Fitusiran for the Treatment of Hemophilia A and B

Abstract

The present disclosure provides methods of using fitusiran for treating patients with hemophilia A or hemophilia B.

Description

【Technical Field】 【0001】 Cross - reference to Related Applications This application claims priority from U.S. Patent Application No. 63 / 350,398 filed on June 8, 2022, U.S. Patent Application No. 63 / 359,695 filed on July 8, 2022, U.S. Patent Application No. 63 / 382,227 filed on November 3, 2022, U.S. Patent Application No. 63 / 386,491 filed on December 7, 2022, U.S. Patent Application No. 63 / 479,337 filed on January 10, 2023, U.S. Patent Application No. 63 / 483,700 filed on February 7, 2023, and U.S. Patent Application No. 63 / 489,611 filed on March 10, 2023. The contents of these priority applications are hereby incorporated by reference in their entirety. 【0002】 Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety. The XML copy (created on June 2, 2023) has the name 122548WO020.xml and a size of 8,023 bytes. 【Background Art】 【0003】 Hemophilia A and hemophilia B are X - linked recessive inherited bleeding disorders characterized by a deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), which cause profound defects in thrombin generation, impair the hemostatic function, and increase the risk of bleeding. Hemophilia A occurs in approximately 1 in 4,000 males, while hemophilia B occurs at a frequency of 1 in 5, or approximately 1 in 20,000 males. In hemophilia A and B, the disease phenotypes are similar. 【0004】 Hemophilia is classified as mild (factor level 6% - 30%), moderate (factor level 1% - 5%), or severe (factor level less than 1%) based on the coagulation factor activity compared to normal values (the factor levels in healthy, non-hemophilic plasma are 50% - 150%). Patients with mild hemophilia typically experience bleeding after severe injury or surgery. Patients with moderate hemophilia experience bleeding episodes related to trauma and may have spontaneous bleeding episodes. Patients with severe hemophilia experience substantial bleeding due to trauma and may have frequent spontaneous bleeding episodes, resulting in consumptive musculoskeletal damage that can significantly impair the patient's mobility and quality of life (QoL). 【0005】 Hemostatic systems aim to maintain vascular integrity by protecting against bleeding due to vascular lesions in combination with multiple options for preventing thrombosis. This hemostatic balance is achieved by the organized control of both procoagulant factors (e.g., factor V (FV), factor VII (FVII), FVIII, FIX, factor X (FX)) and anticoagulant factors (e.g., antithrombin, protein C / protein S, and tissue factor pathway inhibitor). Recent studies have suggested that the co-inheritance of deficiencies in natural anticoagulants may contribute to the mild phenotype in patients with hemophilia. 【0006】 Antithrombin (AT) is a naturally occurring anticoagulant expressed in the liver that plays an important role in the inhibition of thrombin. AT acts as an inhibitor of factor VIIa and factor Xa, which are typically present at normal levels in patients with hemophilia A or B. Reduction of AT has been described as a potentially safe and effective way to correct thrombin generation and control traumatic bleeding episodes in both microvessels and large vessels in extensive preclinical in vitro and in vivo studies. Therefore, suppression of AT production is being investigated as a potential treatment for hemophilia. 【0007】 Replacement with factor concentrates is the current standard of care for hemophilia patients who do not have inhibitory antibodies against FVIII or FIX. The current standard of care for factor replacement therapy, administered either incidentally or as routine prophylaxis, is well established, safe, and effective, but is associated with a high treatment burden due to the need for intravenous (IV) administration on a frequent schedule (more than 2 - 3 times per week) to maintain hemostasis prophylactically. Factor concentrates may also have limited availability in developing countries. In addition, patients receiving factor concentrates may develop inhibitory antibodies to the factor, resulting in a poor prognosis and the need for a change in the treatment regimen to infusion with bypassing agents (BPAs). 【0008】 Hemophilia patients who develop inhibitory antibodies to factor concentrates represent a distinct subset of the population, and these patients typically experience more difficult bleeding episodes and have increased morbidity and mortality. The development of inhibitors to infused factor mainly occurs in severe hemophilia and is more frequent in hemophilia A (up to 39% of patients) compared to hemophilia B (1% - 3.5% of patients), with the highest risk of occurrence on early exposure days. These "inhibitor" patients may be candidates for immune tolerance therapy, but in most cases, bleeding episodes require hemostatic intervention with BPAs (i.e., recombinant factor VIIa (rVIIa) or activated prothrombin complex concentrate (aPPC)) administered intravenously (IV) either prophylactically or as on - demand episode treatment of bleeding episodes. 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0009】 Therefore, there is still a need for alternative treatments for subjects with hemophilia, such as subcutaneous treatments, that can efficiently and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, such as those with inhibitors, while at the same time reducing the treatment burden, improving the clinical outcome, and enhancing the quality of life. 【Means for Solving the Problems】 【0010】 The present disclosure provides a method for prophylactically treating hemophilia A or B, with or without inhibitors, by fitusiran. The patients herein have already received different prophylaxis. In some embodiments, by this method, in human subjects with hemophilia A or B, with or without inhibitors, who are receiving prophylactic treatment with replacement factor or BPA, the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) are reduced, and / or patient-reported outcomes (e.g., quality of life) are improved. In some embodiments, this method includes administering a therapeutically effective amount of fitusiran subcutaneously to a human subject in need thereof, and terminating prophylactic replacement factor treatment or BPA treatment in the subject within about 2 months, within about 1 month, or optionally within about 28 or about 7 days of the first dose of fitusiran. In some embodiments, this method includes administering a therapeutically effective amount of fitusiran subcutaneously to a human subject in need thereof. In some embodiments, by this method, over a period of time, the annual weight-adjusted consumption of replacement factor or BPA in the patient, the total weight-adjusted dose of replacement factor / BPA in the patient, and the average consumption of replacement factor / BPA in the patient are reduced, and over a period of time, the number of injections of replacement factor / BPA required to treat breakthrough bleeding in the patient, or the number of breakthrough bleedings requiring treatment is reduced. 【0011】 Also provided herein are fitusiran for use in these treatment methods, the use of fitusiran in the manufacture of a medicament for treating hemophilia A or B, with or without inhibitors, by the methods herein, and a pharmaceutical composition comprising fitusiran for use in these treatment methods. 【0012】 Other features, objects, and advantages of the present invention will be apparent from the following detailed description. However, it should be understood that this detailed description shows embodiments and aspects of the present invention but is not limiting and is provided for illustrative purposes only. Various modifications and variations within the scope of the present invention will become apparent to those skilled in the art from this detailed description. 【Brief Description of the Drawings】 【0013】 【Figure 1】 Shows the expanded structural formula, chemical formula, and molecular weight of Fitsiran (sodium form). 【Figure 1-1】 Ibid. 【Figure 2】 Shows the clinical trial study design for patients who are prophylactically treated with a replacement factor or BPA prior to the initiation of Fitsiran treatment. AT: Antithrombin. For the subgroup of cohort A patients who are directly enrolled during the Fitsiran treatment period, see Figure 3. "a": The patient continues to receive prophylaxis with the prescribed factor or BPA for the first 7 days of the initiation period. "b": After the final Fitsiran dose, the AT activity level is monitored at monthly intervals after the final Fitsiran dose until the activity level returns to approximately 60% (by the central laboratory) or at the discretion of the principal investigator in consultation with the study medical monitor. 【Figure 3】 Shows the clinical trial study design for patients with hemophilia B who have inhibitory antibodies against factor IX and who have not responded appropriately to prophylactic treatment with BPA (past ABR ≥ 20) and thus are not currently receiving prophylactic treatment with BPA. This patient starts Fitsiran treatment directly without participating in the 6-month factor / BPA period described in Figure 2. "a": The patient receives prophylaxis with the prescribed factor or BPA for the first 7 days of the initiation period. "b": The same meaning as in Figure 2. 【Figure 4】 Shows the median ABR in patients prophylactically treated with Fitsiran or factor / BPA. 【Figure 5】Shows AjBR and AsBR in patients prophylactically treated with Fitsiran or Factor / BPA. 【Figure 6】 Shows the burden of health-related quality of life for all clinical trial patients 6 months before the start of the trial (i.e., at -6 months). 【Figure 6-1】 Ibid. 【Figure 7】 Shows the Haem-A-QoL score in patients prophylactically treated with Fitsiran or Factor / BPA. 【Figure 8】 Shows the converted Haem-A-QoL score in patients prophylactically treated with Fitsiran or Factor / BPA. 【Figure 9】 Shows the TSQM-9 score in patients prophylactically treated with Fitsiran or Factor / BPA. 【Figure 10】 Shows the TSQM-9 score in patients prophylactically treated with Fitsiran or Factor / BPA. 【Figure 11】 A chart showing the average AT level in patients treated with Fitsiran. 【Figure 12】 A chart showing the average change in peak thrombin generation (TG) in patients prophylactically treated with Fitsiran. 【Figure 13】 A bar graph showing bleeding events (median of observed ABR, AjBR, and AsBR) in youths enrolled in the clinical trial. 【Figure 14】 A bar graph showing the average change in the converted total score of Haemo-QoL from baseline in youths enrolled in the clinical trial. For prophylaxis with 80 mg of Fitsiran, n = 14. 【Figure 15】 A pre-trial survey on the impact of hemophilia and its treatment on patients. aPercentage based on 19 participants who received this question; bPercentage based on 22 participants who received this question; cPercentage based on 20 participants who received this question; dPercentage based on 18 participants who received this question; ePercentage based on 16 participants who received this question. 【Figure 16】It is a bar graph showing the degree and importance of improvement in patients prophylactically treated with Fitusiran. 【Figure 17】 It shows the participant satisfaction evaluation in patients prophylactically treated with Fitusiran. 【Mode for Carrying Out the Invention】 【0014】 The present disclosure features a method of using Fitusiran for routine prophylaxis to reduce the frequency of bleeding episodes in adult and adolescent (12 years and older) patients with hemophilia (e.g., hemophilia A (congenital factor VIII deficiency) or hemophilia B (congenital factor IX deficiency)) with or without an inhibitor. By this method, the frequency of total bleeding, including spontaneous bleeding and joint bleeding, is reduced compared to the frequency of bleeding in patients prophylactically treated with replacement factors or BPA instead of Fitusiran. By this method, the patient-reported outcomes (PRO) and quality of life (QoL) are also improved compared to the PRO and QoL in patients prophylactically treated with replacement factors or BPA. 【0015】 In some embodiments, the patient is an adolescent patient (i.e., a patient between 12 and 17 years old, including 12 and 17 years old). Adolescence is accompanied by significant physical, psychological, and social changes. Hemophilia can present additional challenges to adolescents because they may be prevented from experiencing the same social and physically active lifestyle as their peers (see, for example, Hoefnagels et al., Patient Prefer Adherence (2020) 14:163-71). 【0016】 A patient with hemophilia A or B who has an inhibitor refers to a patient in whom an alloantibody has developed against a factor that the patient has previously received (e.g., factor VIII in the case of a hemophilia A patient or factor IX in the case of a hemophilia B patient). A patient with hemophilia A or B who has an inhibitor may become refractory to coagulation factor replacement therapy. A patient who does not have an inhibitor refers to a patient who does not have such an alloantibody. The present treatment method may be beneficial for hemophilia A patients who have an inhibitor and hemophilia B patients who have an inhibitor. As used herein, "hemophilia A or B with inhibitor" refers to hemophilia A with inhibitor or hemophilia B with inhibitor. As used herein, a patient refers to a human patient. 【0017】 Part of the present invention is based on the finding that patients prophylactically treated with fitusiran have improved outcomes (e.g., reduced bleeding rates and improved quality of life) when compared to patients receiving standard prophylactic treatment (replacement factor or BPA). The clinical trial protocols and results disclosed herein are the first direct comparison of these two treatment regimens in hemophilia A and B patients with or without inhibitors. 【0018】 In some embodiments, the mechanism of action and formulation of fitusiran enable consistent protection from bleeding with as few as 6 - 12 subcutaneous injections per year. As a subcutaneous drug, fitusiran has the advantages of reduced administration time, reduced pain due to smaller needle size and volume, and reduced equipment and training requirements compared to intravenous drugs. The reduction in bleeding with fitusiran prophylaxis and the overall reduction in treatment and disease burden can improve the quality of life of hemophilia patients. 【0019】 I. Fitusiran Pharmaceutical Composition Hemophilia results in a severe deficiency in thrombin generation, and furthermore, the severity of hemophilia correlates with the inability to generate thrombin. Without being bound by theory, it is thought that a reduction in fitusiran-mediated antithrombin (AT) levels increases thrombin generation and thus improves hemostasis in patients with hemophilia. Antithrombin is encoded by the SERPINC1 gene. 【0020】 Fitusiran (the structure of which is described herein) is a synthetically chemically modified double-stranded small interfering RNA (siRNA) oligonucleotide that covalently binds to a tri-antennary N-acetyl-galactosamine (GalNAc) ligand that targets AT3 mRNA in the liver, thereby suppressing the synthesis of antithrombin. The nucleosides in each strand of fitusiran are linked by either 3'-5' phosphodiester or phosphorothioate bonds, thus forming the sugar-phosphate backbone of the oligonucleotide. 