Use of non-tumezidine in treatment of hemophilia A and hemophilia B

Abstract

The present disclosure provides methods for treating a patient suffering from hemophilia A or hemophilia B using non-tall brocide.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application Nos. 63 / 350,398, filed June 8, 2022; 63 / 359,695, filed July 8, 2022; 63 / 382,227, filed November 3, 2022; 63 / 386,491, filed December 7, 2022; 63 / 479,337, filed January 10, 2023; 63 / 483,700, filed February 7, 2023; and 63 / 489,611, filed March 10, 2023. The contents of these priority applications are incorporated herein by reference in their entirety. Sequence Listing

[0002] This application contains a sequence listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy created on June 2, 2023 is named 122548WO020.xml and is 8,023 bytes in size. 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), resulting in severe defects in thrombin generation, impaired hemostasis, and an increased risk of bleeding. Hemophilia A affects approximately 1 in 4,000 males, while hemophilia B is five times less common, affecting approximately 1 in 20,000 males. The disease phenotypes of hemophilia A and hemophilia B present in a similar manner.

[0004] Based on the activity of clotting factors relative to normal values ​​(plasma factor levels of 50% to 150% in healthy, non-hemophilic patients), hemophilia is classified as mild (factor levels of 6% to 30%), moderate (factor levels of 1% to 5%), or severe (factor levels <1%). Patients with mild hemophilia commonly experience bleeding after serious injury or surgery. Patients with moderate hemophilia experience bleeding episodes associated with injury and may have spontaneous bleeding episodes. Patients with severe hemophilia experience massive bleeding upon injury and may have frequent spontaneous bleeding episodes, leading to debilitating musculoskeletal injuries, which can severely impair the patient's mobility and quality of life (QoL).

[0005] The purpose of the hemostatic system is to maintain the integrity of the vascular system by preventing vascular lesions from bleeding and combining multiple options for preventing thrombosis. This hemostatic balance is achieved by coordinating and regulating procoagulant factors (e.g., factor V (FV), factor VII (FVII), FVIII, FIX, factor X (FX)) and anticoagulants (e.g., antithrombin, protein C / protein S and tissue factor pathway inhibitors). Recent studies have shown that the common inheritance lacking natural anticoagulants can help alleviate the phenotype of the patient suffering from hemophilia.

[0006] Antithrombin (AT) is a natural anticoagulant expressed by the liver that plays a key role in inhibiting thrombin. AT acts as an inhibitor of factor VIIa and factor Xa, which are usually at normal levels in patients with hemophilia A or hemophilia B. A large number of preclinical in vitro and in vivo studies have shown that reducing AT is a potentially safe and effective method for correcting thrombin generation and controlling microvascular and macrovascular traumatic bleeding episodes in both hemophilia A and hemophilia B. Therefore, inhibiting the generation of AT is being studied as a potential hemophilia treatment method.

[0007] For hemophilia patients who do not have inhibitory antibodies to FVIII or FIX, replacement with factor concentrates is the current standard of care. Although the current standard of care for factor replacement therapy (whether administered sporadically or as routine prophylaxis) is widely recognized and is safe and effective, its treatment burden is high due to the need for intravenous (IV) administration on a frequent schedule (2 to 3 times per week or more) to prophylactically maintain hemostasis. In developing countries, the availability of factor concentrates may also be limited. In addition, patients receiving factor concentrates may develop inhibitory antibodies to the factors, a result that is associated with a poor prognosis and the need to change the treatment regimen to infusion of bypassing agents (BPA).

[0008] Hemophiliacs who develop inhibitory antibodies to factor concentrates represent a distinct subset of the population; these patients often experience bleeding episodes that are more difficult to treat, resulting in increased morbidity and mortality. Development of inhibitors to infused factors occurs primarily in severe hemophilia and is more common in hemophilia A (up to 39% of patients) than in hemophilia B (1% to 3.5% of patients), with the risk greatest during early exposure. These "inhibitor" patients may qualify for immune tolerance therapy; however, in most cases, bleeding episodes require hemostatic intervention with intravenously (IV) administered BPA (i.e., recombinant factor VIIa (rVIIa) or activated prothrombin complex concentrate (aPCC)) as either prophylaxis of bleeding episodes or as an occasional, on-demand treatment of bleeding episodes.

[0009] Therefore, there remains a need to provide subjects with hemophilia with alternative treatments (e.g., subcutaneous therapy) that can effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, including those with inhibitors, while reducing the burden of treatment, improving clinical outcomes, and enhancing quality of life. Summary of the invention

[0010] The present disclosure provides methods for the prophylactic treatment of hemophilia A or B with or without inhibitors using fetucillin. The patients herein have previously received different prophylaxis. In some embodiments, the present method reduces the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR) and / or annualized joint bleeding rate (AjBR) in human subjects with hemophilia A or B with or without inhibitors who have been treated prophylactically with replacement factors or BPA, and / or improves patient-reported outcomes (e.g., quality of life). In some embodiments, the method comprises subcutaneously administering a therapeutically effective amount of fetucillin to a human subject in need thereof, and terminating the prophylactic replacement factor or BPA treatment of the subject within about two months, about one month, or optionally about 28 days or about seven days of the first dose of fetucillin. In some embodiments, the method comprises subcutaneously administering a therapeutically effective amount of fetucillin to a human subject in need thereof. In some embodiments, the method reduces a patient's annualized weight-adjusted replacement factor or BPA consumption, a patient's total weight-adjusted replacement factor / BPA dose, a patient's average replacement factor / BPA consumption in a given time period, the number of replacement factor / BPA injections required to treat breakthrough bleeding in a patient, or the number of breakthrough bleedings required to be treated in a given time period.

[0011] Also provided herein are fetocillin for use in these treatment methods, the use of fetocillin in the preparation of a medicament for treating hemophilia A or B with or without inhibitors in the methods herein, and pharmaceutical compositions comprising fetocillin for use in the present treatment methods.

[0012] Other features, objectives and advantages of the present invention become clear in the following specific embodiments. However, it should be understood that the specific embodiments, although indicating embodiments and aspects of the present invention, are provided only by way of illustration and are not intended to be limiting. According to the specific embodiments, various changes and modifications within the scope of the present invention will become clear to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The expanded structural formula, chemical formula and molecular mass of fetocillin (sodium form) are shown.

[0014] Figure 2Shows the design of a clinical trial study of patients treated prophylactically with replacement factors or BPA prior to starting fetucillin therapy. AT: antithrombin. For the subgroup of cohort A patients who were added directly to the fetucillin treatment period, see Figure 3 "a": Patients will continue to receive prescribed factor or BPA prophylaxis during the first 7 days of the onset period. "b": AT activity levels will be monitored at monthly intervals after the final fentanyl dose until activity levels recover to approximately 60% (according to the central laboratory) or as determined by the Investigator in consultation with the Study Medical Monitor.

[0015] Figure 3 The study design for a clinical trial is shown for patients with hemophilia B who have inhibitory antibodies to factor IX and have not adequately responded to BPA prophylaxis (historical ABR ≥ 20) and who are therefore not currently receiving prophylactic treatment with BPA. These patients were started directly on fetucillin without participating in Figure 2 The six-month factor / BPA phase described in . "a": Patients will receive prescribed factor or BPA prophylaxis for the first 7 days of the initiation phase. "b": Figure 2 The meaning is the same as in.

[0016] Figure 4 Shown are the median ABRs for patients treated prophylactically with fetocilan or factor / BPA.

[0017] Figure 5 AjBR and AsBR are shown for patients treated prophylactically with fetocillin or factor / BPA.

[0018] Figure 6 The health-related quality of life burden for all clinical trial patients six months before the start of the study (ie, month -6) is shown.

[0019] Figure 7 Haem-A-QoL scores are shown for patients treated prophylactically with fetocillin or factor / BPA.

[0020] Figure 8 Transformed Haem-A-QoL scores are shown for patients treated prophylactically with fetocillin or factor / BPA.

[0021] Fig. 9 Shown are TSQM-9 scores for patients treated prophylactically with fetocilan or factor / BPA.

[0022] Fig.10 Shown are TSQM-9 scores for patients treated prophylactically with fetocilan or factor / BPA.

[0023] Fig.11is a graph showing mean AT levels in patients treated with fetocilan.

[0024] Fig.12 is a graph showing the mean change in peak thrombin generation (TG) in patients treated prophylactically with fetocillin.

[0025] Fig.13 is a bar graph showing bleeding events (median observed ABR, AjBR and AsBR) for adolescents enrolled in the clinical trial.

[0026] Fig.14 is a bar graph showing the mean change from baseline in Haemo-QoL transition total score for adolescents enrolled in the clinical trial. For fetucillin 80 mg prevention, n=14.

[0027] Fig.15 is a pre-study investigation into the effects of hemophilia and its treatment on patients. a The percentages are based on the 19 participants who asked this question; b The percentages are based on the 22 participants who were asked this question; c Percentages are based on 20 participants who were asked this question; d The percentages are based on the 18 participants who were asked this question; e Percentages are based on 16 participants who were asked this question.

[0028] Fig.16 is a bar graph showing the magnitude and significance of improvement in patients treated prophylactically with fetocillin.

[0029] Fig.17 Shown are participant satisfaction ratings for patients receiving prophylactic treatment with fetocillin. DETAILED DESCRIPTION

[0030] The disclosure features methods of using fetucillin for routine prophylaxis to reduce the frequency of bleeding episodes in adult and adolescent patients (≥12 years of age) with or without inhibitors who have hemophilia, e.g., hemophilia A (congenital factor VIII deficiency) or hemophilia B (congenital factor IX deficiency). These methods reduce the frequency of total bleeding, including spontaneous bleeding and joint bleeds, compared to the frequency of bleeding in patients treated prophylactically with replacement factors or BPA instead of fetucillin. These methods also improve patient-reported outcomes (PROs) and quality of life (QoL) compared to PROs and QoL in patients treated prophylactically with replacement factors or BPA.

[0031] In some embodiments, the patient is an adolescent patient (i.e., a patient aged 12-17 years (inclusive)). Adolescence is associated with significant physical, psychological, and social changes. Hemophilia may present additional challenges to adolescents because they may not experience the same social and physical activities as their peers (see, e.g., Hoefnagels et al., Patient Prefer Adherence [Patient Preference Compliance] (2020) 14: 163-71).

[0032] A hemophilia A or B patient with an inhibitor is one that has developed alloantibodies to a factor that he / she has previously received (e.g., Factor VIII for hemophilia A patients or Factor IX for hemophilia B patients). Hemophilia A or B patients with inhibitors may be difficult to treat with alternative coagulation factor therapy. Patients without inhibitors are those that do not have such alloantibodies. The present treatment method may be beneficial to hemophilia A patients with inhibitors as well as hemophilia B patients with inhibitors. As used herein, "hemophilia A or B with inhibitors" refers to hemophilia A with inhibitors or hemophilia B with inhibitors. As used herein, a patient refers to a human patient.

[0033] The present invention is based in part on the discovery that patients treated prophylactically with fetocillin have improved outcomes (e.g., reduced bleeding rates and improved quality of life) compared to patients given standard of care prophylactic therapy (replacement factor or BPA). The clinical trial protocol and results disclosed herein are the first direct comparison of these two treatment regimens in hemophilia A and B patients with or without inhibitors.

[0034] In some embodiments, the mechanism of action and formulation of fetocillin allows only 6-12 subcutaneous injections per year to achieve consistent bleeding protection. As a subcutaneously administered drug, fetocillin has the benefits of reduced administration time, less pain due to reduced needle size and volume, and less equipment and training required compared to intravenously administered drugs. Reducing bleeding and reducing the overall treatment and disease burden through fetocillin prophylaxis can improve the quality of life of people with hemophilia. I. Fetocilan pharmaceutical composition

[0035] Hemophilia causes a severe defect in thrombin generation, and in addition, the severity of hemophilia is associated with an inability to generate thrombin. Without being bound by theory, it is believed that a reduction in the level of antithrombin (AT) mediated by fetocillin will increase thrombin generation, and thus improve hemostasis in patients with hemophilia. Antithrombin is encoded by the SERPINC1 gene.

[0036] Fetosilan, whose structure has been described herein, is a synthetic, chemically modified, double-stranded small interfering RNA (siRNA) oligonucleotide covalently linked to a triantennary N-acetyl-galactosamine (GalNAc) ligand that targets AT3 mRNA in the liver, thereby inhibiting the synthesis of antithrombin. The nucleosides in each strand of Fetosilan are linked by 3'-5' phosphodiester or phosphorothioate linkages to form the sugar-phosphate backbone of the oligonucleotide.

[0037] The sense strand and antisense strand of non-toxilan contain 21 and 23 nucleotides respectively. The 3' end of the sense strand is conjugated with a GalNAc-containing part (called L96) by a phosphodiester linkage. The sense strand contains two continuous thiophosphate linkages at its 5' end. The antisense strand contains four thiophosphate linkages, two at the 3' end and two at the 5' end. The 21 nucleotides of the sense strand are hybridized with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs and two bases at the 3' end of the antisense strand. See also U.S. Patent 9,127,274, U.S. Patent 11,091,759 and WO 2019 / 014187.

