Treatments of hereditary angioedema

Abstract

To provide an on-demand method of treating hereditary angioedema (HAE) with less burden on patients, in order to improve patient compliance.SOLUTION: A method for on-demand treatment of hereditary angioedema (HAE), comprises orally administering to a patient in need of treatment on-demand a compound of formula A, which is an inhibitor of plasma kallikrein (or a pharmaceutically acceptable salt and / or solvate thereof).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the treatment of hereditary angioedema (HAE). In particular, the present invention provides on-demand treatment of hereditary angioedema (HAE) by oral administration of a plasma kallikrein inhibitor on-demand to a patient in need of treatment. Periodic (or continuous) treatment of HAE is also provided. [Background technology]

[0002] Inhibitors of plasma kallikrein have numerous therapeutic applications, particularly in the treatment of hereditary angioedema.

[0003] Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see KD Bhoola et al., "Kallikrein-Kinin Cascade", "Encyclopedia of Respiratory Medicine", pp. 483-493; JW Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters", Cardiovascular and hematological agents in medicinal chemistry, 7, pp. 234-250, 2009; KD Bhoola et al., Pharmacological Rev., 1992, 44, 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, pp. 665-677). Plasma kallikrein is an essential member of the intrinsic blood coagulation cascade, although its role in this cascade does not involve the release or enzymatic cleavage of bradykinin. Plasma prekallikrein is encoded by a single gene and can be synthesized in the liver as well as other tissues. Plasma kallikrein is secreted by hepatocytes as inactive plasma prekallikrein, which circulates in plasma as a heterodimeric complex bound to high molecular weight kininogen (HK), but this is activated to produce active plasma kallikrein.This contact activation system (or contact system) can be activated by negatively charged surfaces, which activate factor XII (FXII) to factor XIIa (FXIIa), or by certain proteases that may not require a negatively charged surface, such as plasmin (Hofman et al. Clin Rev Allergy Immunol 2016) or by misfolded proteins (Maas et al. J Clinical Invest 2008). FXIIa mediates the conversion of plasma prekallikrein to plasma kallikrein and the subsequent cleavage of high molecular weight kininogen (HK) to generate the potent inflammatory hormone bradykinin. Kinins are potent mediators of inflammation that act via G protein-coupled receptors, and kinin antagonists (e.g., bradykinin receptor antagonists) have already been investigated as potential therapeutic agents for the treatment of numerous disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).

[0004] Plasma kallikrein is thought to play a role in many inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients with a hereditary deficiency of C1 esterase inhibitor suffer from hereditary angioedema (HAE), which results in intermittent swelling of the face, palms, pharynx, gastrointestinal tract, and genitals. The blisters that form during acute episodes contain high levels of plasma kallikrein, which cleaves high-molecular-weight kininogen (HK), liberating bradykinin and resulting in increased vascular permeability. Treatment with plasma kallikrein inhibitors, large proteins, has been shown to effectively treat HAE by blocking the release of bradykinin, which causes increased vascular permeability (A. Lehmann, "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery", Expert Opin. Biol. Ther., 8, pp. 1187-99).

[0005] Hereditary angioedema is a rare genetic disorder characterized by recurrent acute attacks of fluid accumulation outside blood vessels, blocking normal blood and lymphatic flow and causing rapid swelling of tissues, such as the hands, feet, extremities, face, intestinal tract, or airways. Therefore, "hereditary angioedema" can be defined as any disorder characterized by recurrent episodes of bradykinin-mediated angioedema (e.g., severe swelling) caused by an inherited dysfunction, defect, or mutation. Currently, there are three known categories of HAE: (i) HAE type 1, (ii) HAE type 2, and (iii) normal C1 inhibitor HAE (normal C1-Inh HAE). However, the field of HAE is rapidly evolving, and additional types of HAE may be defined in the future.

[0006] Without wishing to be bound by theory, HAE type 1 is believed to be caused by a mutation in the SERPING1 gene that leads to reduced levels of C1 inhibitor in the blood. Without wishing to be bound by theory, HAE type 2 is believed to be caused by a mutation in the SERPING1 gene that leads to a dysfunction of C1 inhibitor in the blood. Without wishing to be bound by theory, the cause of normal C1-Inh HAE is less clear, and the underlying genetic dysfunction / defect / mutation may remain unknown. What is known is that the cause of normal C1-Inh HAE is not related to reduced levels or dysfunction of C1 inhibitor (in contrast to HAE types 1 and 2). Normal C1-Inh HAE can be diagnosed by establishing a family history and noting that angioedema has been inherited from a previous generation (thus, it is hereditary angioedema). Normal C1-Inh HAE can also be diagnosed by determining the presence of a dysfunction / defect / mutation in a gene other than the C1 inhibitor-related gene. For example, it has been reported that dysfunction / defects / mutations in plasminogen can cause normal C1-Inh HAE (see, e.g., Veronez et al., Front Med (Lausanne). 2019 Feb 21;6:28. doi:10.3389 / fmed.2019.00028; or Recke et al., Clin Transl Allergy. 2019 Feb 14;9:9. doi: 10.1186 / s13601-019-0247-x).It has also been reported that dysfunction / defect / mutation of factor XII can cause normal C1-Inh HAE (see, for example, Mansi et al. 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2015, 277; 585-593; or Maat et al. J Thromb Haemost. 2019 Jan;17(1):183-194. doi: 10.1111 / jth.14325).

[0007] Acute HAE attacks typically progress through three major clinically distinct phases: an early prodromal phase (which can typically last up to 12 hours), followed by a swelling phase, and then a resorption phase. The majority of HAE attacks exhibit prodromal symptoms. Two-thirds of prodromal symptoms appear within six hours of an HAE attack, and prodromal symptoms do not occur before 24 hours of an HAE attack (Magerl et al., Clinical and Experimental Dermatology (2014) 39, pp. 298-303). For example, the following prodromal symptoms may begin to be observed: mild swelling (especially in the face and neck), a typical type of abdominal pain, and a typical reddening of the skin called "erythema marginata." The attack is fully developed when it reaches maximum swelling and maximum expression of pain (e.g., abdominal attacks), discomfort (e.g., peripheral attacks), or life-threatening symptoms (e.g., laryngeal attacks). Once the attack reaches its peak, the period of normalization thereafter depends on the time it takes for the swelling to subside and for the fluid that has seeped into the tissues to be reabsorbed.

[0008] Synthetic plasma kallikrein inhibitors and low-molecular-weight plasma kallikrein inhibitors are described, for example, in Garrett et al. ("Peptide aldehyde...", J. Peptide Res. 52, pp. 62-71 (1998)), T. Griesbacher et al. ("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats", British Journal of Pharmacology, 137, pp. 692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein", WO03 / 076458), Szelke et al. ("Kininogenase inhibitors", WO92 / 04371), and DMEvans et al. (Immunolpharmacology, 32, p115-116(1996)), Szelke et al. ("Kininogen inhibitors", WO95 / 07921), Antonsson et al. ("New peptide derivatives", WO94 / 29335), J. Corte et al. ("Six-membered heterocycles useful as serine protease inhibitors", WO2005 / 123680), J. Stuerzbecher et al. (Brazilian J.Med.Biol.Res, 27, pp1929-34(1994)), Kettner et al. (US5,187,157), N. Teno et al. (Chem.Pharm.Bull., 41, pp1079-1090(1993)), WB Young et al. ("Small molecule inhibitors of plasma kallikrein", Bioorg.Med.Chem.Letts., 16, p2034-2036(2006)), Okada et al. WO08 / 049595), Zhang et al. (``Discovery of highly potent small molecule kallikrein inhibitors'', Medicinal Chemistry 2, p545-553(2006)), Sinha et al. (``Inhibitors of plasma kallikrein'', WO08 / 016883), Shigenaga et al. These have already been reported by Kolte et al. ("Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor", British Journal of Pharmacology (2011), 162(7), pp. 1639-1649) and Steinmetzer et al. ("Serine protease inhibitors", WO2012 / 004678) also describe cyclized peptide analogs that are inhibitors of human plasmin and plasma kallikrein.

[0009] As explained above, HAE can occur in patients who exhibit a genetic deficiency or dysfunction of C1 esterase inhibitor. Accordingly, some current treatments for HAE involve correcting the deficiency or dysfunction of C1 esterase inhibitor by administering a C1 esterase inhibitor. Such treatments can be prophylactic treatments (i.e., administered in the absence of acute HAE attack symptoms to prevent / reduce the likelihood of an acute HAE attack) and / or acute treatments (i.e., administered when acute HAE attack symptoms are observed to attempt to stop or reduce the severity of an acute HAE attack).

[0010] Cinryze® and Haegarda® contain C1 esterase inhibitors and are indicated for preventing acute HAE attacks (i.e., prophylactic treatment). Treatment with Cinryze® requires preparation of a solution from a powder and subsequent injections every three or four days. Similarly, treatment with Haegarda® requires preparation of a solution from a powder and subsequent injections twice weekly. Patients are not always able to administer these treatments themselves, and when they are unable to, they must visit a clinic for treatment. Thus, both of these preventative treatments have a high patient burden. Furthermore, the FDA package insert for Haegarda® states, "Do not use for the treatment of acute HAE attacks," meaning that patients may require additional therapy if an HAE attack occurs.

[0011] Berinert® and Ruconest® contain C1 esterase inhibitors and are indicated for the treatment of acute HAE attacks. Both of these treatments involve the preparation of an injectable solution followed by injection. This process can be burdensome for patients, especially if they are suffering from an acute HAE attack. Self-administration of the dosage is also not always possible, and when this is not possible, significant delays in administration of the medication can occur, increasing the severity of the patient's acute HAE attack. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2003 / 076458 [Patent Document 2] International Publication No. 92 / 04371 [Patent Document 3] International Publication No. 95 / 07921 [Patent Document 4] International Publication No. 94 / 29335 [Patent Document 5] International Publication No. 2005 / 123680 [Patent Document 6] U.S. Patent No. 5,187,157 [Patent Document 7] International Publication No. 2008 / 049595 [Patent Document 8] International Publication No. 2008 / 016883 [Patent Document 9] International Publication No. 2011 / 118672 [Patent Document 10] International Publication No. 2012 / 004678 [Non-patent literature]

[0013] [Non-Patent Document 1] KD Bhoola et al., ``Kallikrein-Kinin Cascade'', ``Encyclopedia of Respiratory Medicine'', p.483-493 [Non-patent document 2] JW Bryant et al, ``Human plasma kallikrein-kinin system:physiological and biochemical parameters'', Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009 [Non-patent document 3] KD Bhoola et al, Pharmacological Rev., 1992, 44, 1

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

[0014] To date, the only selective plasma kallikrein inhibitors approved for medical use in the treatment of HAE are Kalbitor® (active substance ecallantide) and Takhzyro® (active substance lanadelumab). Both treatments are formulated as injectable solutions. Ecallantide is a large protein plasma kallikrein inhibitor that carries a risk of anaphylactic reactions. In fact, the EU marketing authorization application for Kalbitor® was recently withdrawn because its benefits were said not to outweigh its risks. Lanadelumab is a recombinant fully human IgG1 kappa light chain monoclonal antibody. Reported side effects of lanadelumab treatment include hypersensitivity, injection site pain, injection site erythema, and injection site scarring. The approved EMA label for Takhzyro® (active ingredient lanadelumab) states that it is "not intended for the treatment of acute HAE attacks" and that "in breakthrough HAE attacks, individualized treatment with an approved rescue medication should be initiated." Furthermore, as injections, both of these treatments carry a high patient burden.

[0015] Berotralstat (BCX7353) is being investigated as a once-daily oral treatment to prevent HAE attacks. Hwang et al. (Immunotherapy (2019) 11(17), 1439-1444) state that higher doses are associated with more gastrointestinal adverse effects, indicating increased toxicity at higher levels.

[0016] Other plasma kallikrein inhibitors known in the art are generally small molecules, some of which contain highly polar, ionizable functional groups, such as guanidine or amidine. Recently, plasma kallikrein inhibitors that do not feature guanidine or amidine functional groups have been reported. For example, see Brandl et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein", WO2012 / 017020), Evans et al. ("Benzylamine derivatives as inhibitors of plasma kallikrein", WO2013 / 005045), Allan et al. ("Benzylamine derivatives", WO2014 / 108679), Davie et al. ("Heterocyclic derivates", WO2014 / 188211), and Davie et al. ("N-((het)arylmethyl)-heteroaryl-carboxamide compounds as plasma kallikrein inhibitors", WO2016 / 083820).

[0017] The present applicant has developed a series of novel compounds that are inhibitors of plasma kallikrein, as disclosed in WO 2016 / 083820 (PCT / GB2015 / 053615). These compounds exhibit good selectivity for plasma kallikrein. One such compound is N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide. The name N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide refers to the structure depicted in Formula A below.

[0018] [ka]

[0019] Therefore, there is a need for a less invasive treatment for HAE to improve patient compliance. In particular, there is a need for an orally administered HAE treatment. There is also a need for oral treatment of acute HAE attacks on an as-needed basis, for example, when symptoms of an acute HAE attack are recognized. There is also a need for preventative treatments for HAE to reduce the likelihood of acute HAE attacks. There is also a need for a treatment for acute HAE attacks that can be used by patients on demand and does not require regular (or ongoing) medication, for example, a treatment that does not require twice-weekly injections. [Means for solving the problem]

[0020] To date, there are no approved on-demand oral treatments for HAE; all approved treatments are injectable. Because HAE attacks resolve more quickly and are shorter in duration following early treatment (Maurer M et al., PLoS ONE 2013;8(2):e53773. doi:10.1371 / journal.pone.0053773), early intervention when attacks are anticipated or ongoing is essential for successful management of the disease. Injectable treatments suffer from delayed administration, as patients may need to prepare the formulation or travel to a hospital for treatment. Therefore, HAE treatment is often compromised by medication delays caused by the high burden on patients. In fact, Maurer M et al. explained that more than 60% of patients receive HAE injections less than one hour after the onset of an attack. Without wishing to be bound by theory, HAE injection treatments suffer from problems of delayed administration due to inconvenience (self-administration is not always possible), pain (both during and after injection), and desire (patients often just want a less severe attack, not a cure.) The present invention aims to solve this problem.