【0021】 The sense and antisense strands of fitusiran each contain 21 and 23 nucleotides, respectively. The 3' end of the sense strand is conjugated to the GalNAc-containing moiety (also called L96) via a phosphodiester bond. The sense strand contains two consecutive phosphorothioate bonds at its 5' end. The antisense strand contains four phosphorothioate bonds (two at the 3' end and two at the 5' end). The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs and a 2-base overhang at the 3' end of the antisense strand. See also U.S. Patent Nos. 9,127,274, 11,091,759, and International Publication No. WO 2019 / 014187. 【0022】 The two nucleotide strands of fitusiran are shown below: Sense strand: 5’ Gf-ps-Gm-ps-Uf-Um-Af-Am-Cf-Am-Cf-Cf-Af-Um-Uf-Um-Af-Cm-Uf-Um-Cf-Am-Af-L96 3’ (SEQ ID NO: 1), and Antisense strand: 5’ Um-ps-Uf-ps-Gm-Af-Am-Gf-Um-Af-Am-Af-Um-Gm-Gm-Uf-Gm-Uf-Um-Af-Am-Cf-Cm-ps-Am-ps-Gm 3’ (SEQ ID NO: 2), wherein, Af = 2’-fluoroadenosine (i.e., 2’-deoxy-2’-fluoroadenosine) Cf = 2’-fluorocytidine (i.e., 2’-deoxy-2’-fluorocytidine) Gf = 2’-fluoroguanosine (i.e., 2’-deoxy-2’-fluoroguanosine) Uf = 2’-fluorouridine (i.e., 2’-deoxy-2’-fluorouridine) Am = 2’-O-methyladenosine Cm = 2’-O-methylcytidine Gm = 2’-O-methylguanosine Um = 2’-O-methyluridine “-” (hyphen) = 3’-5’ phosphodiester bond sodium salt “-ps-” = 3’-5’ phosphorothioate bond sodium salt, and L96 has the following formula: 【Chemical formula】 has. 【0023】 The expanded structural formula, molecular formula, and molecular weight of ficicilane (sodium form) are shown in Figure 1. As used herein, the term 2'-fluoroadenosine is used synonymously with the term 2'-deoxy-2'-fluoroadenosine, the term 2'-fluorocytidine is used synonymously with the term 2'-deoxy-2'-fluorocytidine, the term 2'-fluoroguanosine is used synonymously with the term 2'-deoxy-2'-fluoroguanosine, and the term 2'-fluorouridine is used synonymously with the term 2'-deoxy-2'-fluorouridine. 【0024】 The structure of ficicilane is also shown in the following figure: [Chemical formula] (wherein X is O) can also be used for explanation. 【0025】 For use in the present treatment method, ficicilane may be provided as a pharmaceutical composition comprising ficicilane and a pharmaceutically acceptable excipient. In certain embodiments, ficicilane is in the form of a sodium salt. 【0026】 In some embodiments, ficicilane is provided as an aqueous solution at a concentration of about 1 to about 200 mg / mL (e.g., about 50 to about 150 mg / mL, about 80 to about 110 mg / mL, or about 90 to about 110 mg / mL). As used herein, intermediate values within the recited ranges and values are also intended to be part of the present disclosure. Additionally, ranges of values using any combination of the recited values as the upper and / or lower limits are intended to be included. In further embodiments, the pharmaceutical composition comprises ficicilane at a concentration of about 6.25, about 12.5, about 25, about 50, about 75, about 100, about 125, about 150, or about 200 mg / mL. 【0027】 Unless otherwise indicated, even if ficiran is subcutaneously injected into a patient in its sodium form (in aqueous solution), the ficiran weights recited in the present disclosure are the weights of ficiran free acid (the active moiety). For example, 100 mg / mL of ficiran means 100 mg of ficiran free acid per 1 mL (equivalent to 106 mg of ficiran sodium drug substance). 【0028】 In some embodiments, the pharmaceutical composition comprises ficiran in phosphate buffered saline. The phosphate concentration in the solution can be about 1 to about 10 mM (e.g., 2, 3, 4, 5, 6, 7, 8, or about 9 mM) at a pH of 6.0 - 8.0. The pharmaceutical compositions herein can include a preservative such as EDTA. Alternatively, the pharmaceutical composition can be preservative-free. In certain embodiments, the ficiran pharmaceutical composition is preservative-free and comprises, consists of, or consists essentially of about 100 mg of ficiran per 1 mL of 5 mM phosphate buffered saline (PBS) solution. This PBS solution is composed of sodium chloride, disodium phosphate (heptahydrate), and monosodium phosphate (monohydrate). The pH of this composition can be adjusted to 7.0 using sodium hydroxide solution and dilute phosphoric acid. 【0029】 The pharmaceutical composition can be provided in a container (e.g., a vial or a syringe). This container can contain a single dose or multiple doses. In some embodiments, the container is a disposable container (e.g., a disposable ampoule or a disposable syringe, e.g., a disposable pre-filled syringe), and each container contains about 10 to about 100 mg of ficitsiran (e.g., about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, or about 80 mg). Ficitsiran is provided in solid form in this container and may be reconstituted in an aqueous solution (e.g., PBS) before use, and the reconstituted solution contains about 1 to about 150 mg / mL (e.g., about 100 mg / mL) of ficitsiran. In some embodiments, ficitsiran is provided in sodium salt form in a disposable glass vial or a disposable pre-filled syringe (e.g., one having a safety system). In further embodiments, each vial or syringe contains about 80 mg of ficitsiran (or about 50 mg of ficitsiran in about 0.5 mL, about 20 mg of ficitsiran in about 0.2 mL, or about 10 mg of ficitsiran in about 0.1 mL) in about 0.8 mL of 5 mM phosphate buffered saline aqueous solution (pH 7.0), and this solution is administered to a patient by subcutaneous injection. This solution can be stored at 2 to 30 °C (e.g., 2 to 8 °C). 【0030】 In certain embodiments, the ficitsiran composition for subcutaneous injection contains ficitsiran in 5 mM phosphate buffered saline at pH 7.0 containing 0.64 mM NaH2PO4, 4.36 mM Na2HPO4, and 84 mM NaCl. In certain specific embodiments, the composition of the ficitsiran solution for subcutaneous injection is shown in Table 1 below. 【0031】 【Table 1】 【0032】 The Ficiran dosage described herein refers to the weight of Ficiran free acid (the active moiety), but administration of Ficiran to a patient herein refers to administration of sodium Ficiran (the drug substance) provided in a pharmaceutically suitable aqueous solution (e.g., phosphate buffered saline at physiological pH). 【0033】 II. Therapeutic Use of Ficiran Ficiran can suppress the hepatic production of antithrombin (AT). In its role as an anticoagulant, AT regulates hemostasis by directly targeting thrombin production or by forming a complex and inactivating uncomplexed FXa, which in turn reduces thrombin production to regulate hemostasis (Quinsey et al., Int J Biochem Cell Biol. (2004) 36(3):386 - 9). Ficiran can be used to treat individuals with a hemostasis disorder. For example, Ficiran can be used to treat patients with hemophilia A or B, with or without inhibitors, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In certain embodiments, Ficiran is used to treat adult and adolescent patients (12 years and older) with hemophilia A or B (congenital factor VIII deficiency or congenital factor IX deficiency), with or without inhibitors. The method includes administering a therapeutically effective amount of Ficiran to a hemophilia patient in need thereof (e.g., a patient with hemophilia A or B). A "therapeutically effective amount" refers to the amount of Ficiran that aids the patient in achieving the desired clinical endpoints. 【0034】 In some embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 50 mg per dose every about two months (or every about eight weeks). In other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 50 mg approximately monthly (or every about four weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 80 mg every about two months (or every about eight weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 80 mg approximately monthly (or every about four weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 20 mg every about two months (or every about eight weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 20 mg approximately monthly (or every about four weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 10 mg approximately monthly (or every about four weeks). 【0035】 III. Administration of Fitusiran Pharmaceutical Composition The fitusiran pharmaceutical composition can be administered by any means known in the art (e.g., but not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, or portal vein administration). In certain embodiments, the pharmaceutical composition is administered by subcutaneous injection at a dose strength of about 10 to about 100 mg per dose (e.g., about 10 to about 95 mg, about 40 to about 90 mg, about 50 to about 100 mg, about 50 to about 90 mg, about 50 to about 85 mg, or about 50 to about 80 mg). In specific embodiments, fitusiran is administered subcutaneously in the above-described PBS solution at about 10, about 20, about 50, or about 80 mg (weight of the active moiety) per dose. 【0036】 Multiple doses of fitusiran can be administered to a subject at intervals of about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, or about 3 months. In certain embodiments, a fixed dose of fitusiran (e.g., a subcutaneous injection of about 50 or about 80 mg) is administered once every about 4 weeks or once every about 1 month, or once every about 8 weeks or once every about 2 months, to a hemophilia patient (e.g., a hemophilia A or hemophilia B patient 12 years of age or older with or without inhibitor expression). 【0037】 In some embodiments, the pharmaceutical composition can be administered in combination with other pharmaceuticals and / or other treatment methods (e.g., those currently employed for treating bleeding disorders). For example, in certain embodiments, fitusiran is administered in combination with a second agent useful in the treatment of hemophilia A and / or B. Examples of such second agents are as follows: fresh frozen plasma (FFP); rFVIIa; aPCC; recombinant or plasma-derived FVIII or FIX; virus-inactivated vWF-containing FVIII concentrate; desensitization therapy that may include large amounts of FVIII or FIX in combination with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide; plasma exchange therapy combined with immunosuppression and infusion of FVIII or FIX, with or without antifibrinolytic therapy; immune tolerance induction (ITI) regardless of the presence or absence of immunosuppressive therapy (e.g., cyclophosphamide, prednisone, and / or anti-CD20); desmopressin acetate (DDAVP); antifibrinolytic agents such as aminocaproic acid and tranexamic acid; antihemophilic agents; corticosteroids; immunosuppressive agents; and estrogens. The fitusiran composition, as well as additional therapeutic agents and / or treatments, can be administered simultaneously and / or in the same combination, e.g., parenterally, or the additional therapeutic agents can be administered as part of separate compositions or at separate times, and / or by another method known in the art or described herein. 【0038】 IV. Treatment with Replacement Factor or BPA The standard treatment for treating hemophilia A and B is the daily prophylactic use of replacement factors or bypassing agents (BPA). In some embodiments, patients treated with current treatment methods have already received prophylactic treatment with factors or bypassing agents. Patients receiving prophylactic treatment with replacement factors or BPA are treated as described in Table 2. Factors and bypassing agents are administered intravenously. 【0039】 【Table 2】 【0040】 In some embodiments, hemophilia patients who carry inhibitors (e.g., hemophilia B patients who carry inhibitors) do not respond appropriately to prophylactic treatment with BPA and thus are not prophylactically treated with BPA. 【0041】 In some embodiments of the present invention, patients prophylactically treated with fitusiran have already been prophylactically treated with replacement factors or BPA. The first 28 days of fitusiran treatment is referred to as the initiation period. During this initiation period, the AT reduction progresses towards the therapeutic level. During this initiation period, the patient continues prophylaxis with factors or BPA at the minimum frequency in Table 2 for the first 7 days. After the 7th day of the fitusiran treatment period, the factor concentrate or BPA is administered only for bleeding episodes or as needed before invasive medical procedures. 【0042】 Recommendations for bleeding episode management During the prophylaxis period with factors or bypassing agents: The bleeding management therapy with factors or BPA is managed based on the local standard practice for treating hemophilia patients. 【0043】 During the Ficiran treatment period: Considering the mechanism of action and pharmacodynamic profile of Ficiran, the factors or the dose of BPA necessary to safely and effectively treat breakthrough bleeding episodes in patients receiving Ficiran during the Ficiran treatment period are lower compared to those that are standardly prescribed. After the administration of Ficiran, the AT reduction progresses towards the therapeutic level. Immediately after 7 days of the first Ficiran dose, the majority of patients have a residual activity of AT levels below 60%. By 14 days after administration, 94% of patients are expected to have a 50% ultra-low reduction of AT, with a median of 66.8%. Based on these AT kinetics, patients are recommended to continue the standard factor or BPA regimen for this patient for the first few days after the start of Ficiran administration and, starting from the 8th day onwards, initiate protocol-specific bleeding management guidelines with reduced factor or BPA (Table 3). 【0044】 【Table 3】 【0045】 Importantly, after the 7th day of the Ficiran treatment period, patients do not use factors, BPA, or other hemostatic agents as prophylaxis for the prevention of bleeding episodes, including doses related to the expected difficulty of hemostasis such as physical activity. 【0046】 Days 1 to 7 of the Ficiran treatment period: Patients continue the standard factor or BPA regimen for this patient. 【0047】 After the 8th day of the Ficiran treatment period: If a patient experiences symptoms that may coincide with a bleeding episode, follow the steps below: - Administer a single dose according to the guidelines in Table 3. - Instruct the patient to re-evaluate the symptoms at 24 hours for bleeding treated with FVIII, FIX, or aPCC and at 2 - 3 hours for bleeding treated with rFVIIa. a. The administration of FIX with an extended half-life is not as frequent as compared to every 5 - 7 days. - Do not administer the dosage at intervals of less than 24 hours (except for rFVIIa as shown in Table 3). - The dosage does not exceed the protocol maximum recommended dosage shown in Table 3. - Do not use antifibrinolytics in combination with factors or BPA. 【0048】 Consumption of factors / BPA in patients prophylactically treated with fitusiran In some embodiments, the treatment method reduces the consumption of replacement factors / BPA in a patient, such as the annual body weight-adjusted consumption of replacement factors / BPA in a patient. In some embodiments, the treatment method reduces the annual body weight-adjusted consumption of aPCC for the treatment of bleeding by about 98.9%; reduces the annual body weight-adjusted consumption of rFVIIa for the treatment of bleeding by about 96.8%; reduces the annual body weight-adjusted consumption of FVIII for the treatment of bleeding by about 79.4%; and / or reduces the annual body weight-adjusted consumption of FIX for the treatment of bleeding by 93.8%. 【0049】 In some embodiments, the treatment method reduces the number of breakthrough bleedings treated in a patient. In some embodiments, the treatment method reduces the total body weight-adjusted dosage of replacement factors / BPA, the average consumption of replacement factors / BPA, or the number of injections of replacement factors / BPA required to treat breakthrough bleeding in a patient. The treatment method can reduce the number of patients who require replacement factors / BPA for the treatment of breakthrough bleeding. 