[0038] The two nucleotide chains of phenobarbital 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), in 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 linkage sodium salt "-ps-" = 3'-5' phosphorothioate linkage sodium salt and wherein L96 has the formula:

[0039] The expanded structural formula, molecular formula and molecular weight of fetocillin (sodium form) are shown in Figure 1 As used herein, the term 2'-fluoroadenosine is used interchangeably with the term 2'-deoxy-2'-fluoroadenosine; the term 2'-fluorocytidine is used interchangeably with the term 2'-deoxy-2'-fluorocytidine; the term 2'-fluoroguanosine is used interchangeably with the term 2'-deoxy-2'-fluoroguanosine, and the term 2'-fluorouridine is used interchangeably with the term 2'-deoxy-2'-fluorouridine.

[0040] The structure of fetosilan can also be described by the following diagram, where X is O:

[0041] For use in the present treatment methods, fetocilan may be provided in a pharmaceutical composition comprising fetocilan and a pharmaceutically acceptable excipient. In certain embodiments, fetocilan is in the form of a sodium salt.

[0042] In some embodiments, fetuxilan is provided in 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, values ​​between the recited ranges and values ​​are also intended to be part of this disclosure. In addition, ranges of values ​​using a combination of any of the recited values ​​as upper and / or lower limits are intended to be included. In further embodiments, the pharmaceutical composition comprises fetuxilan at a concentration of about 6.25 mg / mL, about 12.5 mg / mL, about 25 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, or about 200 mg / mL.

[0043] Unless otherwise specified, the weight of fetocillin described in this disclosure is the weight of fetocillin free acid (active moiety), even if fetocillin is administered to a patient subcutaneously in its sodium form (in aqueous solution). For example, 100 mg / mL fetocillin means that each mL contains 100 mg of fetocillin free acid (equivalent to 106 mg of fetocillin sodium, the drug substance).

[0044] In some embodiments, the pharmaceutical composition comprises fetosilan in phosphate buffered saline. The phosphate concentration in the solution may be about 1 to 10 mM (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 mM), and the pH is 6.0-8.0. The pharmaceutical composition herein may include a preservative, such as EDTA. Alternatively, the pharmaceutical composition is preservative-free. In a particular embodiment, the fetosilan pharmaceutical composition is preservative-free, and each mL of 5 mM phosphate buffered saline (PBS) solution comprises about 100 mg of fetosilan, consists of or is substantially composed of about 100 mg of fetosilan. The PBS solution is composed of sodium chloride, disodium hydrogen phosphate (heptahydrate), and sodium dihydrogen phosphate (monohydrate). The pH of the composition can be adjusted to 7.0 using sodium hydroxide solution and diluted phosphoric acid.

[0045] The pharmaceutical composition can be provided in a container (e.g., a vial or a syringe). The 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, such as a disposable prefilled syringe), wherein each container contains about 10 mg to about 100 mg of fetucillin (e.g., about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, or about 80 mg). Fetucillin can be provided in a solid form in a container and reconstituted in an aqueous solution (e.g., PBS) before use, wherein the reconstituted solution contains about 1 mg / mL to about 150 mg / mL (e.g., 100 mg / mL) of fetucillin. In some embodiments, fetucillin is provided in a disposable glass vial or a disposable prefilled syringe (e.g., a syringe with a safety system) in the form of a sodium salt. In a further embodiment, each vial or syringe contains about 80 mg of fetocillin in about 0.8 mL of 5 mM phosphate buffered saline solution (pH 7.0) (or about 50 mg of fetocillin in about 0.5 mL of 5 mM phosphate buffered saline solution, about 20 mg of fetocillin in about 0.2 mL of 5 mM phosphate buffered saline solution, or about 10 mg of fetocillin in about 0.1 mL of 5 mM phosphate buffered saline solution); and the solution is administered to the patient by subcutaneous injection. The solution can be stored at 2 to 30° C. (e.g., 2 to 8° C.).

[0046] In a specific embodiment, the fetocillin composition for subcutaneous injection contains fetocillin in 5 mM phosphate buffered saline at pH 7.0, the phosphate buffered saline having 0.64 mM NaH 2 PO 4 、4.36mM Na 2 HPO 4 And 84mM NaCl. In certain embodiments, the composition of the fetocillin solution for subcutaneous injection is shown in Table 1 below: Table 1. Exemplary formulations qs: appropriate amount.

[0047] Although the fetocilan dosage weights described herein refer to the weight of fetocilan free acid (active moiety), administration of fetocilan to a patient herein refers to administration of fetocilan sodium (drug substance) provided in a pharmaceutically suitable aqueous solution (e.g., phosphate buffered saline at physiological pH). II. Therapeutic uses of fetocilan

[0048] Fetosilan can inhibit the production of antithrombin (AT) in the liver. As an anticoagulant, AT regulates hemostasis by directly targeting thrombin production or by inactivating uncomplexed FXa, which in turn reduces the production of thrombin (Quinsey et al., Int J Biochem Cell Biol. [International Journal of Biochemistry and Cell Biology] (2004) 36 (3): 386-9). Fetosilan can be used to treat patients with impaired hemostasis. For example, fetosilan can be used to treat patients with hemophilia A or B with or without inhibitors, for routine prevention to prevent or reduce the frequency of bleeding episodes. In a specific embodiment, fetosilan is used to treat adults and adolescents (≥12 years old) with or without inhibitors for hemophilia A or B (congenital factor VIII or factor IX deficiency). The present method includes administering a therapeutically effective amount of fetosilan to a hemophiliac (e.g., hemophilia A or B patient) in need. "Therapeutically effective amount" refers to the amount of fetosilan that helps patients reach the desired clinical endpoint.

[0049] In some embodiments, patients with hemophilia A or B with or without inhibitors are treated with a subcutaneous dose of about 50 mg of fetucillin per dose about every two months (or about every eight weeks). In other embodiments, patients with or without inhibitors for hemophilia A or B are treated with a subcutaneous dose of about 50 mg of fetucillin about every month (or about every four weeks). In still other embodiments, patients with or without inhibitors for hemophilia A or B are treated with a subcutaneous dose of about 80 mg of fetucillin about every two months (or about every eight weeks). In still other embodiments, patients with or without inhibitors for hemophilia A or B are treated with a subcutaneous dose of about 80 mg of fetucillin about every month (or about every four weeks). In still other embodiments, patients with or without inhibitors for hemophilia A or B are treated with a subcutaneous dose of about 20 mg of fetucillin about every two months (or about every eight weeks). In yet other embodiments, patients with hemophilia A or B with or without inhibitors are treated with a subcutaneous dose of about 20 mg of fetucillin about every month (or about every four weeks). In yet other embodiments, patients with hemophilia A or B with or without inhibitors are treated with a subcutaneous dose of about 10 mg of fetucillin about every month (or about every four weeks). III. Administration of the fetocilan pharmaceutical composition

[0050] The fetucillin pharmaceutical composition can be administered by any means known in the art, including but not limited to intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration or hepatic portal vein administration. In certain embodiments, the pharmaceutical composition is administered by subcutaneous injection at a dosage strength of, for example, about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 40 mg to about 90 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, or about 50 mg to about 80 mg) per dose. In a specific embodiment, as described above, fetucillin is administered subcutaneously at a dosage of about 10 mg, about 20 mg, about 50 mg, or about 80 mg (weight of active portion) per dose in PBS solution.

[0051] Multiple doses of fetucillin can be administered to a subject at intervals of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, or about 1 month, about 2 months, or about 3 months. In specific embodiments, a fixed dose of fetucillin (e.g., about 50 mg or about 80 mg subcutaneous injection) is administered to a hemophilia patient (e.g., a hemophilia A or hemophilia B patient 12 years of age or older who has or has not developed an inhibitor) about once every four weeks, or about once a month, or about once every eight weeks, or about once every other month.

[0052] In some embodiments, the pharmaceutical composition can be administered with other drugs and / or other treatments (e.g., drugs and / or treatments currently used to treat bleeding disorders). For example, in certain embodiments, fetocillin is administered in combination with a second agent that can be used to treat hemophilia A and / or B. Examples of such a second dose are fresh frozen plasma (FFP); rFVIIa; aPCC; recombinant or plasma-derived FVIII or FIX; virally inactivated, vWF-containing FVIII concentrate; desensitization therapy, which may include high-dose FVIII or FIX, and steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide; plasma exchange combined with immunosuppression and FVIII or FIX infusion with or without antifibrinolytic therapy; immune tolerance induction (ITI) with or without immunosuppressive therapy (e.g., cyclophosphamide, prednisone and / or anti-CD20); desmopressin acetate (DDAVP); antifibrinolytic drugs, such as aminocaproic acid and tranexamic acid; antihemophilic agents; corticosteroids; immunosuppressants; and estrogens. The non-toxicam composition and the additional therapeutic agent and / or treatment can be administered simultaneously and / or in the same combination (e.g., parenterally), or the additional therapeutic agent can be administered as part of a separate composition or at a separate time and / or by another method known in the art or described herein. IV. Treatment with replacement factors or BPA

[0053] The standard of care for the treatment of hemophilia A and B is routine prophylactic use of replacement factors or bypassing agents (BPA). In some embodiments, patients treated with the current treatment methods have previously 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 by intravenous injection. Table 2. Factor or bypass agent prevention requirements Type of factor or BPA replacement Frequency of application Standard half-life FVIII Twice a week Extended half-life FVIII Once a week Standard half-life FIX Once a week Extended half-life FIX Once every two weeks APC Twice a week rFVIIa Every other day

[0054] In some embodiments, a hemophilia patient with an inhibitor (eg, a hemophilia B patient with an inhibitor) does not respond adequately to BPA prophylaxis and is therefore not treated prophylactically with BPA.

[0055] In some embodiments of the invention, patients undergoing prophylactic treatment with fetucillin have previously undergone prophylactic treatment with replacement factor or BPA. The first 28 days of fetucillin treatment is referred to as the onset period. During the onset period, AT reduction will progress toward therapeutic levels. During the onset period, patients continue to undergo factor or BPA prophylaxis at the lowest frequency as shown in Table 2 for the first seven days. After day 7 of the fetucillin treatment period, factor concentrate or BPA is administered only when needed during a bleeding episode or prior to an invasive medical procedure. Recommendations for management of bleeding episodes

[0056] During factor or bypass agent prophylaxis : Bleeding management therapy with factor or BPA was administered based on local standard practice for treating patients with hemophilia.

[0057] During treatment with fetocillin : Given the mechanism of action and pharmacodynamic profile of fetucillin, the dose of factor or BPA required to safely and effectively treat breakthrough bleeding episodes in patients receiving fetucillin during the fetucillin treatment period will be lower than the standard prescription. Following administration of fetucillin, AT reduction will progress toward therapeutic levels. After only seven days of the initial fetucillin dose, AT levels in most patients rapidly reach or fall below 60% residual activity. At 14 days after dosing, 94% of patients are expected to have an AT reduction of >50%, with a median value of 66.8%. Based on these AT dynamics, patients are advised to continue their standard factor or BPA regimen for the first few days after starting fetucillin administration, and to develop regimen-specific bleeding management guidelines to reduce factor or BPA on Day 8 and beyond (Table 3). Table 3. Dosing Guidelines for Bleeding Management for Specific Products

[0058] Importantly, after day 7 of the fetocillin treatment period, patients did not use factor, BPA, or other hemostatic agents as prophylaxis to prevent bleeding episodes, including doses associated with anticipated hemostatic challenges (e.g., physical activity).

[0059] Day 1 to Day 7 of Fetoxilan treatment period : Patients continued on their standard factor or BPA regimen.

[0060] Day 8 and beyond of fetuxiram treatment : When a patient presents with symptoms that may be consistent with a bleeding episode, follow these steps: -Administer a single dose according to the guidelines in Table 3. - Instruct patients to re-evaluate symptoms of bleeding within 24 hours for treatment with FVIII, FIX, or aPCC, and within 2-3 hours for treatment with rFVIIa. a. FIX extended half-life should not be administered more frequently than every 5-7 days. - Doses should not be administered less than 24 hours apart (except for rFVIIa as shown in Table 3). -Do not exceed the maximum recommended dose for the treatment regimen shown in Table 3. - Antifibrinolytic drugs are not used in combination with factors or BPA. Factor / BPA consumption in patients receiving prophylactic treatment with fetocillin

[0061] In some embodiments, the present treatment method reduces the patient's replacement factor / BPA consumption, including the patient's annualized weight-adjusted replacement factor or BPA consumption. In some embodiments, the present treatment method reduces the annualized weight-adjusted aPCC consumption for bleeding therapy by about 98.9%; reduces the annualized weight-adjusted rFVIIa consumption for bleeding therapy by about 96.8%; reduces the annualized weight-adjusted FVIII consumption for bleeding therapy by about 79.4%; and / or reduces the annualized weight-adjusted FIX consumption for bleeding therapy by 93.8%.

