 12-70 μg / mL, 8-80 μg / mL, 10-80 μg / mL, 12-80 μg / mL, 8-90 μg / mL, 10-90 μg / mL, 12-90 μg / mL, 8-100 μg / mL, 10-100 μg / mL, or 12-100 μg / mL. Blood concentrations can be maintained for or exceeded over the stated time periods by administration of a single dose of antibody. The single dose can be a loading dose or maintenance dose as disclosed herein. For example, an anti-plasma kallikrein antibody is administered as a single dose to achieve a blood concentration (e.g., as measured in plasma or serum) of about 8-60 μg / mL, 10-60 μg / mL, or about 12-60 μg / mL for at least about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, or about 12 months. In one embodiment, the blood concentration is maintained for about 3 months. In one embodiment, the blood concentration is maintained for about 6 months. In one embodiment, the blood concentration is maintained for about 9 months. In one embodiment, the blood concentration is maintained for about 12 months.

[0090]

[0108] In one embodiment, the threshold blood concentration (e.g., as measured in plasma or serum) of an anti-plasma kallikrein antibody administered in accordance with the methods disclosed herein is within the range of about 60-80 nM. For example, the threshold blood concentration is within the range of about 70-80 nM or about 75-80 nM. For example, the threshold blood concentration is within the range of about 150-170 nM. In one embodiment, the blood concentration, e.g., serum concentration or plasma concentration, of the anti-plasma kallikrein antibody is greater than about 60 nM, about 61 nM, about 62 nM, about 63 nM, about 64 nM, about 65 nM, about 66 nM, about 67 nM, about 68 nM, about 69 nM, about 70 nM, about 71 nM, about 72 nM, about 73 nM, about 74 nM, about 75 nM, about 76 nM, about 77 nM, about 78 nM, about 79 nM, or about 80 nM. In another embodiment, the blood concentration, e.g., serum concentration or plasma concentration, of the anti-plasma kallikrein antibody is greater than about 100 nM, or about 110 nM, or about 120 nM, or about 130 nM, or about 140 nM, or about 150 nM, or about 160 nM. For example, in one embodiment, the serum concentration of the antibody is about 167 nM.

[0091]

[0109] The threshold blood concentration of the anti-plasma kallikrein antibody (e.g., as measured in plasma or serum) can be maintained at or exceeded for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more. The threshold blood concentration can be maintained at or exceeded for the stated period by administration of a single dose of the antibody. The single dose can be a loading dose or a maintenance dose as disclosed herein. In a particular embodiment, the threshold blood concentration is maintained at or exceeded for about 3 months. In another embodiment, the blood concentration, e.g., serum concentration or plasma concentration, of the anti-plasma kallikrein antibody is maintained at or exceeded at about 8 μg / mL or about 10 μg / mL, e.g., about 12 μg / mL, for about 3 months. In one embodiment, the anti-plasma kallikrein antibody is administered in a single dose in an amount to achieve a blood concentration, e.g., a serum concentration or plasma concentration, of the antibody that meets or exceeds, e.g., about 10 μg / mL, e.g., about 12 μg / mL, for about 3 months, or about 12 weeks, or about 84 days, or about 90 days.

[0092]

[0110] Threshold blood concentrations (e.g., when measured in plasma or serum) are 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, and 75 days. The duration of the anticoagulant effect may be maintained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 days or more. The threshold blood concentration may be maintained or exceeded for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. The threshold blood concentration may be maintained or exceeded for 3 months. The threshold blood concentration may be maintained or exceeded for 6 months. The threshold blood concentration may be maintained or exceeded for the stated period by administration of a single dose of antibody. The single dose may be a loading dose or a maintenance dose as disclosed herein. The threshold blood concentration may be maintained or exceeded at about 12-100 μg / mL, e.g., about 12 μg / mL, for the stated period by administration of a single dose of anti-plasma kallikrein antibody. The threshold blood concentration may be maintained at or above about 12 μg / mL by administration of a loading dose and subsequent maintenance doses according to the present disclosure. The threshold blood concentration may be maintained at or above about 12 μg / mL by administering constant doses at regular or variable intervals according to the present disclosure.The threshold blood concentration may be maintained at or above about 12 μg / mL by administering treatment cycles according to the present disclosure.

[0093]

[0111] The threshold blood concentration can be maintained or exceeded for about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, or more. The threshold blood concentration can be maintained or exceeded for the stated period by administration of a single dose of antibody. The single dose can be a loading dose or a maintenance dose as disclosed herein. The threshold blood concentration, e.g., serum concentration or plasma concentration, that is maintained or exceeded can be about 8 μg / mL, or about 10 μg / mL, or about 12 μg / mL, for the stated period.

[0094]

[0112] According to the methods disclosed herein, the anti-plasma kallikrein antibody can be administered at a concentration of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 875 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 925 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 975 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 850mg, about 875mg, about 900mg, Approximately 925mg, approximately 950mg, approximately 975mg, approximately 1,000mg, approximately 1,025mg, approximately 1,050mg, approximately 1,075mg, approximately 1,100mg, approximately 1,125mg, approximately 1,150mg, approximately 1,1 75mg, about 1,200mg, about 1,225mg, about 1,250mg, about 1,275mg, about 1,300mg, about 1,325mg, about 1,350mg, about 1,375mg, about 1,400mg, about 1,425mg, about 1,450mg, about 1,475mg, about 1,500mg, about 1,525mg, about 1,550mg, about 1,575mg, about 1,600mg, about 1,625mg, about 1,650mg The antibody is administered as a single dose of about 1,675 mg, about 1,700 mg, about 1,725 ​​mg, about 1,750 mg, about 1,775 mg, about 1,800 mg, about 1,825 mg, about 1,850 mg, about 1,875 mg, about 1,900 mg, about 1,925 mg, about 1,950 mg, about 1,975 mg, or about 2,000 mg to achieve a therapeutically effective level of inhibition of plasma kallikrein in a subject. The single dose may be administered periodically, for example, every 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 12 months. The single dose may be a loading dose or a maintenance dose as disclosed herein. The dose is weight-independent; in other words, the dose is an absolute or fixed dose that is independent of the patient's weight. Doses may be administered chronically and periodically at least every 2, 3, 4, 5, 6 or more months, with 3 months being a preferred period for certain doses, while 6, 9 or 12 months may be preferred for other doses.The dose can be a fixed dose for the duration of treatment (e.g., the first dose and subsequent doses are the same). For example, in one embodiment, the dose is 450 mg, administered, for example, by subcutaneous administration, for example, every three months. In another embodiment, the dose is 1,200 mg, administered, for example, by subcutaneous administration, for example, every six months. In another embodiment, the dose is 600 mg, administered, for example, by intravenous administration, for example, every six months. In another embodiment, the dose is 600 mg, administered, for example, by subcutaneous administration, for example, every six months. In another embodiment, the dose is 1,200 mg, administered, for example, by intravenous administration, for example, every 12 months.

[0095]

[0113] According to the methods disclosed herein, the anti-plasma kallikrein antibody is administered in an amount of about 100 to 600 mg, about 100 to 700 mg, about 100 to 800 mg, about 100 to 900 mg, about 100 to 1,000 mg, about 100 to 1,100 mg, about 100 to 1,200 mg, about 100 to 1,300 mg, about 100 to 1,400 mg, about 100 to 1,500 mg, about 100 to 1,600 mg, about 100 to 1,700 mg, about 100 to 1,800 mg, about 100 to 1,900 mg, about 100 to 2,000 mg, about 200 to 600 mg, about 200 to 700 mg, Approx. 200~800mg, approx. 200~900mg, approx. 200~1,000mg, approx. 200~1,100mg, approx. 200~1,200mg, approx. 200~1,300mg, approx. 200~1,400mg, approx. 700mg, approx. 200~1,800mg, approx. 200~1,900mg, approx. 200~2,000mg, approx. 300~600mg, approx. 300~700mg, approx. 300~800mg, approx. 300~900mg, approx. 300~1,000mg, approx. 300~1,100mg, approx. 1,200mg, approx. 300~1,300mg, approx. 300~1,400mg, approx. 300~1,500mg, approx. 300~1,600mg, approx. 300~1,700mg, approx. 300~1,800mg, approx. 300~1,900mg, approx. 300~2,000mg, approx. 400~600 mg, about 400-700mg, about 400-800mg, about 400-900mg, about 400-1,000mg, about 400-1,100mg, about 400-1,200mg, about 400-1,300mg, about 400-1,400mg, about 400-1,500mg, about 400-1 ,600mg, approx. 400~1,700mg, approx. 400~1,800mg, approx. 400~1,900mg, approx. 400~2,000mg, approx. 500~600mg, approx. 500~700mg, approx. 500~800mg, approx. 500~900mg, approx. ~1,100mg, approximately 500~1,200mg, approximately 500~1,300mg, approximately 500~1,400mg, approximately 500~1,500mg, approximately 500~1,600mg, approximately 500~1,700mg, approximately 500~1,800mg, approximately 500~1,900mg, approximately 500~2,000mg, approximately 600-700mg, approximately 600-800mg, approximately 600-900mg, approximately 600-1,000mg, approximately 600-1,100mg, approximately 600-1,200mg, approximately 600-1,300mg, approximately 600-1,400mg, approximately 600-1,500mg, approximately 600-1,600mg, approximately 600-1,700mg, approximately 600-1,800mg, approximately 600-1,900mg, approximately 600-2,000mg, approximately 700-800mg, approximately 700-900mg, approximately 700-1,000mg, approximately 700-1,100mg, approximately 700-1,200mg, approximately 700-1 300mg, approximately 700~1,400mg, approximately 700~1,500mg, approximately 700~1,600mg, approximately 700~1,700mg, approximately 700~1,800mg, approximately 700~1,900mg, approximately 700~2,000mg, approximately 800~900mg, approximately 800~1,000mg, approximately 800~1,100mg, approximately 800~1,200mg, approximately 800~1,300mg, approximately 800~1,400mg, approximately 800~1,500mg, approximately 800~1,600mg, approximately 800~1,700mg, approximately 800~1,800mg, approximately 800~1,900mg, approximately 800~2,000mg g, approximately 900-1,000 mg, approximately 900-1,100 mg, approximately 900-1,200 mg, approximately 900-1,300 mg, approximately 900-1,400 mg, approximately 900-1,500 mg, approximately 900-1,600 mg, approximately 900-1,700 mg, approximately 900-1,800 mg, approximately 900-1,900 mg, approximately 900-2,000 mg, approximately 1,000-1,100 mg, approximately 1,000-1,200 mg, approximately 1,000-1,300 mg, approximately 1,000-1,400 mg, approximately 1,000-1,500 mg, approximately 1,000-1,600 mg, approximately 1,000-1,700 mg Approximately 1,000-1,800 mg, approximately 1,000-1,900 mg, approximately 1,000-2,000 mg, approximately 1,100-1,200 mg, approximately 1,100-1,300 mg, approximately 1,100-1,400 mg, approximately 1,100-1,500 mg, approximately 1,100-1,600 mg, approximately 1,100-1,700 mg, approximately 1,100-1,800 mg, approximately 1,100-1,900 mg, approximately 1,100-2,000 mg, approximately 1,200-1,300 mg, approximately 1,200-1,400 mg, approximately 1,200-1,500 mg, approximately 1,200-1,600 mg, approximately 1,200-1,1 ...700mg, approx. 1,200~1,800mg, approx. 1,200~1,900mg, approx. 1,200~2,000mg, approx. 1,300~1,400m g, approx. 1,300~1,500mg, approx. 1,300~1,600mg, approx. 1,300~1,700mg, approx. 1,300~1,800mg, approx. 1, 300~1,900mg, approx. 1,300~2,000mg, approx. 1,400~1,500mg, approx. 1,400~1,600mg, approx. 1,400~1 ,700mg, approx. 1,400~1,800mg, approx. 1,400~1,900mg, approx. 1,400~2,000mg, approx. 1,500~1,600m g, about 1,500-1,700 mg, about 1,500-1,800 mg, about 1,500-1,900 mg, about 1,500-2,000 mg, about 1,600-1,700 mg, about 1,600-1,800 mg, about 1,600-1,900 mg, about 1,600-2,000 mg, about 1,700-1,800 mg, about 1,700-1,900 mg, about 1,700-2,000 mg, about 1,800-1,900 mg, about 1,800-2,000 mg, or about 1,900-2,000 mg of antibody to achieve a therapeutically effective level of inhibition of plasma kallikrein in the subject. The single dose can be a loading dose or a maintenance dose as disclosed herein. The dose is weight-independent; in other words, the dose is an absolute or fixed dose independent of the patient's weight. The dose can be administered chronically and regularly at least every 2, 3, 4, 5, 6, or more months, with every 3 months being a preferred period for certain doses, while 6, 9, or 12 months may be preferred for other doses. The dose can be a fixed dose for the duration of treatment (e.g., the first dose and subsequent doses are the same). For example, the dose can be 1,200 mg every 6 months. For example, the dose can be 1,100 to 1,500 mg every 6 months. For example, the dose can be 1,100 to 1,500 mg every 12 months. For example, the dose can be 1,200 mg every 12 months.

[0096]

[0114] Doses can be administered, for example, about monthly, every 2 months, every 3 months, every 4 months, every 5 months, or every 6 months or more, e.g., every 9 months or every 12 months. Doses can be administered at intervals to maintain a therapeutically effective level of inhibition of plasma kallikrein in the subject, e.g., about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, about every 16 weeks, about every 17 weeks, about every 18 weeks, about every 19 weeks, about every 20 weeks, about every 21 weeks, about every 22 weeks, about every 23 weeks, about every 24 weeks, about every 25 weeks, or about every 26 weeks. Doses can be fixed doses for the duration of treatment (e.g., the first dose and subsequent doses are the same), or doses can be maintenance doses (e.g., after a loading dose).

[0097]

[0115] For example, doses can be administered about every 28 days, about every 30 days, about every 35 days, about every 42 days, about every 49 days, about every 56 days, about every 60 days, about every 63 days, about every 70 days, about every 77 days, about every 84 days, about every 90 days, about every 91 days, about every 98 days, about every 105 days, about every 112 days, about every 119 days, about every 120 days, about every 126 days, about every 133 days, about every 140 days, about every 147 days, about every 150 days, about every 154 days, about every 161 days, about every 168 days, about every 175 days, about every 180 days, or about every 182 days. For example, doses are administered about every 3 months, or about every 12 weeks, or about every 90 days.

[0098]

[0116] According to the methods disclosed herein, the anti-plasma kallikrein antibody can be administered at a concentration of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 875 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 925 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 975 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 850mg, about 875mg, about 900mg, Approximately 925mg, approximately 950mg, approximately 975mg, approximately 1,000mg, approximately 1,025mg, approximately 1,050mg, approximately 1,075mg, approximately 1,100mg, approximately 1,125mg, approximately 1,150mg, approximately 1,1 75mg, about 1,200mg, about 1,225mg, about 1,250mg, about 1,275mg, about 1,300mg, about 1,325mg, about 1,350mg, about 1,375mg, about 1,400mg, about 1,425mg, about 1,450mg, about 1,475mg, about 1,500mg, about 1,525mg, about 1,550mg, about 1,575mg, about 1,600mg, about 1,625mg, about 1,650mg The antibody is administered as a single dose of about 1,675 mg, about 1,700 mg, about 1,725 ​​mg, about 1,750 mg, about 1,775 mg, about 1,800 mg, about 1,825 mg, about 1,850 mg, about 1,875 mg, about 1,900 mg, about 1,925 mg, about 1,950 mg, about 1,975 mg, or about 2,000 mg to achieve a therapeutically effective level of inhibition of plasma kallikrein in the subject. The dose can be a fixed dose for the duration of treatment (e.g., the first dose and subsequent doses are the same). The single dose can be a loading dose or a maintenance dose as disclosed herein. The dose is weight-independent; in other words, the dose is an absolute or fixed dose that is independent of the patient's weight. Doses may be administered at regular intervals to maintain a therapeutically effective level of inhibition of plasma kallikrein in the subject, for example, about every month, every two months, every three months, every four months, every five months, or every six months or more, with every three months being the preferred period for dosing.

[0099] (i) Repeated fixed dose administration

[0117] An exemplary approach involving repeated administration of fixed doses (each dose being the same) of anti-plasma kallikrein antibody is described in the following section.

[0100] A. Fixed doses administered at equal time intervals

[0118] In some embodiments of methods of treating a plasma kallikrein-dependent disorder, e.g., hereditary angioedema (HAE), using an anti-plasma kallikrein antibody, a first dose, a second dose, and subsequent doses of the anti-plasma kallikrein antibody are administered at equal intervals over the course of treatment. These doses are fixed doses (e.g., all doses are the same amount). In some embodiments, a first dose of an anti-plasma kallikrein antibody, e.g., STAR-0215, is administered to a subject, and a second dose of the anti-plasma kallikrein antibody is administered to the subject a first period of time after the administration of the first dose. Thereafter, one or more subsequent doses of the anti-plasma kallikrein antibody are administered to the subject at intervals equal to the first period of time. The first dose, second dose, and subsequent doses are the same.

[0101]

[0119] For example, the first period of time is about 3 months to about 9 months, e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. Thus, in one embodiment, if the first period of time is about 3 months, the subject receives a dose of the antibody about every 3 months. Alternatively, if the first period of time is about 4 months, the subject receives a dose of the antibody about every 4 months. Alternatively, if the first period of time is about 5 months, the subject receives a dose of the antibody about every 5 months. Alternatively, if the first period of time is about 6 months, the subject receives a dose of the antibody about every 6 months. Alternatively, if the first period of time is about 7 months, the subject receives a dose of the antibody about every 7 months. Alternatively, if the first period of time is about 8 months, the subject receives a dose of the antibody about every 8 months. Alternatively, if the first period of time is about 9 months, the subject receives a dose of the antibody about every 9 months. Alternatively, if the first period is about 12 months, the subject receives a dose of the antibody about every 12 months.

[0102]

[0120] In some embodiments, the doses are fixed, e.g., the first dose, the second dose, and any subsequent doses are the same amount. For example, the doses are 300 to 2,000 mg. For example, the doses are 500 to 1,500 mg. For example, dosages may range from 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 1,100 to 1,150 mg, 1,150 to 1,200 mg, 1,200 to 1,250 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg, 1,350 to 1,400 mg, 1,400 to 1,450 mg, 1,450 to 1,500 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 650 ... mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg. For example, the dose is 600 to 1,200 mg. For example, the dose is 1,100 to 1,500 mg. For example, the dose is 300 to 450 mg. For example, the dose is 300 mg. For example, the dose is 400 mg. For example, the dose is 450 mg. For example, the dose is 400 to 600 mg. For example, the dose is 600 mg. For example, the dose is 600 to 900 mg. For example, the dose is 700 mg. For example, the dose is 900 mg. For example, the dose is 1,200 mg. For example, in some embodiments, the dose is 1,200 mg every 6 months. In some embodiments, the dose is 600 mg every 3 months. In some embodiments, the dose is 600 mg every 6 months. In some embodiments, the dose is 700 mg every 6 months.In some embodiments, the dose is 300-450 mg every three months. In some embodiments, the dose is 400-600 mg every three months. In some embodiments, the dose is 400-600 mg every six months. In some embodiments, the dose is 600-900 mg every six months. In some embodiments, the dose is 600 mg every six months. In some embodiments, the dose is 900 mg every six months. In some embodiments, the dose is 1,200 mg every six months. In other embodiments, the dose is 1,100-1,500 mg every 12 months. In other embodiments, the dose is 900-1,500 mg every 12 months. In some embodiments, the dose is 1,200 mg every 12 months.

[0103]

[0121] In one embodiment, all doses are administered intravenously. In another embodiment, all doses are administered subcutaneously. In another embodiment, the first dose is administered intravenously, and the second and subsequent doses are administered subcutaneously. For example, the first, second, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg administered subcutaneously. For example, the first, second, and subsequent doses are 600 to 1,200 mg, e.g., 1,200 mg administered subcutaneously. For example, the first, second, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg administered intravenously. For example, the first dose, second dose, and subsequent doses may be 600 to 1,200 mg, e.g., a first dose of 1,200 mg administered intravenously, followed by a second and subsequent doses of 1,200 mg administered subcutaneously. For example, the first dose, second dose, and subsequent doses may be 600 to 1,200 mg, e.g., a first dose of 600 mg administered intravenously, followed by a second and subsequent doses of 600 mg administered subcutaneously. For example, in one embodiment, a first dose of 600 mg is administered intravenously, followed by a second dose of 600 mg administered intravenously about six months later, and then about every six months thereafter. For example, in one embodiment, a first dose of 1,200 mg is administered intravenously, followed by a second dose of 1,200 mg administered subcutaneously about six months later, and then about every six months thereafter. For example, in one embodiment, a first dose of 1,200 mg is administered subcutaneously, followed by a subcutaneous dose of 1,200 mg about six months later, and then about every six months thereafter. For example, in one embodiment, a first dose of 600-1,200 mg is administered subcutaneously, followed by a subcutaneous dose of 600-1,200 mg about six months later, and then about every six months thereafter, where all doses are the same. For example, in one embodiment, a first dose of 600-1,200 mg, e.g., 600 mg, is administered intravenously, followed by a subcutaneous dose of 600-1,200 mg, e.g., 600 mg, about six months later, and then about every six months thereafter, where all doses are the same.For example, in one embodiment, a first dose of 600 to 1,200 mg is administered subcutaneously, followed about six months later by a second dose of 600 to 1,200 mg administered subcutaneously and about every six months thereafter, where all doses are the same.

[0104] B. Fixed doses administered at varying time intervals

[0122] Other embodiments using fixed doses (i.e., doses of the same amount) of an anti-plasma kallikrein antibody, such as STAR-0215 ​​(e.g., all doses are the same) to treat a plasma kallikrein-dependent disorder, e.g., hereditary angioedema (HAE), include initially administering the dose of the antibody at a first, shorter interval and then changing to a second, longer interval between doses. In some embodiments, a first dose of the anti-plasma kallikrein antibody is administered to the subject, a first period after administering the first dose is followed by a second dose of the anti-plasma kallikrein antibody, and a second period equal to the first period is followed by a third dose of the anti-plasma kallikrein antibody. Thereafter, one or more subsequent doses of the anti-plasma kallikrein antibody are administered to the subject at intervals equal to the third period. The third period is longer than the first period and the second period. According to some embodiments, the first period can be about 2 months to about 6 months, e.g., about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months; the third period can be about 4 months to about 9 months, e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. Thus, in one embodiment, the first period is about 2 months and the third period is about 4 months, such that the subject receives a dose of the antibody about every 4 months after the third dose. Alternatively, the first period is about 3 months and the third period is about 6 months, such that the subject receives a dose of the antibody about every 6 months after the third dose. Alternatively, the first period is about 4 months and the third period is about 8 months, such that the subject receives a dose of the antibody about every 8 months after the third dose. Alternatively, the first period is about 4 months and the third period is about 9 months, such that the subject receives a dose of the antibody about every 8 months after the third dose. In some embodiments, the second dose can occur as early as 1 week after the first dose. For example, the first period can be 1 to 4 weeks, e.g., about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. For example, the first period can be about 1 week. In some embodiments, the first period can be about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, e.g., about 1 week, and the third period can be about 3 months, about 4 months, about 5 months, or about 6 months, e.g., about 3 months.In some embodiments, the first period can be about 1-8 weeks, and the third period is about 3-6 months, about 4-8 months, or about 6-9 months.

[0105]

[0123] According to another embodiment, the first period is about 2 months to about 6 months, e.g., about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, and the third period is about 6 months to about 12 months, e.g., about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. For example, the first period is 3 months, and the third period is 12 months.

[0106]

[0124] In these embodiments, the first dose, second dose, third dose, and any subsequent doses are the same amount. For example, the dose is 300 to 2,000 mg. For example, the dose is 500 to 1,500 mg. For example, dosages may range from 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 1,100 to 1,150 mg, 1,150 to 1,200 mg, 1,200 to 1,250 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg, 1,350 to 1,400 mg, 1,400 to 1,450 mg, 1,450 to 1,500 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 650 ... mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg. For example, the dose is 600 to 1,200 mg. For example, the dose is 300 to 450 mg. For example, the dose is 300 mg. For example, the dose is 400 to 600 mg. For example, the dose is 400 mg. For example, the dose is 450 mg. For example, the dose is 600 mg. For example, the dose is 700 mg. For example, the dose is 900 mg. For example, the dose is 1,200 mg. For example, the dose is 1,100 to 1,500 mg. For example, the dose is 600 to 900 mg. For example, the dose is 700 mg. For example, the dose is 900 mg.

[0107]

[0125] In one embodiment, all doses are administered intravenously. In another embodiment, all doses are administered subcutaneously. In another embodiment, the first and second doses are administered intravenously, and the third and subsequent doses are administered subcutaneously. Alternatively, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg, and are all administered subcutaneously. Alternatively, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 1,200 mg administered subcutaneously. For example, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg administered intravenously. For example, the first, second, third, and subsequent doses may be 600 to 1,200 mg, e.g., a first dose of 1,200 mg administered intravenously, followed by a second, third, and subsequent doses of 1,200 mg administered subcutaneously. For example, the first, second, third, and subsequent doses may be 600 to 1,200 mg, e.g., a first and second dose of 600 mg administered intravenously, followed by a third and subsequent doses of 600 mg administered subcutaneously. For example, a first dose of 600 to 1,200 mg may be administered, followed about three months later by a second dose of 600 to 1,200 mg, followed about three months after the second dose by a third dose of 600 to 1,200 mg, followed by doses about every six months after the third dose. All doses may be 600 mg. For example, all doses may be 600 mg, with the first and second doses administered intravenously and the third and subsequent doses administered subcutaneously. Alternatively, all doses may be 1,200 mg. For example, all doses may be 1,200 mg, with the first and second doses administered intravenously and the third and subsequent doses administered subcutaneously. Alternatively, instead of 600 mg or 1,200 mg in the preceding embodiments, the doses may be 400 to 450 mg.