[0021] The present invention provides an improved treatment for HAE compared to all currently available HAE treatments. The present invention provides an oral treatment for HAE that is particularly useful as an on-demand treatment for acute HAE attacks and / or to reduce the likelihood of acute HAE attacks. Specifically, as described herein, treatments according to the present invention (i) have a rapid onset of action, (ii) are potent, (iii) have a favorable safety profile, and (iv) have a prolonged pharmacodynamic effect.

[0022] Thus, in accordance with the present invention, there is provided a method for treating hereditary angioedema (HAE) on demand, comprising orally administering to a patient in need of treatment for HAE a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) on demand.

[0023] Provided is a compound of Formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use in the on-demand treatment of hereditary angioedema (HAE), comprising orally administering the compound of Formula A (or a pharmaceutically acceptable salt and / or solvate thereof) on-demand to a patient in need of such treatment. DETAILED DESCRIPTION OF THE INVENTION

[0024] In any of the treatments of the invention described herein, the term "compound of Formula A" is an abbreviation for "compound of Formula A (or a pharmaceutically acceptable salt and / or solvate thereof)". The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water. The term "hydrate" is used when the solvent is water, and for the avoidance of doubt, the term "hydrate" is encompassed within the term "solvate".

[0025] In any of the treatments of the invention described herein, "pharmaceutically acceptable salts" means physiologically or toxicologically tolerable salts and includes, where appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example, (i) when the compounds of the present invention contain one or more acidic groups, e.g., carboxy groups, pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium, and ammonium salts, or salts with organic amines such as diethylamine, N-methylglucamine, diethanolamine, or amino acids (e.g., lysine); (ii) when the compounds of the present invention contain a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that may be formed include hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, lactate, tartrate, mesylate, succinate, oxalate, phosphate, esylate, tosylate, benzenesulfonate, naphthalenedisulfate, maleate, adipate, fumarate, hippurate, camphorate, xinafoate, p-acetamidobenzoate, dihydroxybenzoate, hydroxynaphthoate, succinate, ascorbate, oleate, bisulfonate, and the like.

[0026] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0027] For a comprehensive list of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0028] Those skilled in the art will understand that "on-demand" treatment in the context of HAE refers to administering a compound of Formula A in response to the need for therapy related to one specific acute HAE attack. As described herein, this one specific HAE attack can be ongoing (e.g., treatment is initiated upon recognition of symptoms of an acute HAE attack) or likely to occur (e.g., when the patient anticipates that an acute HAE attack is likely to be induced or precipitated). Multiple doses of the compound of Formula A can be administered as part of on-demand treatment, but these multiple doses are administered in the context of the same single acute HAE attack. In other words, "on-demand" does not require administering the compound of Formula A continuously at regular intervals (e.g., once weekly, twice weekly, etc.) regardless of the occurrence of an acute HAE attack. This is in contrast to other known treatments for HAE (e.g., the above-mentioned Cinryze® and Haegarda® treatments), which require continuous and regular administration for treatment. Instead, in the treatment of the present invention, the compound of Formula A is administered when the patient requires an immediate therapeutic effect. Specific "on-demand" treatments of the present invention include (i) on-demand treatment of acute attacks of HAE, where a compound of Formula A is administered upon recognition of symptoms of an acute HAE attack, and (ii) on-demand prophylactic reduction of the likelihood of an HAE attack, for example, when it is anticipated that an acute HAE attack may be induced (or caused), as described in more detail below.

[0029] In any of the treatments of the invention described herein, the patient is preferably human. HAE is a genetic disease, and patients of all ages can suffer from HAE attacks. Thus, human patients can be children (0-18 years old) or adults (18 years old or older). Specifically, patients can be 12 years old or older. Patients can also be 2 years old or older.

[0030] As shown in the Examples, the compound of Formula A is a potent inhibitor of plasma kallikrein. As previously described, inhibiting plasma kallikrein inhibits the cleavage of high molecular weight kininogen, which contributes to HAE attacks. Furthermore, as shown in Example 4, the compound of Formula A can also reduce the production of factor XIIa (FXIIa) following cleavage of plasma prekallikrein and activation of the contact system. These additional beneficial effects support the highly effective treatment of the present invention, particularly when the compound of Formula A has a plasma concentration of at least 500 ng / mL. Plasma concentrations of at least 500 ng / mL can be observed after administration of a dose of at least about 60 mg (more specifically, at least about 70 or about 80 mg) of the compound of Formula A.

[0031] Thus, in any of the treatments of the invention disclosed herein, particularly following a dose of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) of a compound of Formula A, in addition to inhibiting plasma kallikrein, the treatment can also, following administration, reduce the cleavage of plasma prekallikrein to produce plasma kallikrein and / or reduce the production of factor XIIa (FXIIa). Thus, in some embodiments, the treatment can block the cleavage of plasma prekallikrein to produce plasma kallikrein and / or block the cleavage of FXII to produce FXIIa, particularly after a dose of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) of a compound of formula A.

[0032] Compounds of Formula A are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which hydrogen is replaced by deuterium or tritium, or carbon is replaced by13 C or 14 Compounds where C is substituted are included within the scope of the present invention.

[0033] The terms "acute attack of HAE" and "acute HAE attack" are used interchangeably herein. The term "hereditary angioedema" refers to bradykinin-mediated angioedema caused by an inherited genetic malfunction, defect, or mutation. As a result, the term "HAE" includes at least HAE type 1, HAE type 2, and normal C1 inhibitor HAE (normal C1-Inh HAE).

[0034] On-demand treatment of acute HAE attacks According to one aspect of the present invention, there is provided a method for treating an acute attack of hereditary angioedema (HAE) on demand, comprising orally administering a compound of formula A to a patient in need of treatment for hereditary angioedema (HAE), wherein the compound of formula A is orally administered on demand upon recognizing symptoms of an acute HAE attack.

[0035] Accordingly, one aspect of the present invention provides a compound of formula A for use in on-demand oral administration of a compound of formula A to a patient in need of on-demand treatment of an acute attack of hereditary angioedema (HAE), including oral administration of a compound of formula A to a patient in need of on-demand treatment of an acute attack of HAE, wherein the compound of formula A is administered orally upon recognition of symptoms of an acute HAE attack.

[0036] Although individual HAE attacks can vary in severity and with respect to the areas affected, patients suffering from HAE, medical professionals knowledgeable about HAE, and caregivers of HAE patients (and indeed, those skilled in the art) are astute in recognizing the symptoms of an acute HAE attack. These symptoms include, but are not limited to, tissue swelling in the hands, feet, extremities, face, intestinal tract, and / or respiratory tract, fatigue, headache, muscle pain, itchy skin, abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing, hoarseness, shortness of breath, and / or mood swings. Thus, in some embodiments, administration of a compound of Formula A can be performed upon recognition of at least one of the above symptoms.

[0037] Those skilled in the art will also understand that "administered upon recognition of symptoms of an acute HAE attack" means administration as soon as possible after the patient recognizes the symptoms of an acute HAE attack. For example, a patient would be expected to have the compound of Formula A (perhaps in the form of a pharmaceutically acceptable composition) readily and readily available at all times to ensure treatment upon recognition of symptoms of an HAE attack. In other words, treatment is provided on demand. For example, in some embodiments, the compound of Formula A can be administered within 1 hour of recognition of symptoms of an acute HAE attack, preferably within 30 minutes, 20 minutes, 10 minutes, or 5 minutes of recognition of symptoms of an acute HAE attack.

[0038] In one embodiment of the present invention, when symptoms of an acute HAE attack are recognized during the prodromal phase, a compound of formula A can be administered during the prodromal phase of an acute HAE attack. In these situations, the recognized symptom can be mild swelling, particularly mild swelling affecting the face and neck. Additionally or alternatively, the symptom can be abdominal pain, particularly abdominal pain, which is considered characteristic of an HAE attack. Additionally or alternatively, the symptom can be redness of the skin, such as erythema marginata.

[0039] Treatment according to the present invention can prevent acute HAE attacks from becoming severe. In some situations, treatment can shorten the duration of an attack and sometimes even stop the attack entirely. For example, treatment can halt the progression of a peripheral HAE attack or an abdominal HAE attack. In some embodiments, treatment according to the present invention can inhibit the subsequent development of swelling, sometimes completely, particularly when treatment is initiated during the prodromal phase. In particular, in some embodiments, treatment can prevent an acute HAE attack from progressing to the swelling stage when treatment is initiated during the prodromal phase.

[0040] The compound of Formula A can be sufficient to treat an acute HAE attack alone, i.e., without administering to the patient any active pharmaceutical ingredients other than the compound of Formula A. Thus, in some embodiments of the present invention, no active pharmaceutical ingredients other than the compound of Formula A are administered to the patient to treat the acute HAE attack. In particular, in some embodiments, the treatment of the present invention does not require the administration of any active pharmaceutical ingredients for treating an HAE attack (e.g., rescue medications such as pdC1INH, rhC1INH, or icatibant) other than the compound of Formula A. More specifically, in some embodiments, no active pharmaceutical ingredients for treating an HAE attack (e.g., rescue medications such as pdC1INH, rhC1INH, or icatibant) other than the compound of Formula A are administered to the patient.

[0041] Alternatively, in some embodiments, the treatments of the present invention can be used in combination with other treatments for HAE. For example, in some embodiments, the on-demand acute treatments described herein can be used as a "top-up" to another treatment for HAE. In some embodiments, a patient may be receiving another preventative treatment for HAE, and may consider using the on-demand treatments described herein to treat acute HAE attacks that were not prevented by the other preventative treatment for HAE.

[0042] For example, in some embodiments, a method of treating HAE in a patient already taking a C1 inhibitor (e.g., Cinryze®, Haegarda®, Berinert®) for prophylaxis is provided, comprising orally administering a compound of Formula A to the patient on demand upon recognizing symptoms of an acute HAE attack. In another embodiment, a method of treating HAE in a patient already taking lanadelumab for prophylaxis is provided, comprising orally administering a compound of Formula A to the patient on demand upon recognizing symptoms of an acute HAE attack. In another embodiment, a method of treating HAE in a patient already taking berotralstat for prophylaxis is provided, comprising orally administering a compound of Formula A to the patient on demand upon recognizing symptoms of an acute HAE attack.

[0043] In any of the above treatments, the symptoms can be recognized by the patient. In any of the above treatments, the symptoms can be recognized by a health care professional, such as a health care professional knowledgeable in HAE. In any of the above treatments, the symptoms can be recognized by the patient's caregiver.

[0044] Treatment according to the invention can reduce the rate of HAE attacks that progress by 1 or more levels on a 5-point Likert scale (5LS). Treatment according to the invention can reduce the rate of HAE attacks that progress by 1 or more levels on the 5LS within 12 hours of administering the compound. Treatment according to the invention can improve the resolution time of HAE attacks on the 5LS to "none." The 5LS is a scale known in the art that can be used to report the severity of HAE attacks (see, e.g., Allergy Asthma Proc. 2018 Jan 1;39(1):74-80. doi:10.2500 / aap. 2018. 39. 4095), and can be used, for example, to report attacks as "none," "mild," "moderate," "severe," or "very severe."

[0045] Treatment according to the invention can reduce the percentage of HAE attacks rated as "worse" or "much worse" on the 7-point transition question (7TQ). Treatment according to the invention can increase the percentage of HAE attacks rated as "better" or "much better." The 7TQ is an art-known scale that can be used to rate the progression of HAE attacks and report attacks as "much better," "good," "slightly better," "no change," "slightly worse," "worse," or "much worse."

[0046] In some embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, a patient may be administered a single dose of a compound of Formula A to treat the acute HAE attack. In some other embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, a patient may be administered multiple doses of a compound of Formula A to treat the acute HAE attack. For example, the on-demand treatment may include administering two doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. Alternatively, the on-demand treatment may include administering three doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. Alternatively, the on-demand treatment may include administering four doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. When multiple doses are administered, the doses may be evenly spaced such that each dose is approximately equally spaced. For example, subsequent doses may be administered 8 hours, 16 hours, and 24 hours after the first dose.

[0047] In some embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, the patient may receive a daily dose in two doses per day. These two doses may be administered simultaneously, separately, or sequentially. In some embodiments, the two doses may be administered at any time within the same day, with the interval between the two doses being specific to the patient and the severity of the acute HAE attack. In some embodiments, the second dose may be administered within about 2 hours of the first dose (more specifically, about 1 to 2 hours after the first dose). In some embodiments, the second dose may be administered between about 1 and about 4 hours after the first dose (more specifically, about 1 to 3 hours, about 2 to 3 hours, or 3 to 4 hours after the first dose). In some embodiments, the second dose may be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours, or about 6 hours after the first dose). In some embodiments, the second dose can be administered about 2 to about 6 hours after the first dose (more specifically, about 3 to about 6 hours after the first dose). In some embodiments, the second dose can be administered within about 8 hours after the first dose (more specifically, about 4 to about 8 hours after the first dose). In some embodiments, the second dose can be administered within about 12 hours after the first dose (more specifically, about 8 to about 12 hours after the first dose). In some embodiments, the second dose can be administered within about 16 hours after the first dose (more specifically, about 12 to about 16 hours after the first dose). In some embodiments, the second dose can be administered within about 20 hours after the first dose (more specifically, about 16 to about 20 hours after the first dose). In some embodiments, the second dose can be administered within about 24 hours after the first dose (more specifically, about 20 to about 24 hours after the first dose). In these embodiments, each of the two doses can be 600 mg of the compound of formula A.

[0048] In any of the on-demand treatments for acute HAE attacks of the present invention, the patient can be administered the daily dose in two doses per day, with the second dose being administered at least about 6 hours after the first dose. The patient can be administered the daily dose in two doses per day, with the second dose being administered at least about 5 to about 7 hours after the first dose. More specifically, the patient can be administered the daily dose in two doses per day, with the second dose being administered about 6 hours after the first dose. In these embodiments, each of the two doses can be 600 mg of the compound of Formula A. Each of these 600 mg doses can be two tablets containing 300 mg of the compound of Formula A.