[0062] In some embodiments, the present treatment methods reduce the number of treated breakthrough bleedings in a patient. In some embodiments, the present treatment methods reduce the total weight-adjusted replacement factor / BPA dose, the average consumption of replacement factor / BPA, or the number of injections of replacement factor / BPA required to treat breakthrough bleeding in a patient. The present treatment methods can reduce the number of patients requiring replacement factor / BPA for breakthrough bleeding treatment. V. Patient selection

[0063] The present treatment can be used to prophylactically treat patients with hemophilia A or hemophilia B. In some embodiments, the patient is a male aged ≥12 years with severe hemophilia A or B. The diagnosis of severe hemophilia is based on a factor VIII level <1% (for hemophilia A) or a factor IX level ≤2% (for hemophilia B). In some embodiments, the patient has been using replacement factors or bypassing agents to prophylactically manage bleeding episodes for at least six months prior to the start of treatment.

[0064] In some embodiments, the patient has inhibitory antibodies to Factor VIII or Factor IX (ie, the patient has an inhibitor). A patient is defined as having an inhibitor if he or she meets at least one of the following Nijmegen-modified Bethesda assay result criteria: a. Inhibitor titer before treatment ≥ 0.6 BU / mL, or b. The inhibitor titer before treatment was <0.6BU / mL, and there is medical record proving that the titer was ≥0.6BU / mL for two consecutive times, or c. Inhibitor titer before treatment <0.6BU / mL, with medical records proving the presence of anamnestic response.

[0065] In some embodiments, the patient has no inhibitory antibodies to Factor VIII or Factor IX (ie, the patient is inhibitor-free). A patient is defined as an inhibitor-free patient if he or she meets at least one of the following Nijmegen Modified Bethesda assay result criteria: a. The inhibitor titer of Nijmegen modified Bethesda assay before treatment was <0.6BU / mL, b. Has not used bypassing agents to treat bleeding episodes in at least the last six months prior to treatment, and c. No history of immune tolerance induction therapy in the past three years before treatment.

[0066] In some embodiments, the patient has inhibitory antibodies to Factor VIII or Factor IX (Cohort A) and has experienced at least two bleeding episodes requiring BPA treatment in the last six months prior to treatment. In some embodiments, the patient has inhibitory antibodies to Factor VIII or Factor IX but is not being treated prophylactically with a bypassing agent. In some embodiments, the patient has hemophilia B, has inhibitory antibodies to Factor IX as defined above, and has not adequately responded to BPA treatment prior to treatment with fentanyl (historical ABR ≥ 20).

[0067] In some embodiments, patients do not have inhibitory antibodies to Factor VIII or Factor IX (Cohort B) and have experienced at least one bleeding episode requiring factor therapy within the last 12 months prior to treatment.

[0068] In some embodiments, the patient has been prescribed (and maintained) prophylactic treatment for hemophilia with factor concentrates or BPA for at least six months prior to treatment. The prophylactic treatment regimen must be consistent with the approved product prescribing information or local recommendations, allow for adjustment based on individual patient response, and be designed to reduce spontaneous bleeding.

[0069] In some embodiments, the patient does not have a known coexisting bleeding disorder other than hemophilia A or B (i.e., Von Willebrand's disease), other 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 before treatment may not be <60%. In some embodiments, the patient does not have clinically significant liver disease indicated by: (i) INR>1.2; ALT and / or AST>1.5×upper limit of normal reference range (ULN); (ii) total bilirubin>ULN (for patients with Gilbert's syndrome,>1.5×ULN); (iii) history of portal hypertension, esophageal varices, or hepatic encephalopathy; or (iv) ascites found on physical examination.

[0070] In some embodiments, the patient is not positive for antibodies to hepatitis C virus. Patients who are positive for antibodies to hepatitis C virus can be treated with the present method only if they: a. Completed curative therapy at least 12 weeks prior to study entry and achieved a sustained virologic response as evidenced by negative HCV RNA prior to treatment, or they had spontaneously cleared the infection as evidenced by negative HCV RNA prior to treatment, and b. No evidence of cirrhosis based on FibroScan <12.5 kPa (if available) or FibroTest score <0.75 and APRI <2 (if FibroScan is not available).

[0071] In some embodiments, the patient does not have acute hepatitis, i.e., 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 does not have (i) a platelet count ≤ 100,000 / μL, (ii) does not appear HIV positive, but has a CD4 count < 200 cells / μL, and / or (iii) an estimated glomerular filtration rate of not ≤ 45 mL / min / 1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] formula).

[0072] Patients 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).

[0073] In some embodiments, the patient does not have a history of antiphospholipid antibody syndrome or arterial or venous thromboembolism, atrial fibrillation, severe valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. Patients who have experienced thrombosis associated with indwelling venous access can be treated with the present method. In some embodiments, the patient has not had a malignancy within two years, except for basal cell carcinoma or squamous cell carcinoma of the skin, which has been successfully treated.

[0074] In some embodiments, the patient meets one or more inclusion criteria and one or more exclusion criteria detailed in Example 1 below. VI. Treatment Outcomes and Evaluation

[0075] In some embodiments, the patient is treated with fetocillin for a period of seven months.

[0076] In some embodiments, the present treatment method reduces the frequency of bleeding episodes in patients. A bleeding episode is defined as the occurrence of any bleeding requiring replacement factor or BPA infusion, such as joint bleeding, muscle or mucosal bleeding. The definitions of the types of bleeding episodes described below are based on the consensus of the International Society of Thrombosis and Hemostasis (ISTH) (Blanchette et al., J Thromb Haemost. [Journal of Thrombosis and Hemostasis] (2014) 12 (11): 1935-9).

[0077] The start time of a bleeding episode is defined as the time when the symptoms of a bleeding episode first appeared. Bleeding or any bleeding symptoms at the same site occurring within 72 hours after the last injection for a bleeding episode at the treatment site are considered part of the original bleeding event and are counted as one bleeding episode for the ABR. Any bleeding symptoms starting more than 72 hours from the last injection for a bleeding episode at the treatment site will constitute a new bleeding event.

[0078] In some embodiments, the present treatment methods result in a 50% or greater reduction in the estimated annualized bleeding rate (ABR) of the treated population compared to a population treated prophylactically with replacement factors or BPA (e.g., a 60% or greater reduction). In some embodiments, the median ABR observed in a population treated with fetocillin is reduced to one or less, such as to zero. In some embodiments, the historical ABR of the human subject is greater than 1 (i.e., greater than 2, 3, 4, 5, 6, or 7).

[0079] Spontaneous bleeding episodes are bleeding events without an obvious or known cause, particularly into joints, muscles, and soft tissues. A joint bleeding episode is characterized by an abnormal sensation (“aura”) within the joint, accompanied by 1) increased swelling or warmth in the skin over the joint, 2) increased pain, or 3) a gradual loss of range of motion or difficulty using a limb compared to baseline. Muscle bleeds may be characterized by pain, swelling, and loss of motion over the affected muscle group. A target joint is defined as a joint in which three or more spontaneous bleeding episodes occur in a single joint within a six-month consecutive period; a joint is no longer considered a target joint if there are less than or equal to two bleeding episodes in the joint within a 12-month consecutive period. A traumatic bleeding episode is a bleeding episode caused by a known injury or trauma. Bleeding episodes sustained during sports and recreation are counted as traumatic bleeding episodes.

[0080] In some embodiments, the treatment method reduces the estimated annualized spontaneous bleeding rate (AsBR) of the treated population by 40% or more (e.g., by 50% or more) compared to a population treated prophylactically with a replacement factor or BPA. In some embodiments, the median AsBR observed in a population treated with fetocillin is reduced to one or less, such as to zero. In some embodiments, the historical AsBR of the human subject is greater than two.

[0081] In some embodiments, the treatment method results in a 40% or greater reduction (e.g., a 50% or greater reduction) in the estimated annualized joint bleed rate (AJBR) in the treated population compared to a population treated prophylactically with replacement factors or BPA. In some embodiments, the median annualized joint bleed rate observed in the population treated with fetocillin is reduced to one or less, such as to zero. In some embodiments, the subject's historical AJBR is greater than two.

[0082] In some embodiments, the present treatment methods produce improved patient-reported outcomes (PROs), as further described below. In some embodiments, the therapeutic efficacy can be measured by the reduction in disease severity assessed by the patient based on an effective and reliable hemophilia-specific PRO tool, such as the Adult Hemophilia Quality of Life Questionnaire ("Haem-A-QoL"; von Mackensen et al., Haematologica [Hematology] (2005) 90 (s2): 115-6, Abstract [Abstract] 0290; Wyrwich et al., Haemophilia [Hemophilia] (2015) 21 (5): 578-84). Any positive changes that produce, for example, a reduction in disease severity measured using an appropriate scale indicate that adequate treatment has been performed using the pharmaceutical composition described herein.

[0083] Hemophilia directly affects the patient's health-related quality of life (HRQoL) due to its associated symptoms, functional limitations and treatment burden. Improving HRQoL is a key aspect of hemophilia disease management. As determined by a carefully designed detailed questionnaire, the present method improves the patient's HRQoL. For example, the HRQoL of an adult patient (17 years of age or older, such as 18 years of age or older) can be measured by the Haem-A-QoL questionnaire. In a particular embodiment, the HRQoL of an adult patient can be measured by a score in the Haem-A-QoL. See, e.g., von Mackensen et al., Value in Health. (2005) 8(6):A127; von Mackensen et al., J Thrombosis and Haemostasis. (2005) 3(Suppl 1):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; Wyrwich, supra. The Haem-A-QoL questionnaire consists of 46 items covering 10 domains, including physical health (5 items), feelings (4 items), self-view (5 items), sports and leisure (5 items), work and school (4 items), management of hemophilia (3 items), treatment (8 items), future (5 items), family plans (4 items), and partnerships and sexual behavior (3 items).

[0084] All Haem-A-QoL items are measured based on a 5-point frequency scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, and 5 = all the time). The "Sports and Recreation", "Work and School", and "Family Planning" domains also have a "not applicable" answer option when the question is not applicable to the participant. The "Total Score" is also used to represent the average of all 10 domains of the Haem-A-QoL questionnaire. The Haem-A-QoL domain scores and the total score are converted to a scale of 0-100, with higher scores indicating more severe impairment. A decrease in the score relative to the corresponding baseline score (the score before the assessment of treatment) indicates that the patient's quality of life has improved. The questionnaire can be conducted before treatment and after treatment with one or more doses (e.g., two or more doses, three or more doses, four or more doses, five or more doses, or six or more doses) of fetucillin (e.g., about 50 mg or about 80 mg subcutaneously administered about once every four weeks or about once a month). For example, the questionnaire may be administered at 8, 12, 16, 20, 24, 25, 26, or 27 weeks after initiation of fetuin therapy.

[0085] In some embodiments, the treatment improves the patient's quality of life in one or more QoL areas (e.g., hemophilia-specific QoL areas). These QoL areas include, for example, areas related to physical health, feelings, self-view, sports and leisure, work and school, hemophilia management, treatment, future, family planning and / or partnership and sexual behavior. Improvements in these areas can be assessed by patient-reported outcomes (PROs) and can be assisted by questionnaires. For example, a patient can report improvements in these areas to his / her doctor, and / or improvements in these areas can be scored by QoL questionnaires.

[0086] In some embodiments, the therapy improves scores in at least one Haem-A-QoL domain (e.g., physical health, feelings, self-view, sports and leisure, work and school, hemophilia management, treatment, future, family plans and / or partnerships, and sexuality) compared to scores in patients treated prophylactically with replacement factors or BPA, and / or improves the total Haem-A-QoL score. In particular, the present methods can improve the quality of life of patients with hemophilia, including improvements (e.g., relief and disappearance) in patient-reported hemophilia-related symptoms (e.g., painful swelling and joint pain) and physical function (e.g., pain with movement and difficulty walking far) as determined by the physical health score and / or total score of the Haem-A-QoL.

[0087] In some embodiments, the treatment methods result in an improvement in a patient reported outcome (PRO) or an improvement in quality of life (QoL). In some embodiments, the improvement is measured using the Haem-A-QoL questionnaire. In some embodiments, the treatment methods reduce the total score or physical health domain score of the Haem-A-QoL questionnaire by at least 2 units (e.g., by at least 3 or at least 4 units) in non-tocillin-prophylactic patients compared to BPA or factor patients undergoing prophylactic treatment.

[0088] EQ-5D-5L is a standardized disease-general tool used as a measure of QoL outcomes. It consists of a questionnaire on five dimensions (mobility, self-care, daily activities, pain / discomfort, and anxiety / depression). The questionnaire is scored based on five levels of disability (none, mild, moderate, severe, or extreme). The higher the score, the better the health status. See also, for example, Herdman et al., Qual Life Res [Quality of Life Survey] (2011) 20 (10): 1727-36.