[0108] C. Fixed doses administered at varying time intervals

[0126] Another embodiment using fixed doses (i.e., doses of the same amount) of an anti-plasma kallikrein antibody, such as STAR-0215 ​​(e.g., all doses are the same) to treat a plasma kallikrein-dependent disorder, e.g., hereditary angioedema (HAE), involves initially administering the antibody with a shorter interval between the first and second doses, and then changing to a second, longer interval between the remaining doses. For example, in one embodiment, a first dose of anti-plasma kallikrein antibody is administered to a subject, a second dose of anti-plasma kallikrein antibody is administered to the subject a first time period after the administration of the first dose, and a third dose of anti-plasma kallikrein antibody is administered to the subject a second time period after the administration of the first dose, which is longer than the first time period. Thereafter, one or more subsequent doses of anti-plasma kallikrein antibody are administered to the subject at intervals equal to the second time period. In these embodiments, the first dose, second dose, third dose, and any subsequent doses are fixed doses, i.e., they are the same amount. The doses may be those disclosed herein below.

[0109]

[0127] According to one embodiment, the first period can be about 2 months to about 6 months, e.g., about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, and the second period can be about 4 months to about 9 months, e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. Thus, in one embodiment, the first period can be about 2 months and the second period about 4 months, such that the subject receives a dose of the antibody about every 4 months after the second dose. Alternatively, the first period can be about 3 months and the second period about 6 months, such that the subject receives a dose of the antibody about every 6 months after the second dose. Alternatively, the first period can be about 4 months and the second period about 8 months, such that the subject receives a dose of the antibody about every 8 months after the second dose. Alternatively, the first period is about 4 months and the second period is about 9 months, such that the subject receives a dose of the antibody about every 9 months after the second dose. In another embodiment, the first period can be about 1 month to about 3 months, e.g., about 1 month. For example, the first period is about 1 month and the second period is about 6 months, such that the subject receives a dose of the antibody about every 8 months after the second dose. In these embodiments, the first dose, second dose, third dose, and any subsequent doses are fixed doses, i.e., they are the same amount. The doses may be those disclosed herein below.

[0110]

[0128] According to another embodiment, the first period is about 2 months to about 6 months, e.g., about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, and the second period is about 6 months to about 12 months, e.g., about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. For example, the first period is 3 months and the third period is 12 months, such that the subject receives a dose of the antibody about every 12 months after the second dose. The doses may be as disclosed herein below.

[0111]

[0129] In other examples, the first period is 2 to 6 weeks, or 4 weeks ± 2 weeks. For example, the first period is 2 weeks, or the first period is 4 weeks, or the first period is 6 weeks. In some examples, the second period is 3 to 9 months, or 3 to 6 months, or 6 months. In one example, the second dose is administered 2 to 6 weeks after the first dose, the third dose is administered 6 months after the second dose, and subsequent doses are administered at 6-month intervals after the third dose, such that the subject receives a dose of the antibody every 6 months after the second dose. For example, the second dose is administered 4 weeks after the first dose, the third dose is administered 6 months after the second dose, and subsequent doses are administered at 6-month intervals after the third dose, such that the subject receives a dose of the antibody every 6 months after the second dose. In another example, the second dose is administered 2-6 weeks after the first dose, the third dose is administered 5 months after the second dose, and subsequent doses are administered at 5-month intervals after the third dose, such that the subject receives a dose of antibody every 5 months after the second dose. In all of these embodiments, the first dose, second dose, third dose, and any subsequent doses are the same amount. The doses may be those disclosed herein below.

[0112]

[0130] In some embodiments, the second dose can occur as early as one week after the first dose. For example, the first period can be one to four weeks, e.g., about one week, about two weeks, about three weeks, or about four weeks. For example, the first period can be about one week. In some embodiments, the first period can be about one week, about two weeks, about three weeks, or about four weeks, e.g., about one week, and the second period can be about three months, about four months, about five months, or about six months, e.g., about three months. In some embodiments, the first period can be about one to eight weeks, and the second period can be about three to six months, about four to eight months, or about six to nine months. In some embodiments, the first period can be about one to two weeks. In some embodiments, the first period can be about one to two weeks, and the second period can be about three months. In some embodiments, the first period can be about one to two weeks, and the second period can be about three months. The doses can be those disclosed herein below.

[0113]

[0131] In one example, a first dose of 300-900 mg is administered, a second dose of 300-900 mg is administered 1-2 weeks after the first dose, a third dose of 300-900 mg is administered 3-6 months after the second dose, followed by subsequent doses of 300-900 mg at 3-6 month intervals after the third dose, such that the subject receives a dose of 300-900 mg of antibody every 3-6 months after the second dose. The first, second, third, and any subsequent doses are the same amount. The doses may be as disclosed herein below.

[0114]

[0132] In one example, a first dose of 300-900 mg is administered, a second dose of 300-900 mg is administered 1-2 weeks after the first dose, a third dose of 300-900 mg is administered 3 months after the second dose, followed by subsequent doses of 300-900 mg at 3-month intervals after the third dose, such that the subject receives a dose of 300-900 mg of antibody every 3 months after the second dose. The first, second, third, and any subsequent doses are the same amount. The doses may be as disclosed herein below.

[0115]

[0133] In one example, a first dose of 300-900 mg is administered, a second dose of 300-900 mg is administered 1-2 weeks after the first dose, a third dose of 300-900 mg is administered 6 months after the second dose, followed by subsequent doses of 300-900 mg at 6-month intervals after the third dose, such that the subject receives a dose of 300-900 mg of antibody every 6 months after the second dose. The first, second, third, and any subsequent doses are the same amount. The doses may be as disclosed herein below.

[0116]

[0134] In one example, a first dose of 600 mg is administered, a second dose of 600 mg is administered 1-2 weeks after the first dose, a third dose of 600 mg is administered 6 months after the second dose, followed by subsequent doses of 600 mg at 6-month intervals after the third dose, such that the subject receives a 600 mg dose of the antibody every 6 months after the second dose.

[0117]

[0135] In one example, a first dose of 400 mg is administered, a second dose of 400 mg is administered 1-2 weeks after the first dose, a third dose of 400 mg is administered 6 months after the second dose, followed by subsequent doses of 400 mg at 6-month intervals after the third dose, such that the subject receives a 400 mg dose of the antibody every 6 months after the second dose.

[0118]

[0136] In one example, a first dose of 400 mg is administered, a second dose of 400 mg is administered 1-2 weeks after the first dose, a third dose of 400 mg is administered 3 months after the second dose, followed by subsequent doses of 400 mg at 3-month intervals after the third dose, such that the subject receives a 400 mg dose of the antibody every 3 months after the second dose.

[0119]

[0137] In one example, a first dose of 600 mg is administered, a second dose of 600 mg is administered 2-6 weeks after the first dose, a third dose of 600 mg is administered 6 months after the second dose, followed by subsequent doses of 600 mg at 6-month intervals after the third dose, such that the subject receives a 600 mg dose of the antibody every 6 months after the second dose.

[0120]

[0138] In another example, a first dose of 600 mg is administered, a second dose of 600 mg is administered 2-6 weeks after the first dose, a third dose of 600 mg is administered 5 months after the second dose, followed by subsequent doses of 600 mg at 5-month intervals after the third dose, such that the subject receives a 600 mg dose of the antibody every 5 months after the second dose.

[0121]

[0139] In one example, a first dose of 700 mg is administered, a second dose of 700 mg is administered 2-6 weeks after the first dose, a third dose of 700 mg is administered 6 months after the second dose, followed by subsequent doses of 700 mg at 6-month intervals after the third dose, such that the subject receives a 700 mg dose of the antibody every 6 months after the second dose.

[0122]

[0140] In another example, a first dose of 1,200 mg is administered, a second dose of 1,200 mg is administered three months later, followed by subsequent doses of 1,200 mg every 12 months after the second dose. In another example, a first dose of 1,200-1,500 mg is administered, a second dose of 1,200-1,500 mg is administered three months later, followed by subsequent doses of 1,200-1,500 mg every 12 months after the second dose, where the first dose, second dose, and subsequent doses are the same.

[0123]

[0141] In some embodiments, for example, the dose is 300 to 2,000 mg. For example, the dose is 500 to 1,500 mg. For example, the dose is 300 to 500 mg. For example, the dose is 300 to 450 mg. For example, the dose is 300 to 900 mg. For example, dosages may range from 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 1,100 to 1,150 mg, 1,150 to 1,200 mg, 1,200 to 1,250 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg, 1,350 to 1,400 mg, 1,400 to 1,450 mg, 1,450 to 1,500 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 650 ... mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg. For example, the dose is 600 to 1,200 mg. For example, the dose is 400 mg. For example, the dose is 450 mg. For example, the dose is 600 mg. For example, the dose is 700 mg. For example, the dose is 900 mg. For example, the dose is 1,200 mg. For example, the dose can be 300 to 900 mg, e.g., 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg. For example, the dose can be 300 to 400 mg, 400 to 500 mg, 500 to 600 mg, 600 to 700 mg, 700 to 800 mg, or 800 to 900 mg.

[0124]

[0142] In one embodiment, all doses are administered intravenously. In another embodiment, all doses are administered subcutaneously. In another embodiment, the first dose is administered intravenously, and the second, third, and subsequent doses are administered subcutaneously. In another embodiment, the first and second doses are administered intravenously, and the third and subsequent doses are administered subcutaneously. For example, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg, and are all administered subcutaneously. For example, the first, second, third, and subsequent doses are 300 to 900 mg, and are all administered subcutaneously. For example, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 600 mg, and are all administered intravenously. Alternatively, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 1,200 mg administered subcutaneously. For example, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., 1,200 mg administered intravenously. For example, the first, second, third, and subsequent doses are 600 to 1,200 mg, e.g., a first dose of 1,200 mg administered intravenously, followed by second, third, and subsequent doses of 1,200 mg administered subcutaneously. For example, the first, second, third and subsequent doses are 600 to 1,200 mg, e.g., a first dose of 600 mg administered intravenously, followed by second, third and subsequent doses of 600 mg administered subcutaneously.

[0125]

[0143] For example, a first dose of 600-1,200 mg is administered, followed three months later by a second dose of 600-1,200 mg, followed six months later by a third dose of 600-1,200 mg, and so on every six months thereafter. For example, the dose is 600 mg. For example, the dose is 700 mg. For example, the dose is 900 mg. For example, the dose is 1,200 mg, or any other dose disclosed herein.

[0126]

[0144] In some embodiments, administration of the first dose, second dose, or subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. For example, a serum concentration of 12 μg / mL is maintained for about 5 months. For example, a serum concentration of 25 μg / mL or higher is maintained for about 5 months, for example, at a dose of 600 mg. For example, a serum concentration of 12 μg / mL or higher is maintained for about 12 months, for example, at a dose of 1,200 mg.

[0127]

[0145] In these embodiments, the antibody is STAR-0215 ​​or any of the anti-plasma kallikrein antibodies disclosed herein.

[0128] (ii) Administration in Repeat Treatment Cycles

[0146] Exemplary approaches for dosing anti-plasma kallikrein antibodies involving repeated treatment cycles, where the cycles involve administration of specific doses at specific time intervals, are described in the following sections.

[0129] D. Fixed Dose in Treatment Cycles - Approach 1

[0147] In yet another embodiment involving fixed doses (e.g., all doses are the same) of an anti-plasma kallikrein antibody such as STAR-0215 ​​for treating a plasma kallikrein-dependent disorder, e.g., hereditary angioedema (HAE), the antibody is initially administered as a first dose, followed by repeated treatment cycles of two doses at set intervals. In one example, a method is disclosed for treating a human subject with a plasma kallikrein-associated disorder, e.g., HAE, in which the subject is administered a first dose of 300-2,000 mg of an anti-plasma kallikrein antibody, followed by one or more subsequent treatment cycles of the antibody, where the treatment cycle comprises two doses: a first subsequent dose of 300-2,000 mg of the antibody, followed by a second subsequent dose of 300-2,000 mg of the antibody. The first subsequent dose is administered a first period of time after the first dose or a third period of time after the second subsequent dose of the previous treatment cycle, the third period of time being equal to the first period of time. The second subsequent dose is administered a second period of time after the first subsequent dose, the first period of time being shorter than the second period of time, and the first dose, first subsequent dose, and second subsequent dose being the same amount.

[0130]

[0148] In one embodiment, the first period (same as the third period) is 2 to 6 weeks. For example, the first period (same as the third period) is 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks, for example, 4 weeks ± 2 weeks, for example, 2 weeks, for example, 4 weeks, for example, 6 weeks. The second period can be 3 to 9 months, for example, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, or 9 months. In one example, the second period is 6 months. In another example, the second period can be 5 months. In another embodiment, the first period can be 2 to 6 months, for example, 3 months, and the second period can be 6 to 12 months, for example, 12 months. In another embodiment, the first period (same as the third period) is about 1 to 2 weeks. For example, the first period is about 1 week. For example, the first period is 2 weeks.

[0131]

[0149] In one specific embodiment, the first subsequent dose is administered 2 to 6 weeks after the first dose or 2 to 6 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 3 to 9 months after the first subsequent dose. In another specific embodiment, the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 6 months after the first subsequent dose. In another specific embodiment, the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 6 months ± 2 weeks after the first subsequent dose. In yet another specific embodiment, the first subsequent dose is administered two weeks after the first dose or two weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered six months after the first subsequent dose. In yet another specific embodiment, the first subsequent dose is administered about one week after the first dose or about one week after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered six months after the first subsequent dose. In yet another specific embodiment, the first subsequent dose is administered about one week after the first dose or about one week after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered three months after the first subsequent dose. In yet a further specific embodiment, the first subsequent dose is administered four weeks after the first dose or four weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered six months after the first subsequent dose. Each dose of antibody can be 600 mg. Each dose of antibody can be 700 mg. Each dose of antibody can be 400 mg. The dose can be any dose disclosed herein.

[0132]

[0150] In another specific embodiment, the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 5 months after the first subsequent dose. In another specific embodiment, the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose or 4 weeks ± 2 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 5 months ± 2 weeks after the first subsequent dose. In yet another specific embodiment, the first subsequent dose is administered 2 weeks after the first dose or 2 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 5 months after the first subsequent dose. In yet a further specific embodiment, the first subsequent dose is administered 4 weeks after the first dose or 4 weeks after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 5 months after the first subsequent dose. Each dose of antibody may be 600 mg. In yet another embodiment, the first subsequent dose is administered 3 months after the first dose or 3 months after the second subsequent dose of the previous treatment cycle, and the second subsequent dose is administered 12 months after the first subsequent dose. Each dose of antibody may be 1,200 to 1,500 mg, for example, 1,200 mg.

[0133]

[0151] Alternatively, each dose of antibody may be 500 to 1,500 mg or 600 to 1,200 mg, for example 600 mg, 900 mg or 1,200 mg, or any of the following: 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 500 mg. g, 950~1,000mg, 1,000~1,050mg, 1,050~1,100mg, 1,100~1,150mg, 1,150~1,200mg, 1,200 ~1,250mg, 1,250~1,300mg, 1,300~1,350mg, 1,350~1,400mg, 1,400~1,450mg, 1,450~1,50 0mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775m g, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1,000mg, 1,025mg, 1,050mg, 1 The doses may be 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg. Each dose may be administered subcutaneously.

[0134]

[0152] Alternatively, the dose can be administered intravenously. In yet another embodiment, the dose can be administered by a combination of intravenous and subcutaneous administration. For example, the first dose and the first subsequent dose can be administered intravenously, while the second subsequent dose can be administered subcutaneously.

[0135]

[0153] In one embodiment, administration of a first dose followed by a first subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months, e.g., 6 months, or administration of a second subsequent dose followed by a first subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months, e.g., 6 months, from the time of administration of the second subsequent dose. For example, a serum concentration of 12 μg / mL or greater is maintained for at least about 5 months, e.g., 6 months. For example, a serum concentration of 25 μg / mL or greater is maintained for at least about 5 months, e.g., about 6 months, for example, when the doses are 600 mg or greater, e.g., 600 mg, respectively.

[0136]

[0154] For example, in one embodiment, the first dose is 600 mg, followed by one or more treatment cycles consisting of a first subsequent dose of 600 mg administered 4 weeks ± 2 weeks after the first dose (or after the second subsequent dose of the previous treatment cycle), and a second subsequent dose of 600 mg administered 6 months after the first subsequent dose. The anti-plasma kallikrein antibody may be, for example, STAR-0215 ​​or any of the anti-plasma kallikrein antibodies disclosed herein. In yet another embodiment, the first dose is 600 mg, followed by one or more treatment cycles consisting of a first subsequent dose of 600 mg administered 4 weeks ± 2 weeks after the first dose (or after the second subsequent dose of the previous treatment cycle), and a second subsequent dose of 600 mg administered 5 months after the first subsequent dose. The anti-plasma kallikrein antibody may be, for example, STAR-0215 ​​or any of the anti-plasma kallikrein antibodies disclosed herein. In these examples, the subject may have HAE.

[0137] E. Fixed Dose in Treatment Cycles - Approach 2

[0155] In yet another embodiment involving a fixed dose of an anti-plasma kallikrein antibody such as STAR-0215 ​​for treating a plasma kallikrein-dependent disorder, e.g., hereditary angioedema (HAE), (e.g., all doses are the same), a method is disclosed for treating a human subject with a plasma kallikrein-associated disorder, e.g., HAE, comprising administering to the subject a treatment cycle of an anti-plasma kallikrein antibody, e.g., STAR-0215, or one of the anti-plasma kallikrein antibodies disclosed herein. The treatment cycle comprises administering to the subject a first dose of 300-2,000 mg of the antibody, followed by administering to the subject a second dose of 300-2,000 mg of the anti-plasma kallikrein antibody a first time period after administration of the first dose. The first and second doses are the same amount. After a second time period from the second dose, administration of the treatment cycle is repeated one or more times, wherein the second time period is longer than the first time period and the first and second doses are the same. Treatment cycles can be administered, for example, 1, 2, 3, 4, 5, 6 or more times. However, for prophylactic treatments, treatment cycles are repeated indefinitely, e.g., chronically, e.g., as long as the subject experiences clinical benefit.

[0138]

[0156] In one embodiment, the first period is 2 to 6 weeks, e.g., 4 weeks ± 2 weeks. For example, the first period can be about 2 weeks, 4 weeks, or 6 weeks. The second period can be 3 to 9 months, e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. In another embodiment, the second period can be 3 months ± 2 weeks, 4 months ± 2 weeks, 5 months ± 2 weeks, 6 months ± 2 weeks, 7 months ± 2 weeks, 8 months ± 2 weeks, or 9 months ± 2 weeks. For example, the second period is 6 months. In another example, the second period is 6 months ± 2 weeks. In another example, the first period is 1 to 2 weeks. For example, the first period is about 1 week. For example, the first period is about 2 weeks.

[0139]

[0157] In one embodiment, the second dose is administered 2 to 6 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose. In another embodiment, the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose. In yet another embodiment, the second dose is administered 2 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose. In yet another embodiment, the second dose is administered 4 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose. The treatment cycle may be repeated, for example, 6 months after the second dose.

[0140]

[0158] In one embodiment, the second dose is administered 1 to 2 weeks after the first dose, and the treatment cycle is repeated 3 to 6 months after the second dose. For example, the second dose is administered 1 week after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose. For example, the second dose is administered 1 week after the first dose, and the treatment cycle is repeated 3 months ± 2 weeks after the second dose. The dose can be any dose disclosed herein. For example, the first and second doses can be 300 to 900 mg, e.g., 300 mg, 450 mg, or 600 mg.

[0141]

[0159] In another embodiment, the second dose is administered 3 months after the first dose, and the treatment cycle is repeated 12 months after the second dose. The dose can be 1,200 mg to 1,500 mg, for example 1,200 mg.

[0142]

[0160] In some embodiments, the treatment cycle lasts about six months, e.g., six months. For example, in some embodiments, the second dose is administered 2-6 weeks after the first dose, such that the first period plus the second period equals six months, and the treatment cycle is repeated six months after the first dose. In other embodiments, the second dose is administered 4 weeks ± 2 weeks after the first dose, such that the first period plus the second period equals six months, and the treatment cycle is repeated six months after the first dose. In yet further embodiments, the second dose is administered 2 weeks after the first dose, such that the first period plus the second period equals six months, and the treatment cycle is repeated six months after the first dose. In yet further embodiments, the second dose is administered 4 weeks after the first dose, such that the first period plus the second period equals six months, and the treatment cycle is repeated six months after the first dose. In some embodiments, the first and second doses can be from about 300 mg to about 900 mg, for example, about 600 mg.

[0143]

[0161] In some embodiments, the second period is 5 months, while in other embodiments, the second period is 5 months ± 2 weeks. For example, in some embodiments, the second dose is administered 2 to 6 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose. In other embodiments, the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose. In yet further embodiments, the second dose is administered 2 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose. In yet further embodiments, the second dose is administered 4 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose. For example, the second dose may be administered 5 months after the second dose. In some embodiments, the first dose and the second dose can be about 300 mg to about 900 mg, for example about 600 mg, although the first dose and the second dose are the same.

[0144]

[0162] In some embodiments, the treatment cycle lasts for 7 months. For example, in some embodiments, the second dose is administered 2-6 weeks after the first dose, so that the first period plus the second period equals 7 months, and the treatment cycle is repeated 7 months after the first dose. In other embodiments, the second dose is administered 4 weeks ± 2 weeks after the first dose, so that the first period plus the second period equals 7 months, and the treatment cycle is repeated 7 months after the first dose. In further embodiments, the second dose is administered 2 weeks after the first dose, so that the first period plus the second period equals 7 months, and the treatment cycle is repeated 7 months after the first dose. In other embodiments, the second dose is administered 4 weeks after the first dose, so that the first period plus the second period equals 7 months, and the treatment cycle is repeated 7 months after the first dose. The first and second doses can be approximately 600 mg.

[0145]

[0163] According to certain embodiments of the method, the administration of the treatment cycle maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months from the time of administration of the first dose. For example, in some embodiments, the serum concentration is maintained at 12 μg / mL or higher for at least 5 months from administration of the first dose, while in other embodiments, the serum concentration is maintained at 25 μg / mL or higher for at least 5 months from administration of the first dose. For example, the serum concentration can be maintained for at least 6 months from administration of the first dose.

[0146]

[0164] In some embodiments, the first and second doses of the treatment cycles disclosed herein are each 500-1,500 mg. For example, the first and second doses can be 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 850-900 mg, 900-50 mg, 950-1,000 mg, 1,000-1,050 mg, 1,050-1,100 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 3,000 mg, 3,500 mg, 4,000 mg, 4,100 mg, 5,100 mg, 5,200 mg, 6,100 mg, 7,100 mg, 8,100 mg, 9,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 3,500 mg, 4,100 mg, 5,200 mg, 5,300 mg, 6,100 mg, 7,100 mg, 8,100 ,100~1,150mg, 1,150~1,200mg, 1,200~1,250mg, 1,250~1,300mg, 1,300~1,350mg, 1,350~1,400mg, 1,400~1,450mg, 1,450~1,500mg, 500mg, 525mg, 550mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg. For example, the first dose and the second dose may be 600 to 1,200 mg. In one embodiment, the first dose and the second dose are each about 600 mg, e.g., 600 mg. In one embodiment, the first dose and the second dose are each about 700 mg, e.g., 700 mg. In yet another embodiment, the first dose and the second dose are each about 900 mg, e.g., 900 mg, while in a further embodiment, the first dose and the second dose are each about 1,200 mg, e.g., 1,200 mg. In some embodiments, the first dose and the second dose are each about 400 to 600 mg. For example, the dose is 400 mg.

[0147]

[0165] According to the method disclosed herein, the first dose and the second dose of the treatment cycle can be administered subcutaneously to the subject. Alternatively, they can be administered intravenously. The first dose can be administered intravenously, and the second dose can be administered subcutaneously. The subcutaneous dose can be administered from a pre-filled syringe, an autoinjector device, or via an on-body or wearable injection device, while the intravenous dose can be administered as a bolus injection or by infusion.

[0148]

[0166] In one embodiment, a treatment cycle is a first dose of 600 mg administered to a subject, followed by a second dose of 600 mg administered to the subject 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the administration of the second dose.For example, a second dose of 600 mg can be administered 2 weeks after the first dose of 600 mg, and the treatment cycle is repeated 6 months after the first dose of 600 mg, for a complete treatment cycle of 6 months.For example, a second dose of 600 mg can be administered 4 weeks after the first dose of 600 mg, and the treatment cycle is repeated 6 months after the first dose of 600 mg, for a complete treatment cycle of 6 months.For example, a second dose of 600 mg can be administered 6 weeks after the first dose of 600 mg, and the treatment cycle is repeated 6 months after the first dose of 600 mg, for a complete treatment cycle of 6 months. For example, a second dose of 600 mg may be administered 2 to 6 weeks after the first dose of 600 mg, and the treatment cycle repeated 6 months after the first dose of 600 mg, resulting in a complete treatment cycle of 6 months. Alternatively, the dose may be 400 mg instead of 600 mg. In yet another alternative, the dose may be 700 mg instead of 600 mg. However, the first and second doses may be any of the doses disclosed herein.

[0149]

[0167] In other embodiments, a second dose of 600 mg may be administered 4 weeks ± 2 weeks after the first dose of 600 mg, with the treatment cycle repeated 6 months after the first dose of 600 mg, resulting in a complete treatment cycle of 6 months. In one embodiment, a treatment cycle involves administering a first dose of 600 mg to a subject, followed by administration of a second dose of 600 mg to the subject 4 weeks ± 2 weeks after the first dose, with the treatment cycle repeated 5 months ± 2 weeks after administration of the second dose. Alternatively, the dose may be 400 mg instead of 600 mg. In yet another alternative, the dose may be 700 mg instead of 600 mg. However, the first and second doses may be any of the doses disclosed herein.