【0050】 V. Patient selection This treatment can be used to prophylactically treat patients with hemophilia A or hemophilia B. In some embodiments, the patient is a male 12 years of age or older with severe hemophilia A or B. The diagnosis of severe hemophilia is based on a factor VIII level of less than 1% (in the case of hemophilia A) or a factor IX level of 2% or less (in the case of hemophilia B). In some embodiments, the patient has been managing bleeding episodes for at least 6 months prior to the start of treatment using replacement factors or bypass agents prophylactically. 【0051】 In some embodiments, the patient has an inhibitory antibody against factor VIII or factor IX (i.e., is a patient with an inhibitor). A patient is defined as a patient with an inhibitor if they meet at least one of the following Nijmegen modified Bethesda assay result criteria: a. The pre-treatment inhibitor titer is 0.6 BU / mL or higher, or b. The pre-treatment inhibitor titer is less than 0.6 BU / mL and there is evidence in the medical record of two consecutive titers being 0.6 BU / mL or higher, or c. The pre-treatment inhibitor titer is less than 0.6 BU / mL and there is evidence in the medical record of a previous reaction. 【0052】 In some embodiments, the patient does not have an inhibitory antibody against factor VIII or factor IX (i.e., is a patient without an inhibitor). A patient is defined as a patient without an inhibitor if they meet at least one of the following Nijmegen modified Bethesda assay result criteria: a. The pre-treatment inhibitor titer of the Nijmegen modified Bethesda assay is less than 0.6 BU / mL, b. Bypass agents have not been used to treat bleeding episodes for at least the past six months prior to treatment, and c. There is no history of immune tolerance induction therapy within the past three years prior to treatment. 【0053】 In some embodiments, the patient has an inhibitory antibody against factor VIII or factor IX (cohort A) and has experienced at least two bleeding episodes requiring BPA treatment within at least six months prior to treatment. In some embodiments, the patient has an inhibitory antibody against factor VIII or factor IX but has not been prophylactically treated with bypass agents. In some embodiments, the patient has hemophilia B with an inhibitory antibody against factor IX as defined above and does not respond appropriately to BPA treatment prior to fitusiran treatment (previous ABR ≥ 20). 【0054】 In some embodiments, the patient does not have an inhibitory antibody against factor VIII or factor IX (cohort B) and has experienced at least one bleeding episode requiring factor treatment within at least 12 months prior to treatment. 【0055】 In some embodiments, the patient has received (and been compliant with) prophylactic treatment for hemophilia with factor concentrates or BPA for at least 6 months prior to treatment. The prophylactic treatment regimen must be consistent with the approved prescribing information for the product or local recommendations (adjustments for individual patient response are possible) and must be designed to reduce spontaneous bleeding. 【0056】 In some embodiments, the patient does not have a known co-existing bleeding disorder other than hemophilia A or B (i.e., von Willebrand disease, additional factor deficiencies, or platelet disorders). In some embodiments, the patient is not currently participating in immune tolerance induction therapy (ITI). The patient's AT activity may be less than 60% prior to treatment. In some embodiments, the patient does not have clinically significant liver disease as indicated by (i) INR > 1.2; ALT and / or AST > 1.5 x the upper limit of the normal reference range (ULN); (ii) total bilirubin > ULN (> 1.5 x ULN in patients with Dubin-Johnson syndrome); (iii) a history of portal hypertension, esophageal varices, or hepatic encephalopathy; or (iv) the presence of ascites on physical examination. 【0057】 In some embodiments, the patient is not positive for hepatitis C virus antibody. A patient positive for hepatitis C virus antibody may be treated by this method only if the patient has: a. completed a curative treatment at least 12 weeks prior to enrollment and achieved a sustained virological response as demonstrated by negative HCV RNA prior to treatment or the infection has been spontaneously cleared as demonstrated by negative HCV RNA prior to treatment, and b. Absence of evidence of cirrhosis as determined by FibroScan (if available) of less than 12.5 kPa, or a FibroTest score of less than 0.75, and an APRI of less than 2 (if FibroScan is not available). 【0058】 In some embodiments, the patient does not have acute hepatitis, i.e., does not have hepatitis A or hepatitis E. In some embodiments, the patient does not have acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or HBsAg positive). In some embodiments, the patient is not HIV positive with (i) a platelet count of not less than 100,000 cells / μL, (ii) a CD4 count of less than 200 cells / μL, and / or (iii) an estimated glomerular filtration rate of not less than 45 mL / min / 1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] formula). 【0059】 The patient may not have a coexisting thrombotic disorder as determined by the presence of any of the following: a. FV Leiden mutation (homozygous or heterozygous), b. Protein S deficiency, c. Protein C deficiency, or d. Prothrombin mutation (G20210A; homozygous and heterozygous). 【0060】 In some embodiments, the patient does not have a history of antiphospholipid antibody syndrome, or arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. A patient who has experienced thrombosis related to an indwelling venous access can be treated by this method. In some embodiments, the patient does not have a malignancy within two years, except for a successfully treated basal cell carcinoma or squamous cell carcinoma of the skin. 【0061】 In some embodiments, the patient meets one or more of the inclusion criteria detailed in Example 1 below and one or more of the exclusion criteria. 【0062】 VI. Treatment Outcome and Evaluation In some embodiments, the patient is treated with fitusiran over a period of 7 months. 【0063】 In some embodiments, the present treatment method reduces the frequency of bleeding episodes in the patient. A bleeding episode is defined as any occurrence of bleeding (e.g., joint bleeding, muscle bleeding, or mucosal bleeding) that requires infusion of replacement factor or BPA. The definitions of bleeding episode types described below are based on the consensus of the International Society on Thrombosis and Haemostasis (ISTH) (Blanchette et al., J Thromb Haemost. (2014) 12(11):1935 - 9). 【0064】 Define the start time of a bleeding episode as the time when the symptoms of the bleeding episode first appear. Any symptoms of bleeding at this location that occur within 72 hours of the bleeding or of the last injection used to treat a bleeding episode at the same location are considered part of the original bleeding event and counted as one bleeding episode for the ABR. Any bleeding symptoms that start more than 72 hours after the last injection used to treat a bleeding episode at this location constitute a new bleeding event. 【0065】 In some embodiments, the present treatment method reduces the estimated annual bleeding rate (ABR) in the treated population by 50% or more (e.g., 60% or more reduction) compared to the population prophylactically treated with replacement factor or BPA. In some embodiments, the median ABR observed in the population treated with fitusiran is reduced to 1 or less, e.g., reduced to zero. In some embodiments, the past ABR of the human subject is greater than 1 (i.e., greater than 2, 3, 4, 5, 6, or 7). 【0066】 A spontaneous bleeding episode refers to a bleeding event that occurs in joints, muscles, and soft tissues without any obvious or known reason. An articular bleeding episode is characterized by 1) swelling of the skin over the joint or increased warmth, 2) increased pain, or 3) abnormal sensation ("warning sign") in the joint combined with progressive loss of range of motion or difficulty in using the limb compared to the baseline. Muscle bleeding may be characterized by pain, swelling, and loss of movement in the affected muscle group. A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred in a single joint within a continuous six - month period. If there are two or fewer bleeding episodes in a joint within a continuous twelve - month period, this joint is no longer considered a target joint. A traumatic bleeding episode is an episode caused by a known injury or trauma. Prolonged bleeding episodes during sports and recreation are counted as traumatic bleeding episodes. 【0067】 In some embodiments, by the present treatment method, the estimated annual spontaneous bleeding rate (AsBR) in the treated population is reduced by 40% or more (e.g., 50% or more) compared to the population prophylactically treated with replacement factors or BPA. In some embodiments, the median AsBR observed in the population treated with fitusiran is reduced to 1 or less, e.g., reduced to zero. In some embodiments, the past AsBR of the human subject exceeds 2. 【0068】 In some embodiments, by the present treatment method, the estimated annual joint bleeding rate (AJBR) in the treated population is reduced by 40% or more (e.g., 50% or more) compared to the population prophylactically treated with replacement factors or BPA. In some embodiments, the median annual joint bleeding rate observed in the population treated with fitusiran is reduced to 1 or less, e.g., reduced to zero. In some embodiments, the past AJBR of the human subject exceeds 2. 【0069】 In some embodiments, as further described below, the patient-reported outcome (PRO) is improved by the present treatment method. In some embodiments, the effectiveness of this treatment is measured by a reduction in disease severity as evaluated by the patient based on a valid and reliable hemophilia-specific PRO instrument (e.g., the Haemophilia Quality of Life Questionnaire for Adults (“Haem-A-QoL”; von Mackensen et al., Haematologica (2005) 90(s2):115-6, Abstract 0290; Wyrwich et al., Haemophilia (2015) 21(5):578-84). For example, any positive change resulting in a decrease in disease severity measured using an appropriate scale represents an appropriate treatment using the pharmaceutical composition described herein. 【0070】 Hemophilia directly affects a patient's health-related quality of life (HRQoL) through its associated symptoms, functional limitations, and treatment burden. Improvement of HRQoL is an important aspect of hemophilia disease management. The present method improves a patient's HRQoL as determined by a well-designed detailed questionnaire. For example, the HRQoL in adult patients (17 years or older, such as 18 years or older) can be measured by the Haem-A-QoL questionnaire. In certain embodiments, the HRQoL of adult patients can be measured by the score of Haem-A-QoL. See, for example, von Mackensen et al., Value in Health. (2005) 8(6):A127; von Mackensen et al., J Thrombosis and Haemostasis. (2005) 3(Sup1):P0813; von Mackensen and Gringeri, “Quality of Life in Hemophilia” In: Handbook of Disease Burdens and Quality of Life Measures. Heidelberg: Springer; 2009, pp.1910-1; and Bullinger et al., Value in Health. (2009) 12(5):808-20; see also Wyrwich, supra. The Haem-A-QoL questionnaire includes 46 items contributing to 10 domains, including physical health (5 items), emotions (4 items), view of self (5 items), sports and leisure (5 items), work and school (4 items), coping with hemophilia (3 items), treatment (8 items), future (5 items), family planning (4 items), and partnership and sexuality (3 items). 【0071】 All Haem-A-QoL items are measured on a 5-point frequency scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, and 5 = always). When a question does not apply to a participant, a "not applicable" response option is also possible for the domains of "Sports & Leisure", "Work & School", and "Family Planning". The "Total Score" is also used to represent the mean of all 10 domains of the Haem-A-QoL questionnaire. The Haem-A-QoL domain scores and total score are converted to a scale of 0 - 100, with higher scores indicating greater dysfunction. A reduction in score relative to the corresponding baseline score (score before the treatment being evaluated) indicates an improvement in the patient's quality of life. This questionnaire can be obtained before and after treatment with one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more) doses of fitusiran (e.g., administered subcutaneously at about 50 mg or about 80 mg once every about 4 weeks or once a month). For example, this questionnaire can be obtained at weeks 8, 12, 16, 20, 24, 25, 26, or 27 after the start of fitusiran treatment. 【0072】 In some embodiments, the treatment improves the patient's quality of life in one or more of the QoL domains (e.g., QoL domains specific to hemophilia). These QoL domains include, for example, domains related to physical health, emotions, self-perception, sports and leisure, work and school, coping with hemophilia, treatment, future, family planning, and / or partnership and sexuality. Improvements in these domains can be evaluated by patient-reported outcomes (PROs) and can be aided by a questionnaire. For example, improvements in these domains can be reported by the patient to their physician and / or scored by a QoL questionnaire. 【0073】 In some embodiments, the present treatment results in an improvement in the score in at least one of the Haem-A-QoL domains (e.g., physical health, emotions, self-perception, sports and leisure, work and school, coping with hemophilia, treatment, future, family planning, and / or partnership and sexuality) from baseline, and / or the Haem-A-QoL total score is improved compared to the score in patients prophylactically treated with replacement factor or BPA. In particular, the present method can improve the quality of life of hemophilia patients, including improvement (e.g., reduction and disappearance) of hemophilia-related symptoms reported by patients (e.g., swelling with pain and joint pain) and physical function (e.g., pain with movement and difficulty walking long distances), as determined by the physical health score and / or total score of Haem-A-QoL. 【0074】 In some embodiments, the present treatment method improves the patient-reported outcome (PRO) or improves the quality of life (QoL). In some embodiments, this improvement is measured using the Hemophilia Quality of Life Questionnaire (Haem-A-QoL) for adults. In some embodiments, the present treatment method reduces the total score or the physical health domain score of the Haem-A-QoL questionnaire by at least 2 units (e.g., at least 3 units or at least 4 units) reduction in prophylaxis patients with fitusiran compared to prophylactically treated BPA or factor patients. 【0075】 The EQ-5D-5L is a standardized disease generic instrument for use as a measure of QoL outcome. It consists of a questionnaire regarding five dimensions (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). The scoring of this questionnaire is based on a five-level disability (none, mild, moderate, severe, or extreme). A higher score indicates a better health state. See also, e.g., Herdman et al., Qual Life Res (2011) 20(10):1727-36. 【0076】 This Fitzalan therapy improves the score from at least one of the EQ-5D-5L dimensions (e.g., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression) as compared to prophylactically treated BPA or factor patients. In some embodiments, one or more of the five dimension scores or the total score in EQ-5D-5L increases by a unit of 0.01 or more (e.g., a unit of 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, 0.09 or more, 0.10 or more, 0.11 or more, 0.12 or more, 0.13 or more, 0.14 or more, 0.15 or more, 0.16 or more, 0.17 or more, 0.18 or more, 0.19 or more, or 0.20 or more). 