[0089] Compared with patients with BPA or factors taking preventive treatment, treatment with fenfluramine improved scores on at least one of the EQ-5D-5L dimensions (e.g., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). In some embodiments, one or more of the five dimension scores or the total score in EQ-5D-5L increases by 0.01 or more units (e.g., 0.02 or more units, 0.03 or more units, 0.04 or more units, 0.05 or more units, 0.06 or more units, 0.07 or more units, 0.08 or more units, 0.9 or more units, 0.10 or more units, 0.11 or more units, 0.12 or more units, 0.13 or more units, 0.14 or more units, 0.15 or more units, 0.16 or more units, 0.17 or more units, 0.18 or more units, 0.19 or more units, or 0.20 or more units).

[0090] The present method improves patient satisfaction with treatment, as determined by carefully designed detailed questionnaires, including the Treatment Satisfaction with Medication Questionnaire (TSQM-9). The TSQM-9 is a validated psychometric tool that provides a general measure of patient satisfaction with medication. See also, for example, 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 covering three domains, including effectiveness, convenience, and overall satisfaction. TSQM-9 domain scores range from 0 to 100, with higher scores indicating improved HRQoL. An increase in the score relative to the corresponding baseline score (the score before the assessment of treatment) indicates that the patient's satisfaction with treatment has increased. The EQ-5D-5L and TSQM-9 surveys were administered to patients aged ≥18 years.

[0091] The present fetocillin therapy improves the score of at least one of the TSQM-9 domains (i.e., effectiveness, convenience, and overall satisfaction) compared to BPA or factor patients undergoing prophylactic treatment. In particular, the present method can improve the treatment satisfaction of hemophilia patients. In some embodiments, one or more of the three domain scores in the TSQM-9 (i.e., effectiveness, convenience, and satisfaction) are increased by 1 or more units (e.g., 2 or more units, 3 or more units, 4 or more units, 5 or more units, 6 or more units, 7 or more units, 8 or more units, 9 or more units, 10 or more units, 11 or more units, 12 or more units, 13 or more units, 14 or more units, 15 or more units, 16 or more units, 17 or more units, 18 or more units, 19 or more units, or 20 or more units).

[0092] The fetocillin therapy improves the score of at least one of the HAL or multiple domains (i.e., lying down / sitting down / kneeling / standing, leg function, arm function, transportation use, self-care, household tasks, leisure activities and sports, basic lower extremity activities, upper extremity activities, and complex lower extremity activities) compared to BPA or factor patients undergoing prophylactic treatment. In particular, the present method can improve the subjective functional ability of hemophilia patients to perform activities of daily living. In some embodiments, one or more of the domain scores in the HAL increases by 1 or more units (e.g., 2 or more units, 3 or more units, 4 or more units, 5 or more units, 6 or more units, 7 or more units, 8 or more units, 9 or more units, 10 or more units, 11 or more units, 12 or more units, 13 or more units, 14 or more units, 15 or more units, 16 or more units, 17 or more units, 18 or more units, 19 or more units, or 20 or more units). In certain embodiments, the present treatment methods produce an improvement indicated by an increase in the total score of the HAL by 0.2 or more units (optionally 0.3 or more units, 0.4 or more units, 0.5 or more units, 0.6 or more units, or 0.7 or more units).

[0093] HRQoL for adolescent patients (12 years or older to 17 years) can be measured, for example, by the Adolescent Hemophilia Quality of Life Questionnaire (Haemo-QoL) (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 an abbreviation of Haem-A-QoL specifically for children and adolescents in the II / III age group (8-16 years). The Haemo-QoL survey has nine domains, including physical health, feelings, self-view, hemophilia management, treatment, family, friends, others, and sports. "Total score" is also used to represent the average of all nine domains of the Haemo-QoL questionnaire. The scoring of the Haemo-QoL tool follows the same method as the Haem-A-QoL tool described above. In some embodiments, treatment with the fetocillin reduces one or more of the nine domain scores in Haemo-QoL (e.g., physical health domain score or total score) by 1 unit or more (e.g., 2 units or more, 3 units or more, 4 units or more, 5 units or more, 6 units or more, 7 units or more, 8 units or more, 9 units or more, 10 units or more, 11 units or more, 12 units or more, 13 units or more, 14 units or more, 15 units or more, 16 units or more, 17 units or more, 18 units or more, 19 units or more, or 20 units or more).

[0094] For all of the above questionnaires, the questionnaire can be conducted before treatment and after treatment with one or more doses (e.g., two or more doses, three or more doses, four or more doses, five or more doses, or six or more doses) of fetucillin (e.g., about 10 mg, about 20 mg, about 50 mg, or about 80 mg subcutaneously administered about once every four weeks, or about once every month, or about once every eight weeks, or about once every two months). For example, the questionnaire can be conducted at 8, 12, 16, 20, 24, 28, 32, 35, 36, 37, or 38 weeks after initiation of fetucillin treatment.

[0095] According to the International Conference on Harmonization (ICH) E2A guidance, Definitions and Criteria for Expedited Reporting, and 21 CFR, Section 312.32, IND Safety Reporting, an adverse event (AE) is any untoward medical occurrence in a patient or clinical investigational subject administered a medicinal product that does not necessarily have a causal relationship to such treatment. Because bleeding episodes are recorded as an efficacy evaluation of fetocillin, these bleeding episodes are not considered AEs unless they meet any of the serious adverse event (SAE) criteria listed below.

[0096] A SAE is any unfortunate medical event at any dose that results in: i. cause death, ii. life-threatening (an event that, at the time of its occurrence, places the patient at an immediate risk of death from the event. It does not include events that could result in death if they occurred in a more severe form), iii. Requires hospitalization or extension of existing hospitalization, iv. causes persistent or significant disability or incapacity, v. is a congenital anomaly or birth defect, or vi. is a significant medical event that may not be immediately life-threatening or result in death or hospitalization but that may endanger the patient and may require intervention to prevent one of the other outcomes listed in the above definition (e.g., events include allergic bronchospasm, hematologic disorders, seizures, or the development of drug dependence or abuse requiring intensive treatment in the emergency department or at home). VII. Products and kits

[0097] The present invention also provides a kit comprising a pharmaceutical composition for use in the present method of treatment. Such a kit includes one or more vials or one or more prefilled syringes, which contain a pharmaceutical composition of the present invention and instructions for use, such as instructions for administering a therapeutically effective amount of fetosilan. The kit may optionally further include a tool for administering fetosilan (e.g., an injection device), or a tool for measuring SERPINC1 inhibition (e.g., a tool for measuring SERPINC1mRNA inhibition, protein expression encoded by SERPINC1, and / or SERPINC1 activity). These tools for measuring SERPINC1 inhibition may include tools for obtaining samples (e.g., plasma samples) from subjects. The kit of the present invention may optionally further include a tool for determining a therapeutically effective or preventive effective amount.

[0098] Additional definitions of terms and exemplary embodiments are described in the Examples and are incorporated herein by reference.

[0099] Unless otherwise defined herein, the scientific and technical terms used in conjunction with this disclosure should have the meanings commonly understood by those of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, exemplary methods and materials are described below. In the event of a conflict, the present specification including the definition shall prevail. Generally, the nomenclature and technology used in conjunction with hematology, medicine, drugs and medicinal chemistry and cell biology described herein are those well known and commonly used in the art. Further, unless the context otherwise requires, singular terms should include plural numbers, and plural terms should include singular numbers. All publications and other references mentioned herein are incorporated by reference in their entirety. Although many documents are cited herein, this citation does not mean that any one of these documents is recognized as a part of common knowledge in the art. As used herein, when applied to one or more target values, the term "about" or "approximately" refers to a value similar to the reference value. In certain aspects, the term refers to a range of values ​​that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less than) of the reference value, unless otherwise specified or clear from the context.

[0100] According to the present disclosure, the back-references in the dependent claims are meant as shorthand for the direct and explicit disclosure of each combination of the claims indicated by the back-references. In addition, the headings herein are created for organizational convenience and are not intended to limit the scope of the claimed invention in any way.

[0101] In order to better understand the present invention, the following examples are described. These examples are only for illustrative purposes and are not to be construed as limiting the scope of the present invention in any way. List of abbreviations and definitions of terms Examples Example 1: Clinical trial protocol for an open-label, switch study to describe the efficacy and safety of fetuin prophylaxis in patients with hemophilia A and B who had previously received factor or bypassing agent prophylaxis.

[0102] This example describes an open-label, phase 3 switch study designed to demonstrate the efficacy and safety of fetucillin in patients with hemophilia A or B who are currently treated with a prophylactic regimen of factor concentrates or BPA. The switch design allowed for within-patient controls to enable examination of the effects of both treatments by comparing the median ABR during the factor or BPA prophylaxis period with the median ABR of the same patient group while receiving fetucillin, while limiting the confounding effects of different patient bleeding phenotypes and changes in prophylactic therapy. Despite prophylactic BPA therapy, the needs of patients with inhibitors in hemophilia B may remain highly unmet, with limited other treatment options. Therefore, a limited number of patients with inhibitors in hemophilia B who do not respond adequately to prophylactic BPA therapy could be enrolled directly in the fetucillin treatment period, thereby skipping the 6-month BPA prophylaxis period. The duration of the onset of action reflects modeling data that estimated that most patients would require approximately 28 days to reach the therapeutic target range. Given the study design employed, which was a single-treatment arm with each patient switched from prophylactic therapy to fetucillin therapy, the study was not blinded.

[0103] The primary endpoint of the study was the ABR during the non-tocillin treatment phase and the factor or BPA prevention phase. The ABR is a well-established endpoint that has been used as a primary endpoint for approval of factor replacement and BPA products worldwide. Secondary endpoints characterized the annualized spontaneous bleeding rate and joint bleed rate, changes in the Haem-A-QoL physical health score and total score in patients ≥17 years of age, the ABR during the onset phase, overall safety, and factor / BPA consumption.

[0104] Characteristics of bleeding episodes are clinically relevant for assessing overall bleeding episode protection. Joint bleeding episodes cause pain and hemarthrosis, leading to progressive joint destruction and are therefore important to assess. The Haem-A-QOL is a hemophilia-specific HRQOL survey tool that has been used in other hemophilia clinical trials, has been validated and reviewed by clinicians, and was considered the most appropriate HRQOL tool for use in this study.

[0105] The study population will consist of males ≥12 years of age; studying fetocillin in adolescents (patients ≥12 to <18 years of age) is appropriate because the pathophysiology of disease progression and management of bleeding episodes is the same as in adults and self-management of hemophilia usually begins at age 12 years.

[0106] If breakthrough bleeding episodes occur, factor or BPA will be allowed on demand throughout the study duration. Duration of treatment

[0107] The duration of treatment with fetocillin was 7 months. For all patients enrolled in the extension study, the total study time per patient (including screening) was estimated to be up to 15 months, except for patients in the subgroup of cohort A, for whom the total study time was estimated to be up to 9 months. For patients who did not enroll in the extension study because an additional six months of follow-up was required to monitor AT levels, the total study time was estimated to be up to 21 months (up to 15 months for patients in the subgroup of cohort A). Study objectives and end points

[0108] The primary objective of this study was to characterize the frequency of bleeding episodes while receiving fetocilan therapy relative to the frequency of bleeding episodes while receiving factor or bypassing agent (BPA) prophylaxis.

[0109] The secondary objectives of this study are to: - Characterizes the following conditions while receiving fetucilan relative to receiving factor or BPA prophylaxis: The frequency of spontaneous bleeding episodes, How often your joint bleeds occur, and health-related quality of life (HRQOL) in patients aged ≥17 years; - Characterize the frequency of bleeding episodes during the onset and treatment periods in patients receiving fetocillin; - Characterize the safety and tolerability of fetuxiram; and - Characterize the annualized weight-adjusted cytokine / BPA consumption while receiving fetuin treatment relative to receiving cytokine or BPA prevention.

[0110] The exploratory objectives are: - To characterize the effects of fetucilan on the following patient-reported outcomes when receiving fetucilan relative to receiving factor or BPA prophylaxis: Patient satisfaction with fetocillin, Patient activities, and HRQOL in adolescents (≥12 to <17 years); - Characterize the pharmacodynamic (PD) effects, pharmacokinetics (PK) and immunogenicity of fetuxilan; - characterize the effects of fetucilan on joint status when receiving fetucilan treatment relative to receiving factor or BPA prevention; and - To characterize the impact of fetuin on patient resource use relative to receiving factor or BPA prophylaxis.

[0111] The primary endpoint of this study was to evaluate the annualized bleeding rate (ABR) during the fetucilan efficacy phase and the factor or BPA prophylaxis phase.

[0112] Secondary endpoints were to assess: - Annualized spontaneous bleeding rate during the non-toxicillin treatment period and factor or BPA prophylaxis period; - Annualized joint bleeding rate (AJBR) during the fetucilan treatment period and the factor or BPA prevention period; and - Changes in the Haem-A-QOL physical health score and total score during the fetuin treatment period and the factor or BPA prevention period.