[0150]

[0168] In yet another embodiment, a second dose of 600 mg may be administered two weeks after the first dose of 600 mg, with the treatment cycle repeated seven months after the first dose of 600 mg, resulting in a complete treatment cycle of seven months. For example, a second dose of 600 mg may be administered four weeks after the first dose of 600 mg, with the treatment cycle repeated seven months after the first dose of 600 mg, resulting in a complete treatment cycle of seven months. For example, a second dose of 600 mg may be administered six weeks after the first dose of 600 mg, with the treatment cycle repeated seven months after the first dose of 600 mg, resulting in a complete treatment cycle of seven months. For example, a second dose of 600 mg may be administered two to six weeks after the first dose of 600 mg, with the treatment cycle repeated six months after the first dose of 600 mg, resulting in a complete treatment cycle of seven months. Alternatively, the dose may be 400 mg instead of 600 mg. In yet another alternative, the dose may be 700 mg instead of 600 mg. However, the first dose and second dose may be any of the doses disclosed herein.

[0151]

[0169] For example, a second dose of 600 mg may be administered 4 weeks ± 2 weeks after the first dose of 600 mg, and the treatment cycle may be repeated 7 months after the first dose of 600 mg, resulting in a complete treatment cycle of 7 months. For example, a second dose of 600 mg may be administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle may be repeated 6 months ± 2 weeks after the administration of the second dose. For example, a second dose of 600 mg may be administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle may be repeated 5 months ± 2 weeks after the administration of the second dose. For example, a second dose of 600 mg may be administered 4 weeks after the administration of the first dose of 600 mg, and the treatment cycle may be repeated 6 months after the administration of the second dose. For example, a second dose of 600 mg may be administered 4 weeks after the administration of the first dose of 600 mg, and the treatment cycle may be repeated 5 months after the administration of the second dose. Alternatively, the dose may be 400 mg instead of 600 mg. In yet another alternative, the dose may be 700 mg instead of 600 mg. However, the first dose and the second dose may be any of the doses disclosed herein.

[0152]

[0170] In these embodiments, the subject may have HAE.

[0153] (iii) Administration of loading and maintenance doses

[0171] Exemplary approaches for dosing anti-plasma kallikrein antibodies, including a dose (e.g., one or more initial high doses) followed by maintenance doses (e.g., lower doses) administered at equal or varying time intervals, are described in the following sections.

[0154] F. Administration of Loading and Maintenance Doses

[0172] According to certain methods of treating plasma kallikrein-dependent disorders, such as hereditary angioedema (HAE), disclosed herein, a loading dose of an anti-plasma kallikrein antibody, such as STAR-0215, is administered, followed by one or more maintenance doses. The loading dose provides an initial rapid increase in circulating blood levels or concentrations, e.g., serum or plasma levels of the antibody, to exceed the threshold blood concentration required for therapeutically effective pKal inhibition. As the antibody is cleared from the circulation over time, the circulating blood levels (e.g., plasma or serum concentrations or levels) decrease. Thus, after administration of the loading dose, the subject is administered a maintenance dose, e.g., for a period of time before the blood concentration falls below the threshold blood concentration required for therapeutically effective pKal inhibition, and periodically thereafter. The subject may be administered one or more maintenance doses. Chronic administration may be required. The maintenance dose typically remains the same. Thus, in some examples, the one or more maintenance doses are the same amount.

[0155]

[0173] The first maintenance dose can be administered about 1 to 6 months after the loading dose. For example, the first maintenance dose can be administered about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more after the loading dose. In one embodiment, the first maintenance dose is administered about 3 months after the loading dose. In another embodiment, the first maintenance dose is administered about 6 months after the loading dose. After the first maintenance dose, subsequent maintenance doses can be administered about every 1 month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, or about every 6 months or more, in certain embodiments, for example, every 3 months or every 6 months. The first dose and the subsequent maintenance doses are the same amount.

[0156]

[0174] The first maintenance dose may be administered about 1 to 8 weeks after the loading dose. For example, the first maintenance dose may be administered about 1 to 4 weeks after the loading dose. For example, the first maintenance dose may be administered about 1 to 2 weeks after the loading dose. For example, the first maintenance dose may be administered about 2 to 4 weeks after the loading dose. For example, the first maintenance dose may be administered about 2 to 6 weeks after the loading dose.

[0157]

[0175] The time period between the loading dose and the first maintenance dose, and between the first maintenance dose and the subsequent maintenance dose, can be the same. For example, the first maintenance dose and the subsequent maintenance doses can be administered at intervals of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more after the loading dose. For example, in one embodiment, the first maintenance dose and the subsequent maintenance doses can be administered every 2 to 6 months, or every 3 to 6 months. For example, in one embodiment, the first maintenance dose and the subsequent maintenance doses can be administered at intervals of about 3 months starting about 3 months after the loading dose, e.g., every 3 months after the loading dose. In another embodiment, the first maintenance dose and the subsequent maintenance doses can be administered at intervals of about 6 months starting about 6 months after the loading dose, e.g., every 6 months after the loading dose. In other embodiments, after the first maintenance dose, subsequent maintenance doses may be administered, in certain instances, about every month, about every two months, about every three months, about every four months, about every five months, or about every six months or more, e.g., every three months or every six months. The first maintenance dose and subsequent maintenance doses may be the same amount.

[0158]

[0176] Alternatively, the period between the first maintenance dose and the subsequent maintenance dose may be different from the period between the loading dose and the first maintenance dose. For example, the period between the loading dose and the first maintenance dose may be 1 week to 3 months, e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months, and the period between the first maintenance dose and the second maintenance dose may be 3 to 9 months, e.g., 3 months, or 6 months. The first maintenance dose may be administered about 1 to 8 weeks after the loading dose. For example, the first maintenance dose may be administered about 1 to 4 weeks after the loading dose. For example, the first maintenance dose may be administered about 2 weeks after the loading dose. For example, the first maintenance dose may be administered about 2 to 4 weeks after the loading dose. For example, the first maintenance dose may be administered about 2 to 6 weeks after the loading dose.

[0159]

[0177] For example, the period between the loading dose and the first maintenance dose can be 1 week to 3 months, and the period between the first maintenance dose and the second maintenance dose can be about 3 to 9 months, e.g., about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months. The second maintenance dose can be 12 months after the first maintenance dose.

[0160]

[0178] For example, the first maintenance dose is administered about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks after the loading dose, and subsequent maintenance doses, in certain embodiments, are administered about every 2 months, about every 3 months, about every 4 months, about every 5 months, or about every 6 months or more, e.g., every 3 months or every 6 months. For example, in one embodiment, the first maintenance dose is administered about 1 to 4 weeks after the loading dose, and subsequent maintenance doses are administered about every 3 to 6 months after the first maintenance dose, e.g., about every 3 months, about every 4 months, about every 5 months, or about every 6 months. For example, in one embodiment, the first maintenance dose is administered about 1 to 2 weeks after the loading dose, and subsequent maintenance doses are administered about every 3 months after the first maintenance dose. For example, in one embodiment, the first maintenance dose is administered about 1 to 2 weeks after the loading dose, and subsequent maintenance doses are administered about every 6 months after the first maintenance dose. For example, in one embodiment, the first maintenance dose is administered about 1 to 8 weeks after the loading dose, and subsequent maintenance doses are administered about every 3 months, about every 4 months, about every 5 months, or about every 6 months after the first maintenance dose. For example, in one embodiment, the first maintenance dose is administered about 2 weeks after the loading dose, and subsequent maintenance doses are administered about every 3 months after the first maintenance dose. For example, in one embodiment, the first maintenance dose is administered about 2 weeks after the loading dose, and subsequent maintenance doses are administered about every 6 months after the first maintenance dose. For example, in one embodiment, the first maintenance dose is administered about 4 weeks after the loading dose, and subsequent maintenance doses are administered about every 6 months after the first maintenance dose.

[0161]

[0179] In one example, a loading dose is administered, a first maintenance dose is administered 1-2 weeks after the loading dose, a second maintenance dose is administered 3-6 months after the first maintenance dose, followed by subsequent maintenance doses at 3-6 month intervals after the second maintenance dose, such that the subject receives a maintenance dose of the antibody every 3-6 months after the first maintenance dose. The intervals between the maintenance doses are the same. The loading dose and / or maintenance dose can be any of the loading doses or maintenance doses disclosed herein. The maintenance dose can be 50% of the loading dose.

[0162]

[0180] In one example, a loading dose of 300-900 mg is administered, a first maintenance dose of 150-700 mg is administered about 1-2 weeks after the loading dose, a second maintenance dose of 150-700 mg is administered about 3-6 months after the first maintenance dose, followed by subsequent maintenance doses at about 3-6 month intervals after the second maintenance dose, such that the subject receives a maintenance dose of antibody about every 3-6 months after the first maintenance dose. The maintenance dose may be 50% of the loading dose. The loading dose may be 600 mg and the maintenance dose may be 300 mg. The loading dose may be 400 mg and the maintenance dose may be 200 mg. The loading dose and maintenance dose may be as disclosed herein below. The intervals between the maintenance doses are the same.

[0163]

[0181] In one example, a loading dose of 300-900 mg is administered, a first maintenance dose of 150-700 mg is administered about 1-2 weeks after the loading dose, a second maintenance dose of 150-700 mg is administered about 3 months after the first maintenance dose, followed by subsequent maintenance doses at about 3-month intervals after the second maintenance dose, such that the subject receives a maintenance dose of antibody about every 3 months after the first maintenance dose. The maintenance dose may be 50% of the loading dose. The loading dose may be 600 mg and the maintenance dose may be 300 mg. The loading dose may be 400 mg and the maintenance dose may be 200 mg. The loading dose and maintenance dose may be as disclosed herein below.

[0164]

[0182] In one example, a loading dose of 300-900 mg is administered, a first maintenance dose of 150-700 mg is administered about 1-2 weeks after the loading dose, a second maintenance dose of 150-700 mg is administered about 6 months after the first maintenance dose, followed by subsequent maintenance doses at about 6-month intervals after the second maintenance dose, such that the subject receives a maintenance dose of antibody about every 6 months after the first maintenance dose. The maintenance dose may be 50% of the loading dose. The loading dose may be 600 mg and the maintenance dose may be 300 mg. The loading dose may be 400 mg and the maintenance dose may be 200 mg. The loading dose and maintenance dose may be as disclosed herein below.

[0165]

[0183] In one embodiment, a subject with a plasma kallikrein-associated disorder, such as HAE, is administered a loading dose of an anti-plasma kallikrein antibody, followed by lower maintenance doses of the antibody administered approximately every two months to treat the disorder. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously.

[0166]

[0184] In one embodiment, a subject with a plasma kallikrein-associated disorder, such as HAE, is administered a loading dose of an anti-plasma kallikrein antibody, followed by lower maintenance doses of the antibody administered approximately every three months to treat the disorder. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously.

[0167]

[0185] In another embodiment, a subject with a plasma kallikrein-associated disorder, e.g., HAE, is administered a loading dose of an anti-plasma kallikrein antibody, followed by lower maintenance doses of the antibody administered approximately every four months to treat the disorder. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously.

[0168]

[0186] In another embodiment, a subject with a plasma kallikrein-associated disorder, e.g., HAE, is administered a loading dose of an anti-plasma kallikrein antibody, followed by lower maintenance doses of the antibody administered about every five months to treat the disorder. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously.

[0169]

[0187] In another embodiment, a subject with a plasma kallikrein-associated disorder, e.g., HAE, is administered a loading dose of an anti-plasma kallikrein antibody, followed by lower maintenance doses of the antibody administered approximately every six months to treat the disorder. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously.

[0170]

[0188] The present invention provides that the loading dose and maintenance dose maintain a blood concentration, e.g., serum concentration, of the antibody, e.g., STAR-0215, above a threshold blood concentration, e.g., serum or plasma concentration, of the antibody required for therapeutically effective inhibition of pKal. For example, the threshold blood concentration, e.g., serum concentration or plasma concentration, is 60-80 nM or 8-12 μg / mL. Thus, any loading dose followed by any maintenance dose administered at regular intervals that achieves a blood concentration, e.g., serum concentration or plasma concentration, of the antibody, e.g., STAR-0215, above a threshold blood concentration, e.g., serum concentration or plasma concentration, e.g., 60-80 nM or 8-12 μg / mL, is contemplated by the present invention.

[0171]

[0189] According to certain methods disclosed herein, the loading dose of an anti-plasma kallikrein antibody, e.g., STAR-0215, may be about 100 to 600 mg, about 100 to 700 mg, about 100 to 800 mg, about 100 to 900 mg, about 100 to 1,000 mg, about 100 to 1,100 mg, about 100 to 1,200 mg, about 100 to 1,300 mg, about 100 to 1,400 mg, about 100 to 1,500 mg, about 100 to 1,600 mg, about 100 to 1,700 mg, about 100 to 1,800 mg, about 100 to 1,900 mg, about 100 to 2,000 mg, about 200 to 3000 mg, about 300 to 4000 mg, about 400 to 5000 mg, about 500 to 6000 mg, about 500 to 700 mg, about 500 to 800 mg, about 500 to 900 mg, about 500 to 1000 mg, about 500 to 1100 mg, about 500 to 1200 mg, about 500 to 1300 mg, about 500 to 1400 mg, about 500 to 1500 mg, about 500 to 1600 mg, about 100 to 1700 mg, about 100 to 1800 mg, about 100 to 1900 mg, about 100 to 2000 mg, about 200 to 3000 mg, about 200 to 3000 mg, about 200 to 3000 mg, about 600mg, about 200-700mg, about 200-800mg, about 200-900mg, about 200-1,000mg, about 200-1,100mg, about 200-1,200mg, about 200-1,300mg, about 200-1,400mg, about 200-1,500mg, about 200-1 , 600mg, about 200~1,700mg, about 200~1,800mg, about 200~1,900mg, about 200~2,000mg, about 300~600mg, about 300~700mg, about 300~800mg, about 300~900mg, about 300~1,000mg, about 300~1, 100mg, approx. 300~1,200mg, approx. 300~1,300mg, approx. 300~1,400mg, approx. 300~1,500mg, approx. 300~1,600mg, approx. 300~1,700mg, approx. 300~1,800mg, approx. 300~1,900mg, approx. 300~2,000mg , about 400-600mg, about 400-700mg, about 400-800mg, about 400-900mg, about 400-1,000mg, about 400-1,100mg, about 400-1,200mg, about 400-1,300mg, about 400-1,400mg, about 400-1,500mg, Approx. 400~1,600mg, approx. 400~1,700mg, approx. 400~1,800mg, approx. 400~1,900mg, approx. 400~2,000mg, approx. 500~600mg, approx. 500~700mg, approx. 500~800mg, approx. 500~1,100mg, approximately 500~1,200mg, approximately 500~1,300mg, approximately 500~1,400mg, approximately 500~1,500mg, approximately 500~1,600mg, approximately 500~1,700mg, approximately 500~1,800mg, approximately 500~1,900mg, approximately 500~2,000mg, approximately 600-700mg, approximately 600-800mg, approximately 600-900mg, approximately 600-1,000mg, approximately 600-1,100mg, approximately 600-1,200mg, approximately 600-1,300mg, approximately 600-1,400mg, approximately 600-1,500mg, approximately 600-1,600mg, approximately 600-1,700mg, approximately 600-1,800mg, approximately 600-1,900mg, approximately 600-2,000mg, approximately 700-800mg, approximately 700-900mg, approximately 700-1,000mg, approximately 700-1,100mg, approximately 700-1,200mg, approximately 700-1 300mg, approximately 700~1,400mg, approximately 700~1,500mg, approximately 700~1,600mg, approximately 700~1,700mg, approximately 700~1,800mg, approximately 700~1,900mg, approximately 700~2,000mg, approximately 800~900mg, approximately 800~1,000mg, approximately 800~1,100mg, approximately 800~1,200mg, approximately 800~1,300mg, approximately 800~1,400mg, approximately 800~1,500mg, approximately 800~1,600mg, approximately 800~1,700mg, approximately 800~1,800mg, approximately 800~1,900mg, approximately 800~2,000mg g, approximately 900-1,000 mg, approximately 900-1,100 mg, approximately 900-1,200 mg, approximately 900-1,300 mg, approximately 900-1,400 mg, approximately 900-1,500 mg, approximately 900-1,600 mg, approximately 900-1,700 mg, approximately 900-1,800 mg, approximately 900-1,900 mg, approximately 900-2,000 mg, approximately 1,000-1,100 mg, approximately 1,000-1,200 mg, approximately 1,000-1,300 mg, approximately 1,000-1,400 mg, approximately 1,000-1,500 mg, approximately 1,000-1,600 mg, approximately 1,000-1,700 mg Approximately 1,000-1,800 mg, approximately 1,000-1,900 mg, approximately 1,000-2,000 mg, approximately 1,100-1,200 mg, approximately 1,100-1,300 mg, approximately 1,100-1,400 mg, approximately 1,100-1,500 mg, approximately 1,100-1,600 mg, approximately 1,100-1,700 mg, approximately 1,100-1,800 mg, approximately 1,100-1,900 mg, approximately 1,100-2,000 mg, approximately 1,200-1,300 mg, approximately 1,200-1,400 mg, approximately 1,200-1,500 mg, approximately 1,200-1,600 mg, approximately 1,200-1,1 ...700mg, approximately 1,200~1,800mg, approximately 1,200~1,900mg, approximately 1,200~2,000mg, approximately 1,300~1,400mg, approximately 1,300~1,500mg, approximately 1,300~1,600mg, approximately 1,300~1,700mg, approximately 1,300~1 ,800mg, about 1,300~1,900mg, about 1,300~2,000mg, about 1,400~1,500mg, about 1,400~1,600mg, about 1,400~1,700mg, about 1,400~1,800mg, about 1,400~1,900mg, about 1,400~2 1,000 mg, about 1,500 to 1,600 mg, about 1,500 to 1,700 mg, about 1,500 to 1,800 mg, about 1,500 to 1,900 mg, about 1,500 to 2,000 mg, about 1,600 to 1,700 mg, about 1,600 to 1,800 mg, about 1,600 to 1,900 mg, about 1,600 to 2,000 mg, about 1,700 to 1,800 mg, about 1,700 to 1,900 mg, about 1,700 to 2,000 mg, about 1,800 to 1,900 mg, about 1,800 to 2,000 mg, or about 1,900 to 2,000 mg. For example, the loading dose may be 600-900 mg in one embodiment, or 900-1,200 mg in another embodiment. For example, the loading dose may be 900 mg, or the loading dose may be 1,200 mg. In another embodiment, the loading dose is 400 mg-600 mg. In one embodiment, the loading dose may be 600 mg. In another embodiment, the loading dose is 400 mg. The loading dose may be administered in a single dosage form, i.e., a single subcutaneous bolus injection, or a single intravenous infusion or bolus injection. The dose may be administered as two or more consecutive subcutaneous injections upon administration. In one embodiment, the loading dose is 400 mg administered via a single subcutaneous bolus injection. In one embodiment, the loading dose is 600 mg administered via a single subcutaneous bolus injection. In another embodiment, the loading dose is 900 mg administered via a single subcutaneous bolus injection. In another embodiment, the loading dose is 1,200 mg administered via a single subcutaneous bolus injection.In another embodiment, the loading dose is 150 mg administered subcutaneously or intravenously weekly for 1, 2, 3, or 4 weeks. In another embodiment, the loading dose is 300 mg administered subcutaneously or intravenously weekly for 1, 2, 3, or 4 weeks.

[0172]

[0190] According to certain methods disclosed herein, the loading dose of an anti-plasma kallikrein antibody, e.g., STAR-0215, is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 1100 mg, about 125 mg, about 150 mg, about 175 mg, about 1800 mg, about 185 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 1950 mg, about 2150 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 3 g, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg , about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950mg, about 975mg, about 1,000mg, about 1,025mg, about 1,050mg, about 1,075mg , about 1,100mg, about 1,125mg, about 1,150mg, about 1,175mg, about 1,200mg, about 1,225mg, about 1,250mg, about 1,275mg, about 1,300mg, about 1, 325mg, approximately 1,350mg, approximately 1,375mg, approximately 1,400mg, approximately 1,425mg, approximately 1,450mg, approximately 1,475mg, approximately 1,500mg, approximately 1,525mg, approximately 1,550m The loading dose may be about 1,575 mg, about 1,600 mg, about 1,625 mg, about 1,650 mg, about 1,675 mg, about 1,700 mg, about 1,725 ​​mg, about 1,750 mg, about 1,775 mg, about 1,800 mg, about 1,825 mg, about 1,850 mg, about 1,875 mg, about 1,900 mg, about 1,925 mg, about 1,950 mg, about 1,975 mg, or about 2,000 mg. The dose may be administered in a single dosage form, i.e., a single subcutaneous injection or a single intravenous infusion. The dose may be administered as two or more consecutive subcutaneous injections upon administration. In one embodiment, the loading dose is 400 mg. For example, 400 mg of antibody is administered by subcutaneous bolus injection as a loading dose. In one embodiment, the loading dose is 600 mg. For example, 600 mg of antibody is administered by subcutaneous bolus injection as a loading dose. In one embodiment, the loading dose is 900 mg. For example, 900 mg of antibody is administered by subcutaneous bolus injection as a loading dose. In one embodiment, the loading dose is 1,200 mg. For example, 1,200 mg of antibody is administered by subcutaneous bolus injection as a loading dose.

[0173]

[0191] According to certain methods disclosed herein, the maintenance dose of an anti-plasma kallikrein antibody, e.g., STAR-0215, may be about 100 to 600 mg, about 100 to 700 mg, about 100 to 800 mg, about 100 to 900 mg, about 100 to 1,000 mg, about 100 to 1,100 mg, about 100 to 1,200 mg, about 100 to 1,300 mg, about 100 to 1,400 mg, about 100 to 1,500 mg, about 100 to 1,600 mg, about 100 to 1,700 mg, about 100 to 1,800 mg, about 100 to 1,900 mg, about 100 to 2,000 mg, about 200 to 3 ... 600mg, about 200-700mg, about 200-800mg, about 200-900mg, about 200-1,000mg, about 200-1,100mg, about 200-1,200mg, about 200-1,300mg, about 200-1,400mg, about 200-1,500mg, about 200-1 , 600mg, about 200~1,700mg, about 200~1,800mg, about 200~1,900mg, about 200~2,000mg, about 300~600mg, about 300~700mg, about 300~800mg, about 300~900mg, about 300~1,000mg, about 300~1, 100mg, approx. 300~1,200mg, approx. 300~1,300mg, approx. 300~1,400mg, approx. 300~1,500mg, approx. 300~1,600mg, approx. 300~1,700mg, approx. 300~1,800mg, approx. 300~1,900mg, approx. 300~2,000mg , about 400-600mg, about 400-700mg, about 400-800mg, about 400-900mg, about 400-1,000mg, about 400-1,100mg, about 400-1,200mg, about 400-1,300mg, about 400-1,400mg, about 400-1,500mg, Approx. 400~1,600mg, approx. 400~1,700mg, approx. 400~1,800mg, approx. 400~1,900mg, approx. 400~2,000mg, approx. 500~600mg, approx. 500~700mg, approx. 500~800mg, approx. 500~1,100mg, approximately 500~1,200mg, approximately 500~1,300mg, approximately 500~1,400mg, approximately 500~1,500mg, approximately 500~1,600mg, approximately 500~1,700mg, approximately 500~1,800mg, approximately 500~1,900mg, approximately 500~2,000mg, approximately 600-700mg, approximately 600-800mg, approximately 600-900mg, approximately 600-1,000mg, approximately 600-1,100mg, approximately 600-1,200mg, approximately 600-1,300mg, approximately 600-1,400mg, approximately 600-1,500mg, approximately 600-1,600mg, approximately 600-1,700mg, approximately 600-1,800mg, approximately 600-1,900mg, approximately 600-2,000mg, approximately 700-800mg, approximately 700-900mg, approximately 700-1,000mg, approximately 700-1,100mg, approximately 700-1,200mg, approximately 700-1 300mg, approximately 700~1,400mg, approximately 700~1,500mg, approximately 700~1,600mg, approximately 700~1,700mg, approximately 700~1,800mg, approximately 700~1,900mg, approximately 700~2,000mg, approximately 800~900mg, approximately 800~1,000mg, approximately 800~1,100mg, approximately 800~1,200mg, approximately 800~1,300mg, approximately 800~1,400mg, approximately 800~1,500mg, approximately 800~1,600mg, approximately 800~1,700mg, approximately 800~1,800mg, approximately 800~1,900mg, approximately 800~2,000mg g, approximately 900-1,000 mg, approximately 900-1,100 mg, approximately 900-1,200 mg, approximately 900-1,300 mg, approximately 900-1,400 mg, approximately 900-1,500 mg, approximately 900-1,600 mg, approximately 900-1,700 mg, approximately 900-1,800 mg, approximately 900-1,900 mg, approximately 900-2,000 mg, approximately 1,000-1,100 mg, approximately 1,000-1,200 mg, approximately 1,000-1,300 mg, approximately 1,000-1,400 mg, approximately 1,000-1,500 mg, approximately 1,000-1,600 mg, approximately 1,000-1,700 mg Approximately 1,000-1,800 mg, approximately 1,000-1,900 mg, approximately 1,000-2,000 mg, approximately 1,100-1,200 mg, approximately 1,100-1,300 mg, approximately 1,100-1,400 mg, approximately 1,100-1,500 mg, approximately 1,100-1,600 mg, approximately 1,100-1,700 mg, approximately 1,100-1,800 mg, approximately 1,100-1,900 mg, approximately 1,100-2,000 mg, approximately 1,200-1,300 mg, approximately 1,200-1,400 mg, approximately 1,200-1,500 mg, approximately 1,200-1,600 mg, approximately 1,200-1,1 ...700mg, approximately 1,200~1,800mg, approximately 1,200~1,900mg, approximately 1,200~2,000mg, approximately 1,300~1,400mg, approximately 1,300~1,500mg, approximately 1,300~1,600mg, approximately 1,300~1,700mg, approximately 1,300~1 ,800mg, about 1,300~1,900mg, about 1,300~2,000mg, about 1,400~1,500mg, about 1,400~1,600mg, about 1,400~1,700mg, about 1,400~1,800mg, about 1,400~1,900mg, about 1,400~2 The dose may be about 1,000 mg, about 1,500-1,600 mg, about 1,500-1,700 mg, about 1,500-1,800 mg, about 1,500-1,900 mg, about 1,500-2,000 mg, about 1,600-1,700 mg, about 1,600-1,800 mg, about 1,600-1,900 mg, about 1,600-2,000 mg, about 1,700-1,800 mg, about 1,700-1,900 mg, about 1,700-2,000 mg, about 1,800-1,900 mg, about 1,800-2,000 mg, or about 1,900-2,000 mg. The dose may be administered in a single dosage form, i.e., a single subcutaneous injection, or a single intravenous infusion. The dose may be administered as two or more consecutive subcutaneous injections. The maintenance dose may be half (or 50%) of the amount of the loading dose, e.g., half the mass of the loading dose.