[0049] In some embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, the patient may receive a daily dose in three doses per day. These three doses may be administered simultaneously, separately, or sequentially. In some embodiments, the three doses may be administered at any time within the same day, with the interval between the three doses being specific to the patient and the severity of the acute HAE attack. In some embodiments, the second and third doses may both be administered within about four hours of the first dose. More specifically, the second dose may be administered about 1 to 3 hours after the first dose, and the third dose may be administered about 3 to 4 hours after the first dose. The second dose may be administered about 4 to 12 hours after the first dose (more specifically, about 4 to 8 hours, or about 6 hours after the first dose), and the third dose may be administered about 4 to 12 hours after the second dose (more specifically, about 4 to 8 hours, or about 6 hours after the second dose). Even more specifically, the second dose can be administered about 2 hours after the first dose, and the third dose can be administered about 4 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 8 hours of the first dose. More specifically, the second dose can be administered about 3 to 5 hours after the first dose, and the third dose can be administered about 7 to 8 hours after the first dose. Even more specifically, the second dose can be administered about 4 hours after the first dose, and the third dose can be administered about 8 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 16 hours after the first dose. More specifically, the second dose can be administered about 7 to 9 hours after the first dose, and the third dose can be administered about 15 to 16 hours after the first dose. Even more specifically, the second dose can be administered about 8 hours after the first dose, and the third dose can be administered about 16 hours after the first dose, In these embodiments, each of the three doses can be 600 mg of the compound of formula A.

[0050] In any of the on-demand treatments for acute HAE attacks of the present invention, the patient may be administered the daily doses in three doses per day, with the second and third doses being administered at least about 6 hours after the preceding dose. The patient may be administered the daily doses in three doses per day, with the second dose being administered about 5 to about 7 hours after the first dose and the third dose being administered about 11 to about 13 hours after the first dose. More specifically, the daily doses may be administered in three doses per day, with the second dose being administered about 6 hours after the first dose and the third dose being administered about 12 hours after the first dose. In these embodiments, each of the three doses may be 600 mg of the compound of Formula A. Each of these 600 mg doses may be two tablets containing 300 mg of the compound of Formula A.

[0051] For example, if an HAE attack persists after administration of the first dose, multiple doses can be administered. As used in this context, "sustained" can mean, for example, that the first dose does not prevent the severity of the acute HAE attack from increasing, or that the first dose does not completely stop the HAE attack, or that the first dose does not reduce the severity of the HAE attack. Thus, an on-demand treatment of an HAE attack of the present invention can include administering a first dose, and then administering a second dose if the HAE attack persists after administration of the first dose. An on-demand treatment of an HAE attack of the present invention can also include administering a first dose, then administering a second dose if the HAE attack persists after administration of the first dose, and then administering a third dose if the HAE attack persists after administration of the second dose. In each case, each subsequent dose can be administered simultaneously, separately, or sequentially. In each case, each subsequent dose can be administered at least about 6 hours (e.g., about 6 hours) after the preceding dose. In each case, each dose may contain 600 mg of compound, administered, for example, as two tablets containing 300 mg each.

[0052] Specifically, an on-demand treatment for an acute HAE attack according to the present invention may include administering a first dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound), followed by a second dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound) if the HAE attack persists after administration of the first dose. The second dose may be administered at least about 6 hours (e.g., at about 6 hours) after the first dose. If the HAE attack persists after the second dose, an on-demand treatment for an acute HAE attack according to the present invention may include administering a third dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound). The third dose may be administered at least about 6 hours (e.g., at about 6 hours) after the second dose.

[0053] Even if the severity of an HAE attack appears to have decreased (or stopped completely) after administration of a first dose, multiple doses can be administered to prevent the attack from becoming more severe again. For example, multiple doses can be used for patient comfort to alleviate patient anxiety. Thus, an on-demand treatment for an HAE attack of the present invention can include administering a first dose and then administering a second dose to prevent the attack from becoming more severe again, even if the severity of an HAE attack appears to have decreased (or stopped completely) after administration of the first dose. Even if the severity of an HAE attack appears to have decreased (or stopped completely) after administration of the first and / or second doses, an on-demand treatment for an HAE attack of the present invention can also include administering a third dose to prevent the attack from becoming more severe again. In each case, each subsequent dose can be administered simultaneously, separately, or sequentially. In each case, each subsequent dose can be administered at least about 6 hours (e.g., at about 6 hours) after the preceding dose. In each case, each dose may contain 600 mg of the compound, administered, for example, as two tablets containing 300 mg of the compound.

[0054] Specifically, an on-demand treatment of an acute HAE attack according to the present invention can include administering a first dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound), followed by a second dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound) to prevent the HAE attack from becoming more severe again, even if the severity of the HAE attack appears to have decreased (or stopped entirely) after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., at about 6 hours) after the first dose. Even if the severity of the HAE attack appears to have decreased (or stopped entirely) after administration of the first and / or second doses, an on-demand treatment of an acute HAE attack according to the present invention can include administering a third dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound) to prevent the HAE attack from becoming more severe again. The third dose can be administered at least about 6 hours (eg, at about 6 hours) after the second dose.

[0055] On-demand treatment of an acute HAE attack according to the present invention may involve administering no more than three doses in a 24-hour period (e.g., three doses containing 600 mg of the compound, optionally as six tablets each containing 300 mg of the compound).

[0056] On-demand prophylactic treatment of acute HAE attacks According to one aspect of the present invention, there is provided a method for the on-demand treatment of hereditary angioedema (HAE), comprising orally administering a compound of formula A to a patient in need of treatment for hereditary angioedema (HAE), wherein the on-demand oral administration of the compound of formula A prophylactically reduces the likelihood of an acute HAE attack.

[0057] Accordingly, one aspect of the present invention provides a compound of formula A for use in the treatment of hereditary angioedema (HAE), comprising orally administering the compound of formula A to a patient in need of treatment, wherein the compound of formula A is administered orally on demand to prophylactically reduce the likelihood of an acute HAE attack.

[0058] In some embodiments, administration of a compound of formula A can prevent acute HAE attacks.

[0059] As described above, treatment according to the present invention does not require the administration of a compound of Formula A on a regular basis to provide preventative treatment. Indeed, in some embodiments, the compound of Formula A can be administered on demand. For example, when an acute HAE attack is expected to be induced (or triggered), i.e., when a patient is expected to suffer from an acute HAE attack, the compound of Formula A can be administered on demand to reduce the likelihood of an acute HAE attack (e.g., to prevent an acute HAE attack). In some embodiments, a medical professional, such as a medical professional knowledgeable about HAE, can predict that an acute HAE attack will be induced (or triggered). In some embodiments, a patient's caregiver can predict that an acute HAE attack will be induced (or triggered). For example, an acute HAE attack can be triggered (or triggered) by various stimuli, such as physical trauma (e.g., medical, dental, or surgical treatment) and / or stress (e.g., a high-stress situation, such as psychological stress, which may be related to an examination or psychological stress associated with medical, dental, or surgical treatment). For example, an acute HAE attack may be triggered (or caused) by an increase in a patient's stress / anxiety level, when the patient may be anticipating an HAE attack. Furthermore, the frequency of acute HAE attack episodes may vary over time in the same patient. Patients often suffer from periods of higher than normal frequency of acute HAE attacks. Thus, an acute HAE attack may be anticipated during a period when the patient is experiencing more frequent acute HAE attack episodes than normal. Those familiar with HAE will recognize that acute HAE attacks may be triggered (or caused) in this manner. Patients, medical professionals knowledgeable about HAE, and patient caregivers may also be sensitive to predicting such triggers. Therefore, according to the present invention, a therapeutic agent may be administered on demand when the patient is expected to be exposed to one or more of these stimuli or situations.

[0060] As described above, the compound of formula A can be administered to a patient as part of an on-demand preventive treatment for acute HAE attacks.As described above, this treatment reduces the possibility of acute HAE attacks.However, in some situations, patients may still suffer from acute HAE attacks.Therefore, an embodiment of the present invention can administer the compound of formula A to a patient as part of an on-demand preventive treatment for acute HAE attacks, as described above, and further includes taking an on-demand dose of the compound of formula A when recognizing the symptoms of acute HAE attacks, to treat acute HAE attacks if they occur.These on-demand treatments for acute HAE attacks have been discussed above.

[0061] Thus, in some embodiments, there is provided a method for treating hereditary angioedema (HAE) on demand, comprising orally administering to a patient in need thereof a compound of Formula A, wherein the on-demand oral administration of the compound of Formula A prophylactically reduces the likelihood of an acute HAE attack, and further comprising orally administering the compound of Formula A on demand upon recognizing symptoms of an acute HAE attack.

[0062] In some embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, a patient may be administered a single dose of a compound of Formula A to treat the acute HAE attack. In some other embodiments of any of the on-demand treatments for acute HAE attacks of the present invention, a patient may be administered multiple doses of a compound of Formula A to treat the acute HAE attack. For example, the on-demand treatment may include administering two doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. Alternatively, the on-demand treatment may include administering three doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. Alternatively, the on-demand treatment may include administering four doses of a compound of Formula A within a 24-hour period starting from the time a first dose is taken. When multiple doses are taken, the doses may be evenly spaced so that the time periods between each dose are approximately equal, for example, subsequent doses are taken 8 hours, 16 hours, and 24 hours after the initial dose.

[0063] In some embodiments of any of the on-demand preventative treatments for acute HAE attacks described herein, a patient may receive two doses per day. These two doses may be administered simultaneously, separately, or sequentially. In some embodiments, the two doses may be administered at any time throughout the day, with the interval between the two doses being specific to the patient. In some embodiments, the second dose may be administered within about 2 hours of the first dose (more specifically, about 1 to 2 hours after the first dose). In some embodiments, the second dose may be administered about 1 to about 4 hours after the first dose (more specifically, about 1 to 3 hours, about 2 to 3 hours, or about 3 to 4 hours after the first dose). In some embodiments, the second dose may be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours, or about 6 hours after the first dose). In some embodiments, the second dose can be administered about 2 hours to about 6 hours after the first dose (more specifically, about 3 hours to about 6 hours after the first dose). In some embodiments, the second dose can be administered within about 8 hours after the first dose (more specifically, about 4 hours to about 8 hours after the first dose). In some embodiments, the second dose can be administered within about 12 hours after the first dose (more specifically, about 8 hours to about 12 hours after the first dose). In some embodiments, the second dose can be administered within about 16 hours after the first dose (more specifically, about 12 hours to about 16 hours after the first dose). In some embodiments, the second dose can be administered within about 20 hours after the first dose (more specifically, about 16 hours to about 20 hours after the first dose). In some embodiments, the second dose can be administered within about 24 hours of the first dose (more specifically, about 20 to about 24 hours after the first dose). In these embodiments, each of the two doses can be 600 mg of the compound of Formula A.

[0064] In any of the on-demand prophylactic treatments for acute HAE attacks described herein, the patient can be administered the daily dose in two doses per day, with the second dose being administered at least about 6 hours after the first dose. The patient can be administered the daily dose in two doses per day, with the second dose being administered about 5 to about 7 hours after the first dose. More specifically, the patient can be administered the daily dose in two doses per day, with the second dose being administered about 6 hours after the first dose. In these embodiments, each of the two doses can be 600 mg of the compound of Formula A. Each of these 600 mg doses can be two tablets containing 300 mg of the compound of Formula A.

[0065] In some embodiments of any of the on-demand preventative treatments for acute HAE attacks described herein, a patient may receive a daily dose in three doses per day. These three doses may be administered simultaneously, separately, or sequentially. In some embodiments, the three doses may be administered at any time throughout the day, with the interval between the three doses being specific to the patient. In some embodiments, the second and third doses may both be administered within about four hours of the first dose. More specifically, the second dose may be administered about 1 to 3 hours after the first dose, and the third dose may be administered about 3 to about 4 hours after the first dose. The second dose may be administered about 4 and about 12 hours after the first dose (more specifically, about 4 to about 8 hours, or about 6 hours after the first dose), and the third dose may be administered about 4 to about 12 hours after the second dose (more specifically, about 4 to about 8 hours, or about 6 hours after the second dose). Even more specifically, the second dose can be administered about 2 hours after the first dose, and the third dose can be administered about 4 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 8 hours of the first dose. More specifically, the second dose can be administered about 3 to 5 hours after the first dose, and the third dose can be administered about 7 to 8 hours after the first dose. Even more specifically, the second dose can be administered about 4 hours after the first dose, and the third dose can be administered about 8 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 16 hours of the first dose. More specifically, the second dose can be administered about 7 to 9 hours after the first dose, and the third dose can be administered about 15 to 16 hours after the first dose. Even more specifically, the second dose can be administered about 8 hours after the first dose, and the third dose can be administered about 16 hours after the first dose. In these embodiments, each of the three doses can be 600 mg of the compound of formula A.

[0066] In any of the on-demand prophylactic treatments for acute HAE attacks described herein, the patient may receive the daily doses in three doses per day, with the second and third doses being administered at least about 6 hours after the preceding dose. The patient may receive the daily doses in three doses per day, with the second dose being administered about 5 to about 7 hours after the first dose and the third dose being administered about 11 to about 13 hours after the first dose. More specifically, the patient may receive the daily doses in three doses per day, with the second dose being administered about 6 hours after the first dose and the third dose being administered about 12 hours after the first dose. In these embodiments, each of the three doses may be 600 mg of the compound of Formula A. Each of these 600 mg doses may be two tablets containing 300 mg of the compound of Formula A.

[0067] For example, multiple doses can be administered if there is an ongoing need to prophylactically reduce the likelihood of an acute HAE attack (e.g., if the patient continues to anticipate that an HAE attack will be induced, as described above). Thus, on-demand treatment of an HAE attack of the present invention can include administering a first dose and, after administering the first dose, administering a second dose if there is an ongoing need to prophylactically reduce the likelihood of an acute HAE attack. On-demand treatment of an HAE attack of the present invention can also include administering a first dose, then administering a second dose if there is an ongoing need to prophylactically reduce the likelihood of an acute HAE attack after administering the first dose, and then administering a third dose if there is an ongoing need to prophylactically reduce the likelihood of an acute HAE attack after administering the second dose. In each case, each subsequent dose can be administered simultaneously, separately, or sequentially. In each case, each subsequent dose can be administered at least about 6 hours (e.g., at about 6 hours) after the preceding dose. In each case, each dose may contain, for example, 600 mg of the compound administered as two tablets containing 300 mg of the compound.

[0068] Specifically, the on-demand prophylactic treatment of an acute HAE attack described herein can include administering a first dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound), followed by a second dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound) if there is a need to prophylactically reduce the likelihood of an acute HAE attack after administering the first dose. The second dose can be administered at least about 6 hours (e.g., at about 6 hours) after the first dose. If there is an ongoing need to prophylactically reduce the likelihood of an acute HAE attack after the second dose, the on-demand treatment of an acute HAE attack of the present invention can include administering a third dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound). The third dose can be administered at least about 6 hours (e.g., at about 6 hours) after the second dose.