[0113] Exploratory endpoints are: - Changes in the following during treatment with fentanyl: Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores, Hemophilia Activity List (HAL) score, Pediatric HAL (pedHAL) score, European EQ-5D score, Haemo-QOL score, and / or Hemophilia Joint Health Score (HJHS); - Number of target joint bleeding episodes; - The incidence and titer of anti-drug antibodies to fetuin during fetuin treatment; - Changes in antithrombin (AT) activity levels over time; - Changes in thrombin generation over time; - fetuin plasma levels; and - Changes in the patient's resource use (e.g., work / school, doctor / hospital visits).

[0114] Safety endpoints were assessments of the incidence, severity, severity, and relevance of adverse events. Study Design

[0115] The study evaluated male patients aged ≥12 years with hemophilia A or B who had switched from prior bypassing agent (BPA, cohort A) or factor (cohort B) prophylaxis. Cohort A patients had inhibitory antibodies to factor VIII or factor IX, while cohort B patients did not have inhibitory antibodies to factor VIII or factor IX.

[0116] A subset of patients in Cohort A included hemophilia B patients with inhibitory antibodies to factor IX who had not responded adequately to BPA prophylaxis (historical ABR ≥ 20).

[0117] The study had three periods defined according to the type of prevention regimen ( Figure 2 ): - a six-month factor or BPA prophylaxis period during which patients continued their pre-study regularly scheduled prophylaxis regimen with factor or BPA, - a 1-month onset period during which patients receive their first dose of fetuin while continuing their factor or BPA prophylaxis for up to 7 days, and - A 6-month fetucilan efficacy period during which patients received fetucilan as prophylaxis.

[0118] A subgroup of Cohort A patients who have not adequately responded to BPA preventive treatment will not participate in the six-month BPA preventive period and will begin receiving fetuin directly after the screening period (within a one-month onset period) ( Figure 3 ).

[0119] The one-month onset period and the six-month fetucilan efficacy period together constitute the fetucilan treatment period.

[0120] On-demand use of factor concentrate or BPA was defined as the use of these agents as needed to treat occasional bleeding rather than as a regular regimen for the prevention of spontaneous bleeding. Patients in the fetucillin treatment period received on-demand treatment for breakthrough bleeding episodes with factor or BPA as needed throughout the study. For patients in the fetucillin treatment period who have received at least 1 dose of fetucillin and are being treated for breakthrough bleeding episodes, it is recommended to follow the guidelines provided in Table 3.

[0121] After the screening and prevention periods (or after the screening period for the subgroup of cohort A who joined the fetucillin treatment period directly), all patients were treated with fetucillin for a total of seven months. Therefore, the entire fetucillin treatment period was defined as the onset period (days 1-28 after the first dose, during which the AT-lowering ability of fetucillin was increasing but had not yet reached therapeutic levels) plus the efficacy period (day 29 and thereafter, when the AT-lowering ability of fetucillin had reached the therapeutic target range). Study Group

[0122] This study will include males aged ≥12 years 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 will be based on a central laboratory measurement or documented medical record of a FVIII level <1% or a FIX level ≤2%. Patients with inhibitors must have been on BPA prophylaxis for at least the last 6 months prior to screening and must meet one of the following Nijmegen modified Bethesda assay result criteria: 1) an inhibitor titer ≥0.6BU / mL at screening; 2) an inhibitor titer <0.6BU / mL at screening with medical record documented 2 consecutive titers ≥0.6BU / mL; or 3) an inhibitor titer <0.6BU / mL at screening with medical record documented an anamnestic response.

[0123] A subgroup of patients in cohort A must also meet the following criteria to be eligible to start treatment with fetucillin directly after the screening period: 1) hemophilia B with inhibitory antibodies to factor IX as described above; 2) no adequate response to BPA treatment prior to study entry (historical ABR ≥ 20); and 3) the 6-month BPA prophylaxis period should be omitted if appropriate. There needs to be at least 2 bleeding episodes requiring BPA treatment in the last 6 months before screening.

[0124] Patients without inhibitors must have been using factor concentrate for prophylaxis in at least the last 6 months before screening and must meet all of the following criteria: 1) inhibitor titer <0.6BU / mL by Nijmegen modified Bethesda assay at screening; 2) no bypassing agents used to treat bleeding episodes in at least the last 6 months before screening; and 3) no history of immune tolerance induction therapy in the last 3 years before screening. At least 1 bleeding episode requiring factor therapy was required in the last 12 months before screening.

[0125] The inclusion criteria are further described as follows: I 01. Male ≥ 12 years old; I 02. Severe hemophilia A or B, as evidenced by measurements at screening or documented medical records showing FVIII <1% or FIX level ≤2%; 1 03. For patients with inhibitory antibodies to factor VIII or factor IX (cohort A), at least two bleeding episodes requiring BPA treatment in the last six months before screening; or for patients without inhibitory antibodies to factor VIII or factor IX (cohort B), at least one bleeding episode requiring factor treatment in the last 12 months before screening; I 04. Must meet the definition of inhibitor or non-inhibitor patient as follows: - Inhibitors (Cohort A): Use of BPA for prophylaxis and treatment of any bleeding episode in at least the last six months prior to screening and meeting one of the following Nijmegen Modified Bethesda Assay result criteria: oInhibitor titer ≥ 0.6 BU / mL at screening, or o Inhibitor titer <0.6BU / mL at screening and medical records show titer ≥0.6BU / mL for 2 consecutive times, or o Inhibitor titer <0.6BU / mL at screening, with medical records demonstrating anamnestic response; o A subset of patients in Cohort A must also meet the following criteria to be eligible to start treatment with fetucillin directly after the screening period: ■Hemophilia B with inhibitory antibodies to Factor IX as described above, and ■No adequate response to BPA treatment before treatment (historical ABR ≥ 20); - No inhibitors: Use of factor concentrates for prophylaxis and treatment of any bleeding episodes for at least the last six months prior to screening and meets each of the following criteria: o Inhibitor titer <0.6 BU / mL using Nijmegen modified Bethesda assay at screening, o Not using bypassing agents to treat bleeding episodes in at least the last 6 months prior to screening, and o No history of immune tolerance induction therapy in the past three years prior to screening; and I 05. Have been prescribed (and maintained) prophylactic treatment with factor concentrate or BPA for hemophilia (documented in medical or pharmacy record) for at least six months prior to screening; the regimen must be consistent with the approved product prescribing information or local recommendations, allow for adjustment based on individual patient response, and be designed to reduce spontaneous bleeding; and I 06. Adherence to prescribed preventive therapy for at least 6 months prior to screening, as assessed by the investigator.

[0126] Exclusion criteria are further described as follows: E 01. Known coexisting bleeding disorder other than hemophilia A or B (i.e., von Willebrand disease), other factor deficiency, or platelet disorder; E 02. Currently participating in immune tolerance induction therapy (ITI); E 03. AT activity < 60% at Screening as determined by central laboratory measurement. E 04. Clinically significant liver disease is present or is indicated by any of the following: - INR > 1.2; -ALT and / or AST>1.5×upper limit of normal reference range (ULN); - Total bilirubin > ULN (> 1.5 x ULN for patients with Gilbert's syndrome); - History of portal hypertension, esophageal varices, or hepatic encephalopathy; or - Ascites found during physical examination; E 05. Hepatitis C virus antibody positive, except for patients with a history of HCV infection and who meet both of the following conditions: - Completed curative therapy for at least 12 weeks prior to study entry and achieved a sustained virologic response as evidenced by negative HCV RNA at Screening, or they had spontaneously cleared the infection as evidenced by negative HCV RNA at Screening. - No evidence of cirrhosis based on one of the following assessments: o Fibroscan <12.5 kPa (if available), or o Fibrotest score < 0.75 and APRI < 2 (if fibroscanner is not available) E 06. E 06. Presence of acute hepatitis, i.e. hepatitis A, hepatitis E; E 07. Presence of acute or chronic hepatitis B infection (positive IgM anti-HBc antibody or positive HBsAg); E 08. Platelet count ≤ 100,000 / μL; E 09. Acute infection at the time of screening; E 010. Known to be HIV positive with CD4 count <200 cells / μL; E 011. Renal insufficiency, as evidenced by an estimated glomerular filtration rate ≤ 45 mL / min / 1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] formula); E012. Coexistent thrombotic disorder as determined by the presence of any of the following as identified in a central laboratory (or by historical results, if available): - FV Leiden mutation (homozygous or heterozygous), - Protein S deficiency, or - Protein C deficiency; - Prothrombin mutation (G20210A; homozygous and heterozygous); E 013. History of antiphospholipid antibody syndrome; E 014. History of arterial or venous thromboembolism, atrial fibrillation, severe valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke; patients who have experienced thrombosis related to indwelling venous access may be included in the study; or E 015. A malignant tumor within the past two years, except for basal cell carcinoma or squamous cell carcinoma of the skin that has been successfully treated. Dosage regimen and formulations

[0127] Fetocillin injection (SC use) is provided as a sterile solution. Patients receive 80 mg of fetocillin as a SC injection once a month (or 50 mg of fetocillin once every two months) for a total of seven months. Antithrombin Level Criteria for Dose Adjustment

[0128] Patients in this study had another AT activity level sampled again within 1 week of receiving the result on site when the first AT level was <15%. If this result was <15%, this was considered a second AT activity level <15%. In this study, patients who received fetucillin at a dose of 50 mg Q2M and had more than 1 AT activity level <15% at any time during the study period discontinued fetucillin. Routine Use of Factor or Bypassing Agent Prophylaxis During the Factor or Bypassing Agent Prophylaxis Period

[0129] During the factor or BPA prophylaxis period, patients should continue to receive prophylaxis using their usual products according to a regimen that is consistent with the recommendations in the approved prescribing information, allows for adjustments based on individual patient response, and is designed to reduce spontaneous bleeding. The regimen used during the factor or BPA prophylaxis period must have the minimum frequency of administration shown in Table 2 (see above).

[0130] The subgroup of Cohort A patients who do not adequately respond to BPA preventive treatment will not participate in this BPA prevention period and will start the non-tocopherol treatment period directly after the screening period. Management of factor or bypassing agent prophylaxis during transition to fetoxicillin therapy

[0131] The first 28 days of fetucillin treatment is called the initiation period. During the initiation period, AT reduction will progress toward therapeutic levels. During the first 7 days of the fetucillin initiation period, patients will continue to take factor or BPA prophylaxis at the lowest frequency shown in Table 2. After day 7 of the fetucillin treatment period, factor concentrate or BPA should be administered only during bleeding episodes or as needed prior to invasive medical procedures. Recommendations for the management of bleeding episodes in patients during the fetucillin treatment period

[0132] See Section IV above for detailed description. Research evaluation

[0133] A bleeding episode was defined as any bleeding requiring BPA or replacement factor infusion, such as hemarthrosis, muscle or mucosal bleeding. The definitions of the types of bleeding episodes 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).

[0134] The start time of a bleeding episode is considered to be the time when the symptoms of the bleeding episode first appeared. Bleeding or any bleeding symptoms at the same site occurring within 72 hours after the last injection for a bleeding episode at the treatment site are considered part of the original bleeding event and are counted as one bleeding episode for the ABR. Any bleeding symptoms starting more than 72 hours from the last injection for a bleeding episode at the treatment site will constitute a new bleeding event.

[0135] Spontaneous bleeding episodes are bleeding events without an obvious or known cause, particularly into joints, muscles, and soft tissues.

[0136] Joint bleed episodes are characterized by abnormal sensations in the joint (“aura”) accompanied by 1) increased swelling or warmth in the skin over the joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty using a limb compared with baseline.

[0137] Muscle bleeds may be characterized by pain, swelling, and loss of motion in the affected muscle group.

[0138] A target joint was defined as a joint with three or more spontaneous bleeding episodes in a single joint within a six-month consecutive period; a joint was no longer considered a target joint if there were two or fewer bleeding episodes in the joint within a 12-month consecutive period.

[0139] Traumatic bleeding episodes are bleeding episodes that are caused by a known injury or trauma. Bleeding episodes that are sustained during sports and recreation are counted as traumatic bleeding episodes.