[0174]

[0192] According to certain methods disclosed herein, the maintenance dose of an anti-plasma kallikrein antibody, e.g., STAR-0215, is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 560 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800m g, about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950mg, about 975mg, about 1,000mg, about 1,025mg, about 1,050mg, about 1,075m g, approximately 1,100mg, approximately 1,125mg, approximately 1,150mg, approximately 1,175mg, approximately 1,200mg, approximately 1,225mg, approximately 1,250mg, approximately 1,275mg, approximately 1,300mg, approximately 1 ,325mg, about 1,350mg, about 1,375mg, about 1,400mg, about 1,425mg, about 1,450mg, about 1,475mg, about 1,500mg, about 1,525mg, about 1,550 The maintenance dose may be about 1,575 mg, about 1,600 mg, about 1,625 mg, about 1,650 mg, about 1,675 mg, about 1,700 mg, about 1,725 ​​mg, about 1,750 mg, about 1,775 mg, about 1,800 mg, about 1,825 mg, about 1,850 mg, about 1,875 mg, about 1,900 mg, about 1,925 mg, about 1,950 mg, about 1,975 mg, or about 2,000 mg. The maintenance dose may be half (or 50%) of the amount of the loading dose, e.g., half the mass of the loading dose. The dose may be administered in a single dosage form, i.e., a single subcutaneous injection or a single intravenous infusion. The dose may be administered as two or more consecutive subcutaneous injections upon administration. In one embodiment, the maintenance dose is 450 mg. In another embodiment, the maintenance dose is 300 mg. In one embodiment, the maintenance dose is 200 mg. In one embodiment, the maintenance dose is 250 mg. In one embodiment, the maintenance dose is 400 mg. In one embodiment, the maintenance dose is 900 mg.

[0175]

[0193] The loading dose may be approximately 300-2,000 mg, and the maintenance dose may be approximately 150-1,500 mg. The loading dose may be approximately 500-2,000 mg, and the maintenance dose may be approximately 250-1,500 mg. The loading dose may be approximately 400-1,000 mg, and the maintenance dose may be approximately 200-750 mg. The loading dose may be approximately 600-1,200 mg, and the maintenance dose may be approximately 300-900 mg. The loading dose may be approximately 900-1,200 mg, and the maintenance dose may be approximately 450-900 mg. The loading dose may be approximately 600-900 mg, and the maintenance dose may be approximately 300-600 mg. The loading dose may be approximately 400-600 mg, and the maintenance dose may be approximately 200-300 mg. The loading dose may be 400 mg, and the maintenance dose may be 200 mg. The loading dose may be 400 mg and the maintenance dose may be 250 mg. The loading dose may be 600 mg and the maintenance dose may be 300 mg. The loading dose may be 600 mg and the maintenance dose may be 450 mg. The loading dose may be about 900 mg and the maintenance dose may be about 675 mg. The loading dose may be about 1,200 mg and the maintenance dose may be about 600 mg. The loading dose may be about 900 mg and the maintenance dose may be about 675 mg. The loading dose may be about 900 mg and the maintenance dose may be about 450 mg. The loading and maintenance doses may be administered subcutaneously. The loading and maintenance doses may be administered intravenously. A loading dose in the range of 900 to 1,200 mg may be administered, with maintenance doses in the range of 450 to 900 mg occurring at six-month intervals after the loading dose. For example, the loading dose may be 1,200 mg and the maintenance dose may be 900 mg. The loading and maintenance doses may be administered subcutaneously. Alternatively, the loading and maintenance doses may be administered intravenously or by a combination of intravenous and subcutaneous administration.

[0176]

[0194] In one embodiment, the loading dose is about 600 mg, followed by a maintenance dose of about 300 mg about every three months after the loading dose. In another embodiment, the loading dose is about 600 mg, followed by a maintenance dose of about 450 mg about every three months after the loading dose. In another embodiment, the loading dose is about 600 mg, followed by a maintenance dose of about 450 mg about every six months after the loading dose. In another embodiment, the loading dose is about 600 mg, followed by a maintenance dose of about 400 mg about every six months after the loading dose. In another embodiment, the loading dose is about 400 mg, followed by a maintenance dose of about 250 mg about every three months after the loading dose. In another embodiment, the loading dose is about 400 mg, followed by a maintenance dose of about 200 mg about every three months after the loading dose. In another embodiment, the loading dose is about 1,200 mg, followed by a maintenance dose of about 900 mg about every six months after the loading dose. In another embodiment, the loading dose is about 1,200 mg, followed by maintenance doses of about 600 mg about every six months after the loading dose.

[0177]

[0195] The loading dose can also be achieved by a series of doses over a period of time to achieve a total loading dose that is one of the loading doses disclosed herein.For example, a loading dose of 600 mg can be administered as a 150 mg dose every week for 1, 2, 3, or 4 weeks, followed by a maintenance dose every three months thereafter, for example, in an amount of 300 mg.The loading dose can also be 150 mg every week for 1, 2, 3, or 4 weeks, followed by a maintenance dose every three months thereafter, for example, in an amount of 450 mg.The loading dose can also be 300 mg every week for 1, 2, 3, or 4 weeks, followed by a maintenance dose every three months thereafter, for example, in an amount of 300 mg.The loading dose can also be 300 mg every week for 1, 2, 3, or 4 weeks, followed by a maintenance dose every three months thereafter, for example, in an amount of 450 mg.The loading dose and maintenance dose can be administered subcutaneously.The loading dose and maintenance dose can be administered intravenously.

[0178]

[0196] In one embodiment, the loading dose and maintenance dose of the anti-plasma kallikrein antibody, e.g., STAR-0215, are selected from one of the combinations of loading doses and maintenance doses provided in Table 5 below (e.g., one of combinations 1-43).

[0179] [Table 5]

[0180]

[0197] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 3 months (or 84 days or 12 weeks) after the loading dose and about every 3 months (or 84 days or 12 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the dose set forth in Table 5.

[0181]

[0198] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 4 months (or 112 days or 16 weeks) after the loading dose and about every 4 months (or 112 days or 16 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0182]

[0199] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 5 months (or 140-150 days or 20 weeks) after the loading dose and about every 5 months (or 140 days or 20 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0183]

[0200] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 6 months (or 160-180 days or 25-26 weeks) after the loading dose and about every 6 months (or 160-180 days or 25-26 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0184]

[0201] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 9 months (or 250-270 days or 36-37 weeks) after the loading dose and about every 9 months (or 250-270 days or 36-37 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0185]

[0202] In one embodiment, a loading dose and maintenance dose combination set forth in Table 5 (e.g., any one of combinations 1-43 or 44-45) is administered such that the maintenance dose is administered about 12 months (or 336-368 days or 48-52 weeks) after the loading dose and about every 12 months (or 336-368 days or 48-52 weeks) thereafter. In one embodiment, the loading dose and maintenance dose are administered subcutaneously. In one embodiment, the loading dose and maintenance dose are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0186]

[0203] In one embodiment, a loading dose and maintenance dose combination (e.g., any one of combinations 1-45) set forth in Table 5 is administered such that the first maintenance dose is administered at least about one week after the loading dose, e.g., about one week to eight weeks after the loading dose, and subsequent maintenance doses are administered about every two months, three months, four months, five months, or six months after the first maintenance dose. For example, the first maintenance dose is administered one week after the loading dose and then every three months thereafter. In another embodiment, the first maintenance dose is administered two weeks after the loading dose and then every three to six months thereafter, e.g., about every three months or about every six months. In one embodiment, the loading dose and maintenance doses are administered subcutaneously. In one embodiment, the loading dose and maintenance doses are administered intravenously. In yet another embodiment, the loading dose is administered intravenously, while the maintenance dose is administered subcutaneously. In another embodiment, the loading dose and maintenance dose are within + / - 10% of the doses set forth in Table 5.

[0187]

[0204] In one embodiment, a subject diagnosed with a plasma kallikrein-associated disorder, e.g., HAE, is administered a loading dose of 300-2,000 mg of an anti-plasma kallikrein antibody disclosed herein, e.g., STAR-0215, followed by a maintenance dose of 150-1,500 mg of the antibody starting at least about every two months, e.g., about every three months, after the loading dose, and then at least about every two months thereafter, e.g., about every three months. In one embodiment, a subject diagnosed with a plasma kallikrein-associated disorder, e.g., HAE, is administered a loading dose of 500-2,000 mg of an anti-plasma kallikrein antibody disclosed herein, e.g., STAR-0215, followed by a maintenance dose of 250-1,500 mg of the antibody starting at least about every two months, e.g., about every three months, after the loading dose, and then at least about every two months thereafter, e.g., about every three months. In one embodiment, the loading dose is 600 mg and the maintenance dose is 300 mg, administered subcutaneously, with the maintenance dose administered subcutaneously about 3 months after the loading dose and about every 3 months thereafter. In one embodiment, the loading dose is 600 mg and the maintenance dose is 450 mg, administered subcutaneously, with the maintenance dose administered about 3 months after the loading dose and about every 3 months thereafter. In one embodiment, the loading dose is about 600 mg and the maintenance dose is about 400 mg or 450 mg, administered subcutaneously, with the maintenance dose administered about 6 months after the loading dose and about every 6 months thereafter. In one embodiment, the loading dose is about 400 mg and the maintenance dose is about 250 mg, administered subcutaneously, with the maintenance dose administered about 3 months after the loading dose and about every 3 months thereafter. In one embodiment, the loading dose is about 400 mg and the maintenance dose is about 200 mg, administered subcutaneously, with the maintenance dose administered about 3 months after the loading dose and about every 3 months thereafter. The loading dose may be about 900 mg and the maintenance dose may be about 675 mg. The loading dose may be about 1,200 mg and the maintenance dose may be about 900 mg, with the maintenance dose administered about 6 months after the loading dose and about every 6 months thereafter. The loading dose and maintenance dose may be administered subcutaneously. The loading dose and maintenance dose may be administered intravenously. The anti-plasma kallikrein antibody may be STAR-0215 ​​according to these embodiments.

[0188]

[0205] The antibodies and methods disclosed herein are used to treat a subject having or suspected of having a plasma kallikrein-associated disorder, which may be any of hereditary angioedema, bradykinin-dependent edema, diabetic macular edema, retinal edema, factor XII-associated cold autoinflammatory syndrome (FACAS), rheumatoid arthritis, gout, intestinal bowel disease, oral mucositis, neuropathic pain, inflammatory pain, spinal stenosis degenerative spinal disease, arterial or venous thrombosis, postoperative ileal aortic aneurysm, osteoarthritis, vasculitis, edema, cerebral edema, pulmonary embolism, stroke, ventricular assist device or stent-induced coagulation, head trauma or peritumoral cerebral edema, sepsis, acute middle cerebral artery (MCA) ischemic event (stroke), restenosis (e.g., after angioplasty), systemic lupus erythematosus nephritis, Alzheimer's disease, and burn injury. In one embodiment, the plasma kallikrein-associated disorder treated according to the methods disclosed herein is FACAS.

[0189]

[0206] The Angioedema Quality of Life Questionnaire (AE-QoL) (Weller et al., 2012, Allergy, 67(10);1289-1298) is a validated angioedema-specific patient-reported outcome measure self-administered and used to assess the impact of recurrent angioedema on patients' quality of life. It is a 17-item questionnaire covering four domains: function, fatigue / mood, fear / shame, and nutrition. Each item has five response options (scored 1 to 5), with higher scores indicating more adverse effects. Raw scores are converted to a linear scale ranging from 0 to 100, with a score of 100 indicating the worst possible impairment in quality of life. A minimally clinically important difference is defined as a 6-point change from baseline. The baseline score is determined before initiating treatment according to the methods disclosed herein.

[0190]

[0207] Thus, subjects treated according to the methods disclosed herein may achieve an improvement in AE-QoL score of at least 6 points from baseline (i.e., the score is reduced by at least 6 points). In some embodiments, the improvement in AE-QoL score is at least 6 points from baseline, at least 10 points from baseline, at least 15 points from baseline, at least 20 points from baseline, at least 25 points from baseline, at least 30 points from baseline, at least 35 points from baseline, at least 40 points from baseline, at least 45 points from baseline, or at least 50 points from baseline. The subject may have HAE.

[0191]

[0208] In some embodiments according to the present invention, a subject treated according to the methods disclosed herein experiences a reduction in the number of attacks, e.g., HAE attacks, compared to baseline. In some embodiments, the baseline number of attacks is 1 to 4 attacks per month. For example, the baseline number of attacks is about 2 attacks per month. According to the methods disclosed herein, a subject may experience a 75 to 90% reduction in monthly attack frequency compared to baseline. A subject's reduction in monthly attack frequency from baseline may even be a 75 to 100% reduction in monthly attack frequency. The baseline may be determined by assessing the number of attacks over a pre-treatment period, e.g., 4 weeks before treatment, 8 weeks before treatment initiation, or 12 weeks before treatment initiation. Comparison to baseline may include a period of the same length or longer than the baseline period since the subject began treatment, or may be assessed on a "per month" basis, to determine whether an improvement over baseline occurred while the patient was receiving treatment with an anti-plasma kallikrein antibody.

[0192]

[0209] In some embodiments according to the present invention, subjects treated according to the methods disclosed herein experience a reduction in the severity of attacks, e.g., HAE attacks, compared to baseline. The baseline can be determined by assessing the severity of attacks for a pre-treatment period, e.g., 4 weeks, 8 weeks, or 12 weeks before treatment begins. The comparison to baseline can include a period from the subject beginning treatment of the same length of time or a longer period than the baseline period to determine whether an improvement over baseline occurs while the patient is receiving treatment with an anti-plasma kallikrein antibody, or it can be assessed monthly, e.g., the average level of attack severity over the month before treatment relative to the month receiving treatment. The severity of attacks can be assessed as mild, moderate, or severe according to the following criteria: mild: transient or mild discomfort; moderate: mild to moderate limitation of activity, some assistance with daily activities required; severe: significant limitation of activity, assistance with daily activities required.

[0193] 4. Pharmaceutical Compositions and Modes of Administration

[0210] The anti-plasma kallikrein antibodies disclosed herein can be formulated, for example, as a pharmaceutical composition for administration to a subject. As used herein, the term "pharmaceutical composition" refers to a combination of an active agent, such as an anti-plasma kallikrein antibody described herein, with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic applications.

[0194]

[0211] Pharmaceutical compositions containing antibodies can be presented in dosage unit form and can be prepared by any suitable method. In some embodiments, to prepare pharmaceutical or sterile compositions of anti-plasma kallikrein antibodies, antibodies or antigen-binding fragments thereof or other proteins provided herein are mixed with a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions should be formulated to be compatible with their intended route of administration, for example, subcutaneous or intravenous administration. Useful formulations can be prepared by methods known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0195]

[0212] Anti-plasma kallikrein antibodies administered according to the methods disclosed herein can be formulated into pharmaceutical compositions for administration by one of skill in the art. Pharmaceutical compositions containing antibodies can contain a variety of agents, including pharmaceutically acceptable buffers (e.g., amino acid buffers, citrate buffers, succinate buffers, acetate buffers, phosphate buffers, etc.), stabilizers (e.g., amino acids such as arginine, glycine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline, or cysteine) or sugars (e.g., polyols, monosaccharides, disaccharides, or oligosaccharides, such as mannitol, sorbitol, glucose, fructose, mannose, sorbose, galactose, trehalose, maltose, raffinose, etc.), tonicity agents (e.g., salts or sugars), surfactants (e.g., ionic surfactants (carboxylates, sulfates, sulfonates, phosphate esters), and the like), among other pharmaceutically acceptable excipients suitable for use in formulating antibodies. ) or ionic surfactants (e.g., polysorbates or polyoxyethylene (Tween), polaxamers, or sorbitan (Spans)), and diluents (e.g., sterile water, phosphate-buffered saline, etc.). The formulation should be suitable for administration to a human subject by the desired mode of administration, for example, subcutaneous or intravenous injection. For example, a formulation for subcutaneous administration may include a dispersion enhancer to aid in dispersion of the subcutaneous injection volume. In one embodiment, an antibody disclosed herein may be formulated at a concentration of 150 mg / mL in a sterile solution at pH 5.8 using histidine, L-methionine, sorbitol, glycine, and polysorbate 80. For example, a formulation of an antibody may include 10 mM histidine-HCl, 75 mM glycine, 10 mM L-methionine, 150 mM sorbitol, and 0.05% w / v polysorbate 80 at pH 5.8.

[0196]

[0213] In some embodiments, the anti-plasma kallikrein antibody administered according to the methods disclosed herein is formulated in a pharmaceutical composition at a concentration of 100-200 μg / mL, e.g., the concentration can be 100-150 μg / mL or 150-200 μg / mL. For example, the concentration is about 100 μg / mL, about 105 μg / mL, about 110 μg / mL, about 115 μg / mL, about 120 μg / mL, about 125 μg / mL, about 130 μg / mL, about 135 μg / mL, about 140 μg / mL, about 145 μg / mL, about 150 μg / mL, about 155 μg / mL, about 160 μg / mL, about 165 μg / mL, about 170 μg / mL, about 175 μg / mL, about 180 μg / mL, about 185 μg / mL, about 190 μg / mL, about 195 μg / mL, or about 200 μg / mL. In one embodiment, the concentration of the antibody is 150 μg / mL.

[0197]

[0214] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), phosphate buffered saline (PBS), or dextrose solution. The carrier should be stable under the conditions of manufacture and storage and preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0198]

[0215] The pharmaceutical preparation is preferably sterile. Sterilization can be achieved, for example, by filtration through sterile filtration membranes. If the composition is lyophilized, filter sterilization can be performed prior to or after lyophilization and reconstitution.

[0199]

[0216] Formulations of antibodies provided herein may be, for example, lyophilized powders, slurries, aqueous solutions, or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and The compositions may be prepared by mixing with an acceptable carrier, excipient, or stabilizer in the form of a pharmaceutical composition (see Kotkoskie (Excipient Toxicity and Safety), Marcel Dekker, Inc., New York, NY).

[0200]

[0217] Antibody formulations may be loaded into fixed-dose vials; needle-equipped syringes; pre-fitted needleless syringes (where the person administering the antibody adds a needle prior to administration); auto-injector pens; or cartridges for auto-injector pens.

[0201]

[0218] The toxicity and therapeutic efficacy of an antibody composition administered alone or in combination with another agent can be measured, for example, by the LD 50 (lethal dose for 50% of the population) and ED 50The dose (therapeutically effective dose in 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is called the therapeutic index (LD 50 / ED 50 In certain embodiments, antibodies that exhibit high therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within the ED range with little or no toxicity. 50 The dosage may vary within this range depending upon the dosage form and route of administration used.

[0202]

[0219] The antibody compositions disclosed herein can be administered to a subject, for example, according to the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0203]

[0220] The mode of administration can vary: suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, dermal, transdermal, or intraarterial.

[0204]

[0221] According to one embodiment, the antibody is administered parenterally according to the methods disclosed herein.

[0205]

[0222] The preferred route of administration according to the methods disclosed herein is subcutaneous administration. The anti-plasma kallikrein antibodies disclosed herein can be administered subcutaneously, e.g., via a pre-filled syringe fitted with a needle, e.g., a 23-27 gauge 5 / 8 inch needle. Alternatively, the antibody can be administered subcutaneously via a pre-filled auto-injector pen or via a pre-filled cartridge inserted into an auto-injector pen. The auto-injector may be an electronic auto-injector. The antibody formulation can be contained in a vial from which a dose is withdrawn and injected subcutaneously through a needle, e.g., a 23-27 gauge 5 / 8 inch needle. Alternatively, the antibody can be administered subcutaneously via a dose-loaded wearable or "on-body" device. In some embodiments, the antibody or antigen-binding fragment thereof can be administered by an invasive route, such as by injection. The subcutaneous injection can be, for example, into the thigh, buttocks, or abdomen of the subject. In some embodiments, the subcutaneous injection is administered by the subject, i.e., the antibody is self-administered.

[0206]

[0223] The antibodies disclosed herein can also be administered intravenously by intravenous infusion, such as by drip infusion or pump infusion. Alternatively, the antibodies disclosed herein can be administered via intravenous push or bolus injection through a port or catheter. The infusion can be through a port or catheter placed in the patient's vein. The port or catheter can be, for example, a PICC line, a tunneled catheter, or an implanted port. In some embodiments, intravenous administration is performed by a medical professional, while in some embodiments, administration is performed by the subject, i.e., the antibody is self-administered. A fixed dose of the antibody can be provided in the port or catheter or in a delivery solution for intravenous administration.

[0207]

[0224] In some embodiments, the anti-plasma kallikrein antibody or antigen-binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to, any therapeutic agent used to treat a disorder provided herein. In some embodiments, the antibody is administered in combination with another treatment for a disorder provided herein. For example, an anti-plasma kallikrein antibody of the invention can be administered with one or more additional therapies used to treat HAE, such as BERINERT® (C1 esterase inhibitor), FIRAZYR® (injectable), KALBITOR® (ecallantide), and RUCONEST® (C1 esterase inhibitor, contestat alfa), CINRYZE® (C1 esterase inhibitor), HAEGARDA® (subcutaneous C1 esterase inhibitor), TAKHZYRO® (lanadelumab-flyo), ORLADEYO™ (berotralstat), galadacimab, donidalorsen, synthetic 17-α-alkylated androgens such as danazol and stanozolol, and / or antifibrinolytic agents such as aminocaproic acid. The anti-plasma kallikrein antibody can be administered simultaneously with one or more of the aforementioned additional therapies, e.g., they can be administered simultaneously. One or more of the aforementioned additional therapies can be chronic therapies (i.e., administered chronically) or on-demand therapies (i.e., administered to treat attacks). The anti-plasma kallikrein antibody can be administered either before or after one of the aforementioned therapies, sequentially, e.g., on different days or weeks or months than any of the aforementioned additional therapies.

[0208]

[0225] Pharmaceutical compositions containing anti-plasma kallikrein antibodies can be administered with medical devices known in the art.For example, the pharmaceutical compositions disclosed herein can be administered by injection with a hypodermic needle, including a pre-filled syringe or an auto-injector.Pharmaceutical compositions can also be administered using needleless hypodermic injection devices, such as those disclosed in U.S. Patent Nos. 6,620,135, 6,096,002, 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824 or 4,596,556.Pharmaceutical compositions can also be administered by injection. Examples of well-known implants and modules for administering pharmaceutical compositions include U.S. Pat. No. 4,487,603 (disclosing an implantable microinfusion pump for dispensing pharmaceuticals at a controlled rate); U.S. Pat. No. 4,447,233 (disclosing a pharmaceutical infusion pump for delivering pharmaceuticals at precise infusion rates); U.S. Pat. No. 4,447,224 (disclosing a variable-flow implantable infusion device for continuous drug delivery); and U.S. Pat. No. 4,439,196 (disclosing an osmotic drug delivery system having multi-chamber compartments). Many other such implants, delivery systems, and modules are well known to those skilled in the art. Infusion can also be performed by intravenous delivery of the antibody in a pharmaceutically acceptable carrier, such as saline, over a defined period of time. Intravenous delivery of the pharmaceutical composition can be performed through a port implanted in the subject's vein or artery.

[0209]

[0226] The methods described herein can be used alone or in combination with other therapeutic methods. The term "administered in combination," as used herein, is understood to mean that two (or more) different treatments are delivered to a subject during the course of the subject's affliction with a disorder, such that the effects of the treatments on the patient overlap at some point. In certain embodiments, there is an overlap in administration, as delivery of one treatment is still occurring when delivery of the second treatment begins. This is sometimes referred to herein as "simultaneous" or "co-delivery." In other embodiments, delivery of one treatment ends before delivery of the other treatment begins. In certain embodiments, in either case, the treatments are more effective due to combined administration. For example, the second treatment requires less of the second treatment to have the same effect, or the second treatment provides greater relief of symptoms, than would be observed if the second treatment were administered in the absence of the first treatment, or in a similar situation with the first treatment. In certain embodiments, the delivery is such that a reduction in symptoms or other parameters associated with the disorder is greater than that observed when one treatment is administered in the absence of the other. The effects of the two treatments may be partially additive, fully additive, or greater than additive. Delivery may be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0210]

[0227] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0211]

[0228] The articles "a" and "an" are used in this disclosure, unless the context is inappropriate, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0212]

[0229] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated. The expression "and / or" in connection with more than two listed items should be understood to have the same meaning unless otherwise understood from the context.

[0213]

[0230] The phrase "at least one of" should be understood to include each of the listed items following the phrase individually, and various combinations of two or more of the listed items, unless otherwise understood from context and usage.

[0214]

[0231] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be understood as open-ended and non-limiting, and for example, does not exclude additional, unrecited elements or steps unless otherwise specified or understood from the context.

[0215]

[0232] When the term "about" is used before a quantitative value, the present disclosure also includes the specific quantitative value itself unless otherwise specified. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. For example, "about 10" contemplates both 10 and 10±10%.

[0216]

[0233] The term "in combination with," as used herein, means that the agents described can be administered to an animal or subject together as a mixture, simultaneously as a single agent, or sequentially as a single agent in any order.

[0217]

[0234] The use of any and all examples or exemplary language herein, such as "such as" or "including," is intended merely to better describe the invention and does not limit the scope of the invention unless and until claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0218]

[0235] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, the previous definition of the variable controls.

[0219]

[0236] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0220]

[0237] Throughout this specification, when compositions are described as having, comprising, or comprising particular ingredients, or when methods and processes are described as having, comprising, or comprising particular steps, it is further contemplated that there are compositions of the invention that consist essentially of, or consist of, the listed ingredients, and there are methods and processes of the invention that consist essentially of, or consist of, the listed process steps.