【0077】 This method improves patient satisfaction with treatment as determined by a well-designed detailed questionnaire such as the Treatment Satisfaction Questionnaire for Medication (TSQM-9). The TSQM-9 is a validated psychometric tool that provides a general measure of patient satisfaction with pharmacotherapy. See, e.g., Atkinson et al., Health Qual Life Outcomes (2004) 2:12, and Bharmal et al., Health Qual Life Outcomes (2009) 7:36. The TSQM-9 questionnaire includes nine items that contribute to three domains including effectiveness, convenience, and overall satisfaction. The TSQM-9 domain scores range from 0 to 100, and the higher the score, the better the HRQoL. An increase in the score relative to the corresponding baseline score (the score before the treatment being evaluated) indicates an improvement in patient satisfaction with the treatment. The EQ-5D-5L and TSQM-9 surveys are performed on patients 18 years of age or older. 【0078】 This fitusiran therapy improves scores from at least one of the TSQM-9 domains (i.e., effectiveness, convenience, and overall satisfaction) compared to prophylactically treated BPA or factor patients. In particular, this method can improve the treatment satisfaction of hemophilia patients. In some embodiments, one or more of the three domain scores in TSQM-9 (i.e., effectiveness, convenience, and satisfaction) increase by 1 or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units). 【0079】 This fitusiran treatment improves scores from at least one of the HAL or domains (i.e., lying / sitting / crouching / standing, leg function, arm function, use of transportation, self-care, housework, leisure activities and sports, basic lower limb activities, upper limb activities, and complex lower limb activities) compared to prophylactically treated BPA or factor patients. In particular, this method can improve the subjective functional ability to perform activities of daily life in hemophilia patients. In some embodiments, one or more of the domain scores in HAL increase by 1 or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units). In certain embodiments, this treatment method results in an improvement indicated by an increase of 0.2 or more units (optionally, 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, or 0.7 or more units) in the total score of HAL. 【0080】 The HRQoL in adolescent patients (12 years and older to 17 years) can be measured, for example, by the Haemo-QoL (Haemophilia Quality of Life questionnaire for teenagers) (see, for example, Bullinger et al., Value Health (2009) 12(5):808-20; and Remor, Int J Behav Med (2013) 20(4):609-17). Haemo-QoL is a shortened version of Haem-A-QoL, which is specifically used for children and adolescents in the age group II / III (8 - 16 years). The Haemo-QoL survey has nine domains including physical health, emotions, self-perception, coping with haemophilia, treatment, family, friends, others, and sports. The "total score" is also used to represent the average of all nine domains of the Haemo-QoL questionnaire. The scoring of the Haemo-QoL instrument follows the same method as described above for the Haem-A-QoL technique. In some embodiments, the fitusiran therapy results in a decrease of one or more of the nine domain scores (e.g., physical health domain score or total score) in Haemo-QoL by one or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units). 【0081】 For all of the above-described questionnaires, the questionnaire can be obtained before and after treatment with one or more doses (e.g., 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more doses) of fitusiran (e.g., administered subcutaneously at about 4 weeks intervals or about once a month, or at about 8 weeks intervals or about once every 2 months, at about 10, about 20, about 50, or about 80 mg). For example, the questionnaire can be obtained at 8, 12, 16, 20, 24, 28, 32, 35, 36, 37, or 38 weeks after the start of fitusiran treatment. 【0082】 According to the International Conference on Harmonisation (ICH) E2A guideline Definitions and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, IND Safety Reporting, an adverse event (AE) is any harmful medical event in a patient or clinical trial subject administered a pharmaceutical product, which is not necessarily causally related to this treatment. Since bleeding episodes are recorded as an efficacy evaluation of ficlatuzan, these are not treated as AEs unless they meet any of the severe adverse event (SAE) criteria listed below. 【0083】 An SAE is at any dose, i. Results in death, ii. Is life-threatening (an event that exposes the patient to an immediate risk of death. Events occurring in a more severe form that have the potential to cause death are not included), iii. Requires hospitalization of an inpatient or prolongation of an existing hospitalization, iv. Results in persistent or significant disability or incapacity, v. Is a congenital anomaly or congenital defect, or vi. Is an important medical event that does not immediately threaten life or result in death or hospitalization, but may place the patient at risk and may require intervention to prevent one of the other outcomes listed in the above definition (e.g., events such as allergic bronchospasm, blood disorders, convulsions, or the onset of drug dependence or abuse that require intensive treatment in the emergency room or at home). Any harmful medical event. 【0084】 VII. Manufactured Products and Kits The present invention also provides a kit comprising a pharmaceutical composition for use in the present treatment method. Such a kit includes one or more vials or one or more pre-filled syringes containing the pharmaceutical composition of the present invention, and instructions for use (for example, instructions for administering a therapeutically effective amount of ficiran). The kit may optionally further include means for administering ficiran (for example, an injection device), or means for measuring the inhibition of SERPINC1 (for example, means for measuring the inhibition of SERPINC1 mRNA, the expression of the protein encoded by SERPINC1, and / or SERPINC1 activity). Such means for measuring the inhibition of SERPINC1 may include, for example, means for obtaining a sample from a subject such as a plasma sample. The kit of the present invention may optionally further include means for determining a therapeutically effective amount or a prophylactically effective amount. 【0085】 Additional definitions of terms and exemplary embodiments are described in the examples and are incorporated herein by reference. 【0086】 Unless otherwise defined in this specification, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, but methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present disclosure. In case of conflict, this specification, including definitions, will control. In general, the nomenclature and techniques used in connection with hematology, medicine, pharmaceuticals and pharmaceutical chemistry, and cell biology as described herein are those known and commonly used in the art. Further, unless the context requires otherwise, singular terms shall include the plural, and plural terms shall include the singular. All publications and other references mentioned herein are incorporated by reference in their entirety. Although many references are cited herein, this citation does not constitute an admission that any of these references forms part of the common general knowledge in the art. As used herein, the term "about" or "approximately" when applied to one or more values of interest refers to a value similar to the recited reference value. In certain embodiments, this term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the recited reference value in either direction (greater than or less than) unless otherwise stated or apparent from the context. 【0087】 According to the present disclosure, a back-reference in a dependent claim means a shorthand notation for the direct and explicit disclosure of any and all combinations of the claims indicated by this back-reference. Further, the headings of this specification are provided for ease of organization and are not intended to limit the scope of the claimed invention in any way. 【0088】 To better understand the present invention, the following examples are described. These examples are for illustrative purposes only and should in no way be construed as limiting the scope of the present invention. 【0089】 [Table 4] 【0090】 【Table 5】 【0091】 【Table 6】 【Example】 【0092】 Example 1: Clinical trial protocol for an open-label switch-over trial to demonstrate the efficacy and safety of prophylaxis with fitusiran in patients with hemophilia A and B who are already receiving prophylaxis with factor or bypassing agent This example describes an open-label, phase 3 switch-over trial designed to demonstrate the efficacy and safety of fitusiran in patients with hemophilia A or B who are currently being treated with a factor concentrate or BPA prophylaxis regimen. This switch-over design allows for an in-patient control to test the effects of the two treatment methods by comparing the median ABR during the prophylaxis period with factor or BPA to the median ABR of the same patient group receiving fitusiran, and furthermore limits the confounding effects of differences in the patient's bleeding phenotype and variability in prophylactic treatment. Hemophilia B inhibitor patients may have high unmet needs despite prophylactic BPA treatment due to limited alternative treatment options. Therefore, a limited number of hemophilia B inhibitor patients who do not respond adequately to prophylactic BPA treatment can be directly enrolled in the fitusiran treatment period, thereby skipping the 6-month prophylaxis period with BPA. This starting period reflects modeling data estimating that it takes approximately 28 days to reach the treatment target range in the majority of patients. Considering that the adopted study design is a single treatment arm where each patient is switched from prophylaxis to fitusiran, this trial is not blinded. 【0093】 The primary endpoints of this trial are the Fitziran duration of efficacy, and the ABR during the prophylaxis period with factor or BPA. ABR is a well-established endpoint that has been used as a primary endpoint in the worldwide approval of factor replacement products and BPA products. The secondary endpoints characterize the annualized spontaneous bleeding rate and joint bleeding rate, the changes in the Haem-A-QoL physical health score and total score in patients 17 years of age and older, the ABR during the initiation period, the overall safety profile, and the factor / BPA consumption. 【0094】 Characterization of bleeding episodes is clinically important in assessing overall bleeding episode protection. Joint bleeding episodes are important to evaluate because they cause pain and hemarthrosis and lead to progressive joint destruction. Haem-A-QOL is a hemophilia-specific HRQOL instrument that has been used, validated, and outlined by clinicians in other hemophilia clinical trials and is considered the most appropriate HRQOL tool available for use in this trial. 【0095】 The study population consists of males 12 years of age and older, and since the pathophysiology of disease progression and bleeding episode management are the same as in adults and self-management of hemophilia typically begins at 12 years of age, it is appropriate to test Fitziran in adolescents (patients 12 years of age and older but less than 18 years of age). 【0096】 In the event of breakthrough bleeding episodes, on-demand use of factor or BPA is permitted throughout the study period. 【0097】 Treatment Period The treatment period with Fitziran is 7 months. The estimated total time of the study, including screening for each patient, is up to 15 months for all patients enrolled in the extension study, except for patients in the subgroup of cohort A (maximum 9 months). The estimated total time of the study can be up to 21 months (up to 15 months for patients in the subgroup of cohort A) for patients not enrolled in the extension study due to the need for an additional 6 months of follow-up for AT level monitoring. 【0098】 Purpose and Evaluation Items of the Test The main purpose of this test is to characterize the frequency of bleeding episodes during the administration of fitusiran compared to the frequency of bleeding episodes during the administration of factor or bypassing agent (BPA). 【0099】 The secondary purposes of this test are as follows: - To characterize the following during the administration of fitusiran compared to the administration of factor or BPA prophylaxis: The frequency of spontaneous bleeding episodes, The frequency of joint bleeding episodes, and Health-related quality of life (HRQOL) in patients 17 years of age and older; - To characterize the frequency of bleeding episodes during the initiation and treatment periods in patients receiving fitusiran; - To characterize the safety and tolerability of fitusiran, and - To characterize the annual body weight-adjusted consumption of factor / BPA during the administration of fitusiran compared to the administration of factor or BPA prophylaxis. 【0100】 The exploratory purposes are as follows: - To characterize the effect of fitusiran on the following patient-reported outcomes during the administration of fitusiran compared to the administration of factor or BPA prophylaxis: Patient satisfaction with fitusiran, Patient activities, and HRQOL in adolescents (12 years of age and older but less than 17 years of age); - To characterize the pharmacodynamic (PD) effect, pharmacokinetics (PK), and immunogenicity of fitusiran; - To characterize the effect of fitusiran on joint status during the administration of fitusiran compared to the administration of factor or BPA prophylaxis; and - To characterize the effect of fitusiran on patient resource use compared to the administration of factor or BPA prophylaxis. 【0101】 The primary endpoint of this study was to evaluate the annual bleeding rate (ABR) during the FVIII treatment period and the prophylaxis period with factor or BPA. 【0102】 The secondary endpoints were to evaluate the following: - Annual spontaneous bleeding rate during the FVIII treatment period and the prophylaxis period with factor or BPA; - Annual joint bleeding rate (AJBR) during the FVIII treatment period and the prophylaxis period with factor or BPA; and - Changes in the Haem-A-QOL physical health score and total score during the FVIII treatment period and the prophylaxis period with factor or BPA. 【0103】 The exploratory endpoints were as follows: - Changes during the FVIII treatment period in the following: Treatment Satisfaction Questionnaire for Medication (TSQM) domain score, Hemophilia Activity List (HAL) score, Pediatric HAL (pedHAL) score, EuroQol-5 Dimensions (EQ-5D) score, Haemo-QOL score, and / or Hemophilia Joint Health Score (HJHS); - Number of target joint bleeding episodes; - Incidence and titer of anti-drug antibodies to FVIII during the FVIII treatment period; - Antithrombin (AT) activity levels over time; - Thrombin generation over time; - FVIII plasma levels; and - Changes in patient resource utilization (e.g., work / school attendance, physician / hospital visits). 【0104】 The safety endpoint was to evaluate the incidence, severity, seriousness, and relatedness of adverse events. 【0105】 Study Design In this study, male patients (aged 12 years and older) with hemophilia A or B who have switched from prophylaxis with a previous bypassing agent (BPA, cohort A) or factor (cohort B) are evaluated. Cohort A patients have inhibitory antibodies against factor VIII or factor IX, while cohort B patients do not have inhibitory antibodies against factor VIII or factor IX. 