[0140] Patient-reported outcomes were used to assess health-related quality of life (HRQOL), physical activity, treatment satisfaction, and health utility. The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) is a psychometrically tested QOL assessment tool for patients with hemophilia. The Haem-A-QOL is given to patients aged ≥17 years and includes 46 items covering 10 QOL domains (physical health, feelings, self-view, sports and leisure, work and school, hemophilia management, treatment, future, family plans, partnerships, and sexuality). Each item is scored on a 5-point Likert scale (never, rarely, sometimes, often, and all the time), with higher scores indicating greater impairment. Antithrombin activity

[0141] AT activity levels will be assessed twice a month (approximately every two weeks) in the first two months, and then monthly (approximately every four weeks). On dosing days, samples will be collected within 4 hours prior to dosing. Antithrombin protein can be measured in a subset of plasma samples for correlation analysis. Statistical methods

[0142] The primary analysis of EAS will be performed and will include all bleeding episodes occurring during the factor or BPA prophylaxis period (Day -162 to Day -1) and the fetucillin efficacy period (Day 29 to Day 190). If a patient does not have bleeding episode data collected after Day 28 (e.g., due to early study discontinuation), available bleeding episode data from Day 1 will be used in the primary analysis. To avoid confounding by treatment effects, bleeding episode data during and after major surgery, antithrombin administration, major trauma, or initiation of factor or BPA prophylaxis during the fetucillin treatment period will be excluded from the primary analysis.

[0143] The number of bleeding episodes will be analyzed using a repeated measures negative binomial model with treatment period fixed effects. The logarithmic number of days each patient spent in the efficacy period matching the bleeding episode data analyzed will be 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 non-tocillin efficacy period to the bleeding rate during the factor or BPA prevention period will be presented with its 95% CI and p-value.

[0144] In addition, as a comparison, a Bayesian analysis will be performed to summarize the point estimates of the posterior probability of a clinically significant treatment effect and the associated uncertainty measures. This model will present the estimated mean ABR and its 95% CI in the 2 periods. In addition, summary statistics of the ABR, including the median and interquartile range, will be presented for each treatment group, where the ABR is defined as: (Total number of eligible bleeding episodes / The total number of days in the corresponding period) × 365.25

[0145] Spontaneous bleeding episodes and joint bleed episodes will be analyzed using the same methods as for the primary analysis of ABR. Summary statistics for the annualized spontaneous bleeding rate and annualized joint bleed rate, including medians and interquartile ranges, will be reported.

[0146] Changes in Haem-A-QOL physical health scores and total scores (in patients ≥17 years old) during the factor or BPA prevention period and the non-tocillin treatment period will be summarized descriptively. Mixed models for repeated measures analyses can be performed where appropriate.

[0147] Bleeding episodes during the non-tocillin onset period and the non-tocillin treatment period will be analyzed using a negative binomial model with the logarithm of follow-up time during the period as an offset parameter. Summary statistics of ABR in both periods will be reported, including medians and interquartile ranges.

[0148] The secondary endpoint of annualized factor / BPA injection consumption adjusted for weight will be summarized using descriptive statistics.

[0149] The fetucillin efficacy period (fetucillin prophylaxis) was defined as the period from day 29 after the first dose of fetucillin to day 190, or the last day of bleeding follow-up, whichever was earlier. The factor / BPA prophylaxis period was defined as the period from day −168 to day −1, or the last day of bleeding follow-up, whichever was earlier. The factor / BPA prophylaxis period was defined as the period from day −168 to day −1, or the last day of bleeding follow-up, whichever was earlier. Example 2: Phase 3 clinical trial results

[0150] The clinical trial results were obtained according to the experimental protocol described in Example 1. Patients were males aged ≥12 years with hemophilia A or B with or without inhibitors who had previously been on factor / BPA prevention. Participants continued factor / BPA prevention (6 months) and then switched to monthly 80 mg SC fetucillin prevention (7 months). The primary endpoint was the ABR during the factor / BPA prevention period (day -168 to day -1) and the fetucillin efficacy period (day 29 to day 190). Secondary endpoints included spontaneous ABR (AsBR), joint ABR (AjBR) and health-related quality of life (HRQoL). Safety and tolerability were evaluated.

[0151] Results are presented for Safety Analysis Set 1 (SAS1) and Efficacy Analysis Set 1 (EAS1), which included participants enrolled in the study and then received 80 mg fetucillin QM. Efficacy Analysis Set 1 included participants who received factor or BPA prophylaxis and at least one dose of fetucillin. Participant Disposition

[0152] Of the 99 participants screened, 80 (normalized to 100%) were enrolled. Thirty participants had inhibitory antibodies to factor VIII or factor IX (Cohort A [inhibitors]), and 50 participants did not have inhibitory antibodies to factor VIII or factor IX (Cohort B [no inhibitors]). Seventy-eight of the 80 enrolled participants (97.5%) entered the factor / BPA prevention period, and 67 (83.8%) completed the factor / BPA prevention period. Two of the 80 enrolled participants (2.5%) started directly on fetucillin 80 mg QM (a subgroup of Cohort A) (Table 4). Table 4. Factor / BPA Prevention: Day -168 to Day -1

[0153] Of the 67 participants who completed the factor / BPA prevention period, 65 started fetocillin 80 mg QM and 2 started fetocillin 50 mg Q2M. Of the 67 participants (83.8%) who started fetocillin 80 mg QM, 13 (16.3%) discontinued fetocillin treatment, and 54 (67.5%) completed fetocillin treatment. Nine (11.3%) participants discontinued fetocillin 80 mg QM due to a voluntary dosing pause at the sponsor's discretion and completed the study. Two (2.5%) participants discontinued fetocillin due to AEs. Of the two participants treated with fetocillin 50 mg Q2M, one discontinued fetocillin due to more than one AT value <15% and completed the study, while the other withdrew consent. 64 (80.0%) participants completed the study (Tables 5 and 6). Table 5. Fetocillin treatment: Day 1 to Day 190 1 Participants received fetucillin 50 mg Q2M after a dose pause and amendment 5 (dated November 25, 2020). They were considered safety analysis set 2 (SAS2) and only safety analyses were performed and not the primary efficacy analysis (efficacy set 1). 2 Efficacy Analysis Set 2 (EAS2) included all participants in SAS2 who received BPA prophylaxis and fetocillin 50 mg Q2M after dose suspension, protocol amendment 5 (dated November 25, 2020), and dose resumption. Table 6. Baseline measurements Group characteristics

[0154] Of the 80 participants enrolled in the study, 57 were participants with hemophilia A (21 in cohort A [inhibitors] and 36 in cohort B [no inhibitors]), and 23 were participants with hemophilia B (9 in cohort A [inhibitors] and 14 in cohort B [no inhibitors]). All participants were male, and the median age was 23.0 years. 19 (29.2%) patients were adolescents (12-17 years), 45 (69.2%) were adults (18-64 years), and one participant was 65 years or older.

[0155] A total of 42 participants (64.6%) were white, 20 (30.8%) were Asian, two (3.1%) were "other race," and one participant was black or African American. The median body mass index was 23.6 kg / m 2 .

[0156] For participants in cohort A (inhibitors), the median number (IQR) of bleeding episodes within the six months before screening was 4.0 (2.0 to 6.0); for participants in cohort B (no inhibitors), the median number of bleeding episodes within the 12 months before screening was 2.0 (1.0 to 4.0). Most participants (18 [94.7%]) in cohort A (inhibitors) had a historical maximum inhibitory antibody titer ≥5 BU / ml. Baseline demographics and characteristics of patients were generally similar between cohorts and are summarized in Table 7. Table 7. Baseline demographics and characteristics of patients in cohort A and cohort B Efficacy Results

[0157] A total of 80 patients were included in the study, and 65 were evaluable for efficacy analysis (inhibitor / no inhibitor, n=19 / 46; hemophilia A / hemophilia B, n=50 / 15). The mean (SD) age was 24.8 (11.2) years.

[0158] Overall, for participants treated with 80 mg QM fetucillin prophylaxis, the ABR estimate was 2.908 (95% confidence interval [CI], 1.727 to 4.898) during the efficacy period and 7.482 (95% CI, 5.520 to 10.141) during the factor or BPA prophylaxis period, indicating a statistically significant reduction in treated bleeding of 61.1% (95% CI, 32.5% to 77.6%) in favor of fetucillin prophylaxis (P = 0.0008). Overall, the observed median ABR (IQR) was 0.00 (0.00; 2.25) and 4.35 (2.17; 10.87) during the fetucillin efficacy period and factor or BPA prophylaxis period, respectively (Table 8). 63.1% of participants did not experience any treated bleeding during the fetuin efficacy period, whereas 16.9% did not experience any treated bleeding during the factor or BPA period (Table 9). In participants with inhibitors (cohort A), fetuin was associated with a lower median ABR (IQR) of 0.00 (0.00; 0.00) and a significant reduction in ABR of 79.7% (95% CI, 43.8% to 92.6%) compared with BPA prevention (P = 0.0021). In participants without inhibitors (cohort B), fetuin was associated with a lower median ABR (IQR) of 0.00 (0.00; 2.65) and a clinically meaningful reduction in ABR of 46.4% (numeric) compared with factor prevention (P = 0.0598) ( Figure 4 Compared with factor / BPA prevention, fetucillin prevention significantly reduced the bleeding rate by 61.1% (p=0.0008).

[0159] Fetocilan achieved the primary endpoint of the study and significantly reduced the frequency of bleeding episodes; the median observed ABR (IQR) for treated bleeding was 0.0 (0.0; 2.3) in the fetocilan efficacy period and 4.35 (2.2; 10.9) in the factor / BPA prevention period. Forty-one participants (63.1%) who were treated prophylactically with fetocilan did not experience any treated bleeding. Table 8. Estimated ABR and rate ratios for factor / BPA prophylaxis and fetuin efficacy periods a The fetuin ratio was divided by the factor / BPA prevention ratio. bP-values ​​are from repeated measures negative binomial regression models with study period (non-tocillin treatment period or factor / BPA prevention period) as a fixed effect and a robust sandwich covariance matrix constructed to account for within-subject dependence, with the logarithm of the duration (in years) that each participant spent in each study period matching the analyzed bleeding episode data as an offset variable (p-values ​​vs. the null hypothesis of ratio = 1). The analysis was based on an on-treatment strategy that included all treated bleeding events during the fetucillin efficacy period and the factor / BPA prophylaxis period and excluded any bleeding events during the intercurrent event period. Table 9. Treated bleeding events observed during the fetucillin efficacy period and the factor / BPA prophylaxis period and duration of follow-up The analysis was based on an on-treatment strategy that included all treated bleeding events during the non-tocillin efficacy period and the factor / BPA prophylaxis period and excluded any bleeding events during the intercurrent period. Key Secondary End Points

[0160] Annualized spontaneous bleeding rate during the fetucilan treatment period and factor or BPA prophylaxis period Overall, for participants treated with 80 mg QM fetucillin prophylaxis, the estimated spontaneous ABR was 2.222 (95% confidence interval [CI], 1.190 to 4.152) during the fetucillin efficacy period and 5.002 (95% CI, 3.424 to 7.305) during the factor or BPA prophylaxis period, indicating a statistically significant reduction of 55.6% (95% CI, 15.8% to 76.6%) in spontaneous bleeding with treatment in favor of fetucillin prophylaxis (P = 0.0129). The estimated AsBR ratio was 0.444 (95% CI, 0.234 to 0.842). The observed means and medians of spontaneous bleeding with treatment are presented in Table 10 below. Table 10. Mean and median observed spontaneous bleeding during treatment

[0161] Annualized joint bleeding rate during the fetucilan treatment period and factor or BPA prevention periodOverall, for participants treated with 80 mg QM fetucillin prophylaxis, the estimated joint ABR was 2.564 (95% confidence interval [CI], 1.440 to 4.566) during the fetucillin efficacy period and 5.282 (95% CI, 3.647 to 7.651) during the factor or BPA prophylaxis period, indicating a statistically significant reduction of 51.5% (95% CI, 9.0% to 74.1%) in treated joint bleeds in favor of fetucillin prophylaxis (P=0.0242). The estimated AjBR ratio was 0.485 (95% CI, 0.259 to 0.910). The mean and median observed treated joint bleeds are presented in Table 11. Table 11. Mean and Median Observed Treated Joint Bleeding

[0162] The data are also shown in Tables 12 and Figure 5 The data were based on an on-treatment strategy that included all treated bleeding events during the fetucillin efficacy period and the CFC / BPA prophylaxis period and excluded any bleeding events during the intercurrent period. Table 12. Bleeding Events (Fetocillin Treatment Period and Factor / BPA Prevention Period*) *The fetucillin efficacy period (fetucillin prophylaxis) was defined as the period from day 29 after the first dose of fetucillin to day 190, or the last day of bleeding follow-up, whichever was earlier. The factor / BPA prophylaxis period was defined as the period from day -168 to day -1, or the last day of bleeding follow-up, whichever was earlier. The factor / BPA prophylaxis period was defined as the period from day -168 to day -1, or the last day of bleeding follow-up, whichever was earlier. All participants who received factor / BPA prophylaxis and who received at least one dose of fetuin prior to dosing resumption (after sponsor-initiated dosing suspension) were included. P-values ​​are from negative binomial regression models with study period (non-tocillin treatment period or factor / BPA prevention period) as a fixed effect and a robust sandwich covariance matrix constructed to account for within-subject dependence, with the logarithm of the duration (in years) that each participant spent in each study period matching the analyzed bleeding episode data as an offset variable (p-values ​​vs. the null hypothesis of ratio = 1).