[0069] On-demand prophylactic treatment of acute HAE attacks as described herein may include administering no more than three doses in a 24-hour period (e.g., three doses containing 600 mg of the compound, optionally as six tablets each containing 300 mg of the compound).

[0070] Ongoing and regular preventative treatment for HAE According to one aspect of the present invention, there is provided a method for treating hereditary angioedema (HAE), comprising orally administering to a patient in need of treatment a compound of formula A, wherein the compound of formula A is administered orally to prophylactically reduce the likelihood of an acute HAE attack, and the compound of formula A is administered to the patient periodically.

[0071] Accordingly, one aspect of the present invention provides a compound of formula A for use in the treatment of hereditary angioedema (HAE), comprising orally administering a compound of formula A to a patient in need of treatment, wherein the compound of formula A is administered orally to prophylactically reduce the likelihood of an acute HAE attack, and the compound of formula A is administered to the patient periodically.

[0072] The term "administered periodically" means that the compound of formula A is administered continuously at regular intervals (e.g., once a week, twice a week, etc.) to provide effective treatment. A medical professional will readily understand what is meant by regular (or continuous) administration.

[0073] In some embodiments, a compound of formula A can be administered to prevent acute HAE attacks.

[0074] In some embodiments, the compound of Formula A can be administered orally once daily. In other embodiments, the compound of Formula A can be administered twice daily. In other embodiments, the compound of Formula A can be administered three times daily. In other embodiments, the compound of Formula A can be administered every other day.

[0075] As described above, the compound of formula A can be administered to patients as part of continuous and regular preventive treatment for HAE.As described above, this treatment reduces the possibility of acute HAE attacks.However, in some situations, patients may still suffer from acute HAE attacks.Therefore, an embodiment of the present invention can be administered to patients as part of continuous and regular preventive treatment for HAE, as described above, and further includes taking an on-demand dose of the compound of formula A when recognizing the symptoms of acute HAE attacks, to treat acute HAE attacks if they occur.These on-demand treatments for acute HAE attacks have been discussed above.

[0076] Thus, in some embodiments, methods are provided for treating hereditary angioedema (HAE), comprising orally administering a compound of Formula A to a patient in need thereof, wherein oral administration of the compound of Formula A prophylactically reduces the likelihood of an acute HAE attack, periodically administering the compound of Formula A to the patient, and further comprising orally administering the compound of Formula A on demand upon recognizing symptoms of an acute HAE attack.

[0077] dosage In any of the treatments of the invention described herein, the compound of formula A is administered orally in a therapeutically effective amount.

[0078] In some embodiments, the compound of formula A can be administered in a daily dosage of about 5 mg to about 2000 mg per day. By "daily dosage" is meant the total amount administered in one day. More specifically, the compound of formula A can be administered at a daily dose of about 100 mg to about 1500 mg, about 300 mg to about 1800 mg, about 100 mg to about 1400 mg, about 200 mg to about 1200 mg, about 300 mg to about 1200 mg, about 600 mg to about 1200 mg, about 450 mg to about 900 mg, about 500 mg to about 1000 mg, about 450 mg to about 600 mg, about 500 mg to about 700 mg (more specifically, 600 mg), about 800 mg to about 1000 mg, about 900 mg to about 1400 mg (more specifically, 1200 mg), or about 900 mg to about 1200 mg. In a specific embodiment, the daily dose is 300 mg. In another specific embodiment, the daily dose is 600 mg. In another specific embodiment, the daily dosage is 900 mg. In another specific embodiment, the daily dosage is 1200 mg. In another specific embodiment, the daily dosage is 1800 mg.

[0079] The daily dose can be administered as a single dose or divided into multiple doses for administration periodically throughout the day. Each dose can then be administered as a single dosage form or divided into multiple dosage forms. For example, a daily dose of 1200 mg can be administered as two 600 mg sub-doses, each of which can be administered as two 300 mg sub-doses. When multiple doses and multiple dosage forms are used, they can be administered simultaneously, separately, or sequentially.

[0080] In some embodiments, each single unit dosage form comprising the compound of formula A contains about 5 mg to about 1000 mg, about 50 mg to about 800 mg, about 100 mg to about 700 mg, about 200 mg to about 700 mg, about 300 mg to about 700 mg, or about 500 mg to about 700 mg of the compound of formula A. In some embodiments, each single unit dosage form comprising the compound of formula A contains about 5 mg, about 10 mg, about 20 mg, about 40, about 80 mg, about 160 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, or about 600 mg.

[0081] Each dose administered to a patient may contain 600 mg of the compound, which may be subdivided into two tablets containing 300 mg of the compound.

[0082] Alternatively, each dose may contain 300 mg of the compound, which may be one tablet containing 300 mg of the compound.

[0083] In a particular embodiment, the patient is administered a daily dose of 600 mg administered as a single dose.

[0084] In another particular embodiment, the patient receives a daily dose of 1200 mg, which is administered as two doses, particularly where the second dose is administered 2-6 hours after the first dose, preferably about 3-6 hours after the first dose.

[0085] In another particular embodiment, a patient is administered a daily dose of 1800 mg, administered as three doses, wherein the second dose is administered 2 to 8 hours after the first dose (e.g., about 2 hours, 4 hours, about 6 hours, or about 8 hours), and the third dose is administered about 4 to 16 hours after the first dose (e.g., about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 16 hours).

[0086] The treatments of the present invention involve oral administration. In any of the treatments of the present invention, the compound of formula A can be administered as an oral dosage form comprising the compound of formula A and a pharmaceutically acceptable excipient. The oral dosage form can be in the form of a tablet or capsule. In one embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a capsule.

[0087] The treatment of the present invention can include administering no more than three doses within a 24-hour period. Specifically, if each dose contains 600 mg of the compound, this means that the treatment of the present invention can include administering no more than 1800 mg of the compound within a 24-hour period. If each dose containing 600 mg of the compound is divided into two doses (e.g., tablets) containing 300 mg of the compound, the treatment of the present invention can include administering no more than six doses each containing 300 mg of the compound within a 24-hour period, and each dose can be a tablet.

[0088] The dosage form can be a tablet containing microcrystalline cellulose as a diluent, croscarmellose sodium as a disintegrant, polyvinylpyrrolidone as a binder, and optionally magnesium stearate as a lubricant. In preferred tablets, the compound of Formula A comprises (i) at least about 40% by weight of the tablet (more specifically, about 40% to about 60% by weight) relative to the total tablet weight, (ii) about 25% to about 60% by weight of the diluent (more specifically, about 25% to about 40% by weight) relative to the total tablet weight, (iii) about 1% to about 15% by weight of the disintegrant (more specifically, about 2% to about 6% by weight) relative to the total tablet weight, (iv) about 1% to about 20% by weight of the binder (more specifically, about 2% to about 5% by weight) relative to the total tablet weight, and, if present, (v) about 0.1 to about 5% by weight of the lubricant (more specifically, about 0.1% to about 1.5% by weight) relative to the total tablet weight. The dosage form can be a tablet containing 300 mg of the compound.

[0089] The tablet may further comprise extragranular excipients including microcrystalline cellulose as an extragranular diluent, croscarmellose sodium as an extragranular disintegrant, polyvinylpyrrolidone as an extragranular binder, and / or magnesium stearate as an extragranular lubricant.

[0090] The dosage forms (e.g., tablets) described herein can be film coated, and the film coating can include one or more of hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

[0091] Further details of the treatment of the present invention As shown herein, the compound of Formula A is rapidly acting. Specifically, the compound of Formula A is a potent inhibitor of plasma kallikrein activity and is highly effective at blocking the positive feedback loop of the contact activation system between plasma kallikrein, prekallikrein, factor XII (FXII), and factor XIIa (FXIIa). The pharmacokinetic and pharmacodynamic data provided herein demonstrate that these effects are exhibited immediately after oral administration of the compound of Formula A. Thus, the treatment of the present invention is fast-acting and, therefore, particularly suitable for on-demand treatment of HAE.

[0092] As noted above, the treatment of the present invention is particularly advantageous when the concentration of the compound of formula A is at least 500 ng / mL in plasma. Plasma concentrations of at least 500 ng / mL can be observed after administration of a dose of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg) of the compound of formula A.

[0093] Treatment according to the present invention provides rapid protection from HK (high molecular weight kininogen) cleavage, which is particularly suitable for prophylactically reducing the likelihood of an acute HAE attack and / or shortening (or even halting) the severity of an ongoing acute HAE attack. As described herein, treatment according to the present invention also provides prolonged pharmacodynamic effects. The pharmacodynamic effects of the compounds of Formula A related to the treatment of HAE include providing protection from HK cleavage, which can cause acute HAE attacks, as described above. For example, the compounds of Formula A can provide protection from HK cleavage by at least (i) inhibiting plasma kallikrein, (ii) reducing plasma prekallikrein cleavage, and / or (iii) reducing the production of factor XIIa from factor XII.

[0094] In some embodiments, treatment according to the present invention can provide protection from HK (high molecular weight kininogen) cleavage within one hour of administration, particularly when the dose of the compound of Formula A is at least about 60 mg (specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg). In some embodiments, treatment according to the present invention can provide protection from HK (high molecular weight kininogen) cleavage within 45 minutes after administration, or within 30 minutes after administration. In these embodiments, protection from HK (high molecular weight kininogen) cleavage is confirmed by comparing HK levels in untreated plasma with HK levels in treated plasma, i.e., plasma from a subject who received a dose of the compound of Formula A, and then activating the plasma with dextran sulfate to activate the contact system and induce HK cleavage. If the HK level in treated plasma exceeds that in untreated plasma, HK is protected from HK cleavage in activated plasma.

[0095] In some embodiments of the invention, the treatment can inhibit at least 80% of plasma kallikrein activity within 30 minutes after administration, particularly when the compound of Formula A is administered in an amount of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg). In some embodiments of the invention, the treatment can inhibit at least 90% of plasma kallikrein activity within 30 minutes after administration, particularly when the compound of Formula A is administered in an amount of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg). In some embodiments of the invention, the treatment can inhibit at least 95% of plasma kallikrein activity within 30 minutes after administration, particularly when the dose of the compound of Formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg). In embodiments where inhibition of plasma kallikrein activity is referred to, inhibition of plasma kallikrein activity is determined by time-dependent hydrolysis of a fluorogenic substrate (e.g., (HD-Pro-Phe-Arg-AFC; Peptide Protection Research) by procedures known in the art. In these embodiments, inhibition of plasma kallikrein activity is confirmed in plasma obtained from subjects who have received a dose of a compound of Formula A, which has subsequently been activated with dextran sulfate to emulate the condition of HAE.

[0096] In some embodiments of the present invention, a therapeutically effective concentration of the compound of formula A may be achieved within 20 minutes after administration.

[0097] In some embodiments of the present invention, the T max The time can be 30 minutes to 3 hours after administration, preferably 30 minutes to 2 hours after administration.

[0098] In some embodiments of the present invention, the treatment can inhibit at least 90% of plasma kallikrein activity over a period of at least 45 minutes to 2 hours after administration, particularly when the dose of the compound of Formula A is 100 mg to 200 mg (preferably 160 mg). In some embodiments, the treatment can inhibit at least 90% of plasma kallikrein activity over a period of at least 20 minutes to 4 hours after administration, particularly when the dose of the compound of Formula A is 100 mg to 200 mg (preferably 160 mg). In some embodiments, the treatment can inhibit at least 90% of plasma kallikrein activity over a period of at least 30 minutes to 10 hours after administration, particularly when the dose of the compound of Formula A is 300 mg to 800 mg (preferably 600 mg). In some embodiments, the treatment can inhibit at least 95% of plasma kallikrein activity over a period of at least 20 minutes to 6 hours after administration, particularly when the dose of the compound of Formula A is 300 mg to 800 mg (preferably 600 mg). In some embodiments, treatment can inhibit at least 99% of plasma kallikrein activity over a period of at least 20 minutes to 6 hours after administration, particularly when the dose of the compound of Formula A is 300 mg to 800 mg (preferably 600 mg). Again, in these embodiments, inhibition of plasma kallikrein activity is observed in plasma obtained from subjects who have received a dose of the compound of Formula A, which has subsequently been activated with dextran sulfate to emulate the condition of HAE.

[0099] In some embodiments, the pharmacodynamic effect of a compound of Formula A in treating HAE can be maintained for at least 12 hours after administration, particularly when the dose of the compound of Formula A is between 300 mg and 800 mg (preferably 600 mg). In some embodiments, the treatment can inhibit at least 50% of plasma kallikrein activity for at least 10 hours after administration, particularly when the dose of the compound of Formula A is between 100 mg and 200 mg (preferably 160 mg). In these embodiments, the pharmacodynamic effect refers to at least (i) inhibition of plasma kallikrein, (ii) protection from / reduction of plasma HK cleavage, (iii) protection from (or reduction of) the generation of factor XIIa via factor XII cleavage, and / or (iv) protection from (or reduction of) the generation of plasma kallikrein via plasma prekallikrein cleavage. Thus, treatments according to the present invention are potent (e.g., inhibitory) for a sufficiently long period of time, making them suitable candidates for advantageously effective treatment of acute HAE attacks.

[0100] As noted above, in any of the treatments of the present invention, the compounds of formula A are capable of inhibiting plasma kallikrein.

[0101] In any of the treatments of the invention, the compound of formula A can inhibit the cleavage of factor XII to produce factor XIIa, particularly following administration of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) of the compound of formula A. In any of the treatments of the invention, the compound of Formula A can inhibit the cleavage of plasma prekallikrein to plasma kallikrein, particularly following administration of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) of a compound of Formula A. In any of the treatments of the invention, particularly following administration of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) of a compound of Formula A, the compound of Formula A can provide inhibition (e.g., blockage) of contact system activation for up to 6 hours after administration. In some embodiments, when a dose of at least about 60 mg (more specifically, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 600 mg, specifically 600 mg) is administered, contact system activation can be inhibited (e.g., blocked) for at least 6 hours, e.g., 6 hours to 12 hours or 18 hours, after administration.