【0106】 The subgroup of cohort A patients includes hemophilia B patients with inhibitory antibodies against factor IX who do not respond adequately to prophylactic treatment with BPA (previous ABR ≥ 20). 【0107】 This study has the following three periods defined by the type of prophylaxis regimen (Figure 2): - A 6-month prophylaxis period with factor or BPA, during which patients continued their pre-study regularly scheduled prophylaxis regimen with factor or BPA, - A 1-month initiation period during which patients received the first dose of fitusiran while continuing prophylaxis with factor or BPA for up to 7 days, and - A 6-month fitusiran efficacy period during which patients received fitusiran as prophylaxis. 【0108】 The subgroup of cohort A patients who did not respond adequately to prophylactic treatment with BPA did not participate in the 6-month prophylaxis period with BPA and started receiving fitusiran directly after the screening period (during the 1-month initiation period) (Figure 3). 【0109】 The 1-month initiation period and the 6-month fitusiran efficacy period together constitute the fitusiran treatment period. 【0110】 The on-demand use of factor concentrates or BPA is defined as the use of these agents for occasional bleeding as needed, and is not a regular regimen intended to prevent spontaneous bleeding. Throughout this trial, patients during the fitusiran treatment period received on-demand treatment for breakthrough bleeding episodes with factor or GPA as needed. For patients during the fitusiran treatment period who have received at least one dose of fitusiran and are being treated for breakthrough bleeding episodes, it is recommended to follow the guidelines provided in Table 3. 【0111】 After the screening and prophylaxis periods (or after the screening period for the subgroup of cohort A who are directly enrolled in the fitusiran treatment period), all patients were treated with fitusiran for a total of 7 months. Thus, the entire fitusiran treatment period was defined as the sum of the initiation period (days 1 to 28 after receiving the first dose, during which the AT-reducing ability of fitusiran is increasing but has not yet reached the therapeutic level) and the effective period (after day 29, when the AT-reducing ability of fitusiran has reached the therapeutic target range). 【0112】 Study population This trial includes male patients (aged 12 years and older) with severe hemophilia A or B, with or without inhibitors, who have been prescribed prophylactic treatment with factor concentrates or BPA for at least 6 months prior to screening. The diagnosis of severe hemophilia A or B is based on measurement results in a central laboratory or evidence from documented medical records of an FVIII level of less than 1% or a FIX level of 2% or less. Patients with inhibitors must not have used BPA for prophylaxis for at least the past 6 months prior to screening and must meet one of the following Nijmegen modified Bethesda assay result criteria: 1) inhibitor titer at screening is 0.6 BU / mL or higher; 2) inhibitor titer at screening is less than 0.6 BU / mL and there is evidence from medical records of two consecutive titers of 0.6 BU / mL or higher; 3) inhibitor titer at screening is less than 0.6 BU / mL and there is evidence from medical records of a previous reaction. 【0113】 The patient subgroup of cohort A patients must further meet the following criteria to be eligible to start treatment with fitusiran immediately after the screening period: 1) hemophilia B with an inhibitory antibody against factor IX as defined above; 2) failure to respond appropriately to previous BPA treatment (previous ABR ≥ 20); and 3) the 6-month prophylaxis period with BPA should be omitted if considered appropriate. At least 2 bleeding episodes requiring BPA treatment within the past 6 months prior to screening are required. 【0114】 Patients without inhibitors must have not used factor concentrates for prophylaxis for at least the past 6 months before screening and must meet each of the following criteria: 1) the inhibitor titer in the Nijmegen modified Bethesda assay at screening is less than 0.6 BU / mL; 2) have not used bypass agents for treating bleeding episodes for at least the past 6 months before screening; and 3) have no history of immune tolerance induction therapy within the past 3 years before screening. At least one bleeding episode requiring factor treatment within the past 12 months before screening is required. 【0115】 The inclusion criteria are further explained as follows: I01. Be male, 12 years of age or older; I02. Have severe hemophilia A or B as evident by measurement results at screening or by evidence of documented medical records of FVIII levels less than 1% or FIX levels 2% or less; I03. Have had at least 2 bleeding episodes requiring BPA within the past 6 months before screening for patients with inhibitors to factor VIII or factor IX (cohort A); or have had at least 1 bleeding episode requiring factor treatment within the past 12 months before screening for patients without inhibitors to factor VIII or factor IX (cohort B); I04. Must meet either of the following definitions of inhibitor patients or non-inhibitor patients: - Inhibitor (cohort A): Have used BPA for prophylaxis and any bleeding episodes for at least the past 6 months before screening and meet one of the following Nijmegen modified Bethesda assay result criteria: ○ The inhibitor titer at screening is 0.6 BU / mL or higher, or ○ There is evidence in the medical record that the inhibitor titer at screening is less than 0.6 BU / mL and the titer is 0.6 BU / mL or higher in two consecutive measurements, or ○ There is evidence in the medical record that the inhibitor titer at screening is less than 0.6 BU / mL and there is a history of previous reaction; ○ A subgroup of Cohort A patients must further meet the following criteria in order to be eligible to initiate treatment with FEIBA immediately after the screening period: ■ Hemophilia B with an inhibitory antibody to factor IX as defined above, and ■ Failure to respond appropriately to prior BPA treatment (previous ABR ≥ 20); - Non-inhibitor: Use of factor concentrate for at least the previous six months prior to screening for prophylaxis and any bleeding episodes, and meeting each of the following criteria: ○ The inhibitor titer in the Nijmegen modified Bethesda assay at screening is less than 0.6 BU / mL, ○ No use of bypassing agents for treating bleeding episodes for at least the previous six months prior to screening, and ○ No history of prior immune tolerance induction therapy within the previous three years prior to screening; and I05. Prophylactic treatment of hemophilia with factor concentrate or BPA (medical record or pharmacy record) for at least six months prior to screening (and compliance); this regimen must be consistent with the approved prescribing information for the product or local recommendations (adjustments for individual patient response are possible) and must be designed to reduce spontaneous bleeding; and I06. Compliance with the prescribed prophylactic therapy for at least six months prior to screening as evaluated by the principal investigator of the clinical trial. 【0116】 Exclusion criteria are further described as follows: E01. The presence of a known co-existing bleeding disorder other than hemophilia A or B (i.e., von Willebrand disease, additional factor deficiencies, or platelet disorders); E02. Currently participating in immune tolerance induction therapy (ITI); E03. AT activity at screening < 60% as determined by measurements in the central laboratory. E04. The presence of clinically significant liver disease, or indicated by any of the following conditions: - INR > 1.2; - ALT and / or AST > 1.5 × upper limit of normal reference range (ULN); - Total bilirubin > ULN (> 1.5 × ULN in patients with Dubin - Johnson syndrome); - History of portal hypertension, esophageal varices, or hepatic encephalopathy; or - Presence of ascites by physical examination; E05. Positive for hepatitis C virus antibody, except for patients with a history of HCV infection who meet both of the following conditions: - Completed a curative treatment at least 12 weeks prior to enrollment and achieved sustained virological response as demonstrated by negative HCV RNA at screening, or the infection has been spontaneously cleared as demonstrated by negative HCV RNA at screening. - Absence of evidence of cirrhosis according to one of the following evaluations: ○ FibroScan < 12.5 kPa (if available), or ○ FibroTest score < 0.75 and APRI < 2 (if FibroScan is not available) E06. E06. The presence of acute hepatitis, i.e., hepatitis A or hepatitis E; E07. The presence of acute or chronic hepatitis B infection (IgM anti - HBc antibody positive or HBsAg positive); E08. Platelet count ≤ 100,000 cells / μL; E09. The presence of an acute infection at screening; E010. Known to be HIV positive with a CD4 count of less than 200 cells / μL; E011. Renal insufficiency as evidenced by an estimated glomerular filtration rate of 45 mL / min / 1.73 m2 or less (using the Modification of Diet in Renal Disease [MDRD] formula); E012. The presence of a thrombotic disorder co - existing as determined by the presence of any of the following identified in the central laboratory (or past results if available): - FV Leiden mutation (homozygous or heterozygous), - Protein S deficiency, or - Protein C deficiency; - Prothrombin mutation (G20210A; homozygous and heterozygous); E013. History of antiphospholipid antibody syndrome; E014. History of arterial thromboembolism or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke; patients who have experienced thrombosis related to an indwelling venous access are eligible for enrollment; or E015. Having had a malignancy within 2 years, excluding basal cell carcinoma or squamous cell carcinoma of the skin successfully treated. 【0117】 Administration Regimen and Formulation Supply the fitusiran solution for injection (for SC use) as a sterile solution. Administer fitusiran 80 mg to the patient as an SC injection once a month for a total of 7 months (or fitusiran 50 mg once every 2 months). 【0118】 Antithrombin Level Criteria for Dose Adjustment At the first AT level of less than 15%, another AT activity level sample is collected from the patients in this trial within one week from the receipt of the results. If this result is less than 15%, this is regarded as the second AT activity level of less than 15%. In this trial, fitusiran is administered at a dose of 50 mg Q2M, and for patients with multiple AT activity levels less than 15% at any time during this trial, fitusiran is interrupted. 【0119】 Regular use of prophylaxis with factor or bypass agent during the prophylaxis period with factor or bypass agent During the prophylaxis period with factor or BPA, the patient continues to receive prophylaxis with the normal product in a regimen that is consistent with the recommendations in the approved prescribing information (adjustable for individual patient response) and is designed to reduce spontaneous bleeding. The regimen used during the prophylaxis period with factor or BPA must have the minimum frequency of administration shown in Table 2 (see above). 【0120】 A subgroup of patients in cohort A who do not respond appropriately to the prophylactic treatment with BPA do not participate in this BPA prophylaxis period and directly start the fitusiran treatment period after the screening period. 【0121】 Management of prophylaxis with factor or bypass agent during the transition to the fitusiran treatment period The first 28 days of the fitusiran treatment period are referred to as the initiation period. During this initiation period, the AT reduction progresses towards the therapeutic level. The patient continues prophylaxis with factor or BPA at the minimum frequency in Table 2 for the first 7 days of this fitusiran initiation period. After the 7th day of the fitusiran treatment period, the factor concentrate or BPA should be administered only for bleeding episodes or as necessary before invasive medical procedures. 【0122】 Recommendations for the management of bleeding episodes in patients during the fitusiran treatment period Please refer to Section IV of the above detailed description. 【0123】 Trial evaluation A bleeding episode is defined as any occurrence of bleeding (e.g., joint bleeding, muscle bleeding, or mucosal bleeding) that requires an injection of BPA or a replacement factor. The definitions of bleeding episode types described below are based on the consensus of the International Society on Thrombosis and Haemostasis (ISTH) (Blanchette et al., J Thromb Haemost. (2014) 12(11):1935-9). 【0124】 The start time of a bleeding episode was considered as the time when the symptoms of the bleeding episode first appeared. Any symptoms of bleeding at this location that occurred within 72 hours of the bleeding, or the last injection used to treat a bleeding episode at the same location, were considered part of the original bleeding event and counted as one bleeding episode for ABR. Any bleeding symptoms that started more than 72 hours after the last injection used to treat a bleeding episode at this location constituted a new bleeding event. 【0125】 A spontaneous bleeding episode is a bleeding event that occurs in joints, muscles, and soft tissues without any obvious or known reason, especially. 【0126】 A joint bleeding episode is characterized by 1) swelling or increased warmth of the skin over the joint, 2) increased pain, or 3) an abnormal sensation ("prodrome") in the joint combined with a progressive loss of range of motion or difficulty in using the limb compared to the baseline. 【0127】 Muscle bleeding may be characterized by pain, swelling, and loss of movement over the affected muscle group. 【0128】 A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred in a single joint within a continuous six-month period, and if there are two or fewer bleeding episodes in the joint within a continuous 12-month period, this joint is no longer considered a target joint. 【0129】 A traumatic bleeding episode is an episode caused by a known injury or trauma. Persistent bleeding episodes during sports and recreation were counted as traumatic bleeding episodes. 【0130】 Patient-reported outcomes are used to evaluate health-related quality of life (HRQOL), physical activity, and treatment satisfaction and utility. The Haemophilia Quality of Life Questionnaire (Haem-A-QOL) for Adults is a QOL assessment instrument that has been psychometrically tested for patients with haemophilia. Haem-A-QOL is provided to patients 17 years of age and older and includes 46 items contributing to 10 QOL domains (physical health, emotions, self-perception, sports and leisure, work and school, coping with haemophilia, treatment, future, family planning, partnership, and sexuality). Scoring for each item is based on a 5-point Likert scale (none at all, rarely, sometimes, often, and always), with higher scores indicating greater dysfunction. 【0131】 Antithrombin activity AT activity levels are evaluated twice a month (approximately every 2 weeks) for the first 2 months and then monthly (approximately every 4 weeks). On the dosing day, samples are collected within 4 hours before dosing. Antithrombin protein can be measured in a subset of plasma samples for correlation. 