[0163] Annualized bleeding rate during the onset of fetocilan: Among the 65 patients analyzed, the estimated annualized bleeding rate during the fetucillin initiation period was 5.419 (95% CI, 3.716 to 7.901). The observed annualized bleeding rate during the fetucillin initiation period was 5.42 (SD 8.28).

[0164] Annualized bleeding rate during fetucilan treatment : Among the 65 patients analyzed, the estimated annualized bleeding rate during the fetucillin treatment period was 3.317 (95% CI, 2.111 to 5.211). The observed annualized bleeding rate during the fetucillin initiation period was 3.48 (SD 6.98).

[0165] Consumption of factor concentrates and bypassing agents for the management of breakthrough bleeding, including annualized weight-adjusted BPA and Factor Consumption : During the prevention period, the weight-adjusted annualized BPA or factor consumption was calculated for each participant as follows: [sum of BPA doses per body weight received during the corresponding period / number of days in the corresponding period]*365.25. In this outcome measure, data on weight-adjusted annualized BPA or factor consumption are reported. The time frame was factor / BPA prevention period: Day -168 to Day -1 or until the last day of bleeding follow-up (until any day before Day -1); 6-month fetocillin efficacy period: Day 29 to Day 190 or until the last day of bleeding follow-up (until any day before Day 190), whichever is earlier. The consumption of BPA is summarized in Table 13. The consumption of factors is summarized in Table 14. Table 13. Annualized BPA Consumption Adjusted by Weight (Cohort A; Patients with Inhibitors) Table 14. Annualized Factor Consumption Adjusted by Weight (Cohort B; Patients Without Inhibitors)

[0166] After switching to fetucilan, fewer participants required clotting factor concentrates (CFC) or BPA for breakthrough bleeding. During CFC / BPA prophylaxis, a total of 36 participants received CFC and 20 participants received BPA for breakthrough bleeding. After switching to fetucilan, these numbers decreased to 20 participants and 4 participants, respectively.

[0167] The total number of treated bleeds was lower among participants receiving fetocillin (total = 18 with inhibitors, total = 54 without inhibitors) compared to participants receiving CFC (total = 126) or BPA (total = 101) prophylaxis.

[0168] The mean total weight-adjusted dose 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) per bleed was significantly lower when participants received fetucillin compared 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) prophylaxis.

[0169] The total mean consumption of FVIII and FIX for the treatment of breakthrough bleeding was lower in patients receiving fetucillin prophylaxis compared with patients receiving CFC prophylaxis (Table 15). The total mean consumption of aPCC and rFVIIa for the treatment of breakthrough bleeding was lower in participants receiving fetucillin prophylaxis compared with patients receiving BPA prophylaxis. Specifically, the weight-adjusted annualized aPCC consumption for bleeding therapy decreased by 98.9% during fetucillin prophylaxis, the weight-adjusted annualized rFVIIa consumption decreased by 96.8% during fetucillin prophylaxis, the weight-adjusted annualized FVIII consumption decreased by 79.4% during fetucillin prophylaxis, and the weight-adjusted annualized FIX consumption decreased by 93.8% during fetucillin prophylaxis.

[0170] Participants who received fetucillin also required fewer injections to treat breakthrough bleeding (total = 26 with inhibitors, total = 59 without inhibitors) compared to participants who received CFC (total = 189) or BPA (total = 419) prophylaxis. The number of treated bleeds was reduced by 82.2% in patients with inhibitors with fetucillin compared to BPA prophylaxis, while the number of treated bleeds in patients without inhibitors was 57.1% during the fetucillin prophylaxis period compared to the factor / bypassing agent prophylaxis period. The total number of BPA injections was reduced by 93.8% in patients with inhibitors with fetucillin compared to BPA prophylaxis, while the total number of replacement factor injections was reduced by 68.8% during the fetucillin prophylaxis period compared to the factor / bypassing agent prophylaxis period in patients without inhibitors. Table 15: CFC / BPA consumption for breakthrough bleeding during the fetucilan efficacy period and CFC / BPA prophylaxis period (EAS1*)

[0171] Overall, the results for the consumption endpoint consistently favored fetucillin prophylaxis over CFC / BPA prophylaxis. Fetucillin prophylaxis reduces patients’ total CFC / BPA consumption by reducing the mean total weight-adjusted dose per bleed, the number of bleeds treated, and the number of injections required to treat bleeds, thereby reducing the treatment burden for patients with hemophilia A or B with and without inhibitors.

[0172] Changes in Haem-A-QOL, EQ-5D-5L, HAL, and TSQM-9 scores: At study inclusion (month -6), people without inhibitors generally had less impairment in PRO scores compared with those with inhibitors ( Figure 6 ).

[0173] For Ham-A-QoL, changes from baseline (month -6) were compared between the two treatments using a repeated measures mixed model (MMRM): change from month -6 to month 7 for non-tocillin prevention vs. change from month -6 to day 1 for factor / BPA prevention. Change from month -6 to day 1 and change from month -6 to month 7 were response variables. Study period (factor / BPA prevention period and non-tocillin treatment period) and month -6 score were fixed effects, and a robust sandwich covariance matrix was constructed to account for within-subject dependence.

[0174] At study inclusion (month -6), the transformed Haem-A-QoL physical health and total scores were 32.87 (SD 23.68) and 31.63 (SD 18.54), respectively. The least squares (LS) mean (95% CI) of the change from baseline in the transformed total score in the Haem-A-QoL score (i.e., the difference between the change from month -6 to baseline (day 1) and the change from month -6 to month 7) was -7.62 (-10.26 to -4.98) for fetucillin prevention and -3.07 (-5.56 to -0.58) for factor / BPA prevention. The LS mean difference was -4.55 (95% CI, -7.56 to -1.54) and significantly decreased in favor of fetucillin (P = .0039) ( Figure 7 and Figure 8 ).

[0175] The LS mean (95% CI) for the change from baseline in the transformed physical health domain score was -9.60 (-15.35, -3.84) for fetucillin prevention and -6.00 (-10.19, -1.81) for factor / BPA prevention (Table 16). The least squares (LS) mean difference between the change from month -6 to baseline (Day 1) and the change from month -6 to month 7 in the Haem-A-QoL score demonstrated a nominal improvement in the physical health score with fetucillin (-3.60 [95%-CI: -10.52, 3.33]) ( Figure 7 and Figure 8 ). Table 16. Changes in Haem-A-QoL scores

[0176] Changes in TSQM-9, EQ-5D-5L, and HAL from month -6 (study inclusion) to day 1 and month 7 were summarized descriptively.

[0177] At study inclusion (month -6), the EQ-5D-5L index score was 0.83 (SD 0.13). Fetosilan also demonstrated a nominal improvement in the EQ-5D-5L index score compared with factor / BPA prevention, with a mean change of 0.04 (SD 0.13) from month -6 to month 7 and a mean change of 0.0 (SD 0.13) from month -6 to day 1.

[0178] At inclusion in the study (month -6), the total HAL score was 79.11 (SD 20.29). In addition to demonstrating good functional ability to carry out activities of daily living, patients even rated their physical abilities better during the two assessment periods of the study, as evidenced by the changes in the HAL scores: the mean changes in the total score were 3.05 (SD 20.04) and 2.45 (SD 19.42) in the fetocillin and factor / BPA prevention groups, respectively.

[0179] At inclusion (month -6), the baseline TSQM-9 scores for 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 mean TSQM-9 scores consistently favored non-tocillin prevention over factor / BPA prevention in the three domains of effectiveness, convenience, and overall satisfaction ( Figure 7 Overall, mean TSQM-9 scores consistently favored non-tocillin prevention over factor / BPA prevention in the three domains of effectiveness, convenience, and overall satisfaction ( Fig.10 ).

[0180] Safety Results: Sixty-seven participants (83.8%) were enrolled in the study, received at least 1 dose of fetucillin before dosing resumption (after sponsor-initiated dosing suspension), and were included in Safety Analysis Set 1. Overall, 22 participants (33.8%) experienced at least 1 adverse event (AE) during the factor / BPA prevention period and 48 participants (71.6%) during the fetucillin prevention period.

[0181] A total of 5 serious adverse events (SAEs) were reported by 5 participants (7.7%) during the factor / BPA prophylaxis period, and 13 SAEs were reported by 9 participants (13.4%) during the non-toxicillin prophylaxis period. The most common SAE during the non-toxicillin prophylaxis period was hemophilic arthropathy (2 [3.0%] participants); all other SAEs during the non-toxicillin prophylaxis period were reported by 1 participant (1.5%) each.

[0182] Two participants (3.1%) in the factor / BPA prophylaxis period and 22 (32.8%) in the non-tocillin prophylaxis period experienced adverse events of special interest (AESI). In the non-tocillin prophylaxis period, these included two participants (3.0%) with suspected or confirmed thromboembolic events (cerebrovascular accident and suspected thrombosis [left eye mastoid thrombosis]). The participant who had a cerebrovascular accident had a history of right lower extremity deep vein thrombosis unknown to the investigators at the time of study enrollment (exclusion criterion).

[0183] Seventeen (25.4%) participants had ALT or AST elevations >3x ULN. One of these participants experienced a laboratory abnormality consistent with Hy's Law that resolved after the last dose of fetuin. Five (7.5%) participants had cholecystitis and 5 (7.5%) had cholelithiasis, with 2 participants experiencing both events. Two (3.0%) participants experienced AEs leading to study drug discontinuation during the fetuin prevention period (cerebrovascular accident and abdominal discomfort).

[0184] No fatal AEs were reported. A summary of the AEs is provided in Tables 17 to 21 below. Table 17. Selected safety results from clinical studies * Includes all participants who were enrolled in the study and then received at least one dose of fetucillin before dosing resumption (after the sponsor initiated a dosing pause); All other SAEs were reported by 1 participant (1.5%) each; AEs included cerebrovascular accident and thrombosis (original text: left eye mastoid thrombosis). Participants who experienced cerebrovascular accident had a history of right lower extremity deep vein thrombosis unknown to the investigator at the time of study enrollment (exclusion criterion); §One of these participants experienced laboratory abnormalities consistent with Hy's law, which resolved after the last dose of fetocillin. AE, adverse event; AESI, adverse event of special interest; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SAE, serious adverse event; ULN, upper limit of normal.

[0185] Antithrombin level : During the fetocillin efficacy period, a decrease in AT levels was observed in patients ( Fig.11 ). In patients with inhibitors, AT levels decreased by an average of 81.4% from baseline on Day 29. In patients without inhibitors, AT levels decreased by an average of 82.3% from baseline on Day 29. AT levels remained decreased throughout the study. In patients with inhibitors, peak thrombin generation (TG) increased by an average of 35.0 nM from baseline on Day 29. In patients without inhibitors, peak TG increased by an average of 34.9 nM from baseline on Day 29. In all three trials, TG remained elevated throughout the study ( Fig.12 ). Subgroup analysis of adolescents

[0186] 19 adolescents (12-17 years old) were enrolled in the study. Table 22 shows the baseline characteristics of the adolescents enrolled in the trial. Table 22. Characteristics of adolescent patients 1 The number of bleeding events in the 12 months before screening was recorded for participants without inhibitors. 2 Inhibitor n=6, no inhibitor n=11.

[0187] The median ABR in the fetucillin group was 0.00, whereas the median ABR in the CFC / BPA group was 2.2. Fig.13 Shown are the median observed ABR, AjBR and AsBR for adolescent patients enrolled in the trial.

[0188] Fentacil prevention improved HRQoL, with a mean change in the transition total score from baseline to month 9 of -4.3 during CFC / BPA prevention and a mean change in the transition total score measured using the Haemo-QoL survey of -6.3 ( Fig.14 The safety profile of fetuin in adolescents was consistent with that observed in adult participants.

[0189] Conclusions: In adolescents with hemophilia A or B with or without inhibitors, fetucillin prophylaxis demonstrated an improvement in the bleeding phenotype. The reduction in Haemo-QoL scores with fetucillin prophylaxis compared with CFC and BPA treatment supports a broad improvement in HRQoL. The benefit / risk assessment was favorable. in conclusion

[0190] In participants with hemophilia A or B with or without inhibitors who switched from previous prophylaxis with factor or BPA, fetucillin 80 mg QM prophylaxis achieved a highly significant reduction in the ABR of 61.1% (95% CI, 32.5% to 77.6%) during the efficacy period (P<0.001). The median observed ABR (IQR) was lower during the fetucillin efficacy period than during the factor / BPA prophylaxis period (0.00 [0.00; 2.25] and 4.35 [2.17; 10.87]).