[0102] drawing In the drawings, the term "compound" means a compound of formula A. [Brief explanation of the drawings]

[0103] [Figure 1]1 is a powder X-ray diffraction pattern of the compound of formula A produced in Example 1. [Figure 2A] 1 is an assay result showing the plasma kallikrein inhibitory activity of the compound of Formula A and C1 inhibitor C1-INH in dextran sulfate (DXS)-activated diluted plasma. [Figure 2B] 1 is an assay result showing the plasma kallikrein inhibitory activity of the compound of Formula A and C1 inhibitor (C1-INH) in DXS-activated undiluted plasma. [Figure 3A] 1 is the results of an assay comparing the plasma kallikrein inhibitory activity of the compound of Formula A and C1-INH in DXS-activated diluted plasma. [Figure 3B] 1 shows the results of an assay comparing the inhibitory activity of the compound of formula A and C1-INH after addition to preactivated undiluted human plasma. Data are presented as the mean ± SEM of total fluorescence (fluorescence units) over time for n=3 experiments. [Figure 4A] 1 is an assay (bioanalytical) result showing plasma concentrations of the compound of formula A from 0 to 24 hours post-dose in fasted subjects from eight single ascending dose cohorts. [Figure 4B] 4B is a table of Cmax values ​​determined from the assay (bioanalysis) results shown in FIG. 4A. [Figure 5A] 1 shows assay results showing plasma kallikrein activity in DXS-activated undiluted plasma from cohorts 6 to 8 (160 mg, 300 mg, and 600 mg). [Figure 5B] 1 is an assay result showing the mean plasma kallikrein activity and mean plasma concentration of the compound of Formula A in undiluted plasma in subjects from Cohort 8 (600 mg dose). [Figure 6A] 1 is an assay result showing mean fluorescence kinetic measurements indicating the lag time in catalytic activity upon contact system activation in DXS-activated undiluted plasma of subjects receiving a 600 mg dose of the compound of Formula A. [Figure 6B] This is an enlarged view of FIG. 6A from 0 to 5 minutes after catalyst activation. [Figure 7]Assay results showing the mean percent HK protection at selected time points after dosing in DXS-activated undiluted plasma for cohorts 6-8 (160 mg, 300 mg, and 600 mg), and representative WES gel images of immunoblot data. [Figure 8] 1 is a representative WES gel image of assay results and immunoblot data showing the effect of compound of Formula A on DXS-activated HK cleavage at selected time points after administration of Cohort 8 (600 mg). [Figure 9] 1 is a representative WES gel image of assay results and immunoblot data showing the effect of the compound of Formula A on DXS-activated plasma prekallikrein (PPK) cleavage at selected time points after administration of Cohort 8 (600 mg). [Figure 10] Representative WES gel images of assay results and immunoblot data showing the effect of compound of formula A on DXS-activated production of FXIIa at selected time points after dosing in cohort 8 (600 mg). [Figure 11] Assay (bioanalytical) results showing the effect of plasma concentrations of the compound of formula A at various stages after administration in cohort 8 (600 mg) at time points selected for HK, FXIIa, and PPK analysis. [Figure 12] Assay results showing no significant food effect on the plasma kallikrein inhibitory activity of the compound of Formula A in DXS-activated undiluted plasma. [Figure 13A] 1 shows assay results and representative blot images showing the time course of dextran sulfate-activated cleavage of HK in HAE whole undiluted plasma as determined using Western blotting. [Figure 13B] 1 shows assay results and representative blot images showing the time course of dextran sulfate-activated cleavage of HK in HAE whole undiluted plasma as determined using Western blotting. [Figure 14A] 1 shows assay results and representative WES system gel images showing the dose response of the compound of formula A on full-length HK levels in dextran sulfate-activated healthy control plasma and HAE plasma. [Figure 14B]1 shows assay results and representative WES system gel images showing the dose response of the compound of formula A on full-length HK levels in dextran sulfate-activated healthy control plasma and HAE plasma. [Figure 15] Preliminary pharmacokinetic data from an ongoing Phase 2 study. [Figure 16A] Mean plasma concentrations over time for 4 cohorts in a Phase I multiple dose study. [Figure 16B] Mean plasma concentrations (semi-log scale) over time for 4 cohorts in a Phase I multiple-dose study.

[0104] The embodiments provided herein can be more fully understood by reference to the following examples, which are intended to illustrate, but in no way limit, the treatments provided herein. Indeed, the scope of the present invention is defined by the claims.

[0105] While examples of certain specific embodiments have been provided herein, it will be apparent to those skilled in the art that various changes and modifications can be made, and such modifications are intended to fall within the scope of the appended claims. [Example]

[0106] General Experimental Details In the examples below, the following abbreviations and definitions are used:

[0107] [Table 1]

[0108] All reactions were carried out under a nitrogen atmosphere unless otherwise stated.

[0109] 1 1 H NMR spectra were recorded on a Bruker (400 MHz) or JEOL (400 MHz) spectrometer at room temperature relative to a deuterated solvent.

[0110] Molecular ions were acquired using LCMS performed using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient from 10% to 90% 0.1% HCOH / MeCN to 0.1% HCOH / H2O over 13 minutes, at a flow rate of 1.5 mL / min, or an Agilent X-Select, acidic, 5% to 95% MeCN / water over 4 minutes. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization coupled with a Thermofinnigan Surveyor LC system.

[0111] Alternatively, molecular ions were obtained using LCMS performed on an Agilent Poroshell 120 EC-C18 (2.7 μm, 3.0 × 50 mm) column using the following gradients: 0.1% by volume formic acid in water [eluent A]; MeCN [eluent B]; flow rate 0.8 mL / min, equilibration time 1.5 min between samples. Mass detection was performed on an API 2000 mass spectrometer (electrospray).

[0112] [Table 2]

[0113] When products were purified by flash chromatography, "silica" refers to silica gel for chromatography, 0.035-0.070 mm (220-440 mesh) (e.g., Merck silica gel 60), and nitrogen-pressurized accelerated column elution up to approximately 69 kPa (10 psi). Reverse-phase preparative HPLC purifications were typically performed using a Waters 2525 binary gradient pump system at a flow rate of 20 mL / min using a Waters 2996 photodiode array detector.

[0114] All solvents and commercial reagents were used as received.

[0115] Chemical names were generated using automated software such as Autonom software provided as part of the ISIS Draw package from MDL Information Systems, or Chemaxon software provided as a component of MarvinSketch or IDBS E-WorkBook.

[0116] X-ray powder diffraction patterns were collected on a Philips X-Pert MPD diffractometer and analyzed using the following experimental conditions (Method A) unless otherwise stated.

[0117] Tube anode:Cu Generator voltage: 40kV Tube current: 40mA Wavelength α1: 1.5406Å Wavelength α2: 1.5444Å Starting angle [2θ]:4 End angle [2θ]: 40 Continuous Scan Approximately 2 mg of the sample under analysis was gently pressed onto an XRPD zero background single obliquely cut silica sample holder. The sample was then mounted in the diffractometer for analysis.

[0118] Example 1 - Preparation of Compound of Formula A A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one 4-(Chloromethyl)benzyl alcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-Hydroxypyridine (3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added, and the reaction mixture was stirred at 50 °C for 3 h. After that, the solvent was removed under reduced pressure, and the residue was taken up in chloroform (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (Na SO ), and evaporated under reduced pressure. The residue was purified by flash chromatography (silica), eluting with 3% MeOH / 97% CHCl to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (5.30 g, 24.62 mmol, 77% yield). [M+Na] + =238.

[0119] B. 1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmol), anhydrous DCM (80 mL), and triethylamine (7.66 mL, 55.0 mmol) were cooled in an ice bath. Methanesulfonyl chloride (3.95 mL, 51.0 mmol) was added and stirred in the ice bath for 15 minutes. The ice bath was removed, and stirring was continued at room temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated aqueous NH4Cl (100 mL). The aqueous layer was further extracted with DCM (2 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one as a pale yellow solid (8.65 g, 36.6 mmol, 93% yield). [MH] + =234.1.

[0120] C. Methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate Potassium carbonate (519 mg, 3.76 mmol) was added to a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (320 mg, 1.88 mmol; CAS number 318496-66-1 (synthesized according to the method described in WO 2012 / 00909)) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg, 2.26 mmol) in DMF (5 mL) and heated at 60 °C overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered, and reduced in vacuo. The crude product was purified by flash chromatography (40 g column, 0% to 100% EtOAc / isohexane) to give two regioisomers. The second isomer from the column was collected to give methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (378 mg, 1.01 mmol, 53.7% yield) as a colorless gum. [MH] + =368.2.

[0121] D. 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid To 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2 M NaOH solution (15.39 mL, 30.8 mmol) and stirred at room temperature overnight. 1 M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and reduced in vacuo to give 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (1.22 g, 3.45 mmol, 33.6% yield) as a white powder. [MH] + =354.2.

[0122] E. 3-Fluoro-4-methoxy-pyridine-2-carbonitrile In a large microwave vial, copper(I) cyanide (1.304 g, 14.56 mmol) was added to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100 °C for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The resulting viscous suspension was sonicated, and additional water (40 mL) and EtOAc (2 x 50 mL) were added and sonicated to break up the precipitated solid. The combined layers were filtered through a pad of Celite, and the organic layer was isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to give a pale green solid identified as the desired compound, 3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield).

[0123] F. (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester 3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added, followed by di-tert-butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled to -5 °C in an ice-salt bath, and then sodium borohydride (153 mg, 4.05 mmol) was added in small portions, maintaining the reaction temperature at approximately 0 °C. The deep brown solution was stirred at 0 °C, slowly warmed to room temperature, and then stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness at 40 °C to give a black residue, which was diluted with DCM (10 mL) and washed with sodium bicarbonate (10 mL). An emulsion formed, so the organic phase was separated via a phase separator cartridge and concentrated. The resulting crude liquid was purified by chromatography eluting with EtOAc / iso-hexane to give the title compound (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62% yield). [MH] + =257.

[0124] GC-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was taken up in isopropyl alcohol (1 mL), then HCl (6N solution in isopropyl alcohol) (1 mL, 0.578 mmol) was added at room temperature and stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure, then triturated with ether, sonicated, and then decanted to give a cream-colored solid (75 mg, 55% yield) identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride. [MH] + =157.

[0125] Example 1a—N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide (Compound of Formula A) 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (825 mg, 2.34 mmol) and C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (450 mg, 2.34 mmol) were dissolved in DCM with cooling to 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (627.0 mg, 3.27 mmol), HOBt (378.8 mg, 2.80 mmol), and triethylamine (1.63 mL, 1182 mmol) were added with stirring, and the mixture was allowed to warm to room temperature and stirring was continued for 20 h. Chloroform (50 mL) was added, and the mixture was washed with saturated NaHCO (aq) and reduced in vacuo. The crude material was purified by chromatography eluting with methanol / DCM. The solvent was removed in vacuo and the resulting solid was triturated with diethyl ether. The resulting solid was collected by filtration to give the compound of formula A. [MH] + =492.0. NMR (CD3OD)δ: 3.41 (3H, s), 4.03 (3H, s), 4.65 (2H, s), 4.72 (2H, d, J=2.3Hz), 5.24 (2H, s), 5.37 (2H, s), 6.44 (1H, td, J=1.4, 6.8Hz), 6.62 (1H , d, J=9.0Hz), 7.18-7.22(1H, m), 7.31-7.38(4H, m), 7.56-7.60(1H, m), 7.75(1H, dd, J=1.9, 7.1Hz), 8.18(1H, s), 8.27(1H, d, J=5.6Hz)ppm.

[0126] The XRPD diffractogram of the compound of formula A obtained from the above procedure is shown in FIG.

[0127] [Table 3]

[0128] Example 2 - Preparation of a dosage form containing a compound of formula A Mixing and roller compaction Equipment: Freund Vector TFC Lab Micro roller compactor and granulator (the roller compactor and granulator are separate items). Equipment parameters are as follows:

[0129] [Table 4]

[0130] method Two tablet formulations (Tablets A and B) were prepared according to the following method at a 30 g blend scale to produce tablets with the amounts of ingredients shown below.

[0131] [Table 5]

[0132] For each tablet, a blend was prepared by forcing the granular ingredients through a 355 μm sieve in a glass container using a Turbula Blender at 34 rpm, scaled to fit the roller compactor range. The blend was then passed through the roller compactor using the parameters described above. The resulting ribbons were collected in an appropriately sized container. The collected ribbons were then passed through a granulator fitted with a 1 mm sieve, and the resulting granules were collected for further downstream processing.

[0133] Tablet compression Equipment: RIVA Mini single station tablet press. Equipment parameters are as follows:

[0134] [Table 6]

[0135] The granules were then blended with their respective extragranular excipients. The extragranular excipients were prepared by sieving through a 355 μm sieve in a glass container using a Turbula Blender at 34 rpm. Target tablet weights were then dispensed and manually compressed into tablets. Tablet A was compressed at a compression force of 7.2 to 8.8 kN. Tablet B was compressed at a compression force of 6.9 to 7.7 kN.

[0136] The tablets were found to be hard. Tablets A and B were then submitted for long-term stability testing.

[0137] Tablet production by the above method was scaled to 180 g with a roller compaction time of approximately 60 minutes.

[0138] Example 3 - Comparison of Compound of Formula A with C1 Inhibitor (C1-INH) Objective: To identify the biochemical and biophysical properties of compound of formula A that contribute to optimal efficacy in regulating the kallikrein-kinin system in plasma, and then compare these properties to C1-INH as a therapeutic benchmark for HAE.

[0139] method : In vitro plasma kallikrein inhibitory activity was determined using standard published methods (e.g., Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of test compounds at 25°C. Residual enzyme activity (initial velocity of reaction) was determined by measuring the change in absorbance at 410 nm, and the IC value of the test compound was calculated. 50 The value was calculated.

[0140] The rate of formation of the enzyme-inhibitor complex (Kon The K was determined using purified PKa rapidly mixed with a solution containing a fluorogenic substrate and a range of inhibitor concentrations. The time-dependent rate of inhibition was then used to calculate the rate of enzyme-inhibitor complex formation for each inhibitor concentration. K was determined by plotting the percent inhibition versus inhibitor concentration. on The data in Table 1 are in μM. -1 seconds -1 It was provided by.