[0221]

[0238] In this application where an element or component is said to be included in and / or selected from a recited list of elements or components, it is understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0222]

[0239] Furthermore, it should be understood that elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, can be combined in various ways without departing from the spirit and scope of the present invention. For example, when a particular compound is referenced, that compound can be used in various embodiments of the compositions of the present invention and / or methods of the present invention, unless otherwise understood from the context. In other words, although embodiments have been described and illustrated within this application in a manner that allows for clear and concise description and depiction of the application, it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention. For example, it should be understood that all features described and illustrated herein may be applicable to all aspects of the invention described and illustrated herein.

[0223]

[0240] The subject matter will be described with reference to the following examples. These examples are provided for illustrative purposes only, and the claims should in no way be construed as being limited to these examples, but rather as encompassing any and all variations that become apparent as a result of the teachings provided herein. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially similar results. [Example]

[0224] Example Example 1. STAR-0215 ​​inhibits pKal-mediated cleavage of HMWK in cynomolgus monkeys.

[0241] The presence of cleaved high-molecular-weight kininogen (cHMWK) in plasma is a potential endogenous physiological pharmacodynamic (PD) marker of STAR-0215 ​​pKal inhibitory activity in normal cynomolgus monkeys. Western blotting analysis was used to assess the presence of cHMWK in plasma samples after subcutaneous (SC) administration of STAR-0215 ​​at 10, 30, or 100 mg / kg. Cynomolgus monkeys have low, non-pathological levels of plasma kallikrein and therefore low levels of cHMWK, so ex vivo activation of plasma by an exogenous trigger, such as activated FXIIa, is required to generate high levels of cHMWK. This methodology has been previously utilized during the early development of other plasma kallikrein inhibitors (see, e.g., Banerji et al., 2017, N Engl J Med, 376:717-728; Kenniston et al., 2014, J. Biol Chem, 289:23596-23608).

[0225]

[0242] Animals were administered STAR-0215 ​​or vehicle control (10 mM histidine-HCl, 75 mM glycine, 10 mM L-methionine, 150 mM sorbitol, 0.05% w / v PS80) via SC at 10, 30, or 100 mg / kg, with an 84-day dose-free period between doses. Plasma samples were collected using 3.2% Na-citrate tubes, rapidly aliquoted, and flash-frozen. Samples were thawed on ice and either left untreated or treated with activated human factor XII (hFXIIa) at a final concentration of 10 nM for 10 minutes at 37°C to simulate contact pathway activation to induce PK activation and pKal formation.

[0226]

[0243] To monitor the enzymatic reaction, a TQC control (a pool of cynomolgus monkey plasma samples without added protease inhibitors) was also treated with hFXIIa identically to the treated samples in each run. After treatment, both the hFXIIa-treated and untreated samples were spiked with a protease inhibitor cocktail. All samples, including the High Positive Control (HQC; 100% cHMWK), Mid Positive Control (MQC; 60% cHMWK), Low Positive Control (LQC; 15% cHMWK), and the treated TQC samples, were further diluted (1:20) with ice-cold 1x PBS containing protease inhibitors. For SDS-PAGE electrophoresis, samples were loaded onto Novex™ 4-20% Tris-Glycine Protein Gels (ThermoFisher). Proteins were transferred to nitrocellulose membranes and blocked with Intercept® (TBS) Blocking Buffer (LI-COR, Lincoln, NE) for 1 hour. Subsequently, they were incubated with anti-kininogen / kininostatin antibody (0.1 ng / μL; R&D Systems) overnight at 4°C. The membranes were washed four times with 1×TBST (20 mM Tris, 150 mM NaCl, 0.1% Tween-20). An infrared dye-conjugated secondary antibody (IRDye® 800CW Donkey anti-Goat IgG) was added at a 1:10,000 dilution. The membranes were washed again and scanned with a LI-COR Odyssey scanner to obtain blot images. Using LI-COR Odyssey software, the signal intensities of the single-stranded (approximately 110 kDa) and double-stranded HMWK bands (approximately 45 and 55 kDa) were analyzed, and the ratio of double-stranded HMWK to total HMWK in the absence (% of cleavage) and presence (% of cleavage under 10 nM FXIIa) of 10 nM FXIIa treatment was reported as a percentage for each sample.

[0227]

[0244] Western blotting can distinguish between HMWK and cHMWK, allowing for quantification of both forms. Because ex vivo activation mediated the production of cHMWK in pre-dose samples and varied between animals, data were normalized as a percentage change from pre-dose for each animal.

[0228]

[0245] Western blots presented in Figures 2A and 2C show intact (endogenous pKal substrate) and cleaved HMWK at specific time points after STAR-0215 ​​dosing on days 1, 14, and 29 (main study period), with or without treatment with FXIIa. The High Positive Control (HQC), Mid Positive Control (MQC), and Low Positive Control (LQC) are prealiquoted cynomolgus monkey plasma samples containing approximately 99, 67, and 18% cHMWK, respectively, and are visible to the right of each blot. TQC is an aliquot of the LQC sample treated with FXIIa as an additional treatment control. Figure 2A shows Western blots of intact HMWK and cHMWK from control animals and animals treated with 10, 30, and 100 mg / kg STAR-0215 ​​up to day 43. Figure 2B shows an analysis of STAR-0215 ​​inhibitory activity (% of cHMWK) from both the main study period (days 0–43) derived from Figure 2A and the extension study period (days 44–127) with an additional dose given on day 113. Representative Western blots from control and animals dosed with STAR-0215 ​​(100 mg / kg) through day 127 are shown in Figure 2C. Using LI-COR Odyssey software, the signal intensities of single-chain (approximately 110 kDa) and double-chain HMWK (cHMWK) bands (approximately 45 and 55 kDa) were analyzed, and the ratio of double-chain HMWK to total HMWK in the absence (% of cleavage) and presence of 10 nM FXIIa treatment was reported as a percentage for each sample. n = 6–10 for the main study period and n = 4 for the extension study period.

[0229]

[0246] The percent change in ex vivo FXIIa-activated cHMWK from pre-dose values ​​in post-dose plasma samples compared to pre-dose values ​​demonstrated a clear PD effect, with strong inhibition of cHMWK observed at all doses of STAR-0215 ​​(10, 30, and 100 mg / kg) (Figures 2A and 2B). The greatest inhibition of cHMWK compared to pre-dose values ​​was observed at the 100 mg / kg dose level (Figures 2B and 2C). At the two lowest dose levels of STAR-0215, cHMWK inhibition was sustained throughout the study duration, including an 84-day dose-free period (between doses on Days 29 and 113).

[0230]

[0247] This demonstrates that STAR-0215 ​​inhibits pKal-mediated cleavage of HMWK in cynomolgus monkeys, but more importantly demonstrates that long-term inhibition of pKal is achievable after a single subcutaneous dose of STAR-0215.

[0231] Example 2. Pharmacokinetic modeling to suggest STAR-0215 ​​exposure required to suppress HAE attacks.

[0248] Data from the cynomolgus monkey PK study was used to establish a minimal physiologically based pharmacokinetic (mPBPK) model. Simulations were performed to determine the exposure of STAR-0215 ​​required to achieve target exposure levels in humans. The human PK profiles of STAR-0215 ​​over a 3-month period at single subcutaneous doses of 100, 300, and 600 mg were simulated for a typical 70 kg healthy subject.

[0232]

[0249] The mPBPK model and simulations were performed using Phoenix WinNonlin (version 8.3). The model uses physiological constants and inputs from the literature (Cao et al., J Pharmacokinet Pharacodyn, 40:597-607; Offman et al., 2016, In Silico Pharmacol, 4:3). The Cao et al. mPBPK model was implemented in WinNonlin for IV exposure and modified according to Offman et al. for subcutaneous exposure. The mPBPK model was fitted to the IV data to estimate chemical-specific PK parameters (i.e., nonspecific plasma clearance). The IV mPBPK parameters were then used to estimate SC-specific mPBPK model parameters (related to absorption rate and bioavailability) using SC data. Baseline body weights were based on actual measured body weights from animal studies. A human model was obtained by substituting the physiological parameters of monkeys with human values ​​from the literature. All other parameters (bioavailability and tissue refraction coefficient) used the model-fitted values. The human model simulation was based on a typical 70 kg body weight.

[0233]

[0250] The mPBPK model demonstrates the long-term circulation of STAR-0215 ​​in humans 1 / 2 The simulated profile (semi-logarithmic scale) is shown in Figure 3. The simulation is contrasted with a target exposure range of 12 μg / mL (approximately 80 nM), the concentration for sufficient inhibition of circulating plasma kallikrein to resolve HAE attacks in patients. The simulated PK profile of STAR-0215 ​​indicates that a single SC administration of STAR-0215 ​​at dose levels of 100 mg or greater achieves exposures that completely inhibit circulating plasma kallikrein and suppress HAE attacks in patients over a sustained period of 3 months or more. The predicted PK profile suggests that STAR-0215 ​​has a long duration of action to suppress HAE attacks, making long-term preventative therapy feasible.

[0234]

[0251] The mPBPK model demonstrated that STAR-0215 ​​was rapidly absorbed after SC administration and maintained in the circulation for approximately 108 days. 1 / 2 Based on the predicted PK profile, after a single SC administration, the blood concentrations of STAR-0215 ​​required to control plasma kallikrein activity to prevent HAE attacks would be achievable within 7 days after a single SC administration. At the dose levels evaluated, the mPBPK model predicts that STAR-0215 ​​will be maintained at blood concentrations that inhibit plasma kallikrein activity for at least 3 months.

[0235]

[0252] These data support that a STAR-0215 ​​serum concentration of approximately 80 nM may be sufficient to produce 90% inhibition of plasma kallikrein activity during an HAE attack and may represent the minimum required trough serum concentration necessary to prevent HAE attacks. The PK model predicts that STAR-0215 ​​only needs to be administered once every three months to provide protection from HAE attacks. This indicates that STAR-0215 ​​may be an improvement over other currently approved preventative treatments in terms of efficacy and dosing regimens. In contrast, the small molecule inhibitor ORLADEYO® (Berotralstat) exhibits a short t 1 / 2 SC-injected plasma-derived HAEGARDA® (C1 Esterase Inhibitor Subcutaneous (Human)) has a relatively short circulating 1 / 2 and has a dosing schedule of every 3 to 4 days; TAKHZYRO® (lanadelumab) has a significantly longer 1 / 2 Although it has the potential to reduce the risk of side effects, it still requires administration every two weeks.

[0236]

[0253] As shown in Table 6 below, the population PK model demonstrated that at steady state, approximately 85% of subjects had a C > 25 μg / mL after 84 days at maintenance dose levels of 600 mg or higher. minTherefore, higher doses of STAR-0215, for example, 600 mg or more, may in some cases result in longer duration of inhibition of HAE attacks.

[0237] [Table 6]

[0238]

[0254] Further population PK modeling was performed to assess the pharmacokinetic duration of the 600 mg dose, as shown in Figures 16 and 17C. The model predicts that by administering 600 mg of STAR-0215 ​​on Day 1 and again on Day 14, or on Day 1 and again on Day 28, plasma serum concentrations of STAR-0215 ​​can be maintained for up to 5 months (Figures 16, 17C). Serum levels of STAR-0215 ​​will reach the target C of 12 μg / mL in approximately 7 months. min Although the predicted serum levels of STAR-0215 ​​are expected to be below the target C of 25 μg / mL in approximately 5 months, min Day 1 / 14 dosing was associated with a C max The predictions indicate some flexibility around the timing of the second dose, as the data for the day 1 / 28 and day 1 / 14 regimens were very similar, with the 25 μg / mL target threshold exceeded by both regimens for 142 days (5 months) and 134 days (4.9 months), respectively, and the 12 μg / mL target threshold exceeded by both regimens for 197 days (7 months) and 204 days (7.3 months), respectively. Thus, the model predicts that dosing regimens involving a 600 mg second dose administered anywhere from 2 to 6 weeks, e.g., 2, 4, or 6 weeks, after a 600 mg first dose can all achieve pharmacokinetic profiles similar to each other.

[0239]

[0255] Furthermore, as shown in Figure 17A, population PK modeling predicts that serum concentrations of STAR-0215 ​​can be maintained for at least 3 months after administration of a 450 mg dose of STAR-0215 ​​on Day 1, with the target threshold of 12 μg / mL being exceeded by the regimen for more than 112 days. Furthermore, as shown in Figure 17B, population PK modeling predicts that plasma serum concentrations of STAR-0215 ​​above the threshold concentration of 12 μg / mL can be maintained by administering an initial loading dose of 600 mg on Day 1, followed by a 300 mg dose on Day 84, suggesting that a dosing regimen of an initial loading dose of 600 mg, followed by 300 mg every three months thereafter, may be sufficient to suppress HAE attacks.

[0240]

[0256] PK modeling was further used to evaluate the pharmacokinetics of various dosing regimens using data from a Phase 1a study in healthy volunteers, described below in Example 4. Figure 20A shows the results of the model for a 600 mg loading dose of STAR-0215 ​​administered on day 1, followed by 300 mg maintenance doses administered every 3 months (84 days) thereafter. The model was run up to 336 days after the first dose. trough was 25.1 μg / mL, which is the concentration of STAR-0215 ​​at the end of the dosing interval. Figures 20B and 20G show the results of a model in which a 600 mg dose was administered on day 1, followed by a 600 mg dose on day 28 and again 6 months later. The model was run for 336 days (12 months) past the first dose in Figure 20B and 24 months past the first dose in Figure 20G. troughwas 27.0 μg / mL, which is the concentration of STAR-0215 ​​at the end of the dosing interval. Figure 20C shows the results of a model using a 1,200 mg dose on day 1 followed by a 1,200 mg dose on day 168. The model was run for 336 days past the first dose. Figure 20D shows the results of a 1,200 mg loading dose followed by a 900 mg maintenance dose every 6 months thereafter. The model was run for 24 months past the first dose. The model showed that these dosing regimens were sufficient to maintain simulated median STAR-0215 ​​concentrations above 12 μg / mL throughout the duration of the model, suggesting that these dosing regimens would be sufficient to suppress HAE attacks when administered to adult subjects. Figure 20E shows the results of pK modeling for a 1,200 mg dose on day 1, followed by 1,200 mg three months later, and then 1,200 mg every 12 months thereafter. The model was run for 36 months after the first dose. These results demonstrate that this dosing regimen for STAR-0215 ​​can achieve blood levels of STAR-0215 ​​sufficient to suppress HAE attacks in the majority of HAE patients. Therefore, a range of doses administered every 3 to 6 months may be effective in preventing HAE attacks.

[0241] Example 3: Quantitative Systems Pharmacology Modeling (QSP) to Examine the Impact of STAR-0215 ​​Dosing Regimen on Suppression of HAE Attacks

[0257] To investigate the potential and duration of HAE attack suppression by STAR-0215, a simplified mechanistic quantitative system pharmacology (QSP) model was established based on known reaction parameters of the plasma kallikrein-kininogen pathway adjacent to the vascular space and endothelial surface. A schematic diagram of the model is shown in Figure 18.

[0242]

[0258] The QSP model was constructed to represent simplified biological processes of the contact system, including the production of bradykinin and cleaved HMWK (cHMWK), and to determine the likelihood of an HAE attack. When combined with specific pharmacokinetic information for adult subjects receiving STAR-0215, this model can be used to evaluate plasma kallikrein binding and inhibition, inhibition of HMWK cleavage, and the production of bradykinin and cHMWK, and then predict the likelihood of a given dosing regimen to suppress HAE attacks.

[0243]

[0259] The QSP model utilized a "virtual" HAE patient for the simulation. The baseline HAE attack frequency of the virtual HAE patient was set to 3 attacks per month (per 28 days), and the timing of attack events was randomly assigned using a Poisson distribution. Attacks were triggered by increased FXII autoactivation, and the duration of autoactivation was set to 12 hours. An attack event was defined as a bradykinin level reaching a threshold of 20 pM. PK parameter variations were identified from PK data obtained from healthy adult subjects in a Phase 1a study of STAR-0215 ​​(see Example 4 below). Each simulation was performed on a virtual cohort of HAE patients (n=500 per cohort), and C1 inhibitor was set to 30% of the healthy control level.

[0244]

[0260] In the first simulation, a first hypothetical cohort (n=500) received a dosing regimen of a single subcutaneous loading dose of 600 mg STAR-0215 ​​on Day 1, followed by subcutaneous maintenance doses of 300 mg STAR-0215 ​​every 3 months (84 days) thereafter. In the second simulation, a second hypothetical cohort (n=500) received a dosing regimen of subcutaneous doses of 600 mg STAR-0215 ​​on Day 1, again on Day 28, then every 6 months (every 168 days) thereafter.

[0245]

[0261] Figure 19 presents the results of the simulation as a bar graph, showing the number of HAE attacks per month for individuals in each of the hypothetical cohorts. The simulation showed that baseline attack frequency decreased after STAR-0215 ​​administration. With a dosing regimen of STAR-0215 ​​at a dose of 600 mg on day 1, followed by a subcutaneous maintenance dose of 300 mg every three months (84 days) thereafter, the attack frequency for the cohort decreased to an average of 0.12 attacks in the first month and remained below an average of 0.25 attacks per month thereafter (Cohort 1 in Figure 19). Similarly, with a dosing regimen of STAR-0215 ​​at a subcutaneous dose of 600 mg on day 1, again on day 28, then every six months (every 168 days) thereafter, the attack frequency decreased to an average of 0.12 attacks in the first month and remained below an average of 0.25 attacks per month thereafter (Cohort 2 in Figure 19). The model estimated a greater than 90% reduction in monthly HAE attack rates for both dosing regimens, beginning with the first month of treatment. The model also estimated that an average of 80% of treated HAE patients would be attack-free during the first 6 months of treatment for both dosing regimens.

[0246]

[0262] Therefore, results from the QSP model indicated that a 600 mg loading dose, followed by a 300 mg maintenance dose every 3 months, provided effective control of HAE attacks. Six-monthly dosing options were also evaluated, and results indicated that an initial dose of 600 mg, followed by a 600 mg dose 1 month later, followed by a 600 mg dose every 6 months thereafter, also adequately suppressed HAE attacks.

[0247] Example 4: Phase 1a Clinical Trial

[0263] A first-in-human, Phase 1a, randomized, double-blind, placebo-controlled, single ascending dose study was conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of STAR-0215 ​​in healthy adult subjects. A schematic illustrating the steps of the Phase 1 study design is provided in Figure 4. The primary objective of the study was to evaluate the safety and tolerability of single ascending subcutaneous doses of STAR-0215 ​​in healthy adult subjects. Secondary objectives of the study were to characterize the pharmacokinetics (PK) of single ascending subcutaneous doses of STAR-0215 ​​in healthy adult subjects, characterize the pharmacodynamics (PD) of single ascending subcutaneous doses of STAR-0215 ​​in healthy adult subjects, and evaluate the immunogenicity of single ascending subcutaneous doses of STAR-0215 ​​in healthy adult subjects.

[0248]

[0264] The primary endpoints of the study were to observe adverse events (AEs) and serious adverse events (SAEs), and to obtain clinical laboratory results, 12-lead ECGs, and vital signs. Secondary endpoints were to obtain serum concentrations and derived pharmacokinetic parameters of STAR-0215.

[0249]

[0265] The exploratory objective of this study was to evaluate exploratory laboratory biomarkers. The exploratory endpoint was to obtain an orthogonal measure of plasma kallikrein activity.

[0250]

[0266] The study design employed a standard approach to distinguish the safety profiles of active and placebo treatments when administered to subjects. The safety measures employed in this protocol were standard measures routinely used to evaluate the safety and tolerability of investigational drugs.

[0251] Methods and study design

[0267] Healthy adult subjects aged 18 to 60 years were eligible to participate in the study. Eligible subjects were randomized 3:1 to receive STAR-0215 ​​or placebo in cohorts of eight subjects each. In each cohort, subjects received one dose of study drug (STAR-0215, supplied as a sterile solution for subcutaneous administration in single-use vials at a concentration of 150 mg / ml) or placebo (sterile solution of 0.9% saline for subcutaneous administration) administered subcutaneously by bolus injection into the abdomen on Day 0. There were three cohorts with dose levels of 100 mg, 300 mg, and 600 mg, with the possibility of adding up to three additional cohorts. Two additional cohorts were added after the start of the study: one administered 1,200 mg by subcutaneous bolus injection and the other administered 600 mg by IV administration. These additional cohorts each contained eight subjects randomized 3:1 to receive STAR-0215 ​​or placebo.

[0252]

[0268] Appropriately consented, screened, and eligible subjects were admitted to the clinic on Day -1 and remained there through the assessment conducted 120 hours after study drug administration. Subjects were discharged from the clinic on Day 6 after all required study procedures were completed and authorized by the investigator or designee. Subjects returned to the study site for 10 follow-up visits over 224 days after study drug administration: three visits through the first month (Day 28) after study drug administration and seven monthly visits thereafter. Safety visits were conducted by telephone between monthly visits. Within each cohort, a sentinel group of two subjects was randomized and dosed on Day 1 (one active and one placebo). The remaining six subjects in each cohort were dosed after the sentinel group had no clinically significant safety or tolerability issues within the first 24 hours after dosing. Available data from individual cohorts over the 14 days following STAR-0215 ​​administration were reviewed prior to dose escalation. STAR-0215 ​​SC absorption profile and predicted T for 2-8 days max Based on this, a 14-day safety review period was adopted.

[0253]

[0269] The dosing regimen was as shown in Table 7.

[0254] [Table 7]

[0255]

[0270] The maximum study participation period for each subject was 252 days, including screening.

[0256]

[0271] Safety assessments included adverse events (AEs), vital signs, physical examination, electrocardiogram, and clinical laboratory results including chemistry, hematology, coagulation, and urinalysis. For pharmacokinetic analysis, blood samples were collected to measure serum concentrations of STAR-0215 ​​before and after study drug administration. For pharmacodynamic analysis, samples were collected to measure plasma levels of cleaved high-molecular-weight kininogen (cHMWK; a measure of plasma kallikrein activity). For immunogenicity assessment, blood samples were collected to assess the formation of STAR-0215 ​​anti-drug antibodies in serum before and after study drug administration.

[0257]

[0272] Forty-one healthy subjects were randomized in this study, which was deemed adequate to characterize the safety, tolerability, PK, PD, and immunogenicity of STAR-0215. Data were summarized using descriptive statistics (mean, median, standard deviation, minimum and maximum) or frequency counts and percentages, as appropriate. Results are presented by dose of STAR-0215 ​​relative to combination placebo.

[0258] result

[0273] Pharmacodynamic Analysis: Plasma samples obtained from each cohort (placebo, 100 mg, 300 mg, 600 mg, and 1,200 mg SC, and 600 mg IV) were evaluated to determine the level of plasma kallikrein inhibition resulting from administration of STAR-0215. Because study volunteers were healthy and therefore had low, non-pathological levels of plasma kallikrein and consequently low levels of cHMWK, plasma was activated ex vivo by FXIIa, resulting in increased plasma kallikrein activity and, therefore, increased cleavage of HMWK to cHMWK. It was hypothesized that STAR-0215 ​​inhibits pKal activity, and therefore, lower levels of cHMWK would be observed. Western blot analysis was performed to determine the levels of both HMWK and cHMWK in plasma samples from each cohort.

[0259]

[0274] As shown in Figure 5, STAR-0215 ​​demonstrated sustained engagement with the target pKal, resulting in functional pKal inhibition. There was a significant reduction in HMWK cleavage levels compared to pre-dose levels from at least Day 2 to Day 84 in the 600 mg cohort and from at least Day 6 to Day 84 in the 300 mg cohort.

[0260]

[0275] As shown in Figure 6, engagement of pKal by STAR-0215 ​​was rapid and dose-related, resulting in a statistically significant reduction in cHMWK levels by day 6 at the 300 mg dose and by day 2 at the 600 mg dose.

[0261]

[0276] As shown in Figure 7A, STAR-0215 ​​achieved sustained inhibition of ex vivo FXIIa-activated pKal, as determined by cHMWK, for the 300 mg and 600 mg doses out to day 84 compared to pre-dose (P) levels. These cHMWK levels are similar to the levels of pKal activation observed by Chyung et al. (Ann Allergy Asthma Immunol, 2014, 113:460-466) for lanadelumab, another commercially available anti-pKal antibody. Data for the 1,200 mg SC cohort out to day 84 are presented in Figure 7B, which shows that STAR-0215 ​​also achieved sustained inhibition of ex vivo FXIIa-activated pKal as determined by cHMWK. Figure 7B, which also includes pKal inhibition for the 600 mg cohort, shows that inhibition of plasma kallikrein activity persisted for up to 224 days after a single 600 mg dose of STAR-0215, suggesting that potential clinical efficacy in reducing / inhibiting HAE attacks was sustained over the sustained period for the 600 mg and 1,200 mg doses.

[0262]

[0277] Pharmacodynamic analysis also revealed that suppression of cHMWK to levels consistent with robust plasma kallikrein inhibition by STAR-0215 ​​was achieved by day 84, as observed in the ex vivo FXIIa-induced cleavage of plasma HMWK Western blot assay (the results of which are shown in Figures 13 and 14) and in the orthogonal chromogenic reporter substrate (PFR-pNA) assay (the results of which are shown in Figure 15). As shown in Figure 23, statistically significant (p<0.005) inhibition of ex vivo FXIIa-activated plasma kallikrein activity was observed by day 84 after subcutaneous administration of single doses of 300 mg and 600 mg, and by day 224 after subcutaneous administration of a single dose of 1,200 mg. This data suggests the potential for the 1,200 mg dose to be administered less frequently, e.g., at least every 6 months or more, e.g., every 7, 8, or 9 months or more, while still inhibiting pKal activity.