【0132】 Statistical methodology A primary analysis is performed for the EAS and includes all bleeding episodes that occurred during the prophylaxis period (-162 days to -1 day) by factor or BPA and the fitusiran efficacy period (days 29 to 190). If a patient does not have bleeding episode data collected after day 28 (e.g., due to early trial termination), the available bleeding episode data starting from day 1 are used in the primary analysis. To avoid confounding of treatment effects, bleeding episode data during and after major surgery, antithrombin administration, major trauma, or initiation of prophylactic treatment by factor or BPA during the fitusiran treatment period are excluded from the primary analysis. 【0133】 The number of bleeding episodes is analyzed using a repeated measures negative binomial model with a fixed effect for the treatment period. The logarithm of the number of days each patient spends during the valid period that coincides with the bleeding episode data to be analyzed is included as an offset variable to account for unequal follow-up times due to early withdrawal or surgery. The ratio of the bleeding rate during the Fitzalan effective period to the prevention period by factor or BPA, along with its 95% CI and p-value, is presented. 【0134】 In addition, in contrast, Bayesian analysis is performed to summarize the point estimate of the posterior probability of a clinically significant treatment effect, along with a measure of the associated uncertainty. From this model, the estimated mean ABRs in these two periods are presented along with their 95% CIs. In addition, summary statistics of ABR including the median and interquartile range are presented for each treatment arm, where ABR is defined as: (Total number of eligible bleeding episodes / total number of days in each period) × 365.25 【0135】 Spontaneous bleeding episodes and joint bleeding episodes are analyzed using the same method as the primary analysis of ABR. Summary statistics (including the median and interquartile range) for the annual spontaneous bleeding rate and the annual joint bleeding rate are reported. 【0136】 The changes in the Haem-A-QOL physical health score and total score (for patients 17 years and older) during the prevention period by factor or BPA and the Fitzalan treatment period are descriptively summarized. A mixed model for repeated measures analysis may be performed if considered appropriate. 【0137】 Bleeding episodes during the Fitzalan start period and the Fitzalan treatment period are analyzed using a negative binomial model with the logarithm of the follow-up time in the period as an offset parameter. Summary statistics (including the median and interquartile range) for ABR in the two periods are reported. 【0138】 Summarize the secondary evaluation items of the annual weight-adjusted consumption of factor / BPA injection using descriptive statistics. 【0139】 The fitusiran effective period (prevention by fitusiran) was defined as from the 29th day to the earlier of the 190th day or the last day of the bleeding follow-up survey after the first dose of fitusiran. The prevention period by factor / BPA was defined as from the -168th day to the earlier of the -1st day or the last day of the bleeding follow-up survey. The prevention period by factor / BPA is defined as from the -168th day to the earlier of the -1st day or the last day of the bleeding follow-up survey. 【0140】 Example 2: Phase 3 clinical trial results Clinical trial results were obtained according to the test protocol described in Example 1. The patients were male over 12 years old with hemophilia A or B (with or without inhibitors) who had been previously prevented with factor / BPA. The participants continued prophylaxis with factor / BPA (6 months) before switching to prophylaxis with 80 mg SC fitusiran once a month (7 months). The primary evaluation item was the ABR during the prophylaxis period by factor / BPA (-168th day to -1st day) and the fitusiran effective period (29th day to 190th day). The secondary evaluation items included spontaneous ABR (AsBR), joint ABR (AjBR), and health-related quality of life (HRQoL). Safety and tolerability were evaluated. 【0141】 Present the results of safety analysis set 1 (SAS1) and efficacy analysis set 1 (EAS1) including participants who were registered and received 80 mg of fitusiran QM. The efficacy analysis set 1 included participants who received prophylaxis with factor or BPA and at least one dose of fitusiran. 【0142】 Nature of participants Of the 99 screened participants, 80 (normalized to 100%) were enrolled. Thirty participants had inhibitory antibodies against factor VIII or factor IX (cohort A [inhibitor]), and 50 participants did not have inhibitory antibodies against factor VIII or factor IX (cohort B [non-inhibitor]). Of the 80 enrolled participants, 78 (97.5%) were enrolled during the prophylaxis period with factor / BPA, and 67 (83.8%) completed the prophylaxis period with factor / BPA. Two (2.5%) of the 80 enrolled participants started ficlatuzumab 80 mg QM directly (subgroup of cohort A) (Table 4). 【0143】 【Table 7】 【0144】 Of the 67 participants who completed the prophylaxis period with factor / BPA, 65 started ficlatuzumab 80 mg QM and 2 started ficlatuzumab 50 mg Q2M. Of the 67 (83.8%) participants who started ficlatuzumab 80 mg QM, 13 (16.3%) discontinued, and 54 (67.5%) completed the ficlatuzumab treatment. Nine (11.3%) participants discontinued ficlatuzumab 80 mg QM due to voluntary discontinuation at the discretion of the sponsor and completed the trial. Two (2.5%) participants discontinued ficlatuzumab due to AE. Of the 2 participants treated with ficlatuzumab 50 mg Q2M, 1 discontinued ficlatuzumab due to multiple AT values of less than 15% and completed the trial, and 1 withdrew consent. Sixty-four (80.0%) participants completed the trial (Tables 5 and 6). 【0145】 【Table 8】 【0146】 【Table 9】 【0147】 Group characteristics Among the 80 registered participants, 57 were participants with hemophilia A (21 in cohort A [inhibitor] and 36 in cohort B [non-inhibitor]), and 23 were participants with hemophilia B (9 in cohort A [inhibitor] and 14 in cohort B [non-inhibitor]). All participants were male, and the median age was 23.0 years. 19 patients (29.2%) were adolescents (12 - 17 years old), 45 (69.2%) were adults (18 - 64 years old), and 1 participant was 65 years or older. 【0148】 A total of 42 participants (64.6%) were white, 20 (30.8%) were Asian, 2 (3.1%) were "other", and 1 participant was black or African American. The median body mass index was 23.6 kg / m 2 2. 【0149】 For participants in cohort A (inhibitor), the median (IQR) number of bleeding episodes in the 6 months before screening was 4.0 (2.0 - 6.0); for participants in cohort B (non-inhibitor), the median number of bleeding episodes in the 12 months before screening was 2.0 (1.0 - 4.0). Most participants (18 [94.7%]) in cohort A (inhibitor) had a previous peak inhibitor titer of 5 BU / ml or higher. The patient baseline demographics and characteristics were generally similar between cohorts and are summarized in Table 7. 【0150】 【Table 10】 【0151】 Efficacy results A total of 80 patients were enrolled, and 65 were evaluable for efficacy analysis (inhibitor / non-inhibitor, n = 19 / 46; hemophilia A / hemophilia B, n = 50 / 15). The mean (SD) age was 24.8 (11.2) years. 【0152】 Overall, for participants treated with prophylactic fitusiran 80 mg QM, the estimated ABR was 2.908 (95% confidence interval [CI], 1.727 - 4.898) during the active period and 7.482 (95% CI, 5.520 - 10.141) during the prophylaxis period with factor or BPA, representing a statistically significant 61.1% (95% CI, 32.5% - 77.6%) reduction in treated bleeds supporting prophylaxis with fitusiran (P = 0.0008). Overall, the median (IQR) of the observed ABR during the fitusiran active period and the prophylaxis period with factor or BPA was 0.00 (0.00; 2.25) and 4.35 (2.17; 10.87), respectively (Table 8). 63.1% of participants had zero bleeds treated during the fitusiran active period compared with 16.9% during the factor or BPA period (Table 9). Among participants with inhibitors (cohort A), fitusiran was associated with a lower median (IQR) ABR of 0.00 (0.00; 0.00) and a significant 79.7% (95% CI, 43.8% - 92.6%) ABR reduction compared with prophylaxis with BPA (P = 0.0021). Among participants without inhibitors (cohort B), fitusiran was associated with a lower median (IQR) ABR of 0.00 (0.00; 2.65) and a clinically meaningful 46.4% ABR reduction (numerical) compared with prophylaxis with factor (P = 0.0598) (Figure 4). Prophylaxis with fitusiran significantly reduced the bleeding rate by 61.1% compared with prophylaxis with factor / BPA. (p = 0.0008). 【0153】 Fitusiran has achieved the primary endpoints of the trial, significantly reducing the frequency of bleeding episodes; the median (IQR) ABR observed for treated bleeds was 0.0 (0.0; 2.3) during the Fitusiran active period and 4.35 (2.2; 10.9) during the prophylaxis period with factor / BPA. Forty-one (63.1%) participants prophylactically treated with Fitusiran had zero treated bleeds. 【0154】 【Table 11】 【0155】 【Table 12】 【0156】 Major secondary endpoints Annualized spontaneous bleeding rate during the Fitusiran active period and prophylaxis period with factor or BPA: Overall, for participants treated prophylactically with 80 mg QM Fitusiran, the estimated spontaneous ABR was 2.222 (95% confidence interval [CI], 1.190 - 4.152) during the Fitusiran active period and 5.002 (95% CI, 3.424 - 7.305) during the prophylaxis period with factor or BPA, representing a statistically significant reduction of 55.6% (95% CI, 15.8% - 76.6%) in treated spontaneous bleeding supporting prophylaxis with Fitusiran (P = 0.0129). The estimated AsBR ratio was 0.444 (95% CI, 0.234 - 0.842). The mean and median of treated spontaneous bleeding are presented in Table 10 below. 【0157】 【Table 13】 【0158】 Annual joint bleeding rate during the Ficiran effective period and the prophylaxis period with factor or BPA: Overall, for participants treated with prophylaxis with 80 mg QM Ficiran, the estimated joint ABR was 2.564 (95% confidence interval [CI], 1.440 - 4.566) during the Ficiran effective period and 5.282 (95% CI, 3.647 - 7.651) during the prophylaxis period with factor or BPA, representing a statistically significant reduction of 51.5% (95% CI, 9.0% - 74.1%) in treated joint bleeding supporting prophylaxis with Ficiran (P = 0.0242). The estimated AjBR ratio was 0.485 (95% CI, 0.259 - 0.910). The mean and median of the treated joint bleeding observations are presented in Table 11. 【0159】 【Table 14】 【0160】 This data is also shown in Table 12 and Figure 5 below. This data is based on an on-treatment strategy that includes all bleeding events treated during the Ficiran effective period and the prophylaxis period with CFC / BPA and excludes any bleeding events during the intermediate event period. 【0161】 【Table 15】 【0162】 Annual bleeding rate during the Ficiran initiation period: In the 65 patients analyzed, the estimated annual bleeding rate during the Ficiran initiation period was 5.419 (95% CI, 3.716 - 7.901). The observed annual bleeding rate during the Ficiran initiation period was 5.42 (SD 8.28). 【0163】 Annual bleeding rate during the fitusiran treatment period: Among the 65 patients analyzed, the estimated annual bleeding rate during the fitusiran treatment period was 3.317 (95% CI, 2.111 - 5.211). The observed annual bleeding rate at the start of fitusiran was 3.48 (SD 6.98). 【0164】 Consumption of factor concentrates and bypass agents for the management of breakthrough bleeding (including annual body weight-adjusted consumption of BPA and factors): The annual body weight-adjusted consumption of BPA or factors was calculated for each participant during the prophylaxis period as [total BPA dose per body weight administered during the corresponding period / number of days in the corresponding period] × 365.25. For this outcome measure, data on the annual body weight-adjusted consumption of BPA or factors were reported. The time frames were as follows: Prophylaxis period with factor / BPA: from day -168 to day -1 or the last day of bleeding follow-up (any day up to day -1); 6-month fitusiran effective period: whichever was earlier, from day 29 to day 190 or the last day of bleeding follow-up (any day up to day 190). A summary of BPA consumption is presented in Table 13. A summary of factor consumption is presented in Table 14. 【0165】 【Table 16】 【0166】 【Table 17】 【0167】 Fewer participants required coagulation factor concentrate (CFC) or BPA for the treatment of breakthrough bleeding after switching to fitusiran. A total of 36 participants received CFC, and 20 participants received BPA for the treatment of breakthrough bleeding during prophylaxis with CFC / BPA. After switching to fitusiran, the number of participants decreased to 20 and 4, respectively. 【0168】 The total number of treated bleeds was lower in participants receiving fitusiran (total inhibitor carriers = 18, total non-inhibitor carriers = 54) compared to participants receiving prophylaxis with CFC (total = 126) or BPA (total = 101). 【0169】 The mean total body weight-adjusted dose per bleed of CFC (FVIII = 13.4 IU / kg, SD = 5.5; FIX = 26.2 IU / kg, SD = 0.0), and BPA (aPCC = 34.1 U / kg, SD = 16.1; rFVIIa = 38.2 μg / kg, SD = 17.0) was significantly reduced when participants were administered fitusiran compared to prophylaxis with CFC (FVIII = 45.3 IU / kg, SD = 41.8; FIX = 73.6 IU / kg, SD = 54.7), or BPA (aPCC = 199.8 U / kg, SD = 366.1; rFVIIa = 709.9 μg / kg, SD = 1163.8). 【0170】 The total mean consumption of FVIII and FIX for breakthrough bleeds was lower in patients receiving prophylaxis with fitusiran compared to patients receiving prophylaxis with CFC (Table 15). The total mean consumption of aPCC and rFVIIa for breakthrough bleeds was lower in participants receiving prophylaxis with fitusiran compared to patients receiving prophylaxis with BPA. In particular, the annual body weight-adjusted consumption of aPCC for bleed treatment was 98.9% lower during prophylaxis with fitusiran, the annual body weight-adjusted consumption of rFVIIa was 96.8% lower during prophylaxis with fitusiran, the annual body weight-adjusted consumption of FVIII was 79.4% lower during prophylaxis with fitusiran, and the annual body weight-adjusted consumption of FIX was 93.8% lower during prophylaxis with fitusiran. 【0171】 Participants who received fitusiran also required fewer injections to treat breakthrough bleeding compared to participants who received prophylaxis with CFC (total = 189) or BPA (total = 419) (total with inhibitor = 26, total without inhibitor = 59). The number of treated bleeds in patients with an inhibitor was 82.2% lower with fitusiran treatment compared to prophylaxis with BPA, while the number of treated bleeds in patients without an inhibitor was 57.1% during the prophylaxis period with fitusiran compared to the prophylaxis period with factor / bypass agents. The total number of BPA injections in patients with an inhibitor was 93.8% lower with fitusiran treatment compared to prophylaxis with BPA, while the total number of replacement factor injections in patients without an inhibitor was 68.8% lower during the prophylaxis period with fitusiran compared to the prophylaxis period with factor / bypass agents. 【0172】 【Table 18】 【0173】 Overall, the results of the consumption assessment items consistently supported prophylaxis with fitusiran over prophylaxis with CFC / BPA. Prophylaxis with fitusiran reduced total CFC / BPA consumption in patients by reducing the mean total body weight-adjusted dose per bleed, the number of treated bleeds, and the number of injections required to treat bleeding, thereby reducing the treatment burden in patients with hemophilia A or B with and without inhibitors. 【0174】 Changes in Haem-A-QOL, EQ-5D-5L, HAL, and TSQM-9 scores: At registration (-6 months), individuals without an inhibitor generally had less of a decrease in PRO scores compared to those with an inhibitor (Figure 6). 