[0141] The catalytic activity of PKa in dextran sulfate-activated (DXS, Sigma; 10 μg / mL) plasma (1:4 diluted or undiluted, VisuCon-F control plasma, Affinity Biologicals Inc.) was determined by the time-dependent hydrolysis of a fluorogenic substrate. 50 To determine efficacy, the compound of formula A or C1-INH (Sigma catalog number E0518) was added to plasma either before (FIGS. 2A and 2B) or after (FIG. 3A) the addition of DXS.

[0142] DXS-activated cleavage of HK in undiluted plasma was performed in the absence or presence of 300 nM PKa inhibitor and quantified by SDS-PAGE gel electrophoresis using 7.5% Criterion TGX Precast gels (Biorad). Transfer to Immunobilon-FL PVDF membranes was performed. Image analysis was performed using a LICOR imaging system. For conventional immunoblotting, a mouse monoclonal anti-HK antibody (MAB15692, R&D systems) was used. Data are expressed as the percentage of HK remaining after 20 min of incubation with DXS compared to HK levels in non-activated plasma (Table 1).

[0143] The plasma-free fraction was determined using a "Rapid Equilibrium Dialysis" system (Thermo Scientific). Test compounds were prepared at 5 μM in undiluted human plasma and dialyzed against phosphate buffer at 37° C. for 5 hours. Quantitation of compounds distributed into the two chambers of the dialysis device was performed via LCMS / MS. The proportion of compound not bound to plasma proteins was expressed as a % of the total.

[0144] The ability of compounds to inhibit enzyme activity in preactivated plasma was assessed by adding compounds after DXS stimulation. Aliquots of plasma (20 μL) were mixed with 2.5 μL of a solution containing 1,300 mM fluorogenic substrate (H-DPro-Phe-Arg-AFC) and 2.5 μL of a solution of dextran sulfate (DXS; 100 μg / mL), which acts as an activator of the plasma kallikrein-kinin pathway. Enzyme activity was immediately measured by monitoring the accumulation of fluorescence released from the substrate upon substrate cleavage over a 16-minute period. 3.5 minutes after DXS addition, 5 μL of inhibitor or water control was added to each well. Compounds were tested at concentrations of 300, 1000, and 3000 nM. C1-INH at 3000 nM and a vehicle control were also included. Data are presented in Figure 3B.

[0145] result: As shown in Figure 2, in assays using fluorogenic substrates, the compound of formula A appears to be a highly potent inhibitor of PKa, with 17-fold and 20-fold greater potency than exogenously added C1-INH in diluted plasma (Figure 2A) and undiluted plasma (Figure 2B), respectively.

[0146] Table 1 is a table showing the biochemical profiles of the therapies investigated in this example.

[0147] [Table 7]

[0148] Figure 3A shows a comparison of the effects of two inhibitors (the compound of formula A and C1-INH) on plasma kallikrein activity in DXS-activated plasma (1:4 dilution). Approximately 100 seconds after the addition of DXS, both inhibitors reached their IC 50 The antibody was added to plasma at a concentration 10 times higher than that of the antibody.

[0149] FIG. 3B shows that addition of the compound of formula A after activation of the plasma causes a rapid and dose-dependent inhibition of enzyme activity compared to the slower action of C1-INH.

[0150] Table 2 demonstrates the biochemical potency and selectivity of compounds of formula A against the human isolated enzyme using the literature method for the in vitro plasma kallikrein assay described above.

[0151] [Table 8]

[0152] Example 4 - Phase I single-ascending dose study in healthy men and food effect of compound Objective: To evaluate the pharmacodynamic (PD) effects of compound of formula A when administered orally using ex vivo whole plasma assays of plasma kallikrein catalytic activity and HK cleavage in samples from a phase 1, single-ascending-dose study in healthy adult males. Additionally, an objective was to investigate the safety, tolerability, and pharmacokinetic (PK) effects of compound of formula A when administered orally.

[0153] method The study was a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and crossover study of food effect and capsule / tablet formulations.

[0154] Sixty-four healthy male participants (n=6 active, 2 placebo per cohort, 8 SAD cohorts) were administered single ascending doses of the compound of formula A in capsules: 5, 10, 20, 40, 80, 160, 300, or 600 mg.

[0155] Eight participants were administered 100 mg of the compound of formula A in a crossover study of capsule and tablet formulations.

[0156] Twelve participants were administered 600 mg of compound of formula A in a food-effect crossover study.

[0157] Samples for pharmacokinetic (PK) and PD assessments were collected at repeated intervals over 48 hours.

[0158] Plasma samples used for PK evaluation were analyzed using a validated liquid chromatography tandem mass spectrometry (LCMS / MS) method.

[0159] PD measurements were determined in dextran sulfate (DXS) stimulated undiluted plasma using a fluorescent enzyme assay and a capillary-based HK cleavage immunoassay.

[0160] The catalytic activity of PKa in DXS-stimulated (Sigma; 10 μg / mL) plasma samples from the Formula A compound Phase 1 study was determined by the time-dependent hydrolysis of a fluorogenic substrate in all samples from all parts of the study.

[0161] The time until detectable amidolytic activity appeared in DXS-stimulated plasma (lag time) was calculated from the catalytic activity assay. The sensitivity for detecting the rate of catalytic activity in plasma based on the use of a Spark (Tecan) fluorometer is an increase in fluorescence of 1 ΔF unit / sec.

[0162] DXS-stimulated cleavage of HK in undiluted plasma was quantified by a capillary-based immunoassay on the Wes System (ProteinSimple) using a monoclonal anti-HK antibody and chemiluminescence-based detection. In selected samples from the SAD phase, plasma kallikrein-mediated HK cleavage in undiluted citrated human plasma was induced by contact activation with DXS (6.25 μg / mL) at 4°C.

[0163] DXS-stimulated cleavage of plasma prekallikrein and factor XII (FXII) was also quantified by capillary-based immunoassays on the Wes System (ProteinSimple).

[0164] result: Figure 4A shows the plasma concentrations of the compound of Formula A from 0 to 24 hours after administration. As can be seen, when administered orally, the compound of Formula A achieved rapid and dose-dependent plasma exposure over the dose range tested, from 5 mg to 600 mg. Figure 4A shows the concentration curves, and Figure 4B shows the C curves for each SAD cohort. max The compound of formula A was administered as a capsule formulation and subjects were in the fasted state.

[0165] Figure 5A shows the activated undiluted plasma enzyme assays performed on samples from cohorts 6, 7, and 8. Doses of 160 mg and above showed a mean inhibition of greater than 90% of plasma kallikrein catalytic activity over 45 minutes to 2 hours for cohort 6 and over 20 minutes to 4 hours for cohort 7. The 600 mg dose (cohort 8) provided >90% inhibition of plasma kallikrein catalytic activity over 30 minutes to 6 hours and >50% inhibition over 10 hours after administration (Figure 5B).

[0166] Kinetic fluorescence measurements from undiluted plasma enzyme assays can be plotted as assay progress curves (Figures 6A and 6B). These curves highlight that the compound of Formula A not only has an inhibitory effect on enzyme activity, but also increases the time (lag time) for catalytic activity to appear upon catalytic system activation. At early time points after administration, plasma samples showed no detectable catalytic activity, even after prolonged activation with the potent activator DXS. In this study, subjects were administered a 600 mg dose in tablet formulation.

[0167] Figure 7 shows the mean percent HK protection in DXS-activated undiluted plasma (SAD cohorts 6 (160 mg), 7 (300 mg), and 8 (600 mg)). As shown, all three doses of the compound of Formula A were able to inhibit plasma kallikrein catalytic activity by greater than 90% over a period of time. The duration of these PD effects was dose-proportional. The compound of Formula A has been shown to protect HK from DXS-activated cleavage in undiluted plasma for at least 10 hours after a single 600 mg dose.

[0168] In Figure 7, a representative WES system gel image was obtained for duplicate undiluted plasma samples + / - DXS activation from one subject in Cohort 8 who received 600 mg of the compound of Formula A compared to pre-dose (PD).

[0169] In Figure 7, HK cleavage was assessed after DXS activation of undiluted plasma samples at selected time points from cohorts 6 to 8. Data are presented as mean ± SEM, n = 6.

[0170] To assess whether compound of Formula A also reduced plasma kallikrein and factor XIIa production, immunoassays were used to quantify contact activation system protein levels in DXS-activated plasma before and up to 12 hours after oral administration of 600 mg capsules. The results of these assays are shown in Figures 8-11 and indicate that compound of Formula A not only reduces HK cleavage, but also PPK cleavage and reduces FXIIa production. These results suggest that compound of Formula A inhibits the contact activation system through interruption of the positive feedback loop mediated by PKa-stimulated activation of FXII.

[0171] Figure 12 shows that no significant food effect was observed in the pharmacodynamic (PD) profile of the 600 mg tablet provided in the fed and fasted states. As can be seen, the PD effect is observed rapidly in both the fed and fasted states, with >90% plasma kallikrein inhibition achieved by 30 minutes in both states.

[0172] No serious adverse events were reported in the phase I study, there were no signals of tolerability, and no subjects discontinued the study.

[0173] These data demonstrate that the compound of formula A has inhibitory effects on the bradykinin and contact activation systems. As discussed above, these pharmacodynamic effects are relevant to disorders such as HAE. These data also demonstrate that the compound of formula A has a pharmacokinetic profile suitable for oral administration.

[0174] Example 5 - Immunoassay to examine compounds of formula A in protecting high molecular weight kininogen (HK) from PKa-mediated cleavage in HAE and control plasma method: High molecular weight kininogen (HK) cleavage in undiluted citrated human plasma was induced by contact activation with dextran sulfate (DXS, Sigma #31395-10G; 6.25 μg / mL) on wet ice. Pooled normal (CONTROL) human plasma (VisuCon-F frozen normal control plasma) was purchased from Affinity Biologicals Inc. A working stock solution of 10 mM compound of formula A ("Compound") in DMSO was prepared and diluted with 1X PBS to the respective final concentrations listed. HAE plasma was obtained from HAE subjects (n=6), and C1 inhibitor deficiency was confirmed by Western blotting. Next, protection of HK from PKa-mediated cleavage in DXS-stimulated undiluted whole plasma was determined by two methods: conventional Western blotting and a semi-automated capillary-based immunoassay.

[0175] Western blotting: SDS-PAGE gel electrophoresis was performed using 7.5% Criterion TGX Precast gels (Bio-Rad). Transfer to Immobilon-FL PVDF membranes was performed. Image analysis was performed using a LICOR imaging system. For conventional immunoblotting, a mouse monoclonal anti-human HK antibody (MAB15692, R&D Systems) was used.

[0176] Capillary-based immunoassay on WES systems (ProteinSimple): Sample preparation: Combine 1 part 5x fluorescent master mix with 4 parts 1:200 plasma sample. Vortex to mix. Heat sample + fluorescent master mix and biotinylated ladder to 95°C for 5 minutes, vortex, and load onto WES plate. A monoclonal anti-human HK antibody was used for this chemiluminescence-based detection method using the WES System (ProteinSimple).

[0177] Analysis: Peak area measurements were collected using Compass software (cbz files) for full-length HK molecular weights from samples at each time point of DXS-induced activation. Peak area was defined as the area calculated for the HK spectral peak profile. To measure compound-mediated inhibition of plasma kallikrein, the percentage of detected full-length HK was calculated.

[0178] result: Figures 13A and 13B show the time course of dextran sulfate-activated cleavage of HK in HAE whole undiluted plasma measured using Western blotting and representative blots.

[0179] Figures 14A and 14B show representative gel images of the WES system, demonstrating that the compound of formula A provides dose-dependent protection against HK cleavage in both dextran sulfate-stimulated HAE and healthy control plasma as measured by capillary-based immunoassay using the WES system.

[0180] Example 6 - Phase 2 Study of Compound of Formula A Objective: To evaluate the efficacy and safety of the compound of formula A for the on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type I or II.

[0181] method: This study is a randomized, double-blind, placebo-controlled, phase 2 crossover clinical trial evaluating the efficacy and safety of the compound of Formula A (the "Compound"), an oral plasma kallikrein inhibitor, for the on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type I or II (EudraCT number: 2018-004489-32).

[0182] the purpose: Main purpose: To determine the efficacy of the compound compared to placebo in halting the progression of peripheral or abdominal hereditary angioedema (HAE) attacks.

[0183] Secondary purpose: - To determine the safety and tolerability of the compound. To investigate the pharmacokinetic (PK) profile of the compound when taken during the critical period between HAE attacks. To investigate the pharmacodynamic (PD) profile of the compound in reducing the concentration of residual cleaved high molecular weight kininogen (HK) during the critical inter-attack period between HAE attacks. To investigate the PD profile of the compound in reducing activated plasma enzyme activity during the critical inter-attack period between HAE attacks.

[0184] setting: This is a two-phase, two-part, two-sequence, two-period (2x2) crossover clinical trial. Subjects with HA E1 or II will be recruited through HAE treatment centers in Europe and the United States.

[0185] Part 1 Subjects will receive a single oral dose of 600 mg of the compound to assess its safety, PK, and PD during the critical period between HAE attacks.

[0186] Eligible adult subjects aged 18 years or older will undergo screening assessments for study entry, receive study medication, and undergo a 4-hour in-hospital safety and PK / PD assessment.

[0187] Part 2 In this study, subjects will be randomly assigned to a 1:1 to 2 treatment sequence. This part of the study will be conducted away from the clinic or hospital. In sequence 1 (study arm 1), subjects will receive a single 600 mg dose of the compound to treat their first qualifying HAE attack. After this attack resolves, subjects will receive a second single dose of placebo to treat their second qualifying HAE attack.

[0188] In sequence 2 (study arm 2), subjects receive a single dose of placebo to treat their first qualifying HAE attack, and after that attack has resolved, subjects receive a second single dose of 600 mg of the compound to treat their second qualifying HAE attack.

[0189] A minimum washout period of 48 hours is required between each dose of study drug.

[0190] Laryngeal or facial attacks are not eligible for treatment. HAE attacks must be treated within the first hour of onset and before they become severe on the Global Attack Severity Scale. Subjects must also be able to identify the onset of an HAE attack. Upon the onset of a qualifying HAE attack, subjects notify the designated investigator or qualified designee with a description of the HAE attack. The designated investigator or qualified designee confirms the eligibility of the HAE attack and consents to the administration of study medication. HAE attacks must be documented in a subject diary with the location of the attack, attack symptoms, time of onset, attack severity, and time of the last substantial meal before medication administration. Subjects take the study medication as directed and complete a timed assessment of HAE attack symptoms over a 48-hour period, as described in Table 3 below. The designated investigator or qualified designee will contact the subject within 24 hours of the qualifying HAE attack to ensure the subject's safety and well-being. Instruct subjects to contact the dedicated investigator or qualified designee if they have any safety concerns. In case of hypersensitivity, subjects should contact the dedicated investigator or qualified designee or contact the nearest emergency services. A dedicated investigator or qualified designee will be available to answer subjects' phone calls 24 hours a day, 7 days a week.