[0263]

[0278] For the ex vivo FXIIa-induced cleavage of plasma HMWK Western blot assay, sodium citrate plasma samples from subjects in each cohort were incubated ex vivo in the presence or absence of 5 nM FXIIa to activate plasma kallikrein. (A sample without exogenous FXIIa was used as a control and is shown in Figure 13 as the row marked "-".) Samples were protease-inhibited and prepared for loading onto a 4-20% Tris-glycine polyacrylamide gel followed by transfer to a PVDF membrane. Separated HMWK and cHMWK bands were visualized with a goat anti-human kininogen antibody and an IR dye-conjugated donkey anti-goat IgG secondary antibody. Target band signal intensities were captured using an Odyssey Imager, and the percentage of cHMWK in the sample relative to total HMWK + cHMWK was calculated.

[0264]

[0279] As shown in Figure 13, the presence of STAR-0215 ​​inhibited plasma kallikrein activity, and therefore cHMWK formation, compared to the pre-dose activated sample. The cleaved HMWK band was strongest for the 100 mg cohort and weakest for the 600 mg cohort for all time points, indicating that the 600 mg dose resulted in lower cleavage from higher pKal inhibition. Results for the 300 mg cohort were similar to those for the 600 mg cohort.

[0265]

[0280] As shown in Figure 14, the percent change in cHMWK relative to total HMWK + cHMWK, as measured by signal intensity, in the 300 mg and 600 mg cohorts was statistically significant up to day 84, indicating significant inhibition of cHMWK at all time points post-dosing for these two cohorts, while the percent change for the 100 mg cohort was not statistically significant (p<0.05) from day 56 onwards.

[0266]

[0281] Figure 15 shows the results of an orthogonal chromogenic reporter substrate (PFR-pNA) assay to determine the percent inhibition of plasma kallikrein activity when exogenously activated by factor XIIa. Sodium citrate plasma samples were incubated ex vivo in the presence or absence of 10 nM FXIIa to activate plasma kallikrein, followed by the addition of the Pro-Phe-Arg-p-nitroaniline (PFR-pNA) chromogenic substrate. Plasma kallikrein activity was measured by the increase in absorbance due to cleavage of the substrate to p-nitroaniline. The presence of STAR-0215 ​​inhibited plasma kallikrein activity and, therefore, inhibited the formation of the colorimetric product p-nitroaniline compared to the pre-dose FXIIa-activated sample. As shown in Figure 15, for each of the 100 mg, 300 mg, and 600 mg cohorts, the results were statistically significant (p<0.05) for each time point. This assay demonstrates dose-responsive, robust, and long-lasting inhibition of plasma kallikrein activity after a single dose of STAR-0215. As shown in Figure 23, statistically significant (p<0.005) inhibition of ex vivo FXIIa-activated plasma kallikrein activity was observed up to 84 days after subcutaneous administration of single doses of 300 mg and 600 mg, and up to 224 days after subcutaneous administration of a single dose of 1,200 mg.

[0267]

[0282] Overall, the plasma kallikrein inhibitory effects of STAR-0215 ​​were found to be rapid, sustained, and consistent with or superior to those achieved by lanadelumab.

[0268]

[0283] Pharmacokinetic Analysis: Levels of STAR-0215 ​​in the plasma of patients from each cohort were determined over the study period. Results, as shown in Figure 8, showed that subcutaneous dosing of 100 mg, 300 mg, and 600 mg of STAR-0215 ​​significantly reduced C maxFigure 8 shows that STAR-0215 ​​serum concentrations are dose-proportional with an estimated half-life of 117 days, followed by sustained concentrations of STAR-0215 ​​through Day 84. Thus, as shown in Figure 8, serum concentrations of STAR-0215 ​​are dose-proportional with an estimated half-life of 117 days. Both the 300 mg and 600 mg doses maintained or exceeded the threshold concentration of 12 μg / mL (80 nM) considered to be associated with clinical benefit through Day 84, suggesting that these doses may be effective in inhibiting pKal when dosed at 3-month intervals. The antibody clearance phase is shown to be long.

[0269]

[0284] A summary of the pharmacokinetic parameters of STAR-0215 ​​based on the final analysis at Day 224 in the 100 mg SC, 300 mg SC, and 600 mg SC cohorts, and the ongoing interim analyses of the 1,200 mg SC and 600 mg IV cohorts (Days 112 and 84, respectively), is provided below in Table 8. (Data for the 100 mg cohort are presented once for the full group of study patients based on n=7, and twice, again based on n=6*, excluding one patient who received a partial dose.)

[0270] [Table 8]

[0271]

[0285] Pharmacokinetic analysis demonstrated that STAR-0215 ​​had a mean T of 4.8 to 13 days for the SC cohort. max and an estimated t of up to 127 days 1 / 2 demonstrated dose-dependent PK, rapid absorption. maxA dose-related increase in β and AUC was observed. STAR-0215 ​​concentrations exceeded 12 μg / mL (80 nM) (the threshold for potential efficacy) approximately 11 hours after administration. At Day 84, mean concentrations remained above 12 μg / mL (80 nM) after a single 300 mg SC dose and exceeded 80 nM threefold after 600 mg SC dosing, suggesting that the 300 mg and 600 mg doses may be dosing less frequently, e.g., every 3 months. Data from the 1,200 mg SC cohort and 600 mg IV cohort suggest less frequent dosing at longer intervals, e.g., at least every 6 months or more.

[0272]

[0286] As shown in Figures 9A-B, serum levels of STAR-0215 ​​at 300 mg and 600 mg were compared with those of lanadelumab, as reported by Chyung et al. (Ann Allergy Asthma Immunol, 2014, 113:460-466). Plasma concentrations of lanadelumab significantly decreased after 28 days. In contrast, serum concentrations of STAR-0215 ​​remained stable for the 300 mg and 600 mg dose cohorts through day 84. The estimated half-life of STAR-0215 ​​at the 600 mg dose based on Figure 9A was 90 ± 14 h, compared with 110 ± 46 h at 300 mg and 21.2 ± 5.1 h for lanadelumab. The clearance rate (CL) of STAR-0215 ​​was also significantly lower compared with lanadelumab. As shown in Figure 9B, when the day 84 data for the 600 mg cohort was included, the half-life of STAR-0215 ​​at the 600 mg dose was 117 ± 14 days compared to 21.2 ± 5.1 for lanadelumab. CL was not available for the 600 mg cohort, as shown in Figure 9B, because none of the cohort members met the calculation criteria (*); in the 300 mg cohort, as shown in Figure 9B, only one subject met the CL calculation criteria and had a reportable CL (**). (The difference in the PK values ​​provided in Figures 9A and 9B for the 300 mg cohort may be due to the fact that the number of subjects in the cohort changed over time.) For the 1,200 mg SC cohort, data available at Day 84 showed that the mean STAR-0215 ​​concentration was 72.7 μg / mL (FIG. 21) and 66.6 μg / mL at Day 112 (FIG. 22), both time points well above the 12 μg / mL threshold considered necessary for HAE inhibition. At Day 28, the mean STAR-0215 ​​concentration for the 600 mg iv cohort was 75.4 μg / mL (FIG. 21) and 55.5 μg / mL at Day 84 (FIG. 22), well above the 12 μg / mL threshold considered necessary for HAE inhibition.

[0273]

[0287] These pharmacokinetic data demonstrate a rapid increase in STAR-0215 ​​concentrations in the blood after both subcutaneous and intravenous administration, as well as a dose-related increase in concentration and a parallel elimination phase. The rapid (≦1 day) attainment or exceedance of the therapeutic threshold at these doses implies a rapid onset clinical benefit in preventing HAE, and the potential for sustained clinical benefit over 3 months or more at doses >100 mg SC, as for each cohort (except the 100 mg SC cohort), mean concentrations remained at 12 μg / mL for ≧84 days (FIG. 22). These data suggest that STAR-0215 ​​has the potential to be a best-in-class molecule for treating HAE, given the demonstrated long half-life and sustained circulating concentrations out to Day 84 for the 300 mg cohort, which demonstrated sustained levels of STAR-0215 ​​above the therapeutic threshold in the 300 mg SC and 600 mg SC cohorts, allowing for dosing approximately every 3 months and approximately every 6 months, based on the 600 mg cohort results out to Day 168 (Figure 22). Extrapolating the results from the 600 mg IV cohort (Day 84) and 1,200 mg SC cohort (Day 112), as shown in Figure 22, suggests that similarly long inter-dose intervals, e.g., at least every 6 months or more, may be possible, due to the demonstrated sustained levels of STAR-0215 ​​above the therapeutic threshold.

[0274]

[0288] Based on the PK data obtained from the Phase 1a study, an updated PK model was generated that suggests that single doses of 300-450 mg or greater could achieve target plasma levels of STAR-0215 ​​over a 3-month duration. The results of the PK modeling are shown in Figure 10.

[0275]

[0289] Based on the PK data and results from the updated modeling, a simulated human PK profile was generated, as shown in Figure 11A. The model indicated that a loading dose of 600 mg on day 0, followed by maintenance doses of 300 mg at 84-day (3-month) intervals thereafter, was sufficient to maintain serum concentrations of STAR-0215 ​​above the threshold concentration of 80 nM (12 μg / mL), which is believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The steady-state concentration believed to be achieved by this model was 27 μg / mL, which is believed to be sufficient to confer HAE attack protection.

[0276]

[0290] A second simulated human PK profile was generated, as shown in Figure 11B. An initial dose of 600 mg on day 1, followed by 600 mg doses on day 28 and every 6 months thereafter (168 days) was shown by the model to be sufficient to maintain serum concentrations of STAR-0215 ​​above the threshold concentration of 80 nM (12 μg / mL), believed to be necessary for sufficient pKal inhibition to prevent HAE attacks. The steady-state concentration believed to be achieved by the model is 16 μg / mL. This simulation was extended for 24 months, as shown in Figure 20G; the simulation showed a 27.0 μg / mL (C) with every 6 months dosing. trough ) can be maintained at concentrations exceeding 100mg / mL. This level of STAR-0215 ​​is believed to provide protection from HAE attacks. Therefore, based on these simulations, dosing every three or six months is believed to provide clinical benefit.

[0277]

[0291] Based on data from other antibody and protein inhibitors of pKal, 80 nM (12 μg / mL) was conservatively selected as the target level for STAR-0215. Ecallantide, a recombinant protein composed of 60 amino acids, is a human plasma kallikrein inhibitor approved for the symptomatic treatment of acute HAE attacks. At the 30 mg dose level, subcutaneous administration of ecallantide has been shown to result in sufficient plasma kallikrein inhibition for the symptomatic treatment of acute HAE attacks (see, e.g., EMA Assessment Report for Kalbitor, 2011). This evidence is supported by the C of ecallantide (586 ng / mL [approximately 80 nM]) after subcutaneous administration at 30 mg. max These results suggest that sufficient inhibition of circulating plasma kallikrein during HAE attacks is an important goal. The correlation between clinical efficacy (resolution of pKal-induced HAE attacks) and an 80 nM ecallantide concentration implies that the circulating level of pKal is approximately 80 nM during an acute attack.

[0278]

[0292] Furthermore, lanadelumab, a monoclonal antibody plasma kallikrein inhibitor, has been approved for the prophylactic treatment of HAE. A clinical trial examining dose regimens of 150 mg q4 weeks, 300 mg q4 weeks, and 300 mg q2 weeks reported that the efficacy of the 300 mg q2 weeks and 300 mg q4 weeks dose regimens in suppressing HAE attacks was similar (although the 150 mg q4 weeks regimen was less effective) (Wang et al., 2020, Clin Transl Sci, 13:1208-1216). This evidence suggests that a steady-state maintenance concentration of lanadelumab at a dose level of 300 mg q4 weeks (8.77 μg / mL [approximately 60 nM]) is necessary for effective HAE attack suppression, and that a dose of 150 mg q4 weeks (4.81 μg / mL [approximately 33 nM]) may not be sufficient. For lanadelumab, these data suggest that the concentration of pKal during seizures is approximately 60 nM.

[0279]

[0293] Collectively, the data suggest that the minimum circulating concentration of pKal inhibitors to induce clinical benefit in HAE-C1INH is 60-80 nM. Therefore, 80 nM was conservatively selected as the target serum concentration level for STAR-0215.

[0280]

[0294] Study data from all cohorts demonstrated that STAR-0215 ​​was safe and well tolerated at the dose administered to 31 subjects receiving STAR-0215 ​​and 10 subjects receiving placebo. Related treatment-emergent adverse events (TEAEs) were observed in 11 subjects (STAR-0215 ​​n=10; placebo n=1), were mild in severity (Grade 1), and resolved without intervention. The most common related treatment-emergent adverse events occurring in more than two STAR-0215 ​​subjects included injection site reactions of erythema (22.6%), pruritus (12.9%), and swelling (12.9%). One subject (100 mg cohort) experienced unexpected weight gain, while another subject (placebo group) experienced headache, and another subject in the 1,200 mg SC cohort experienced injection site pain. There were no serious adverse events or discontinuations due to adverse events. No clinically significant changes in vital signs, ECG parameters, or laboratory assessments, including activated partial thromboplastin time (aPTT), were observed. Regarding immunogenicity, treatment-emergent anti-drug antibodies (ADAs) were detected in six subjects. Table 9 summarizes treatment-emergent adverse events. The results indicate that STAR-0215 ​​was well tolerated and had a favorable safety profile with a low risk of injection site pain.

[0281] [Table 9]

[0282]

[0295] With rapid absorption and an estimated half-life of up to 127 days, STAR-0215 ​​was found to have a favorable safety profile and demonstrate robust inhibition of plasma kallikrein for at least 84 days (at least 3 months) after a single subcutaneous dose in healthy subjects. These results demonstrate the potential of STAR-0215 ​​as a long-acting preventative therapy for, for example, HAE.

[0283]

[0296] Additional cohorts of 600 mg IV bolus and 1,200 mg subcutaneous were added to the study to evaluate the possibility of every 6 months dosing. As shown in Figure 21, data from the 1,200 mg cohort available at day 84 indicated that the mean STAR-0215 ​​concentration was 72.7 μg / mL, well above the 12 μg / mL threshold believed to be necessary for HAE inhibition. At day 28, data from the 600 mg iv cohort indicated that the mean STAR-0215 ​​concentration was 75.4 μg / mL, well above the 12 μg / mL threshold believed to be necessary for HAE inhibition. As shown in Figure 22, the STAR-0215 ​​concentrations at day 84 for the 300 mg dose suggest the potential for therapeutic dosing at least every three months, while the STAR-0215 ​​concentration data for the 600 mg SC extrapolated from the data for the 1,200 mg SC dose, and similarly, the 600 mg IV dose contemplates the potential for therapeutic dosing at least, e.g., every six months or more (maintenance of blood levels above 12 μg / mL).

[0284]

[0297] Study data demonstrated that STAR-0215 ​​demonstrated dose-dependent concentrations, rapid absorption, slow clearance, and t 1 / 2The results demonstrated median concentrations of STAR-0215. At day 84, median concentrations remained 1x, 3x, and 6x above 12 μg / mL (the potential efficacy threshold) after 300 mg SC, 600 mg SC, and 1,200 mg SC, respectively. Suppression of cHMWK formation was achieved, consistent with plasma kallikrein inhibition. Based on data from healthy subjects, it is contemplated that STAR-0215's favorable safety profile, long half-life, and sustained PD may provide a potential HAE therapy with potent seizure control and low treatment burden.

[0285] Example 5: Phase 1b / 2 Clinical Trial

[0298] Phase 1b / 2 single- and multiple-dose studies are planned to evaluate the safety, tolerability, clinical activity, pharmacokinetics, pharmacodynamics, and immunogenicity of STAR-0215 ​​in participants with hereditary angioedema (HAE). A schematic outlining the clinical trial protocol is shown in Figure 12.

[0286]

[0299] The primary objective of this study is to evaluate the safety and tolerability of single- and multiple-dose subcutaneous (SC) administration of STAR-0215 ​​in participants with hereditary angioedema (HAE) type 1 or type 2. The primary endpoints of the study are to assess the incidence of adverse events, changes in vital signs, electrocardiogram (ECG) findings, physical examination findings, and clinical laboratory assessments.

[0287]

[0300] Secondary objectives of the study include: to evaluate the clinical activity of single and multiple SC doses of STAR-0215 ​​in participants with Type I or II HAE; to characterize the pharmacokinetics (PK) of single and multiple SC doses of STAR-0215 ​​in participants with Type I or II HAE; to characterize the pharmacodynamics (PD) of single and multiple SC doses of STAR-0215 ​​in participants with Type I or II HAE; and to evaluate the immunogenicity of single and multiple SC doses of STAR-0215 ​​in participants with Type I or II HAE.

[0288]

[0301] Secondary endpoints include (i) change from baseline in monthly HAE attack rate and incidence of HAE attack severity (mild, moderate, severe); (ii) duration of HAE attacks (<12 hours, 12-24 hours, 24-48 hours, >48 hours); (iii) number of HAE attacks requiring on-demand therapy; (iv) time to first HAE attack after first and last dose; (v) concentration and derived PK parameters of STAR-0215; (vi) change in plasma kallikrein activity (plasma levels of cleaved HMWK); and (vii) assessment of anti-drug (STAR-0215) antibody formation.

[0289]

[0302] Exploratory objectives include assessing the impact of STAR-0215 ​​on serum or plasma biomarkers related to the disease mechanism of action or effect of STAR-0215, and conducting an exploratory evaluation of the effect of STAR-0215 ​​on health-related quality of life in participants with HAE Type 1 or Type 2. Exploratory endpoints include assessing change from baseline in biomarkers related to the disease mechanism of action or treatment effect of STAR-0215, and change from baseline in angioedema quality of life total and domain scores.

[0290] Methods and study design:

[0303] The study is a Phase 1b / 2, multicenter, single- and multiple-dose study to evaluate the safety, tolerability, clinical activity, PK, PD, and immunogenicity of STAR-0215 ​​in participants with type 1 or type 2 HAE.

[0291]

[0304] Properly consented participants undergo a screening assessment according to the inclusion and exclusion criteria and immediately enter the run-in period. During the run-in period, HAE attack information is collected to determine whether participants meet the eligibility requirement of experiencing at least two HAE attacks during this period and to establish a baseline before STAR-0215 ​​administration. If a participant experiences an HAE attack during the run-in period before Day 1 (first dose of STAR-0215), all signs and symptoms of the attack must resolve before dosing. No washout period is required for on-demand treatment. The run-in period may be extended after consultation with the medical monitor. In cohorts 2 and 3, if a participant experiences an attack immediately prior to the second dose (Day 84 for cohort 2; Day 28 for cohort 3), the signs and symptoms of the HAE attack must be participant-reported improvement before STAR-0215 ​​administration; no washout period is required for on-demand treatment before the second dose is administered.

[0292]

[0305] The dosing regimens and dose levels for each cohort are outlined below in Table 10. There is no placebo group in this study.

[0293] [Table 10]

[0294]

[0306] In Cohort 1, each participant who completes the run-in period and is eligible for STAR-0215 ​​will receive a single dose of 450 mg of STAR-0215 ​​on Day 1. Once Cohort 1 completes dosing, a safety review committee will review the cohort's cumulative safety data from the screening / run-in period through 21 days after dosing. If there are no safety signals, progression to Cohort 2 will occur. In Cohort 2, each eligible participant will receive two doses of STAR-0215: a first dose of 600 mg on Day 1 and a second dose of 300 mg on Day 84. Once six participants in Cohort 2 have received Dose 1, progression to Cohort 3 will begin. In Cohort 3, each eligible participant will receive two doses of STAR-0215: a first dose of 600 mg on Day 1 and a second dose of 600 mg on Day 28. Unless a cumulative review of safety data from this study and the ongoing first-in-human study described in Example 4 indicates safety concerns, other dose levels and dosing regimens may be investigated in additional cohorts. STAR-0215 ​​will be administered by subcutaneous (SC) bolus injection into the peritoneal cavity. Cohort 1 will have four participants, Cohort 2 will have six participants, and Cohort 3 will have six participants. Based on the results of the interim analysis, up to six additional participants may be added to Cohort 2 and / or Cohort 3 (for a total of up to 12 participants in Cohorts 2 and 3). Study evaluations will be conducted over a six-month period following the last dose of STAR-0215 ​​in all cohorts (Day 168 for Cohort 1; Day 251 for Cohort 2; Day 195 for Cohort 3). Safety assessments (including adverse events (AEs), clinical laboratory assessments, physical examination, electrocardiogram (ECG), and vital signs) will be performed, as well as assessments of clinical activity, PK, PD, immunogenicity, biomarkers, and quality of life.

[0295]

[0307] The starting dose of STAR-0215 ​​for participants with HAE in this study was based on PK / PD modeling. Information evaluated for dose selection in this study included (1) the estimated plasma kallikrein inhibition required for HAE attack suppression based on literature reports and human PK models (empirical and minimal physiologically based PK (mPBPK)). Based on overall PK / PD modeling, the 450 mg dose level is considered safe and is estimated to provide adequate target coverage for HAE attack suppression in participants with HAE over the long term. Therefore, 450 mg will be selected as the starting dose for this Phase 1b / 2 study. The planned dosing regimen for Cohort 2 is 600 mg, followed by 300 mg 84 days later. Based on PK / PD modeling, this regimen, with the first dose as a loading dose, is expected to achieve a C min The study has the potential to rapidly increase STAR-0215 ​​concentrations to levels believed to provide robust and durable inhibition of plasma kallikrein, which may lead to immediate and sustained clinical reduction in HAE attacks. The planned dosing regimen for Cohort 3 is 600 mg, followed by 600 mg 28 days later. This regimen involves a first dose on day 1 and a second dose on day 28, and is expected to result in higher STAR-0215 ​​concentrations during the follow-up period. Considering new data from the ongoing Phase 1a study and Cohorts 1, 2, and 3 from this study, other dose levels and dosing regimens may be investigated in additional cohorts.

[0296]

[0308] An ongoing Phase 1a study (Example 4) in healthy adult participants is evaluating single doses of up to 1,200 mg. Initial clinical PK data from the Phase 1a study support human administration of STAR-0215 ​​at dose levels of at least 1,600 mg, 1,600 mg for SC administration and 1,200 mg for IV administration. The study intends to enroll up to 28 participants with HAE. If participants experience an HAE attack during the study, they will be allowed on-demand treatment with standard of care prescribed by their physician.

[0297] Inclusion criteria

[0309] Inclusion criteria were that subjects were at least 18 years old at screening and: 1. Able to read, understand, and sign an Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / Research Ethics Committee (REC) approved Informed Consent Form (ICF). 2. Documented diagnosis of HAE (Type I or Type II). All of the following must be met: 3. Documented medical history consistent with HAE (e.g., SC or mucosal non-pruritic swelling episodes without urticaria). 4. C1-INH antigen or functional levels less than 40% of normal. Participants with antigen or functional C1-INH levels between 40% and 50% of normal may be eligible if they also have C4 levels below the normal range and a family history consistent with HAE type I or II. C1-INH and C4 testing will be performed at screening. Previous C1-INH test results can be used to confirm eligibility. 5. Age ≤30 years at the time of the first reported angioedema symptom or a family history consistent with HAE type I or II. 6. Agree not to receive any vaccine dose within 7 days before or after receiving STAR-0215. 7. Participants of childbearing potential must have a negative serum pregnancy test at screening, must not be pregnant or nursing at screening, and agree to use one of the protocol-defined forms of highly effective contraception during the study. Note: Participants who are unable to conceive according to the protocol (e.g., sterilized or postmenopausal) are not required to use any form of contraception during the study. 8. Participants who are capable of producing sperm and have a childbearing partner must agree to use one of the protocol-defined forms of contraception during the study, unless the participant is azoospermic or the partner is surgically sterilized (as defined in the protocol). 9. Agree not to donate or store sperm for the purpose of insemination or engage in any other activity intended to produce sperm during the study unless sperm are collected prior to administration of the first dose. 10. Agree not to donate or store eggs or undergo assisted reproductive or sterilization procedures during the study. 11. Experienced at least two HAE attacks during the run-in period as confirmed by the investigator based on meeting the protocol-specified definition of an HAE attack.

[0298] Exclusion criteria

[0310] The study exclusion criteria were as follows: 1. Any concomitant diagnosis of another form of chronic angioedema such as acquired C1 inhibitor deficiency, HAE with normal C1-INH (also known as HAE type III), idiopathic angioedema, or angioedema associated with urticaria. 2. Exposure to any investigational drug or device within 90 days or 5 half-lives (whichever is longer) prior to screening. 3. Exposure to a monoclonal antibody or recombinant protein (such as a soluble receptor-Fc fusion protein) containing an Fc domain within 5 half-lives prior to screening. 4. Use of prescribed therapy for prevention of HAE attacks prior to screening: a. Lanadelumab within 90 days b. Berotralstat within 21 days c. All other preventive therapies, within 7 days 5. Exposure to either angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medication with systemic absorption (such as hormonal contraceptives or hormone replacement therapy) within 28 days prior to screening. 6. Any exposure to androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 7 days prior to screening. 7. History of chronic viral infection with a positive test for HIV, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) that has not been adequately cured. 8. Active liver disease (e.g., acute or chronic hepatitis B or C, alcoholic or non-alcoholic steatohepatitis). 9. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN), or aspartate aminotransferase (AST) greater than 3 times the ULN, or total bilirubin greater than 1.5 times the ULN (unless the participant has known Gilbert's syndrome). 10. History of drug or alcohol abuse in the 12 months prior to screening. 11. Participant has active cancer, excluding the following: basal cell carcinoma of the skin. Active cancer is defined as requiring therapy or intervention to prevent disease recurrence / progression. 12. Known sensitivity to any component of STAR-0215. 13. The participant is employed by or is an immediate family member of the sponsor or research facility staff. 14. The participant has any medical or psychiatric condition that, in the opinion of the investigator, may compromise the safety or compliance of the trial participant, interfere with the successful conduct of the trial, or interfere with the interpretation of the results (e.g., a significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of the trial results).