【0175】 For Ham-A-QoL, the changes from baseline (-6 months) for both treatments were compared with the change from -6 months to day 1 for prophylaxis by factor / BPA using a mixed model for repeated measures (MMRM), and with the change from -6 months to 7 months for prophylaxis by ficilitran. The changes from -6 months to day 1 and from -6 months to 7 months were the response variables. The study period (prophylaxis period by factor / BPA and treatment period by ficilitran), and the scores at -6 months were fixed effects, and a robust sandwich covariance matrix was constructed to account for within-subject dependence. 【0176】 At registration (-6 months), the converted physical health score and total score of Haem-A-QoL were 32.87 (SD 23.68) and 31.63 (SD 18.54), respectively. The least squares (LS) mean (95% CI) of the change in the converted total score from baseline in the Haem-A-QoL score (i.e., the difference between the change from -6 months to baseline (day 1) and the change from -6 months to 7 months) was -7.62 (-10.26 to -4.98) for prophylaxis by ficilitran and -3.07 (-5.56 to -0.58) for prophylaxis by factor / BPA. The LS mean difference was -4.55 (95% CI, -7.56 to -1.54), and it significantly decreased in support of ficilitran (P = 0.0039) (Figures 7 and 8). 【0177】 The LS mean (95% CI) of the change in the converted physical health domain score from baseline was -9.60 (-15.35, -3.84) for prophylaxis by ficilitran and -6.00 (-10.19, -1.81) for prophylaxis by factor / BPA (Table 16). A nominal improvement in the physical health score in support of ficilitran was demonstrated from the least squares (LS) mean difference between the change from -6 months to baseline (day 1) and the change from -6 months to 7 months in the Haem-A-QoL score (-3.60 [95%-CI: -10.52, 3.33]) (Figures 7 and 8). 【0178】 【Table 19】 【0179】 The overview of the changes in TSQM-9, EQ-5D-5L, and HAL from the 6th month (registration) to the 1st day and up to the 7th month was descriptively summarized. 【0180】 At registration (-6 months), the EQ-5D-5L index score was 0.83 (SD 0.13). Ficiran also demonstrated a nominal improvement in the EQ-5D-5L index score compared to prevention with factor / BPA, with an average change from the 6th month to the 7th month of 0.04 (SD 0.13) compared to an average change of 0.0 (SD 0.13) from the 6th month to the 1st day. 【0181】 At registration (-6 months), the HAL total score was 79.11 (SD 20.29). In addition to demonstrating good functional ability to perform activities of daily life, patients were graded as having even better physical ability over the two evaluation periods of the trial as shown by the change in the HAL score: the average change in the total score was 3.05 (SD 20.04) and 2.45 (SD 19.42) for the Ficiran and prevention arms with factor / BPA, respectively. 【0182】 At registration (-6 months), the TSQM-9 baseline scores regarding effectiveness, convenience, and satisfaction were 66.76 (SD 18.06), 61.29 (SD 17.97), and 69.35 (SD 15.91), respectively. The overall results of the average TSQM-9 scores consistently supported prevention with Ficiran over prevention with factor / BPA in all three domains of effectiveness, convenience, and overall satisfaction (Figure 7). Overall, the average TSQM-9 scores consistently supported prevention with Ficiran compared to prevention with factor / BPA in all three domains of effectiveness, convenience, and overall satisfaction (Figure 10). 【0183】 Safety results: 67 (83.8%) participants were registered, received at least one dose of ficiran before dose resumption (after the sponsor initiated dose interruption), and were included in Safety Analysis Set 1. Overall, 22 (33.8%) participants during the prophylaxis period with factor / BPA and 48 (71.6%) participants during the prophylaxis period with ficiran experienced at least one adverse event (AE). 【0184】 A total of 5 serious adverse events (SAEs) were reported in 5 (7.7%) participants during the prophylaxis period with factor / BPA, and 13 SAEs were reported in 9 (13.4%) participants during the prophylaxis period with ficiran. The most common SAE during the prophylaxis period with ficiran was hemophilic arthropathy (2 [3.0%] participants); all other SAEs during the prophylaxis period with ficiran were reported in 1 (1.5%) participant each. 【0185】 2 (3.1%) participants during the prophylaxis period with factor / BPA and 22 (32.8%) participants during the prophylaxis period with ficiran experienced particularly notable adverse events (AESIs). During the prophylaxis period with ficiran, these included 2 (3.0%) participants in whom thromboembolic events were suspected or confirmed (cerebrovascular disorder and probable thrombosis [thrombosis of the left optic papilla]). The participant with the cerebrovascular disorder had a history of deep vein thrombosis in the right lower limb that was not known to the principal investigator at the time of registration (exclusion criterion). 【0186】 17 (25.4%) participants had an increase in ALT or AST greater than 3 times the ULN. One of these participants experienced laboratory abnormalities consistent with Hy's law, which resolved after the last dose of ficiran. 5 (7.5%) participants had cholecystitis and 5 (7.5%) participants had cholelithiasis (including 2 participants with both events). 2 (3.0%) participants during the prophylaxis period with ficiran experienced AEs (cerebrovascular disorder and abdominal discomfort) that led to discontinuation of the investigational drug. 【0187】 Fatal AEs were not reported. The summary of AEs is shown in Tables 17 - 21 below. 【0188】 【Table 20】 【0189】 【Table 21】 【0190】 【Table 22】 【0191】 【Table 23】 【0192】 【Table 24】 【0193】 【Table 25】 【0194】 【Table 26】 【0195】 【Table 27】 【0196】 【Table 28】 【0197】 【Table 29】 【0198】 Antithrombin level: In patients during the fexeran effective period, a decrease in AT level was observed (Figure 11). In patients with the inhibitor, on the 29th day, the AT level was reduced by an average of 81.4% from the baseline. In patients without the inhibitor, on the 29th day, the AT level was reduced by an average of 82.3% from the baseline. The AT level remained reduced throughout the test period. In patients with the inhibitor, on the 29th day, the peak thrombin generation (TG) increased by an average of 35.0 nM from the baseline. In patients without the inhibitor, on the 29th day, the peak TG increased by an average of 34.9 nM from the baseline. TG remained elevated throughout the test period in all three tests (Figure 12). 【0199】 Analysis of the young subgroup Nineteen young people (12 - 17 years old) were enrolled. The baseline characteristics of the young people enrolled in this test are shown in Table 22. 【0200】 【Table 30】 【0201】 The median of ABR was 0.00 in the fexeran arm compared to 2.2 in the CFC / BPA arm. The medians of ABR, AjBR, and AsBR observed in the young patients enrolled in this test are shown in Figure 13. 【0202】 Prevention with fexeran improved HRQoL. When measured using the Haemo-QoL survey, the average change in the converted total score at the 9th month from the baseline during the prevention period with CFC / BPA was -4.3 compared to -6.3 throughout the test period (Figure 14). The safety profile of fexeran in young people was consistent with that observed in adult participants. 【0203】 In adolescents with hemophilia A or B (with or without inhibitors), prophylaxis with fitusiran has demonstrated an improvement in the bleeding phenotype. Reduction in the Haemo-QoL score supports a broad improvement in HRQoL with prophylaxis with fitusiran compared to CFC and BPA treatments. The benefit / risk assessment was favorable. 【0204】 Conclusion Prophylaxis with fitusiran 80mg QM achieved a highly significant 61.1% (95% CI, 32.5% - 77.6%) reduction in ABR during the period of effectiveness in participants with hemophilia A or B with or without inhibitors, switched from previous prophylaxis with factor or BPA (P<0.001). The median (IQR) of the observed ABR was lower during the fitusiran period of effectiveness compared to the period of prophylaxis with factor / BPA (0.00 [0.00; 2.25] and 4.35 [2.17; 10.87]). 【0205】 63.1% of participants had zero bleeding episodes during the fitusiran period of effectiveness compared to 16.9% during the period of prophylaxis with factor or BPA. This finding was supported by substantially lower rates of other bleeding-related assessment items (spontaneous bleeding, joint bleeding events) during prophylaxis with fitusiran compared to prophylaxis with factor or BPA. These results demonstrate that monthly prophylaxis with fitusiran 80mg provides a significant level of protection against bleeding in participants with hemophilia A or B with or without inhibitors. Prophylaxis with fitusiran significantly improved health-related quality of life as measured by the Haem-A-QOL total score. Nominal results suggest improvement in subdomains of the physical health domain. Reported AEs were generally consistent with the risks of fitusiran already identified. The safety and efficacy of the revised dosage and regimen are currently being evaluated in ongoing clinical trials. 【0206】 In conclusion, in patients with hemophilia A or B with and without inhibitors, prophylaxis with fitusiran once monthly significantly reduced bleeding compared to prophylaxis with factor / BPA, the median ABR was zero, and as a result, HRQoL was significantly improved. The reported AEs generally corresponded to the already identified risks of fitusiran. Therefore, these results support that fitusiran can provide a monthly subcutaneous prophylactic treatment option for patients with hemophilia A or B with and without inhibitors who are already receiving prophylaxis with factor concentrates or BPA. In addition, prophylaxis with fitusiran significantly reduced the bleeding rate compared to past prophylaxis with factor / BPA, with a zero bleeding rate in over 60%, indicating that prophylactic efficacy at hemostatic levels was achieved with fitusiran. Fewer bleedings led to a reduction in factor / BPA consumption with prophylaxis with fitusiran compared to prophylaxis with factor / BPA, with fewer factor / BPA injections and doses required to treat each bleeding. The relatively infrequent subcutaneous route of administration of prophylaxis with fitusiran could reduce the overall treatment and disease burden, improve QoL, and increase adherence for patients with hemophilia A or B (with or without inhibitors) compared to prophylaxis with factor / BPA. 【0207】 Example 3: Qualitative Semi-Structured Interviews of Participants in the ATLAS-OLE Trial In addition to the clinical trials (ATLAS-PPX) described in Examples 1 and 2, fitusiran is being evaluated in two additional Phase 3 trials: ATLAS-INH (a trial in patients with inhibitors) and ATLAS-A / B (a trial in patients without inhibitors). After completion of any of these three trials, patients were eligible to participate in an open-label extension (OLE) trial (ATLAS-OLE). 【0208】 This example relates to semi-structured interviews of patients located in the United States and India who are enrolled in the OLE trial. The objective was to better understand the experiences of patients and caregivers with hemophilia A or B (with or without inhibitors) and the treatment of this hemophilia (including fitusiran), as well as the recognition and satisfaction of patients and caregivers with fitusiran during the OLE trial. 【0209】 The interview subjects included patients aged 18 years or older. For patients who were cognitively unable to participate in the interview or for patients aged 12 to 18 years, the caregivers were interviewed. All patients were interviewed at least 1 month after the second dose of fitusiran was administered in the OLE trial. 【0210】 One-hour semi-structured interviews were conducted by phone. The audio was recorded and transcribed. Each interview began with open-ended questions focused on the participants' experiences with hemophilia and its treatment prior to entering the ATLAS program, the impact of hemophilia and the recognition of its treatment in daily life, and the expectations of the treatment. Next, the interview discussion focused on the participants' experiences during the OLE trial (including any changes and benefits noticed by the participants). A 5-point rating scale was used to evaluate various attributes of a hypothetical hemophilia treatment, and a 3-point rating scale was used to evaluate the degree of improvement, if any, noted in these aspects during the OLE trial. Statistical analysis of the qualitative interview data was performed using anonymized interview transcripts and ATLAS.ti 9 software. A summary of descriptive demographic and clinical information was compiled for the entire sample and is shown in Table 23. 【0211】 【Table 31】 【0212】 A total of 24 participants were interviewed. The mean (SD) age of the participants was 27 (8.9) years. As shown in Figure 15, prior to enrollment in the FIX trial, participants reported that their (or their child's) hemophilia-related bleeding (joint and muscle), pain, fatigue, stiff joints, and swelling had a significant negative impact on daily life in many areas. Almost all participants (n = 21; 87.5%) reported that hemophilia treatment affected their daily physical activities and subsequently affected their work or school. 【0213】 Figure 16 shows that participants rated "bleeding reduction" as the most important attribute of hemophilia treatment and as one of the top two items where they experienced the most improvement during the OLE trial. Other very important attributes for the hypothetical hemophilia treatment included "improvement in joint health", "improvement in joint mobility / ease of movement", "protection from bleeding over a full month", and "minimizing anxiety or stress related to hemophilia management". All participants reported that the improvements observed during the ATLAS-OLE trial had a positive impact on quality of life, as well as the ability and confidence to participate in daily physical activities, enjoy family life, participate in social activities, and improve overall mood or feelings (Table 24). Most participants (85%) also reported a positive impact of the improvement at work or school. 【0214】 【Table 32】 【0215】 Figure 17 shows that 75% of the participants were "satisfied" with their pre-treatment prior to adoption in the ATLAS trial, but almost 92% of these participants were "very satisfied" with FIX, particularly with regard to the ability to prevent bleeding, duration of effect, and convenience. In addition, almost all (23 / 24) participants preferred prophylaxis with FIX over their prior hemophilia treatment. 【0216】 Among the statements recorded during the interviews, participants reported, for example, "After taking Fitsiran, I became like a normal person," "I can walk normally," and "[I am] very confident that there will be no bleeding if I take Fitsiran." 【0217】 In conclusion, Fitsiran meets the expectations for the treatment of patients with hemophilia and their caregivers. Almost all participants were very satisfied with the Fitsiran therapy and preferred Fitsiran over previous therapies. All participants treated with Fitsiran reported improvements in their daily physical activities, family life, social activities, feeling safer, and positive changes in mood. These findings reflect the impact on the quality of life of participants provided by the prevention with Fitsiran by improving the bleeding phenotype. 【0218】 Almost all participants were very satisfied with the Fitsiran therapy and preferred Fitsiran over previous therapies. This qualitative study provides valuable and forward-looking insights into the experiences of patients and caregivers regarding hemophilia and its treatment.