[0191] [Table 9]

[0192] Subjects will return to the clinic after their first HAE attack and before their second HAE attack for safety checks, including adverse event (AE) reporting, vital signs recording, and subject diary review.

[0193] Once two HAE attacks have been treated in Part 2, subjects will return to the clinic for a final safety check, including AE reporting, vital signs recording, and blood sampling for laboratory safety measurements.

[0194] If HAE attack symptoms are deemed severe enough by the subject to require treatment according to the subject's usual treatment, or if the subject is deemed ineligible for study drug treatment, or if associated with laryngeal or facial symptoms, conventional attack therapy may be administered 4 hours after study drug ingestion or earlier as needed. Prior to using conventional attack therapy, subjects must notify the designated investigator or qualified designee, who will confirm that conventional therapy is appropriate based on the protocol and subject report of symptom severity. Subjects may treat HAE attacks with conventional attack therapy (intravenous pdC1INH or rhC1INH [iv] or icatibant).

[0195] Investigational Products: Compound of Formula A - 100 mg film-coated tablets. These contain the following excipients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, and an aesthetic coating containing hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

[0196] Placebo versus 100 mg film-coated tablets of the compound. These contain microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, and sodium stearyl fumarate, and are film-coated with an aesthetic coating containing hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

[0197] Dose modifications of the investigational drug were not permitted in this study.

[0198] Number of subjects: Approximately 60 subjects will be enrolled in the study, with 50 subjects completing the study.

[0199] population: The study population included male and female subjects aged 18 years and older with HA Type 1 or Type 2.

[0200] Selection criteria: 1. Adult subjects, male or female, 18 years of age or older.

[0201] 2. Confirmed diagnosis of HAEI or II at any time in the medical history: a. A documented medical history consistent with HAE (episodes of subcutaneous or mucosal non-pruritic swelling without urticaria) AND b. C1-esterase inhibitor (C1-INH) antigen or functional levels <40% of normal. Subjects with antigen or functional C1-INH levels between 40% and 50% of normal levels may be enrolled if they have C4 levels below the normal range and a family history consistent with HA type 1 or type 2.

[0202] 3. At least three HAE attacks documented in the past 93 days, supported by medical history.

[0203] 4. Access to and ability to use conventional seizure treatments for HAE attacks.

[0204] 5. Adequate organ function as defined below: Hemoglobin within normal range; b. International normalized ratio (INR) < 1.2; c. Activated partial thromboplastin time (aPTT) ≤ upper limit of normal (ULN); d. Creatinine <1 × ULN; e. Creatinine clearance (CrCl) ≥ 60 mL / min; f. alanine aminotransferase (ALT) ≤ 2 × ULN; g. aspartate aminotransferase (AST) ≤ 2 × ULN; h.Total bilirubin ≤ 1.5 × ULN; i.Leukocytes ≦1.5×ULN; j. Platelets ≤1.5×ULN.

[0205] 6. Women of childbearing potential must agree to use highly effective contraception from the screening visit until the end of study follow-up procedures. Highly effective methods of contraception include: a. Progestogen-only hormonal contraceptives associated with suppression of ovulation: oral / injectable / implant. (Estrogen-containing hormonal contraceptives are excluded due to Exclusion Criterion 3.) b. Intrauterine device (IUD) c. Intrauterine hormone-releasing system (IUS) d. Bilateral tubal obstruction e. Vasectomized partner (if the partner is the only sexual partner of the female subject of childbearing potential and the vasectomized partner is undergoing medical evaluation for surgical success). f. Sexual abstinence (this method is not accepted in Switzerland). NOTE: Sexual abstinence is considered a highly effective method only if it is defined as abstinence from heterosexual intercourse. The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the subject's preferred and usual lifestyle.

[0206] 7. Women who are not capable of childbearing, defined as being surgically sterile (following hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or at least 12 months postmenopausal, do not require contraception during the study.

[0207] 8. Men with female partners of childbearing potential must agree to abstain or use highly effective contraception as defined in Inclusion Criterion 6 from the screening visit until the end of the study follow-up procedures.

[0208] 9.Ability to provide signed informed consent and to voluntarily comply with the requirements and procedures of the study.

[0209] Exclusion criteria: 1. Concurrent 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.

[0210] 2.Currently using C1INH, androgen, lanadelumab, or tranexamic acid for HAE prophylaxis.

[0211] 3. Use of angiotensin-converting enzyme (ACE) inhibitors or estrogen-containing medications with systemic absorption (e.g., oral contraceptives or hormone replacement therapy) within 93 days prior to first study treatment.

[0212] 4. Use of androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterones, testosterone) or antifibrinolytic agents within 30 days prior to first study treatment.

[0213] 5. Use of lanadelumab within 10 weeks prior to first study treatment.

[0214] 6. Use of strong CYP3A4 / CYP2C9 inhibitors and inducers during participation in the clinical trial. NOTE: These medications include, but are not limited to, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir, boceprevir, telaprevir, troleandomycin, clarithromycin, carbamazepine, enzalutamide, mitotane, phenytoin, phenobarbital, fluconazole, isoniazid, metronidazole, paroxetine, sulfamethoxazole, rifampicin, St. John's wort, diltiazem, idelalisib, nefazodone, and nelfinavir.

[0215] 7. Clinically significant abnormal electrocardiogram (ECG) at Visit 1 and prior medication at Visit 2. This includes, but is not limited to, QTcF >470 msec (for women) or >450 msec (for men), PR >220 msec or occasional premature ventricular and / or atrial beats that are more frequent or occur as couplets or more in groupings.

[0216] 8. Clinically significant history of angina pectoris, myocardial infarction, syncope, clinically significant cardiac arrhythmia, left ventricular hypertrophy, cardiomyopathy, or other cardiovascular abnormality.

[0217] 9. Any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory, cardiovascular, etc.) or significant disease or disorder that, in the opinion of the investigator, could jeopardize the subject's safety by participating in the clinical trial.

[0218] 10. History of substance abuse or dependence that would affect study completion, as determined by the investigator.

[0219] 11. Known lactose allergy or intolerance.

[0220] 12. Known hypersensitivity to the compound or placebo or any of the excipients.

[0221] 13. Participation in an interventional clinical trial within 93 days or 5 half-lives (whichever is longer) of the last dose of an investigational drug prior to the first study treatment.

[0222] 14. Pregnant or lactating subjects.

[0223] evaluation: Part 1: Blood samples for PK and PD measurements will be collected at the following time points: pre-dose (0 hours), 15, 30, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, and 4 hours post-dose. Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate [PR], respiratory rate [RR], and temperature) will be measured pre-dose (0 hours), 1 hour, and 4 hours post-dose. Samples for post-treatment safety laboratory evaluations will be collected at the 4-hour PK / PD sample.

[0224] Part 2: After ingestion of study medication, subject assessment of overall HAE attack severity and change in HAE attack severity will be performed for 48 hours as described in Table 3 above.

[0225] Efficacy variables: Assessing time on conventional attack medications. Subject diaries will record time on conventional attack medications and efficacy endpoints such as severity of HAE attacks.

[0226] Overall HAE attack severity is assessed on a 5-point Likert scale (5LS) rated as none, mild, moderate, severe, and very severe.

[0227] Changes in the severity of HAE attacks are assessed using a 7-point transition question (7TQ) rated as much better / good / slightly better / no change / slightly worse / worse / much worse.

[0228] The types of HAE attack symptoms (abdominal pain, skin pain, and skin swelling) are rated on a 100-mm visual analog scale (VAS) anchored at 0 (none) and 100 (very severe), respectively.

[0229] Safety variables: AEs, including serious adverse events (SAEs) Laboratory test results (clinical chemistry, hematology, coagulation, and urinalysis) Vital signs (SBP, DBP, PR, RR, temperature) Physical examination findings ·ECG results Pregnancy testing (female subjects of childbearing potential).

[0230] Efficacy evaluation criteria Primary Efficacy Endpoint: · Time spent using conventional seizure medications.

[0231] Secondary Efficacy Endpoints: The proportion of HAE attacks that progress by ≥1 level on the 5LS or require conventional attack treatment within 12 hours of study drug. Treatment and time to either (1) progression of overall seizure severity by 1 level or more on the 5LS, or (2) use of conventional seizure treatment, whichever occurs first, within 12 hours.

[0232] Exploratory endpoints: Cumulative overall seizure severity for 5LS after study drug administration, expressed as area under the curve (AUC) for compound 600 mg versus placebo. · The proportion of HAE attacks requiring conventional attack treatment. Percentage of HAE attacks rated as "worse" or "much worse" on the TQ. Percentage of HAE attacks rated as "better" or "much better" on the TQ. Time from study drug administration to complete resolution of HAE attacks (rated as none) on the Global Attack Severity Scale (5LS). Time to HAE attack rated as worse or much worse on the TQ. Time to HAE attack rated as better or much better by TQ.

[0233] Common statistical methods and types of analysis Analysis population: Safety population (SAF): subjects who received at least one dose of study drug (including any dose of study drug in Part 1). Full Analysis Set (for efficacy) (FAS): All randomized subjects who received both doses of study drug in Part 2. Per-Protocol Population (for Efficacy) (PPS): Part 2 randomized subjects who received both doses of study compound in Part 2 and had no major protocol deviations. PK / PD analysis population: All subjects from whom PK / PD samples were collected in Part 1.

[0234] Number of samples: A sample size of 50 subjects (25 per sequence) is proposed to provide 90% power to test at a 5% alpha level (two-sided) for the primary endpoint of time on conventional seizure medication. This sample size was derived based on the assumption that 40% of subjects would use conventional seizure medication in the control arm and 10% would use conventional seizure medication in the experimental arm, with minimal correlation within the subject data. The assumption of minimal correlation should be a conservative assumption regarding sample size. Approximately 60 subjects will be enrolled to ensure 50 subjects complete the study.

[0235] A 20% (10 subject) oversampling is proposed to account for subjects who may not complete both treatment periods due to rare or ineligible HAE attacks, or who discontinue the study early for any reason. Therefore, study enrollment will be deemed sufficient to address the primary efficacy hypothesis after 50 subjects have completed both treatment periods. Ongoing subjects who have not completed both periods will be asked to return to the investigational site and complete Visit 4 (Early Discontinuation Visit), as further exposure will be deemed unnecessary. Data from all completing and non-completing subjects will be analyzed in the safety population.

[0236] General considerations: Individual subject data will be displayed in the Subject Data List. Appropriate descriptive statistics will be calculated for continuous and categorical data and summarized in tabular form.

[0237] Sample analysis: AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary (v21.0 or later) and categorized by preferred term and system organ class (SOC). Lists of treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to early discontinuation will be provided by sequence group and further categorized by TEAE severity and relationship to study drug.

[0238] Efficacy Analysis: Primary endpoint The primary endpoint, time on conventional seizure medication, will be analyzed using a generalization of the Gehan test proposed by Feingold and Gillespie (1996) (crossover design with censored data. Statistics in Medicine 1996;15(10):953-967) to reflect repeated measurements for each subject. Subjects will be treated as censored if no exacerbation occurs within 12 hours of study drug administration.

[0239] Secondary endpoints The proportion of HAE attacks that worsen by ≥1 level on the 5LS or require conventional attack treatment within 12 hours of study drug will be analyzed using Prescott's test (1981) (Comparison of success rates in crossover studies in the presence of order effects. Applied Statistics 1981;30:9-15) to compare treatment arms.

[0240] Methods similar to those used for the primary endpoint will be used to analyze time to either the investigational drug and an HAE attack worsening by ≥1 level on the 5LS, or the use of conventional attack treatment, within 12 hours, whichever occurs first. In addition to the above tests, descriptive statistics are provided for the primary, secondary, and exploratory endpoints, which in each case compare the compound to placebo, such as those listed below. Cumulative overall seizure severity at 5LS after study drug expressed as AUC for 600 mg of the compound versus placebo. · The proportion of HAE attacks requiring conventional attack treatment. Percentage of HAE attacks rated as "worse" or "much worse" on the TQ. Percentage of HAE attacks rated as "better" or "much better" on the TQ. Time from study drug administration to complete HAE attack resolution (rating of none) on the Global Attack Severity Scale (5LS). Time to HAE attack rated as worse or much worse by TQ. Time to HAE attack rated as better or much better by TQ.

[0241] PK analysis: Non-compartmental PK parameters include maximum plasma concentration (Cmax), time to reach Cmax in plasma (tmax), and area under the curve from time 0 to the last sample (AUC0-t). Compartmental PK modeling describes the PK of a compound and generates the underlying Cmax, tmax, AUC, apparent clearance (CL / F), apparent volume of distribution (Vd / F), and estimated terminal elimination half-life (t1 / 2).

[0242] PK parameters for the compound are determined from the individual concentration and time data using Phoenix WinNonlin. If there is deviation from the theoretical times, the actual times of the blood samples are used to calculate the derived PK parameters. Individual concentrations of the compound in plasma and derived PK parameters are listed and summarized for each treatment. Individual geometric mean concentration-time data are plotted on linear and semi-log scales.

[0243] PD analysis: The effect of the compounds on plasma kallikrein (PKa) activity is analyzed using two exploratory measures of PKa enzyme activity in plasma. An assay for measuring the inhibition of exogenously activated plasma kallikrein enzyme activity from plasma samples obtained before and after administration of the compound. Assay to measure the level of protection from plasma kallikrein enzyme activity in the cleavage of high molecular weight kininogen (HK) substrate (contained in whole plasma).

[0244] PD will be summarized for each treatment, with individual and mean data provided as a report addendum in the appendix to the final clinical trial report.

[0245] Preliminary PK data from Part 1 of the study: At the time of filing this application, preliminary PK data from 27 HAE patients had been collated and analyzed and are shown in Table 4 and FIG.

[0246] [Table 10]

[0247] Thus, these preliminary results demonstrate that the compound of Formula A exhibits a pharmacokinetic profile suitable for on-demand oral administration in patients with HAE. Studies are ongoing at the time of filing.