[0299]

[0311] The STAR-0215 ​​drug will be supplied as a sterile, preservative-free solution for SC injection in single-use vials at a concentration of 150 mg / mL. It will be administered in doses of 300 mg, 450 mg, or 600 mg. Individual participants will receive one dose of STAR-0215 ​​(Cohort 1; Day 1) or two doses of STAR-0215 ​​(Cohort 2; Days 1 and 84 and Cohort 3; Days 1 and 28). Each participant's study participation period, including the screening and run-in periods, will be up to 224, 307, or 251 days for Cohorts 1, 2, and 3, respectively. The study will consist of three periods: a. Introduction: Approximately 56 days b. Treatment Period: Individual participants will receive STAR-0215 ​​on Day 1 (Cohort 1), Days 1 and 84 (Cohort 2), or Days 1 and 28 (Cohort 3). c. Follow-up period: Approximately 6 months after the last dose of STAR-0215, Day 168 for Cohort 1, Day 251 for Cohort 2, and Day 195 for Cohort 3.

[0300]

[0312] Defining an event as an HAE attack is based on evaluation of the signs and symptoms of the event against predetermined criteria and the investigator's clinical judgment. To be considered an HAE attack, the investigator must confirm that the event has signs or symptoms consistent with an attack that meet at least one of the following criteria: Peripheral angioedema: skin swelling involving the extremities, face, neck, trunk, and / or genitourinary area Abdominal angioedema: abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea Laryngeal angioedema: wheezing, difficulty breathing, difficulty speaking, difficulty swallowing, throat tightness, or swelling of the tongue, palate, uvula, or larynx

[0301]

[0313] Meeting at least one of the above criteria alone is not sufficient to confirm a seizure. The investigator will use their clinical judgment to assess other characteristics of the event before confirming that a seizure has occurred. Examples of characteristics that may result in an event not being confirmed as a seizure are symptoms inconsistent with an HAE seizure, the duration of the event being longer than typical for an HAE seizure, or the event having a plausible alternative etiology. Prodromal symptoms or participant-reported use of on-demand HAE seizure treatment alone are not sufficient to define an event as an HAE seizure.

[0302]

[0314] Each HAE attack must be unique. To distinguish from a previous attack, new symptoms must occur at least 24 hours after the resolution of the symptoms of the previous attack. Resolution of an attack is defined as a subject no longer experiencing symptoms of the attack.

[0303]

[0315] Seizure severity will be graded by the investigator according to the following definitions: Mild: Transient or mild discomfort Moderate: Mild to moderate limitation of activity, some assistance with daily activities required Severe: Significant limitation of activity, assistance with daily activities required

[0304] Evaluation criteria

[0316] Safety will be assessed by adverse events, vital sign assessments, ECG findings, physical examination findings, and clinical laboratory assessments including chemistry, hematology, coagulation, and urinalysis.

[0305]

[0317] Clinical activity will be assessed by investigator-confirmed HAE attacks and weekly collection of accompanying HAE attack information.

[0306]

[0318] Blood samples will be collected for pharmacokinetic evaluation to measure concentrations of STAR 0215 before and after administration of STAR 0215. Concentrations of STAR-0215 ​​will be measured using current, validated bioanalytical methods.

[0307]

[0319] Blood samples will be collected for pharmacodynamic analysis to assess plasma kallikrein inhibition associated with STAR-0215 ​​administration. Samples will be evaluated using a suitable validated assay to measure plasma kallikrein activity.

[0308]

[0320] Blood samples will be collected for immunogenicity analysis to measure anti-drug (STAR-0215) antibodies. Detection and characterization of antibodies to STAR-0215 ​​will be measured using current, validated bioanalytical methods.

[0309]

[0321] Mechanistic and disease biomarkers may be assessed in serum and plasma. These assessments may provide a better understanding of disease mechanisms or factors associated with HAE attacks, and biomarkers that may change as a result of or affect response to STAR-0215. Assessments may include, but are not limited to, circulating plasma kallikrein and prekallikrein concentrations, surrogate measures of plasma kallikrein activity, functional C1-INH levels over time, and other biomarkers in contact activation, complement, coagulation, fibrinolysis, or other related disease pathways.

[0310]

[0322] Whole blood samples are collected in PAXgene® Blood RNA to isolate RNA for evaluation of expression levels of genes or pathways associated with HAE, such as the contact activation or complement pathways, or expression transcripts that may change in response to STAR-0215 ​​administration. These evaluations may be performed using technologies such as microarrays and RNA-seq, or other sequencing technologies.

[0311]

[0323] With participant consent, whole blood will be collected into PAXgene® blood DNA tubes for pharmacogenomic assessment, including genetic polymorphisms (baseline) and epigenetic modifications associated with HAE or that may influence the participant's response to STAR-0215 ​​or result from STAR-0215 ​​administration.

[0312]

[0324] HAE cases (types I and II) are caused by mutations in the SERPING1 gene, which result in reduced amounts or function of C1-INH, which is encoded by this gene. Variants in the SERPING1 gene or other genes in contact activation, kinin, coagulation, or related pathways have been shown to affect the severity of HAE. Assessment of epigenetics (e.g., DNA methylation) and genetic variations in genes related to HAE pathogenesis or drug disposition may be beneficial in understanding participants' response to STAR-0215 ​​treatment. Whole genome sequencing will not be performed.

[0313]

[0325] The Angioedema Quality of Life Questionnaire (Weller et al., 2012, Allergy, 67(10);1289-1298) is a validated angioedema-specific patient-reported outcome measure self-administered and used to assess the impact of recurrent angioedema on patients' quality of life. It is a 17-item questionnaire covering four domains: function, fatigue / mood, fear / shame, and nutrition. Each item has five response options (scored 1 to 5), with higher scores indicating more adverse effects. Raw scores are converted to a linear scale ranging from 0 to 100, with a score of 100 indicating the worst possible impairment in quality of life. A minimally clinically important difference is defined as a 6-point change from baseline.

[0314]

[0326] Data will be summarized using descriptive statistics (mean, median, standard deviation, minimum and maximum) or frequency counts and percentages, as appropriate. Results will be presented by cohort.

[0315]

[0327] Unless otherwise specified, all analyses of HAE attack data will be presented similarly during the run-in and treatment periods. Data will be analyzed for all investigators with confirmed HAE attacks.

[0316]

[0328] Frequency and duration of HAE attacks are presented as overall descriptive statistics and by participant. The following categories are presented for attack duration (<12 hours, 12-24 hours, 24-48 hours, and >48 hours):

[0317]

[0329] Attack severity, categorized as mild, moderate, or severe, will be presented overall and by participant. The number and type of on-demand therapy used to treat HAE attacks will be summarized. The proportion of subjects free of HAE attacks during the treatment period will be summarized. The time-normalized number of investigator-confirmed HAE attacks per month (attack rate) will be presented at the end of the study at 4-week intervals. Monthly mean rates and 95% confidence intervals are shown.

[0318]

[0330] To assess within-participant HAE attacks, actual percent change from baseline (run-in period) in monthly attack rate versus on-treatment attack rate will be calculated. Mean changes and 95% confidence intervals will be presented. Percentages of participants with a clinical response to treatment with 40%, 50%, 70%, 90%, and 100% or greater reduction in HAE attacks compared to baseline will be presented. Time to first HAE attack after first and last dose of STAR-0215 ​​will be presented using Kaplan-Meier estimates.

[0319]

[0331] Quality of life will be assessed by the Angioedema Quality of Life Questionnaire (AE-QoL). Descriptive statistics of the change from baseline to each visit in total score are presented. The 95% confidence intervals of the changes are also presented. Individual domain scores are also presented.

[0320]

[0332] In preparation for future clinical development of STAR-0215 ​​and subsequent study planning, two interim analyses of data as cohorts accrue are planned. The first interim analysis will occur after the fourth participant in Cohort 1 reaches the Day 84 visit and will include all available data from Cohorts 1 and 2. The second interim analysis will occur after the fourth participant in Cohort 3 reaches Day 84 (Day 111) after the second dose of STAR-0215 ​​and will include all available data from Cohorts 1, 2, and 3. Details of any additional interim analyses, if necessary, will be specified in the Interim Analysis Statistical Analysis Plan (SAP). The sponsor will review the safety, PK, PD, immunogenicity, and efficacy results from each interim analysis and may decide to enroll up to six additional participants in Cohort 2 and / or Cohort 3 (for a total of up to 12 participants each). If no safety concerns are identified after the interim analysis, other dose levels (300 mg to 1,200 mg) and dosing regimens (single or multiple doses) may be investigated in additional cohorts. All analyses will be predefined in the SAP, as appropriate.

[0321]

[0333] Participants may have the opportunity to receive STAR-0215 ​​as participants in a long-term, open-label study under a separate protocol.

[0322] Expected Results

[0334] It is contemplated that subjects enrolled in cohorts 1, 2, and 3 will demonstrate a clinical response in response to treatment with STAR-0215. It is contemplated that subjects enrolled in the study will experience a statistically significant reduction in the frequency and number of HAE attacks compared to baseline as a result of receiving STAR-0215. It is contemplated that administering an initial loading dose at a level of 600 mg, followed by either a 300 mg or 450 mg maintenance dose administered at repeat intervals of 84 days (3 months) after the loading dose, will result in a clinical response in study subjects that may extend beyond 3 months. It is also contemplated that administering a first dose of 600 mg of STAR-0215, followed by a second dose of 600 mg 28 days later, will result in a clinical response in study subjects that may extend beyond 6 months from the first dose. It is further contemplated that a significant proportion of subjects will be attack-free for 3 to 6 months after the first dose, improving their quality of life. It is also contemplated that the clinical response may extend to at least 6 months from the second dose. STAR-0215 ​​is expected to be safe and well tolerated and may improve quality of life (QoL), as measured, for example, by the AE-QoL score. It is also contemplated that the reduction in HAE attack frequency in study subjects from a baseline of an expected 1-4 attacks / month (average 2 attacks / month) will be about 75-90% or greater.

[0323] Example 6: Open-label extension of a Phase 2 clinical trial

[0335] The primary objective of this study is to evaluate the long-term safety and tolerability of STAR-0215 ​​in participants with HAE type 1 or type 2. Primary endpoints include the incidence of adverse events, changes in vital signs, ECG findings, physical examination findings, and clinical laboratory assessments.

[0324]

[0336] Secondary objectives include evaluating the long-term efficacy of STAR-0215 ​​in participants with Type 1 or II HAE, characterizing the PK, PD, and immunogenicity of long-term STAR-0215 ​​administration in participants with Type 1 or II HAE, and assessing the impact of long-term administration on serum or plasma biomarkers related to disease mechanisms, as well as conducting an exploratory evaluation of the effect of long-term STAR-0215 ​​administration on participants' health-related quality of life. Secondary endpoints include change from baseline in monthly HAE attack rate, incidence of monthly HAE attack severity, duration of monthly HAE attacks, number of HAE attacks requiring on-demand therapy, time to first HAE attack after each dose, number of attack-free days, proportion of HAE attack-free participants, STAR-0215 ​​concentration and derived PK parameters, change in plasma kallikrein activity, formation of anti-drug antibodies, change from baseline in biomarkers related to the disease mechanism of action or therapeutic effect of STAR-0215, and change from baseline in Angioedema-Quality of Life (AE-QoL) total and domain scores.

[0325]

[0337] Patients who completed all visits through 6 months in the Phase 2 study described in Example 5, and patients who entered the Phase 2 study run-in period but were ineligible for the treatment period because they did not meet the minimum number of HAE attacks during the run-in period, are eligible to enroll in this open-label extension study. A maximum of 56 participants will be enrolled.

[0326] ...

Claims

1. 1. A method of treating a human subject having a plasma kallikrein-associated disorder, comprising: administering to said subject a loading dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody; administering to said subject a maintenance dose of 150 to 1,500 mg of said anti-plasma kallikrein antibody beginning at least about two months after administration of said loading dose and at least about every two months thereafter; Including; The anti-plasma kallikrein antibody i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 A method comprising:

2. 1. A method of achieving a circulating concentration of anti-plasma kallikrein antibodies greater than 10 μg / mL for at least two months in a subject with a plasma kallikrein-associated disorder, comprising administering to the subject a loading dose followed by a maintenance dose of: i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 20. A method comprising administering an anti-plasma kallikrein antibody comprising:

3. 1. A method of treating a human subject having a plasma kallikrein-associated disorder, comprising: administering to said subject a loading dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody; administering to the subject a first maintenance dose of 150 to 1,500 mg of the anti-plasma kallikrein antibody about 1 to 8 weeks after administering the loading dose; administering a second maintenance dose of 150 to 1,500 mg 2 to 9 months after the first maintenance dose; administering subsequent maintenance doses every 2 to 9 months after said second maintenance dose. Including; the first maintenance dose, the second maintenance dose, and any subsequent maintenance doses are the same dose; The anti-plasma kallikrein antibody i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 A method comprising:

4. 3. The method of claim 2, wherein the loading dose is in the range of 300 to 2000 mg and the maintenance dose is in the range of 150 to 1500 mg.

5. 5. The method of any one of claims 1 to 4, wherein the loading dose is in the range of 300 to 900 mg.

6. 6. The method of any one of claims 1 to 5, wherein the loading dose is within a range selected from 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, or 450 to 500 mg.

7. The method of any one of claims 1 to 6, wherein the loading dose is within a range selected from 600 to 900 mg.

8. 8. The method of any one of claims 1 to 7, wherein the loading dose is within a range selected from 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, 450 to 500 mg, 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, or 850 to 900 mg.

9. 9. The method of any one of claims 1 to 8, wherein the loading dose is about 400 to 450 mg.

10. 10. The method of any one of claims 1-6, 8, or 9, wherein the loading dose is 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.

11. 11. The method of any one of claims 1-5 or 7-10, wherein the loading dose is selected from 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, or 900 mg.

12. The method of any one of claims 1 to 4, wherein the loading dose is within a range selected from 900 to 1,200 mg.

13. 5. The method of any one of claims 1 to 4, wherein the loading dose is in the range of 500 to 2,000 mg.

14. The loading dose is 350 to 400 mg, 400 to 450 mg, 450 to 500 mg, 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 1,100 to 1,150 mg, 1,150 to 1,200 mg, 1,200 to 1,250 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg , 1,350 to 1,400 mg, 1,400 to 1,450 mg, 1,450 to 1,500 mg, 1,500 to 1,550 mg, 1,550 to 1,600 mg, 1,600 to 1,650 mg, 1,650 to 1,700 mg, 1,700 to 1,750 mg, 1,750 to 1,800 mg, 1,800 to 1,850 mg, 1,850 to 1,900 mg, 1,900 to 1,950 mg, or 1,950 to 2,000 mg.

15. The loading dose may be 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1, 15. The method of any one of claims 1-8 or 12-14, wherein the dose is selected from the group consisting of 375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, 1,500 mg, 1,525 mg, 1,550 mg, 1,575 mg, 1,600 mg, 1,600 mg, 1,625 mg, 1,650 mg, 1,675 mg, 1,700 mg, 1,725 ​​mg, 1,750 mg, 1,775 mg, 1,800 mg, 1,825 mg, 1,850 mg, 1,875 mg, 1,900 mg, 1,925 mg, 1,950 mg, 1,975 mg, or 2,000 mg.

16. 16. The method of any one of claims 1-5, 7, 8, or 11-15, wherein the loading dose is 600 mg.

17. 16. The method of any one of claims 1-5, 7, 8, or 11-15, wherein the loading dose is 900 mg.

18. 16. The method of any one of claims 1 to 4, or 11 to 15, wherein the loading dose is 1,200 mg.

19. 19. The method of any one of claims 1 to 18, wherein the maintenance dose is in the range of 250 to 1,500 mg.

20. 19. The method of any one of claims 1 to 18, wherein the maintenance dose is in the range of 200 mg to 1,500 mg.

21. 21. The method of any one of claims 1 to 20, wherein the maintenance dose is 150 to 450 mg.

22. The maintenance dose is 250 to 300 mg, 300 to 350 mg, 350 to 400 mg, 450 to 500 mg, 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,05 ...

22. The method of any one of claims 1 to 21, wherein the dose is in a range selected from 0 to 1,100 mg, 1,100 to 1,150 mg, 1,150 to 1,200 mg, 1,200 to 1,250 mg, 1,250 to 1,300 mg, 1,300 to 1,350 mg, 1,350 to 1,400 mg, 1,400 to 1,450 mg, or 1,450 to 1,500 mg.

23. 23. The method of any one of claims 1 to 22, wherein the maintenance dose is in the range of 150 to 250 mg, or is 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg.

24. 23. The method of any one of claims 1 to 22, wherein the maintenance dose is in the range of 300 to 450 mg.

25. 23. The method of any one of claims 1 to 22, wherein the maintenance dose is in the range of 300 to 900 mg.

26. 23. The method of any one of claims 1 to 22, wherein the maintenance dose is in the range of 200 to 250 mg.

27. 26. The method of any one of claims 1 to 22, 24 or 25, wherein the maintenance dose is 300 mg or 450 mg.

28. The maintenance dose is 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg 28. The method of any one of claims 1 to 27, wherein the amount of hydroxybenzoates is selected from the group consisting of 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg.

29. The method of any one of claims 1 to 28, wherein the maintenance dose is half the amount of the loading dose.

30. 30. The method of any one of claims 2-29, wherein the first maintenance dose is administered to the subject about 1 to 2 weeks after administration of the loading dose.

31. 31. The method of any one of claims 2-30, wherein the second maintenance dose is administered about 3 to 6 months after the first maintenance dose, and the subsequent maintenance doses are administered every 3 to 6 months after the second maintenance dose, and the time between the first and second maintenance doses and the second and subsequent maintenance doses is the same.

32. 32. The method of any one of claims 2-31, wherein the second maintenance dose is administered three months after the first maintenance dose, and the subsequent maintenance doses are administered every three months after the second maintenance dose.

33. 32. The method of any one of claims 2-31, wherein the second maintenance dose is administered 6 months after the first maintenance dose, and the subsequent maintenance doses are administered every 6 months after the second maintenance dose.

34. 34. The method of any one of claims 1 to 33, wherein the loading dose and the maintenance dose are administered subcutaneously to the subject.

35. 34. The method of any one of claims 1 to 33, wherein the loading dose and the maintenance dose are administered intravenously to the subject.

36. 34. The method of any one of claims 1 to 33, wherein the loading dose is administered intravenously and the maintenance dose is administered subcutaneously.

37. 37. The method of claim 34 or 36, wherein the subcutaneous dose is administered from a pre-filled syringe, an automatic injection device, or via an on-body or wearable injection device.

38. 37. The method of claim 35 or 36, wherein the intravenous dose is administered as a bolus injection or by infusion.

39. 39. The method of any one of claims 1-38, wherein the loading dose maintains a serum concentration of the antibody above about 10 μg / mL for about 2 months.

40. 40. The method of any one of claims 1-39, wherein the loading dose maintains a serum concentration of the antibody above about 12 μg / mL for about 3 months.

41. 41. The method of any one of claims 1-40, wherein the maintenance dose maintains a serum concentration of the antibody above about 10 μg / mL for about 2 months.

42. 42. The method of any one of claims 1-41, wherein the maintenance dose maintains a serum concentration of the antibody above about 12 μg / mL for about 3 months.

43. 43. The method of any one of claims 1-42, wherein the maintenance dose is administered about 3 months after the loading dose, and then about every 3 months thereafter.

44. 44. The method of claim 43, wherein the loading dose is about 600 mg and the maintenance dose is about 300 mg.

45. 44. The method of claim 43, wherein the loading dose is about 400-450 mg and the maintenance dose is about 200-250 mg.

46. 46. ​​The method of any one of claims 1-45, wherein the maintenance dose is administered about 6 months after the loading dose, and then about every 6 months thereafter.

47. 47. The method of claim 46, wherein the loading dose is about 1,200 mg and the maintenance dose is about 900 mg.

48. 48. The method of any one of claims 1-47, wherein the maintenance dose is administered about 9 months after the loading dose, and then about every 9 months thereafter.

49. 48. The method of any one of claims 1-47, wherein the maintenance dose is administered about every 12 months after the loading dose.

50. 1. A method of treating a human subject having a plasma kallikrein-associated disorder, comprising: administering to the subject a first dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody; After a first period of time after administering the first dose, (i) administering to said subject a second dose of 300 to 2,000 mg of said anti-plasma kallikrein antibody, followed by administering to said subject one or more subsequent doses of 300 to 2,000 mg of said anti-plasma kallikrein antibody at intervals equal to said first period; or (ii) administering to the subject a second dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody; after a second period of time equal to the first period of time, administering to the subject a third dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody, followed by administering to the subject one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody at intervals equal to a third period of time longer than the first and second periods of time; or (iii) administering to the subject a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody, and after a second period of time longer than the first period of time, administering to the subject a third dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody, and thereafter, at intervals equal to the second period of time, administering to the subject one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody; the first dose, the second dose, any third dose, and any one or more subsequent doses are the same amount; and The anti-plasma kallikrein antibody i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 A method comprising:

51. 51. The method of claim 50, wherein a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody is administered to the subject a first period of time after administering the first dose, followed by one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody administered to the subject at intervals equal to the first period of time.

52. 52. The method of claim 51, wherein the first period of time is from about 3 months to about 9 months.

53. 53. The method of any one of claims 51 or 52, wherein the first period of time is selected from about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months.

54. 54. The method of any one of claims 51-53, wherein the first period of time is three months such that the subject receives a dose of the antibody every three months.

55. 54. The method of any one of claims 51-53, wherein the first period of time is about 4 months such that the subject receives a dose of the antibody about every 4 months.

56. 54. The method of any one of claims 51-53, wherein the first period of time is about 5 months such that the subject receives a dose of the antibody about every 5 months.

57. 54. The method of any one of claims 51-53, wherein the first period of time is about 6 months such that the subject receives a dose of the antibody about every 6 months.

58. 54. The method of any one of claims 51-53, wherein the first period of time is about 7 months such that the subject receives a dose of the antibody about every 7 months.

59. 54. The method of any one of claims 51-53, wherein the first period of time is about 8 months such that the subject receives a dose of the antibody about every 8 months.

60. 54. The method of any one of claims 51-53, wherein the first period of time is about 9 months such that the subject receives a dose of the antibody about every 9 months.

61. 54. The method of any one of claims 51-53, wherein the first period of time is about 12 months such that the subject receives a dose of the antibody about every 12 months.

62. 62. The method of any one of claims 51-61, wherein administration of the first dose, the second dose, or a subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months following said administration of said dose.

63. 63. The method of any one of claims 51-62, wherein administration of the first dose, the second dose, or a subsequent dose maintains a serum concentration of the antibody above about 12 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months following said administration of said dose.

64. 64. The method of any one of claims 51-63, wherein administration of the first dose, the second dose, or a subsequent dose maintains a serum concentration of the antibody above about 25 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months following said administration of said dose.

65. 65. The method of any one of claims 51-64, wherein the first dose is in the range of 300-900 mg.

66. 66. The method of any one of claims 51 to 65, wherein the first period of time is between 3 months and 6 months.

67. 67. The method of any one of claims 51-66, wherein the first dose is 700 mg and the first period of time is 6 months.

68. 65. The method of any one of claims 51-64, wherein the first dose is 1,200 mg and the first period of time is 6 months.

69. 67. The method of any one of claims 51-66, wherein the first dose is 600 mg and the first period of time is 6 months.

70. 67. The method of any one of claims 51-66, wherein the first dose is 300-450 mg and the first period of time is 3 months.

71. 51. The method of claim 50, wherein after the first period of time following administration of the first dose, a second dose of 300 to 2,000 mg of an anti-plasma kallikrein antibody is administered to the subject; after a second period of time equal to the first period of time, a third dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody is administered to the subject, followed by one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody administered to the subject at intervals equal to a third period of time that is longer than the first and second periods of time.

72. 72. The method of claim 71, wherein the first period of time is from about 2 months to about 6 months and the third period of time is from about 4 months to about 9 months.

73. 73. The method of any one of claims 71 or 72, wherein the first period of time is selected from about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, and the third period of time is selected from about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months.

74. 74. The method of any one of claims 71-73, wherein the first period of time is two months and the third period of time is about four months, whereby the subject receives a dose of the antibody about every four months after the third dose.

75. 74. The method of any one of claims 71-73, wherein the first period of time is about 3 months and the third period of time is about 6 months, whereby the subject receives a dose of the antibody about every 6 months after the third dose.

76. 74. The method of any one of claims 71-73, wherein the first period of time is about 4 months and the third period of time is about 8 months, whereby the subject receives a dose of the antibody about every 8 months after the third dose.

77. 74. The method of any one of claims 71-73, wherein the first period of time is about 4 months and the third period of time is about 9 months, and the subject receives a dose of the antibody about every 9 months after the third dose.

78. 72. The method of claim 71, wherein the first period of time is about 1 to 4 weeks.

79. 79. The method of claim 78, wherein the first period of time is about 1 week or about 2 weeks.

80. 80. The method of claim 78 or 79, wherein the third period of time is from about 3 months to about 6 months.

81. 81. The method of any one of claims 78 to 80, wherein the third period of time is 3 months or 6 months.

82. 82. The method of any one of claims 71-81, wherein administration of the first dose followed by the second dose, or the third dose, or subsequent doses maintains a serum concentration of the antibody above about 10 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after said administration of the doses.

83. 82. The method of any one of claims 71-81, wherein administration of the first dose followed by the second dose, or the third dose, or any subsequent doses maintains a serum concentration of the antibody above about 12 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after said administration of the doses.

84. 82. The method of any one of claims 71-81, wherein administration of the first dose followed by the second dose, or the third dose, or any subsequent doses maintains a serum concentration of the antibody above about 25 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after said administration of the doses.

85. 51. The method of claim 50, wherein after the first period of time following administration of the first dose, a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody is administered to the subject, and after a second period of time longer than the first period of time, a third dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody is administered to the subject, followed by one or more subsequent doses of 300 to 2,000 mg of the anti-plasma kallikrein antibody administered to the subject at intervals equal to the second period of time.

86. 86. The method of claim 85, wherein the first period of time is about 1 to 8 weeks.

87. 86. The method of claim 85, wherein the first period of time is about 1 to 4 weeks.

88. 86. The method of claim 85, wherein the first period of time is about 1 to 2 weeks.

89. 86. The method of claim 85, wherein the first period of time is about one week.

90. 86. The method of claim 85, wherein the first period of time is about 2 to 6 weeks.