Claims

[Claim 1] A pharmaceutical composition comprising fitsilane for use in a method to reduce the annual bleeding rate (ABR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective amount of fitsilan subcutaneously to the necessary human patients, and The prophylactic supplementation or BPA treatment in the patient should be terminated within approximately two months, one month, 28 days, or seven days of the initial dose of Fitsilan. A pharmaceutical composition containing the following: [Claim 2] A pharmaceutical composition comprising fitsiran for use in a method of reducing the annual bleeding rate (ABR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method comprises subcutaneously administering a therapeutically effective amount of fitsiran to the required human patient. [Claim 3] The pharmaceutical composition according to claim 1 or 2, wherein, upon administration, the ABR in the patient is reduced by more than 10%, 20%, 30%, 40%, or 50% compared to the human patient's past ABR, and optionally by more than 60%. [Claim 4] The pharmaceutical composition according to claim 1 or 2, wherein the administration reduces the median ABR of the patient to 2 or less, 1 or less, or 0, and optionally, the patient's past ABR is greater than 4. [Claim 5] A pharmaceutical composition comprising fitsilane for use in a method to reduce the annual spontaneous bleeding rate (AsBR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective amount of fitsilan subcutaneously to the necessary human patients, and The prophylactic supplementation or BPA treatment in the patient should be terminated within approximately one month, approximately 28 days, or approximately 7 days of the first dose of Fitsilan. A pharmaceutical composition containing the following: [Claim 6] A pharmaceutical composition comprising fitsiran for use in a method to reduce the annual spontaneous bleeding rate (AsBR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method comprises subcutaneously administering a therapeutically effective amount of fitsiran to the required human patient. [Claim 7] The pharmaceutical composition according to claim 5 or 6, wherein the administration reduces AsBR by more than 40% and optionally by more than 50% compared to the patient's past AsBR. [Claim 8] The pharmaceutical composition according to claim 5 or 6, wherein the administration reduces the patient's AsBR to 1 or less or to 0, and optionally, the patient's past AsBR was greater than 2. [Claim 9] A pharmaceutical composition comprising fitsiran for use in a method to reduce the annual joint bleeding rate (AjBR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective amount of fitsilan subcutaneously to the necessary human patients, and The prophylactic supplementation or BPA treatment in the patient should be terminated within approximately one month, approximately 28 days, or approximately 7 days of the first dose of Fitsilan. A pharmaceutical composition containing the following: [Claim 10] A pharmaceutical composition comprising fitsiran for use in a method to reduce the annual joint bleeding rate (AjBR) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method comprises subcutaneously administering a therapeutically effective amount of fitsiran to the required human patient. [Claim 11] The pharmaceutical composition according to claim 9 or 10, wherein the administration reduces the AjBR by more than 40% and optionally by more than 50% compared to the patient's past AjBR. [Claim 12] The pharmaceutical composition according to claim 9 or 10, wherein the administration reduces the patient's AjBR to 1 or less or to 0, and optionally, the patient's past AjBR is greater than 2. [Claim 13] A pharmaceutical composition comprising fitsilane for use in a method to improve patient-reported outcomes (PROs) in human patients with hemophilia A or B with or without inhibitors who are receiving prophylactic treatment with replacement factors or bypass agents (BPAs), wherein the method is: To administer a therapeutically effective amount of fitsilan subcutaneously to the necessary human patients, and The prophylactic supplementation or BPA treatment in the patient should be terminated within approximately one month, approximately 28 days, or approximately 7 days of the first dose of Fitsilan. Includes, A pharmaceutical composition wherein the PRO is optionally improved in one or more quality of life (QoL) domains. [Claim 14] A pharmaceutical composition comprising fitsiran for use in a method to improve patient-reported outcomes (PROs) in human patients with or without inhibitors of hemophilia A or B who are receiving prophylactic treatment with replacement factors or bypass agents (BPAs), wherein the method comprises subcutaneously administering a therapeutically effective amount of fitsiran to the required human patient, and optionally, the PRO is improved in one or more quality of life (QoL) domains. [Claim 15] A pharmaceutical composition comprising fitsilane for use in a method to improve the quality of life (QoL) in human patients with or without inhibitors of hemophilia A or who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective amount of fitsilan subcutaneously to the necessary human patients, and The prophylactic supplementation or BPA treatment in the patient should be terminated within approximately one month, approximately 28 days, or approximately 7 days of the first dose of Fitsilan. Includes, A pharmaceutical composition in which the quality of life (QoL) is selectively improved in one or more QoL domains. [Claim 16] A pharmaceutical composition comprising fitsiran for use in a method to improve the quality of life (QoL) in human patients with or without inhibitors of hemophilia A or who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method comprises subcutaneously administering a therapeutically effective amount of fitsiran to the required human patient, and optionally, the QoL is improved in one or more QoL domains. [Claim 17] The pharmaceutical composition according to any one of claims 13 to 16, wherein the one or more QoL domains are domains of a QoL questionnaire, and optionally the QoL questionnaire is the Haem-A-QoL Quality of Life Questionnaire for Adults with Hemophilia. [Claim 18] The pharmaceutical composition according to claim 17, wherein the administration results in an improvement indicated by a reduction of two or more units in one or more of the total score and physical health domain scores of the questionnaire, and optionally results in an improvement indicated by a reduction of three or more or four or more units. [Claim 19] The pharmaceutical composition according to any one of claims 13 to 16, wherein the one or more QoL domains are domains of a QoL questionnaire, and optionally the QoL questionnaire is a hemophilia activity list (HAL). [Claim 20] The pharmaceutical composition according to claim 19, wherein the administration results in an improvement indicated by an increase of 0.4 or more units (optionally, 0.5 or more units or 0.6 or more units) in the total score of the questionnaire. [Claim 21] The pharmaceutical composition according to any one of claims 13 to 16, wherein the one or more QoL domains are domains of a QoL questionnaire, and optionally the QoL questionnaire is the Treatment Satisfaction Questionnaire for Pharmacotherapy version 9 (TSQM-9). [Claim 22] The pharmaceutical composition according to any one of claims 13 to 16, wherein the administration results in an improvement indicated by an increase of 7 or more units, optionally, 8 or more units, 9 or more units, or 10 or more units, in one or more of the efficacy, satisfaction, and convenience domain scores of the questionnaire. [Claim 23] The pharmaceutical composition according to any one of claims 13 to 16, wherein the one or more QoL domains are domains of a QoL questionnaire, and optionally the QoL questionnaire is EuroQol 5-dimension (EQ-5D-5L). [Claim 24] The pharmaceutical composition according to claim 23, wherein the administration results in an improvement indicated by an increase of 0.02 units or more in the total score of the questionnaire, or optionally, an increase of 0.03 units or more, 0.04 units or more, or 0.05 units or more. [Claim 25] The pharmaceutical composition according to any one of claims 13 to 16, wherein the one or more QoL domains are domains of a QoL questionnaire, and optionally the QoL questionnaire is the Haemo-QoL Quality of Life Questionnaire for Children and Adolescents with Hemophilia. [Claim 26] The pharmaceutical composition according to claim 25, wherein the administration brings about an improvement indicated by a reduction of one or more units (optionally, two or more or three or more units) in the total score of the questionnaire. [Claim 27] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the dose of the aforementioned fitsilan is administered to the patient approximately once a month or once every four weeks, or once every two months or once every eight weeks. [Claim 28] The therapeutically effective amount of the fitsilan administered to the patient is about 10 to about 100 mg, and optionally, the therapeutically effective amount is about 50 mg, about 20 mg, or about 10 mg, according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16. [Claim 29] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the patient is a hemophilia A patient who has an inhibitor, or a hemophilia B patient who has an inhibitor. [Claim 30] The pharmaceutical composition according to claim 29, wherein the method further comprises administering an effective amount of BPA to treat a bleeding episode, the effective amount of BPA being reduced compared to a recommended effective amount of BPA. [Claim 31] The pharmaceutical composition according to claim 30, wherein the BPA is an activated prothrombin complex concentrate (aPCC), the single dose of the aPCC is 50 U / kg or less, optionally 30 U / kg, and optionally the administration of the aPCC is repeated for 24 hours or more as needed. [Claim 32] The pharmaceutical composition according to claim 30, wherein the BPA is recombinant factor VIIa (rFVIIa), the single dose of rFVIIa is 45 μg / kg or less, and the administration of rFVIIa is optionally repeated at intervals of 2 hours or more as needed. [Claim 33] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the patient is a hemophilia A patient who does not have an inhibitor, or a hemophilia B patient who does not have an inhibitor. [Claim 34] The pharmaceutical composition according to claim 33, further comprising administering an effective amount of a supplement factor to treat a bleeding episode, wherein the effective amount of the supplement factor is reduced compared to a recommended effective amount of the supplement factor. [Claim 35] The pharmaceutical composition according to claim 34, wherein the supplementation factor is factor VIII (FVIII), the single dose of FVIII is 20 IU / kg or less, optionally 10 IU / kg, and optionally, the administration of FVIII is repeated for 24 hours or more as needed. [Claim 36] The supplemental factor is factor IX (FIX), and the single dose of FIX is 30 IU / kg or less, optionally 20 IU / kg, and optionally, the administration of factor IX is repeated as needed, at intervals of 24 hours or more if FIX has a standard half-life, or half The pharmaceutical composition according to claim 34, which is repeated for 5 to 7 days or more in the case of FIX with an extended decay period. [Claim 37] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the subcutaneous administration step comprises administering approximately 50 mg of fitsilan once every approximately two months or once every approximately eight weeks. [Claim 38] The aforementioned subcutaneous administration step is: To obtain a measurement of the steady-state antithrombin (AT) level in the patient, and Perform one of the following steps: (i) If the AT activity level is 15-35%, administer fitsiran repeatedly at approximately 50 mg; (ii) If the AT activity level is greater than 35%, administer fitsilan subcutaneously to the patient at a dose of approximately 50 mg once every month or once every four weeks, or (iii) If the AT activity level is less than 15%, discontinue or interrupt the phytosis treatment. The pharmaceutical composition according to claim 37, further comprising: [Claim 39] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the subcutaneous administration step comprises administering approximately 50 mg of fitsilan once every approximately one month or once every approximately four weeks. [Claim 40] The aforementioned patient, (i) Clinically significant liver disease, (ii) ALT > 1.5 × Upper limit of the normal reference range (ULN), (iii) AST > 1.5 × Upper limit of the normal reference range (ULN), (iv) hepatitis C; (v) hepatitis A; (vi) Hepatitis E, and / or (vii) Hepatitis B A pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10 and 13 to 16, which does not have [the specified characteristic]. [Claim 41] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the patient is an adult or adolescent patient aged 12 years or older with hemophilia A or B, with or without inhibitors. [Claim 42] The pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the annual weight-adjusting consumption of supplement factors or BPA in the patient is reduced by the method described above. [Claim 43] By the above method, (i) The number of breakthrough bleeding episodes in the patient requiring treatment over a certain period of time, (ii) Total body weight adjusted dose of replacement factor / BPA in the patient over a certain period of time, (iii) The average consumption of replacement factors / BPA in the patient over a certain period of time, or (iv) The number of replacement factor / BPA injections required to treat breakthrough bleeding in the patient. A pharmaceutical composition according to any one of claims 1 to 2, 5 to 6, 9 to 10, and 13 to 16, wherein the amount of the substance is reduced. [Claim 44] A pharmaceutical composition comprising fitsilane for use in a method to reduce the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), the annual joint bleeding rate (AjBR), improve patient-reported outcomes (PRO), and / or improve quality of life (QoL) in human patients with hemophilia A or B, with or without inhibitors, who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective dose of fitsiran subcutaneously to human patients who require it, and Within approximately two months, one month, 28 days, or seven days of the initial dose of Fitsilan, the prophylactic supplementation or BPA treatment in the patient should be terminated. Includes, The subcutaneous administration step is as follows: (a) The patient shall be given approximately 50 mg of fitsilan subcutaneously once every two months or once every eight weeks; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; and (c) Perform one of the following steps: (i) If the AT activity level is 15-35%, repeat step (a); (ii) If the AT activity level exceeds 35%, administer phyturacin subcutaneously to the patient at a dose of approximately 50 mg once every month or once every four weeks, or (iii) If the AT activity level is less than 15%, discontinue or interrupt the phytosis treatment. A pharmaceutical composition containing the following: [Claim 45] A pharmaceutical composition comprising fitsilane for use in human patients with hemophilia A or B, with or without inhibitors, who are receiving prophylactic treatment with replacement factors or bypass agents (BPAs), to reduce annual bleeding rates (ABR), annual spontaneous bleeding rates (AsBR), annual joint bleeding rates (AjBR), improve patient-reported outcomes (PROs), and / or improve quality of life (QoL), The method described above includes subcutaneously administering a therapeutically effective amount of fitsilan to the required human patient. The subcutaneous administration step is as follows: (a) The patient shall be given approximately 50 mg of fitsilan subcutaneously once every two months or once every eight weeks; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; and (c) Perform one of the following steps: (i) If the AT activity level is 15-35%, repeat step (a); (ii) If the AT activity level exceeds 35%, administer phyturacin subcutaneously to the patient at a dose of approximately 50 mg once every month or once every four weeks, or (iii) If the AT activity level is less than 15%, discontinue or interrupt the phytosis treatment. A pharmaceutical composition containing the following: [Claim 46] A pharmaceutical composition comprising fitsilane for use in a method to reduce the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), the annual joint bleeding rate (AjBR), improve patient-reported outcomes (PRO), and / or improve quality of life (QoL) in human patients with hemophilia A or B, with or without inhibitors, who are receiving prophylactic treatment with replacement factors or bypass agents (BPA), wherein the method is: To administer a therapeutically effective dose of fitsiran subcutaneously to human patients who require it, and Within approximately two months, one month, 28 days, or seven days of the initial dose of Fitsilan, the prophylactic supplementation or BPA treatment in the patient should be terminated. Includes, The subcutaneous administration step involves administering fitsilan to the patient. (a) Approximately 50 mg once every two months or once every eight weeks; (b) Approximately 50 mg once every month or once every four weeks; (c) Approximately 20 mg once every two months or once every eight weeks; (d) Approximately 20 mg once every month or once every four weeks; or (e) Approximately 10 mg once every month or once every four weeks A pharmaceutical composition, including one administered subcutaneously. [Claim 47] A pharmaceutical composition comprising fitsilane for use in human patients with hemophilia A or B, with or without inhibitors, who are receiving prophylactic treatment with replacement factors or bypass agents (BPAs), to reduce annual bleeding rates (ABR), annual spontaneous bleeding rates (AsBR), annual joint bleeding rates (AjBR), improve patient-reported outcomes (PROs), and / or improve quality of life (QoL), The method described above includes subcutaneously administering a therapeutically effective amount of fitsilan to the required human patient. The subcutaneous administration step involves administering fitsilan to the patient. (a) Approximately 50 mg once every two months or once every eight weeks; (b) Approximately 50 mg once every month or once every four weeks; (c) Approximately 20 mg once every two months or once every eight weeks; (d) Approximately 20 mg once every month or once every four weeks; or (e) Approximately 10 mg once every month or once every four weeks A pharmaceutical composition, including one administered subcutaneously.

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