[0248] Example 7 - Phase 1 Multiple Dose Study in Healthy Adult Subjects the purpose To evaluate the safety, tolerability, pharmacokinetics, and change from baseline in QTc following administration of the compound formulated as 100 mg film-coated tablets to healthy adult subjects.

[0249] Main purpose: - To investigate the safety and tolerability of multiple doses of the compound.

[0250] Secondary purpose: To study the multiple-dose pharmacokinetics (PK) of the compound. To evaluate the effect of the compound on ECG parameters, including concentration-QTc relationships, after administration of 100 mg film-coated tablets (KalVista Pharmaceuticals) to healthy adult subjects.

[0251] Exploratory purpose: To investigate the multiple-dose pharmacodynamics (PD) of the compound.

[0252] method: This is a phase 1, double-blind, placebo-controlled, multiple-dose, multiple-cohort study to evaluate the safety and tolerability of the compound, as well as the ECG effects of the compound formulated as 100 mg film-coated tablets in healthy adult male and female subjects.

[0253] Four cohorts are planned for evaluation: Cohorts 1, 2, and 3 will each contain 8 subjects; Cohort 4 will contain 18 subjects. Every attempt will be made to include an equal number of male and female subjects in each cohort.

[0254] During the study, an oral dose of 600 mg of the compound as film-coated tablets (six 100 mg tablets) or six matching placebo tablets will be administered orally every 8 hours (Cohort 1), every 4 hours (Cohort 2), or every 2 hours (Cohorts 3 and 4) to healthy adult male and female subjects, up to a maximum total dose of 1800 mg. In Cohorts 1, 2, and 3, six subjects will receive the compound as 100 mg film-coated tablets, and two subjects will receive placebo for a total of eight subjects per cohort. In Cohort 4, 12 subjects will receive the compound as 100 mg film-coated tablets, and six subjects will receive placebo for a total of 18 subjects.

[0255] Progression from Cohort 1 to Cohort 2 and from Cohort 2 to Cohort 3 will occur after review of safety data (laboratory values, vital signs, safety ECGs, and adverse events) obtained during the conduct of Cohort 1 and Cohort 2. Progression to Cohort 4 will occur after review of safety and pharmacokinetic data from Cohort 3. Pharmacokinetic data from Cohort 3 will be reviewed to ensure that the Cmax of the third dose is high enough to support assessment of the QTcvc interval from baseline.

[0256] A Holter monitor will be attached to each subject for continuous ECG recording. The monitor will be attached one hour before the first dose and will remain attached until after the final blood sample is drawn. The Holter electrodes will be checked by clinic personnel at appropriate intervals to ensure they remain attached.

[0257] Blood samples will be collected pre-dose, at intervals after the first dose, and at least 24 hours after the final (third) dose in each cohort (40 hours after the first dose in Cohort 1, 32 hours after the first dose in Cohort 2, and 28 hours after the first dose in Cohorts 3 and 4). Subjects will be restricted to the clinical site from at least 10 hours before dosing until after the final blood sample collection in each study cohort, returning to the clinic 5-7 days after the final dose for safety evaluations.

[0258] The pharmacokinetics of the compounds will be measured by fully validated analytical procedures, and the pharmacodynamic effects on plasma kallikrein inhibitor enzyme activity will be assessed by exploratory pharmacodynamic evaluations.

[0259] Statistical analysis is performed to assess the relationship between plasma drug concentrations and the change from baseline in ECG effects of the test formulations.

[0260] Therapeutic administration Cohort 1 Subjects will receive test or placebo treatment every 8 hours over a 16-hour period according to a two-treatment randomization schedule under direct observation (three doses: three doses of six 100 mg compound or placebo doses as 100 mg film-coated tablets at 0, 8, and 16 hours, for a total dose of 1800 mg compound or placebo). Each dose will be administered with 240 mL of room temperature water. Subjects will be instructed to swallow the tablet whole without chewing or chewing. Subjects who chew or chew tablets will be dropped from the study. An oral check will be performed immediately after administration.

[0261] Cohort 2 Subjects will receive test or placebo treatment every 4 hours over an 8-hour period according to a two-treatment randomization schedule under direct observation (3 doses: 3 doses of 6 100 mg compound or placebo doses as 100 mg film-coated tablets at 0, 4, and 8 hours, for a total dose of 1800 mg compound or placebo). Each dose will be administered with 240 mL of room temperature water. Subjects will be instructed to swallow the tablet whole without chewing or chewing. Subjects who chew or chew tablets will be withdrawn from the study. An oral check will be performed immediately after administration to ensure that the tablet has been completely swallowed without chewing or chewing.

[0262] Cohorts 3 and 4 Subjects will receive test or placebo treatment every 2 hours over a 4-hour period according to a two-treatment randomization schedule under direct observation (3 doses: 3 doses of 6 100 mg compound or placebo doses as 100 mg film-coated tablets at 0, 2, and 4 hours, for a total dose of 1800 mg compound or placebo). Each dose will be administered with 240 mL of room temperature water. Subjects will be instructed to swallow the tablet whole without chewing or chewing. Subjects who chew or chew the tablet will be withdrawn from the study. An oral check will be performed immediately after administration to ensure the tablet has been completely swallowed without chewing or chewing.

[0263] All subjects will fast (except for water) for at least 8 hours prior to the first dose. After the first dose, subjects will continue to fast until at least 6 hours after the first dose.

[0264] Method of assigning subjects to treatment groups: Cohorts 1, 2, and 3 Subjects will be randomized so that 6 subjects receive the test product and 2 subjects receive the placebo. As a safety measure, each cohort will incorporate a sentinel dosing scheme, with 1 subject receiving the test product and 1 subject receiving the placebo product, followed by the remainder of the cohort.

[0265] Cohort 4 The subjects are randomized so that 12 subjects receive the test product and 10 subjects receive the placebo.

[0266] The randomization schedule will be generated prior to the first dosing cohort using SAS® version 9.4 or later.

[0267] result: No serious adverse events were reported during the study, and no subjects discontinued due to AEs. All reported adverse events were considered "mild" in severity and had an outcome of "recovery / resolution" after study completion.

[0268] No clinically relevant effects on the ECG parameters tested were identified.

[0269] FIG. 16A shows the mean plasma concentrations of the compound of formula A after the first dose for each cohort.

[0270] FIG. 16B shows the mean plasma concentrations (semi-log scale) of the compound of formula A for each cohort.

[0271] These data indicate that the compound of formula A has a pharmacokinetic profile suitable for oral administration when administered in multiple doses, and the results further suggest that the compound of formula A can be safely administered periodically.

Claims

1. A method for treating hereditary angioedema (HAE) on demand, comprising orally administering to a patient in need of treatment for HAE a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) on demand. 【Chemical 1】

2. A compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use in the on-demand treatment of hereditary angioedema (HAE), comprising orally administering the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) on-demand to a patient in need of such treatment. 【Chemistry 2】

3. 1. Use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) in the manufacture of a medicament for the on-demand treatment of hereditary angioedema (HAE), comprising orally administering a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) on-demand to a patient in need of such treatment. 【Chemistry 3】

4. 2. The method of claim 1, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is for use in the on-demand treatment of acute attacks of hereditary angioedema (HAE) and is orally administered on-demand upon recognition of symptoms of an acute HAE attack; 3. The method of claim 1, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is for use in the on-demand treatment of acute attacks of hereditary angioedema (HAE) and is orally administered on-demand upon recognition of symptoms of an acute HAE attack; 4. The compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 2, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered on-demand upon recognition of symptoms of an acute HAE attack;

5. The method of claim 4, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 4, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 4, wherein the recognized symptoms of an acute HAE attack are at least one of tissue swelling, fatigue, headache, muscle pain, skin tingling, abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing, hoarseness, shortness of breath, and / or mood swings.

6. 6. The method of claim 4 or 5, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered orally on demand within one hour of the symptoms of an acute HAE attack being recognized, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 4 or 5, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 4 or 5.

7. The method of any one of claims 4 to 6, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 4 to 6, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 4 to 6, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered orally on demand within 30 minutes, within 20 minutes, within 10 minutes, or within 5 minutes of symptoms of an acute HAE attack being recognized.

8. The method of any one of claims 4 to 7, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 4 to 7, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 4 to 7, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered on demand during the prodromal phase of an acute HAE attack.

9. 9. The method of claim 8, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 8, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 8, wherein the recognized symptom is at least one of mild swelling, abdominal pain, or redness of the skin.

10. 10. The method of claim 9, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use according to claim 9, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 9, wherein the recognized symptom is marginal erythema.

11. 11. The method of any one of claims 1 and 4 to 10, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 2 and 4 to 10, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 3 to 10, wherein said treatment reduces the duration of said acute HAE attack.

12. 9. The method of claim 8, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 8, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 8, wherein the treatment prevents the acute HAE attack from progressing to the swelling stage of an acute HAE attack.

13. 2. The method of claim 1, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered on demand to prophylactically reduce the likelihood of an acute HAE attack, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 2, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 3.

14. 14. The method of claim 13, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered on demand when an acute HAE attack is expected to be induced, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use of claim 13, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) of claim 13.

15. 15. The method of claim 14, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered on demand when an acute HAE attack is expected to be precipitated by physical trauma and / or stress; the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 14; or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 14.

16. The method of claim 15, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use according to claim 15, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 15, wherein the acute HAE attack is expected to be triggered by the physical trauma of the dental procedure and / or the psychological stress associated with the dental procedure.

17. 17. The method of any one of claims 13 to 16, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 13 to 16, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 13 to 16, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered orally on demand to prevent acute HAE attacks.

18. 1. A method of treating hereditary angioedema (HAE), comprising orally administering to a patient in need thereof a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof), wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered prophylactically to reduce the likelihood of an acute HAE attack, and the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered periodically to the patient. 【Chemistry 4】

19. 1. A compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use in the treatment of hereditary angioedema (HAE), comprising orally administering a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) to a patient in need thereof, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered prophylactically orally to reduce the likelihood of an acute HAE attack, and the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered periodically to the patient. 【Chemistry 5】

20. 1. Use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) in the manufacture of a medicament for the treatment of hereditary angioedema (HAE), comprising orally administering a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) to a patient in need thereof, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered prophylactically orally to reduce the likelihood of an acute HAE attack, and the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered periodically to the patient. 【Chemistry 6】

21. 20. The method of claim 18, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered to prevent acute HAE attacks; the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 19; or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 20.

22. 22. The method of claim 18 or 21, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 19 or 21, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 20 or 21, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is orally administered once daily.

23. 22. The method of claim 18 or 21, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 19 or 21, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 20 or 21, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered orally twice daily.

24. 22. The method of claim 18 or 21, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 19 or 21, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 20 or 21, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered orally three times daily.

25. 25. The method of any one of claims 1 to 24, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 24, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 24, wherein the compound (or a pharmaceutically acceptable salt and / or solvate thereof) is administered as an oral dosage form comprising (i) the compound (or a pharmaceutically acceptable salt and / or solvate thereof), and (ii) a pharmaceutically acceptable excipient.

26. 26. The method of claim 25, wherein the oral dosage form is a tablet comprising microcrystalline cellulose as a diluent, croscarmellose sodium as a disintegrant, polyvinylpyrrolidone as a binder, and optionally magnesium stearate as a lubricant; the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use according to claim 25; or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 25.

27. 27. The method of any one of claims 1 to 26, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 26, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 26, wherein the compound (or a pharmaceutically acceptable salt and / or solvate thereof) (i) inhibits plasma kallikrein, (ii) reduces the cleavage of plasma prekallikrein, and / or (iii) reduces the production of factor XIIa from factor XII.

28. 28. The method of claim 27, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 27, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 27, wherein the patient is administered a dose of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) such that the patient's plasma has a concentration of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) of at least 500 ng / mL.

29. 29. The method of claim 28, wherein the patient is administered at least 60 mg of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof), the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 28, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 28.

30. 30. The method of any one of claims 1 to 29, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 29, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 29, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) blocks activation of the contact system for up to 6 hours.

31. 31. The method of any one of claims 1 to 30, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 30, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 30, wherein the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) is administered in a daily dosage of from 5 mg to 2000 mg.

32. 32. The method of any one of claims 1 to 31, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 31, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 31, wherein the compound of formula A is administered at a daily dosage of 100 mg to 1500 mg, 300 mg to 1800 mg, 100 mg to 1400 mg / day, 200 mg to 1200 mg, 300 mg to 1200 mg, 600 mg to 1200 mg, 450 mg to 900 mg, 500 mg to 1000 mg, 450 mg to 600 mg, 500 mg to 700 mg, 800 mg to 1000 mg / day, 900 mg to 1400 mg, or 900 mg to 1200 mg.

33. 33. The method of any one of claims 1 to 32, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 1 to 32, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 1 to 32, wherein the patient is administered a daily dose in two doses within a 24 hour period starting from when the first dose is taken.

34. 34. The method of claim 33, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use of claim 33, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) of claim 33, wherein the two doses are administered simultaneously, separately or sequentially.

35. 35. The method of claim 33 or 34, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 33 or 34, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 33 or 34, wherein the second dose is administered 2 to 6 hours after the first dose, preferably about 3 to 6 hours after the first dose.

36. 35. The method of claim 33 or 34, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 33 or 34, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 33 or 34, wherein the second dose can be administered at least about 6 hours after the first dose.

37. 32. The method of any one of claims 1, 4 to 18 or 21 to 32, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 2, 4 to 17, 19 or 21 to 32, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 3 to 17 or 20 to 32, wherein the patient is administered the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) as a dose three times daily.

38. 38. The method of claim 37, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for the use of claim 37, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) of claim 36, wherein the three doses are administered simultaneously, separately or sequentially.

39. 39. The method of claim 37 or 38, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 37 or 38, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 37 or 38, wherein the second and third doses can be administered at least about 6 hours after the preceding dose.

40. 40. The method of any one of claims 30 to 39, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to any one of claims 30 to 39, or the use of a compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to any one of claims 30 to 39, wherein each dose comprises about 600 mg of the compound of formula A.

41. 41. The method of claim 40, the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) for use according to claim 40, or the use of the compound of formula A (or a pharmaceutically acceptable salt and / or solvate thereof) according to claim 40, wherein each dose is administered as two tablets each containing about 300 mg of the compound of formula A.

Images