91. 86. The method of claim 85, wherein the first period of time is 4 weeks ± 2 weeks.

92. 92. The method of claim 91, wherein the first period of time is about two weeks.

93. 92. The method of claim 91, wherein the first period of time is about 4 weeks.

94. 92. The method of claim 91, wherein the first period of time is about 6 weeks.

95. 86. The method of claim 85, wherein the first period of time is about 2 months, 3 months, 4 months, 5 months, or 6 months.

96. 96. The method of claim 85 or 95, wherein the first period of time is about 3 months.

97. 97. The method of any one of claims 85 to 96, wherein the second period of time is about 6 to 12 months.

98. 97. The method of any one of claims 85 to 96, wherein the second period of time is 3 to 9 months.

99. 97. The method of any one of claims 85 to 96, wherein the second period of time is 3 to 6 months.

100. 100. The method of any one of claims 85 to 99, wherein the second period of time is about 6 months.

101. 99. The method of any one of claims 85 to 98, wherein the second period of time is about 9 months.

102. 98. The method of any one of claims 85 to 97, wherein the second period of time is about 12 months.

103. 101. The method of any one of claims 85-88, 90-94, or 97-100, wherein the second dose is administered 2 to 6 weeks after the first dose, the third dose is administered about 6 months after the second dose, and subsequent doses are administered at about 6 month intervals after the third dose, whereby the subject receives a dose of the antibody about every 6 months after the second dose.

104. 104. The method of claim 103, wherein the second dose is administered about 4 weeks after the first dose.

105. 100. The method of any one of claims 85-92, 98, or 99, wherein the second dose is administered 1 to 2 weeks after the first dose, the third dose is administered 3 months after the second dose, and subsequent doses are administered at about three month intervals after the third dose, whereby the subject receives a dose of the antibody about every three months after the second dose.

106. 101. The method of any one of claims 85-92 or 97-100, wherein the second dose is administered 1 to 2 weeks after the first dose, the third dose is administered 6 months after the second dose, and subsequent doses are administered at about 6 month intervals after the third dose, whereby the subject receives a dose of the antibody about every 6 months after the second dose.

107. 103. The method of any one of claims 85, 95-97, or 102, wherein the second dose is administered about 3 months after the first dose, the third dose is administered about 12 months after the second dose, and subsequent doses are administered at about 12 month intervals after the third dose, whereby the subject receives a dose of the antibody about every 12 months after the second dose.

108. 100. The method of any one of claims 85 to 99, wherein the second period of time is about 5 months.

109. 100. The method of any one of claims 85, 86, 90-94, or 97-99, wherein the second dose is administered 2 to 6 weeks after the first dose, the third dose is administered about 5 months after the second dose, and subsequent doses are administered at about 5 month intervals after the third dose, whereby the subject receives a dose of the antibody every 5 months after the second dose.

110. 86. The method of claim 85, wherein the first period of time is from about 2 months to about 6 months and the second period of time is from about 4 months to about 9 months.

111. 111. The method of any one of claims 85 or 110, wherein the first period of time is selected from about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, and the second period of time is selected from about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months.

112. 112. The method of any one of claims 85, 110, or 111, wherein the first period of time is about 2 months and the second period of time is about 4 months, whereby the subject receives a dose of the antibody about every 4 months after the second dose.

113. 112. The method of any one of claims 85, 110, or 111, wherein the first period of time is about 3 months and the second period of time is about 6 months, whereby the subject receives a dose of the antibody about every 6 months after the second dose.

114. 112. The method of any one of claims 85, 110, or 111, wherein the first period of time is about 4 months and the second period of time is about 8 months, whereby the subject receives a dose of the antibody about every 8 months after the second dose.

115. 112. The method of any one of claims 85, 110, or 111, wherein the first period of time is about 4 months and the second period of time is about 9 months, whereby the subject receives a dose of the antibody about every 9 months after the second dose.

116. 116. The method of any one of claims 85-115, wherein administration of the first dose, the second dose, the third dose, or a subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months.

117. 117. The method of any one of claims 85-116, wherein administration of the first dose, the second dose, the third dose, or a subsequent dose maintains a serum concentration of the antibody above about 12 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months.

118. 118. The method of any one of claims 85-117, wherein administration of the first dose, the second dose, the third dose, or a subsequent dose maintains a serum concentration of the antibody greater than or equal to 25 μg / mL for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months.

119. 119. The method of any one of claims 50-118, wherein the first dose, second dose, third dose, and subsequent doses are each about 300-900 mg.

120. 120. The method of any one of claims 50-119, wherein the first dose, second dose, third dose and subsequent doses are about 600 mg.

121. 120. The method of any one of claims 50-119, wherein the first dose, second dose, third dose and subsequent doses are about 300-450 mg.

122. 120. The method of any one of claims 50-119, wherein the first dose, second dose, third dose and subsequent doses are about 900 mg.

123. 119. The method of any one of claims 50-118, wherein the first dose, second dose, third dose, and subsequent doses are each about 1,200 mg.

124. 119. The method of any one of claims 50-118, wherein the first dose, second dose, any third dose, or any one or more subsequent doses is each 500-1,500 mg.

125. The first dose, second dose, optional third dose, and any one or more subsequent doses may be 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 850-900 mg, 900-50 mg, 950-1,000 mg, 1,000-1,050 mg, 1,050-2,050 mg, 1,050-2,050 mg, 1,050-3,050 mg, 1,050-3,050 mg, 1,050-4,050 mg, 1,050-4,050 mg, 1,050-5,050 mg, 1,050-6,050 mg, 1,050-7,050 mg, 1,050-8,050 mg, 1,050-1,050 mg, 1,050-2,050 mg, 1,050-3 ...1,050 mg, 1,050-2,050 mg, 1,050-3,050 mg, 1,050- 0-1,100mg, 1,100-1,150mg, 1,150-1,200mg, 1,200-1,250mg, 1,250-1,300mg, 1,300-1, 350mg, 1,350-1,400mg, 1,400-1,450mg, 1,450-1,500mg, 500mg, 525mg, 550mg, 575mg, 600 120. The method of any one of claims 50-119, wherein the hydroxybenzoate is selected from one of the following: 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg.

126. 120. The method of any one of claims 50-119, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are each 600-1,200 mg.

127. 119. The method of any one of claims 50-66, 69, 71-118, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are each 600 mg.

128. 119. The method of any one of claims 50-66, or 71-118, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are each 900 mg.

129. 119. The method of any one of claims 50-66, 68, or 71-118, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are each 1,200 mg.

130. 130. The method of any one of claims 50-129, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are administered subcutaneously to the subject.

131. 130. The method of any one of claims 50-129, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are administered intravenously to the subject.

132. 130. The method of any one of claims 50-129, wherein the first dose is administered intravenously, and the second dose, any third dose, and any one or more subsequent doses are administered subcutaneously.

133. 130. The method of any one of claims 50-129, wherein the first and second doses are administered intravenously, and any third dose and any one or more subsequent doses are administered subcutaneously.

134. 130. The method of any one of claims 50-129, wherein the first dose, second dose, optional third dose, and any one or more subsequent doses are administered to the subject using a combination of intravenous and subcutaneous administration.

135. 134. The method of any one of claims 130, 132, or 133, wherein the subcutaneously administered dose(s) is administered from a pre-filled syringe, an automatic injection device, or via an on-body or wearable injection device.

136. 135. The method of any one of claims 131, 133, or 134, wherein the dose(s) administered intravenously are administered as a bolus injection or by infusion.

137. 1. A method of treating a human subject having a plasma kallikrein-associated disorder, comprising: administering to the subject a first dose of 300-2,000 mg of an anti-plasma kallikrein antibody, followed by one or more treatment cycles consisting of a first subsequent dose of 300-2,000 mg of the antibody, followed by a second subsequent dose of 300-2,000 mg of the antibody; the first subsequent dose is administered a first period of time from the first dose or a third period of time from the second subsequent dose of a previous treatment cycle, the third period of time being equal to the first period of time; the second subsequent dose is administered a second period of time from the first subsequent dose; the first period of time is shorter than the second period of time; the first dose, the first subsequent dose, and the second subsequent dose are the same amount; The anti-plasma kallikrein antibody i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 A method comprising:

138. 138. The method of claim 137, wherein the first period of time is about 2 to 6 weeks.

139. 139. The method of any one of claims 137 or 138, wherein the first period of time is about 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks.

140. 139. The method of any one of claims 137 or 138, wherein the first period of time is 4 weeks ± 2 weeks.

141. 141. The method of any one of claims 137 to 140, wherein the first period of time is about two weeks.

142. 141. The method of any one of claims 137 to 140, wherein the first period of time is about 4 weeks.

143. 141. The method of any one of claims 137 to 140, wherein the first period of time is about 6 weeks.

144. 141. The method of any one of claims 137 to 140, wherein the second period of time is 3 to 9 months.

145. 145. The method of any one of claims 137-144, wherein the second period of time is about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months.

146. 145. The method of any one of claims 137-144, wherein the second period of time is 3 months ± 2 weeks, 4 months ± 2 weeks, 5 months ± 2 weeks, 6 months ± 2 weeks, 7 months ± 2 weeks, 8 months ± 2 weeks, or 9 months ± 2 weeks.

147. 145. The method of any one of claims 137 to 144, wherein the second period of time is about 6 months.

148. 145. The method of any one of claims 137 to 144, wherein the second period of time is 6 months ± 2 weeks.

149. 139. The method of any one of claims 137-138, wherein (a) the first subsequent dose is administered 2 to 6 weeks after the first dose or 2 to 6 weeks after the second subsequent dose of a previous treatment cycle, and (b) the second subsequent dose is administered 3 to 9 months after the first subsequent dose.

150. 139. The method of any one of claims 137-138, wherein (a) the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose of a previous treatment cycle or 4 weeks ± 2 weeks after the second subsequent dose, and (b) the second subsequent dose is administered 6 months ± 2 weeks after the first subsequent dose.

151. 139. The method of any one of claims 137-138, wherein (a) the first subsequent dose is administered two weeks after the first dose or two weeks after the second subsequent dose of a previous treatment cycle, and (b) the second subsequent dose is administered 6 months ± 2 weeks after the first subsequent dose.

152. 139. The method of any one of claims 137-138, wherein (a) the first subsequent dose is administered 4 weeks after the first dose or 4 weeks after the second subsequent dose of a previous treatment cycle, and (b) the second subsequent dose is administered 6 months ± 2 weeks after the first subsequent dose.

153. 153. The method of any one of claims 149-152, wherein the second subsequent dose is administered six months after the first subsequent dose.

154. 146. The method of any one of claims 137 to 145, wherein the second period of time is about 5 months.

155. 147. The method of any one of claims 137 to 146, wherein the second period of time is 5 months ± 2 weeks.

156. 138. The method of claim 137, wherein (a) the first subsequent dose is administered 4 weeks ± 2 weeks after the first dose of a previous treatment cycle or 4 weeks ± 2 weeks after the second subsequent dose, and (b) the second subsequent dose is administered 5 months ± 2 weeks after the first subsequent dose.

157. 138. The method of claim 137, wherein (a) the first subsequent dose is administered two weeks after the first dose or two weeks after the second subsequent dose of a previous treatment cycle, and (b) the second subsequent dose is administered five months ± two weeks after the first subsequent dose.

158. 138. The method of claim 137, wherein (a) the first subsequent dose is administered 4 weeks after the first dose of a previous treatment cycle or 4 weeks after the second subsequent dose, and (b) the second subsequent dose is administered 5 months ± 2 weeks after the first subsequent dose.

159. 159. The method of any one of claims 156-158, wherein the second subsequent dose is administered 5 months after the first subsequent dose.

160. 160. The method of any one of claims 137-159, wherein administration of the first dose followed by a first subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months from the time of administration of the first dose, or administration of a second subsequent dose followed by a first subsequent dose maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months from the time of administration of the second subsequent dose.

161. 161. The method of claim 160, wherein the serum concentration is maintained at or above 12 μg / mL for 5 months.

162. 162. The method of claim 161, wherein the serum concentration is maintained at 25 μg / mL or greater for 5 months.

163. 163. The method of any one of claims 137-162, wherein the first dose, the first subsequent dose, and the second subsequent dose are each 500 to 1,500 mg.

164. The first dose, the first subsequent dose, and the second subsequent dose are selected from the group consisting of 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 0mg, 1,100-1,150mg, 1,150-1,200mg, 1,200-1,250mg, 1,250-1,300mg, 1,300-1,350mg, 1,350-1,400mg, 1,400-1,450mg, 1,450-1,500mg, 500mg, 525mg, 550mg, 575mg, 600mg, 62 164. The method of any one of claims 137-163, wherein the hydroxybenzoate is selected from one of the following: 5 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg.

165. 165. The method of any one of claims 137-164, wherein the first dose, the first subsequent dose, and the second subsequent dose are each 600-1,200 mg.

166. 166. The method of any one of claims 137-165, wherein the first dose, the first subsequent dose, and the second subsequent dose are each 600 mg.

167. 167. The method of claim 166, wherein the first period is one month and the second period is six months.

168. 166. The method of any one of claims 137-165, wherein the first dose, the first subsequent dose, and the second subsequent dose are each 900 mg.

169. 169. The method of claim 168, wherein the first period is one month and the second period is six months.

170. 166. The method of any one of claims 137-165, wherein the first dose, the first subsequent dose, and the second subsequent dose are each 1,200 mg.

171. 171. The method of any one of claims 137-170, wherein the first dose, first subsequent dose, and second subsequent dose are administered subcutaneously to the subject.

172. 171. The method of any one of claims 137-170, wherein the first dose, first subsequent dose, and second subsequent dose are administered intravenously to the subject.

173. 171. The method of any one of claims 137-170, wherein the first dose and the first subsequent dose are administered to the subject intravenously, and the second subsequent dose is administered subcutaneously.

174. 171. The method of any one of claims 137-170, wherein the first dose, first subsequent dose, and second subsequent dose are administered to the subject using a combination of intravenous and subcutaneous administration.

175. 175. The method of any one of claims 171, 173, or 174, wherein the subcutaneously administered dose is administered from a pre-filled syringe, an automatic injection device, or via an on-body or wearable injection device.

176. 175. The method of any one of claims 172 to 174, wherein the intravenously administered dose is administered as a bolus injection or by infusion.

177. 1. A method of treating a human subject having a plasma kallikrein-associated disorder, comprising: administering a treatment cycle of an anti-plasma kallikrein antibody to the subject, the treatment cycle comprising administering a first dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody to the subject, then administering a second dose of 300 to 2,000 mg of the anti-plasma kallikrein antibody to the subject a first time period after administering the first dose, and then repeating the administration of the treatment cycle one or more times a second time period after administering the second dose, wherein the second time period is longer than the first time period and the first dose and the second dose are the same; The anti-plasma kallikrein antibody i) a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index; ii) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising the mutations M252Y, S254T, and T256E, numbered according to the EU numbering index; or iii) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 A method comprising:

178. 178. The method of claim 177, wherein the first period of time is 2 to 6 weeks.

179. 179. The method of any one of claims 177-178, wherein the first period of time is about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks.

180. 180. The method of any one of claims 177 to 179, wherein the first period of time is 4 weeks ± 2 weeks.

181. 181. The method of any one of claims 177 to 180, wherein the first period of time is about two weeks.

182. 181. The method of any one of claims 177-180, wherein the first period of time is about 4 weeks.

183. 181. The method of any one of claims 177-180, wherein the first period of time is about 6 weeks.

184. 184. The method of any one of claims 177 to 183, wherein the second period of time is 3 to 9 months.

185. 185. The method of any one of claims 177-184, wherein the second period of time is about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months.

186. 185. The method of any one of claims 177-184, wherein the second period of time is 3 months ± 2 weeks, 4 months ± 2 weeks, 5 months ± 2 weeks, 6 months ± 2 weeks, 7 months ± 2 weeks, 8 months ± 2 weeks, or 9 months ± 2 weeks.

187. 186. The method of any one of claims 177 to 185, wherein the second period of time is about 6 months.

188. 187. The method of any one of claims 177 to 186, wherein the second period of time is 6 months ± 2 weeks.

189. 189. The method of any one of claims 177-188, wherein the second dose is administered 2 to 6 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose.

190. 189. The method of any one of claims 177-188, wherein the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose.

191. 189. The method of any one of claims 177-188, wherein the second dose is administered 2 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose.

192. 189. The method of any one of claims 177-188, wherein the second dose is administered 4 weeks after the first dose, and the treatment cycle is repeated 6 months ± 2 weeks after the second dose.

193. 193. The method of any one of claims 188-192, wherein the treatment cycle is repeated 6 months after the second dose.

194. 189. The method of any one of claims 177-188, wherein said second dose is administered 2-6 weeks after said first dose, and said treatment cycle is repeated 6 months after said first dose, so that said first period plus said second period equals 6 months.

195. 189. The method of any one of claims 177-188, wherein the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 6 months after the first dose, so that the first period plus the second period equals 6 months.

196. 189. The method of any one of claims 177-188, wherein said second dose is administered two weeks after said first dose, and said treatment cycle is repeated six months after said first dose, so that said first period plus said second period equals six months.

197. 189. The method of any one of claims 177-188, wherein said second dose is administered 4 weeks after said first dose, and said treatment cycle is repeated 6 months after said first dose, so that said first period plus said second period equals 6 months.

198. 198. The method of any one of claims 177 to 197, wherein the second period of time is 5 months.

199. 198. The method of any one of claims 177 to 197, wherein the second period of time is 5 months ± 2 weeks.

200. 178. The method of claim 177, wherein the second dose is administered 2 to 6 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose.

201. 178. The method of claim 177, wherein the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose.

202. 178. The method of claim 177, wherein the second dose is administered 2 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose.

203. 178. The method of claim 177, wherein the second dose is administered 4 weeks after the first dose, and the treatment cycle is repeated 5 months ± 2 weeks after the second dose.

204. 204. The method of any one of claims 200-203, wherein the second dose is administered 5 months after the second dose.

205. 178. The method of claim 177, wherein said second dose is administered 2 to 6 weeks after said first dose, and said treatment cycle is repeated 7 months after said first dose, whereby said first period plus said second period equals 7 months.

206. 178. The method of claim 177, wherein the second dose is administered 4 weeks ± 2 weeks after the first dose, and the treatment cycle is repeated 7 months after the first dose, so that the first period plus the second period equals 7 months.

207. 178. The method of claim 177, wherein the second dose is administered two weeks after the first dose, and the treatment cycle is repeated seven months after the first dose, so that the first period plus the second period equals seven months.

208. 178. The method of claim 177, wherein the second dose is administered 4 weeks after the first dose, and the treatment cycle is repeated 7 months after the first dose, so that the first period plus the second period equals 7 months.

209. 178. The method of claim 177, wherein the first period of time is 1 to 2 weeks.

210. 210. The method of claim 209, wherein the second period of time is about 3 to 6 months.

211. 210. The method of claim 209, wherein the second period is 6 months ± 2 weeks.

212. 210. The method of claim 209, wherein the second period is 3 months ± 2 weeks.

213. 212. The method of claim 210 or 211, wherein the first period of time plus the second period of time totals six months.

214. 213. The method of claim 210 or 212, wherein the first period of time plus the second period of time totals three months.

215. 215. The method of any one of claims 177-214, wherein administration of a treatment cycle maintains a serum concentration of the antibody above about 10 μg / mL for at least about 5 months from the time of administration of the first dose.

216. 216. The method of claim 215, wherein the serum concentration is maintained at or above 12 μg / mL for at least 5 months following the administration of the first dose.

217. 217. The method of claim 215 or 216, wherein the serum concentration is maintained at or above 25 μg / mL for at least 5 months following the administration of the first dose.

218. 218. The method of any one of claims 215-217, wherein the serum concentration is maintained for at least 6 months from administration of the first dose.

219. 219. The method of any one of claims 177 to 218, wherein the first dose and the second dose are each 500 to 1,500 mg.

220. 219. The method of any one of claims 177 to 218, wherein the first dose and the second dose are each 300 to 990 mg.

221. 219. The method of any one of claims 177 to 218, wherein the first dose and the second dose are each 600 to 1,200 mg.

222. The first dose and the second dose are 500 to 550 mg, 550 to 600 mg, 600 to 650 mg, 650 to 700 mg, 700 to 750 mg, 750 to 800 mg, 850 to 900 mg, 900 to 50 mg, 950 to 1,000 mg, 1,000 to 1,050 mg, 1,050 to 1,100 mg, 1,100 to 1 , 150mg, 1,150-1,200mg, 1,200-1,250mg, 1,250-1,300mg, 1,300-1,350mg, 1,350-1,4 00mg, 1,400-1,450mg, 1,450-1,500mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650 222. The method of any one of claims 177-221, wherein the hydroxybenzoate is selected from one of the following: 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1,000 mg, 1,025 mg, 1,050 mg, 1,075 mg, 1,100 mg, 1,125 mg, 1,150 mg, 1,175 mg, 1,200 mg, 1,225 mg, 1,250 mg, 1,275 mg, 1,300 mg, 1,325 mg, 1,350 mg, 1,375 mg, 1,400 mg, 1,425 mg, 1,450 mg, 1,475 mg, or 1,500 mg.

223. 223. The method of any one of claims 177-222, wherein the first dose and the second dose are each about 600 mg.

224. 223. The method of any one of claims 177-222, wherein the first dose and the second dose are each about 900 mg.

225. 223. The method of any one of claims 177-219, or 221-222, wherein the first dose and the second dose are each about 1,200 mg.

226. 226. The method of any one of claims 177-225, wherein the first dose and the second dose are administered subcutaneously to the subject.

227. 227. The method of any one of claims 177-226, wherein the first dose and the second dose are administered intravenously to the subject.

228. 228. The method of any one of claims 177-227, wherein the first dose is administered to the subject intravenously and the second dose is administered subcutaneously.

229. 229. The method of any one of claims 226 or 228, wherein the subcutaneously administered dose is administered from a pre-filled syringe, an automatic injection device, or via an on-body or wearable injection device.

230. 229. The method of any one of claims 227 or 228, wherein the dose administered intravenously is administered as a bolus injection or by infusion.

231. 231. The method of any one of claims 1 to 230, wherein the plasma kallikrein-associated disorder is hereditary angioedema (HAE).

232. 232. The method of any one of claims 1 to 231, wherein the antibody comprises a heavy chain variable region complementarity determining sequence (CDR) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region CDR having the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

233. 233. The method of any one of claims 1 to 232, wherein the antibody comprises an immunoglobulin heavy chain variable region comprising CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, and CDRH3 comprising the amino acid sequence of SEQ ID NO: 3; and an immunoglobulin light chain variable region comprising CDRL1 comprising the amino acid sequence of SEQ ID NO: 4, CDRL2 comprising the amino acid sequence of SEQ ID NO: 5, and CDRL3 comprising the amino acid sequence of SEQ ID NO: 6; and the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

234. 234. The method of any one of claims 1 to 233, wherein the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody further comprises a constant region comprising M252Y, S254T, and T256E mutations numbered according to the EU numbering index.

235. The method of any one of claims 1 to 234, wherein the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

236. The method of any one of claims 1 to 235, wherein the antibody comprises an IgG1 constant domain.

237. 237. The method of any one of claims 1 to 236, wherein the anti-plasma kallikrein antibody is administered to the subject at a concentration of 100 to 200 mg / mL.

238. 238. The method of any one of claims 1 to 237, wherein the anti-plasma kallikrein antibody is administered to the subject at a concentration of 100-150 mg / mL or 150-200 mg / mL.

239. 239. The method of any one of claims 1-238, wherein the anti-plasma kallikrein antibody is administered to the subject at a concentration of 100 mg / mL, 150 mg / mL, or 200 mg / mL.

240. The method of any one of claims 1-239, wherein the subject experiences a reduction in the number of HAE attacks per month compared to the subject's baseline number of attacks per month before treatment began.

241. 241. The method of claim 240, wherein the reduction from baseline is 75 to 90% or 75 to 100%.

242. 242. The method of any one of claims 1-241, wherein the method reduces the severity of HAE attacks in the subject compared to the subject's baseline attack severity before treatment begins.

243. 243. The method of any one of claims 1-242, wherein the subject's angioedema quality of life score (AEQoL) is reduced by at least 6 points, at least 10 points, at least 15 points, or at least 20 points compared to the subject's AEQoL score before treatment began.

244. 244. The method of any one of claims 1-243, wherein administration of the antibody reduces the level of activated plasma kallikrein in the subject compared to the subject's baseline before treatment begins, and optionally the level of plasma kallikrein is measured about once per month.

245. 245. The method of any one of claims 1 to 244, wherein the anti-plasma kallikrein antibody is formulated into a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

246. 246. The method of any one of claims 1 to 245, wherein the pharmaceutical composition comprises histidine, L-methionine, sorbitol, glycine, and polysorbate 80.

247. 247. The method of any one of claims 1-246, wherein the pharmaceutical composition comprises 10 mM histidine-HCl, 75 mM glycine, 10 mM L-methionine, 150 mM sorbitol, and 0.05% w / v polysorbate 80 at pH 5.

8.

248. The method of any one of claims 1 to 247, wherein the anti-plasma kallikrein antibody is STAR-0215.

249. 249. The method of any one of claims 1-230 or 232-248, wherein the plasma kallikrein-associated disorder is selected from hereditary angioedema (including type I, type II, or type III), bradykinin-dependent edema, diabetic macular edema, retinal edema, factor XII-associated cold autoinflammatory syndrome (FACAS), rheumatoid arthritis, gout, bowel disease, oral mucositis, neuropathic pain, inflammatory pain, spinal stenosis degenerative spinal disease, arterial or venous thrombosis, post-operative ileum, aortic aneurysm, osteoarthritis, vasculitis, edema, cerebral edema, pulmonary embolism, stroke, ventricular assist device or stent-induced coagulation, head trauma or peritumoral cerebral edema, sepsis, acute middle cerebral artery (MCA) ischemic event (stroke), restenosis (e.g., after angioplasty), systemic lupus erythematosus nephritis, Alzheimer's disease, and burn injury.

250. The method of any one of claims 1 to 249, wherein the subject is a human.

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