[0191] 63.1% of participants did not experience any treated bleeding during the fetucillin efficacy period, while 16.9% did not experience any treated bleeding during the factor or BPA prophylaxis period. These findings were supported by a significant reduction in the incidence of other bleeding-related endpoints (spontaneous bleeding, joint bleeding events) during fetucillin prophylaxis compared with factor or BPA prophylaxis. These results demonstrate that fetucillin prophylaxis at 80 mg once monthly provides a significant level of protection against bleeding in participants with hemophilia A or B with or without inhibitors. Fetucillin prophylaxis significantly improved health-related quality of life as measured by the Haem-A-QOL total score. Nominal results demonstrated improvements in subdomains of the physical health domain. Reported AEs were generally consistent with previously identified risks of fetucillin. Ongoing clinical studies are currently evaluating the safety and efficacy of revised doses and schedules.

[0192] In conclusion, in patients with hemophilia A or B with and without inhibitors, monthly fetucillin prophylaxis significantly reduced bleeding, with a median ABR of zero, compared with factor / BPA prophylaxis, resulting in significant improvements in HRQoL. The reported AEs were generally consistent with previously identified risks of fetucillin. Thus, these results support fetucillin as a monthly subcutaneous prophylactic treatment option for patients with hemophilia A or B with and without inhibitors who had previously received factor concentrate or BPA prophylaxis. In addition, fetucillin prophylaxis significantly reduced bleeding rates compared with previous factor / BPA prophylaxis, with zero bleeding rates of >60%, suggesting that fetucillin prophylaxis achieved hemostatic levels of efficacy. Fewer bleedings resulted in lower factor / BPA consumption with fetucillin prophylaxis, fewer injections, and lower factor / BPA doses required to treat each bleed, compared with factor / BPA prophylaxis. The relatively infrequent subcutaneous route of administration of fentanyl prophylaxis compared with factor / BPA prophylaxis may reduce overall treatment and disease burden, improve QoL, and increase compliance in patients with hemophilia A or B with or without inhibitors. Example 3: Qualitative semi-structured interviews with ATLAS-OLE trial participants

[0193] In addition to the clinical trials described in Examples 1 and 2 (ATLAS-PPX), fetucillin was evaluated in two additional Phase 3 trials: ATLAS-INH (a study of patients with inhibitors) and ATLAS-A / B (a study of patients without inhibitors). After completion of any of these three studies, patients were eligible to participate in the open-label extension (OLE) study (ATLAS-OLE).

[0194] This example involved semistructured interviews with patients in the United States and India who were enrolled in the OLE study. The goal was to better understand patients’ and caregivers’ experiences with hemophilia A or B (with or without inhibitors) and their treatments, including fetuin, as well as their perceptions and satisfaction with fetuin during the OLE trial.

[0195] Interviewees included patients aged ≥18 years. Caregivers were interviewed for patients who were cognitively unable to participate in the interview or for patients between 12 and 18 years of age. In the OLE trial, all patients were interviewed at least one month after receiving their second dose of fetuxiram.

[0196] The one-hour semi-structured interview was conducted by telephone. Audio was recorded and transcribed. Each interview began with targeted open-ended questions, asking participants about their hemophilia and treatment experience before entering the ATLAS program and their views on the impact of hemophilia and its treatment on their daily lives and treatment expectations. Then, the focus of the interview discussion was placed on the experience of the participant during the OLE study, including any changes and favorable results that the participant noticed. During the OLE trial, the different attributes of hypothetical hemophilia treatment were evaluated using a five-point rating scale, and the degree of improvement (if present) noted in these respects was evaluated using a three-point rating scale. Anonymous interview records and ATLAS.ti 9 software were used to perform statistical analysis of qualitative interview data. Descriptive demographics and clinical information of the entire sample were summarized, and are shown in Table 23. Table 23. Characteristics of participants

[0197] A total of 24 participants were interviewed. The mean (SD) age of the participants was 27 (8.9) years. Fig.15 As shown, before joining the fetocillin clinical trial, participants stated that their (or their children's) hemophilia-related bleeding (joint and muscle), pain, weakness, joint stiffness and swelling had a significant negative impact on their daily life in many aspects. Almost all participants (n=21; 87.5%) reported that hemophilia treatment affected their daily physical activities, followed by the impact on work or school life.

[0198] Fig.16 The results showed that participants rated "reduced bleeding" as the most important attribute of hemophilia treatment, which was also one of the top two items in which they experienced the most improvement during the OLE trial. Other highly important attributes of hypothetical hemophilia treatment included "improved joint health", "improved joint mobility / ability to move easily", "bleeding protection throughout the month", and "minimizing anxiety or stress associated with hemophilia management". All participants reported that the improvements they observed during the ATLAS-OLE trial had a positive impact on their quality of life and their ability and confidence to participate in daily physical activities, enjoy family life, participate in social activities, and improve their overall mood or emotions (Table 24). Most participants (85%) also reported a positive impact from improvements in work or school life. Table 24. Improved quality of life of participants

[0199] Fig.17The results of the ATLAS trial showed that while 75% of participants were "satisfied" with their previous treatment before joining the ATLAS trial, nearly 92% of participants were "very satisfied" with treatment with fetucillin, especially with regard to its ability to prevent bleeding, its duration of action, and its convenience. In addition, almost all (23 / 24) participants preferred fetucillin prophylaxis to their previous hemophilia treatment.

[0200] Among the quotations recorded during the interviews, participants reported, for example, “After using Fetoxilan, I became like a normal person,” “…I can walk normally,” and “…[I]… am very confident because if I use Fetoxilan, I can say that bleeding will not occur.”

[0201] In conclusion, fetocillin met the treatment expectations of people with hemophilia and their caregivers. Almost all participants were very satisfied with fetocillin therapy and preferred fetocillin to their previous therapy. All participants treated with fetocillin reported positive changes in daily physical activities, family life, social activities, sense of security, and mood. These findings reflect the impact of fetocillin prophylaxis on participants' quality of life by improving the bleeding phenotype.

[0202] Almost all participants were very satisfied with fetucillin therapy and preferred fetucillin to their previous therapy.This qualitative study provides valuable positive insights into the patient and caregiver experience of hemophilia and its treatment.

Claims

1. A method of reducing the annualized bleeding rate (ABR) in a human subject with or without inhibitors who has hemophilia A or B and has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising: administering subcutaneously to the human subject in need thereof a therapeutically effective amount of fetucillin, and The subject's prophylactic replacement factor or BPA treatment is terminated within about two months, about one month, or optionally about 28 days or about seven days of the first dose of fetoxilan.

2. A method of reducing the annualized bleeding rate (ABR) in a human subject with or without inhibitors having hemophilia A or B who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising subcutaneously administering to the human subject in need thereof a therapeutically effective amount of fetucillin.

3. The method of claim 1 or 2, wherein the administration reduces the subject's ABR by more than 10%, 20%, 30%, 40% or 50%, optionally by more than 60%, compared to the human subject's historical ABR.

4. The method of claim 1 or 2, wherein the administration reduces the subject's median ABR to two or less than two, one or less than one, or zero, further optionally wherein the subject's historical ABR was greater than 4.

5. A method of reducing the annualized spontaneous bleeding rate (AsBR) in a human subject with hemophilia A or B with or without inhibitors who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising administering subcutaneously to the human subject in need thereof a therapeutically effective amount of fetucillin, and The subject's prophylactic replacement factor or BPA treatment is terminated within one month, optionally within about 28 days or about seven days of the first dose of fetoxilan.

6. A method of reducing the annualized spontaneous bleeding rate (AsBR) in a human subject with hemophilia A or B with or without inhibitors who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising subcutaneously administering to the human subject in need thereof a therapeutically effective amount of fetocillin.

7. The method of claim 5 or 6, wherein the administration reduces the AsBR by more than 40%, optionally by more than 50%, compared to the subject's historical AsBR.

8. The method of claim 5 or 6, wherein the administration reduces the subject's AsBR to one or less than one, or zero, optionally wherein the subject's historical AsBR is greater than 2.

9. A method of reducing the annualized joint bleeding rate (AjBR) in a human subject with hemophilia A or B with or without inhibitors who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising administering subcutaneously to the human subject in need thereof a therapeutically effective amount of fetucillin, and The subject's prophylactic replacement factor or BPA treatment is terminated within about one month, optionally within about 28 days or about seven days of the first dose of fetoxilan.

10. A method of reducing the annualized joint bleeding rate (AjBR) in a human subject with hemophilia A or B with or without inhibitors who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising subcutaneously administering to the human subject in need thereof a therapeutically effective amount of fetucillin.

11. The method of claim 9 or 10, wherein the administration reduces the AjBR by more than 40%, optionally by more than 50%, compared to the subject's historical AjBR.

12. The method of claim 9 or 10, wherein the administration reduces the subject's AjBR to one or less than one, or zero, optionally wherein the subject's historical AjBR was greater than 2.

13. A method of improving patient reported outcomes (PROs) in a human subject with hemophilia A or B with or without inhibitors who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising administering subcutaneously to the human subject in need thereof a therapeutically effective amount of fetucillin, and terminating the subject's prophylactic replacement factor or BPA treatment within about one month, optionally within about 28 days or about seven days of the first dose of fetuxiram, Optionally, wherein the PRO is improved in one or more quality of life (QoL) domains.

14. A method of improving patient reported outcomes (PROs) in a human subject with hemophilia A or B, with or without inhibitors, who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising subcutaneously administering to the human subject in need thereof a therapeutically effective amount of fetocillin, optionally wherein the PROs are improved in one or more quality of life (QoL) domains.

15. A method of improving the quality of life (QoL) of a human subject with hemophilia A or IBD, with or without inhibitors, who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising administering subcutaneously to the human subject in need thereof a therapeutically effective amount of fetucillin, and terminating the subject's prophylactic replacement factor or BPA treatment within about one month, optionally within about 28 days or about seven days of the first dose of fetuxiram, Optionally, wherein the QoL is improved in one or more QoL domains.

16. A method of improving the quality of life (QoL) of a human subject with hemophilia A or IBD, with or without inhibitors, who has been treated prophylactically with a replacement factor or bypassing agent (BPA), the method comprising subcutaneously administering to the human subject in need thereof a therapeutically effective amount of fetocillin, optionally wherein the QoL is improved in one or more QoL domains.

17. The method of any one of claims 13-16, wherein the one or more QoL domains are domains in a QoL questionnaire, optionally wherein the QoL questionnaire is the Haemophilia Adult Quality of Life Questionnaire (Haem-A-QoL).

18. The method of claim 17, wherein the administration produces an improvement indicated by a decrease in one or more of the total score and the physical health domain score of the questionnaire by 2 or more units, optionally 3 or more units, or 4 or more units.

19. The method of any one of claims 13-16, wherein the one or more QoL domains are domains in a QoL questionnaire, optionally wherein the QoL questionnaire is the Hemophilia Activity List (HAL).

20. The method of claim 19, wherein the administration produces an improvement indicated by an increase in the total score of the questionnaire of 0.4 units or more (optionally 0.5 units or more, or 0.6 units or more).

21. The method of any one of claims 13-16, wherein the one or more QoL domains are domains in a QoL questionnaire, optionally wherein the QoL questionnaire is the Treatment Satisfaction with Medication Questionnaire version 9 (TSQM-9).

22. The method of any one of claims 13-16, wherein the administration produces 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 effectiveness, satisfaction, and convenience domain scores of the questionnaire.

23. The method of any one of claims 13-16, wherein the one or more QoL domains are domains in a QoL questionnaire, optionally wherein the QoL questionnaire is the European Five Dimensions Health Assessment (EQ-5D-5L).

24. The method of claim 23, wherein the administration produces an improvement indicated by an increase in the total score of the questionnaire by 0.02 units or more (optionally 0.03 units or more, 0.04 units or more, or 0.05 units or more).

25. The method of any one of claims 13-16, wherein the one or more QoL domains are domains in a QoL questionnaire, optionally wherein the QoL questionnaire is the Children and Adolescents Hemophilia Quality of Life Questionnaire (Haemo-QoL).

26. The method of claim 25, wherein the administration produces an improvement indicated by a decrease in the total score of the questionnaire by 1 or more units (optionally 2 or more units, or 3 or more units).

27. The method of any one of claims 1-26, wherein the dose of fetocillin is administered to the subject about once a month, or about once every four weeks, or about once every other month, or about once every eight weeks.

28. The method of any one of claims 1-27, wherein the therapeutically effective amount of fetocilan administered to the subject is about 10 mg to about 100 mg, optionally wherein the therapeutically effective amount is about 80 mg, about 50 mg, about 20 mg, or about 10 mg.

29. The method of any one of claims 1-28, wherein the subject is a hemophilia A patient with inhibitors or a hemophilia B patient with inhibitors.

30. The method of claim 29, further comprising administering an effective amount of BPA to treat a bleeding episode, wherein the effective amount of BPA is reduced compared to a recommended effective amount of BPA.

31. The method of claim 30, wherein the BPA is activated prothrombin complex concentrate (aPCC), and a single dose of aPCC does not exceed 50 U / kg and optionally is 30 U / kg, optionally wherein the aPCC is administered repeatedly in no less than 24 hours if necessary.

32. The method of claim 30, wherein the BPA is recombinant Factor VIIa (rFVIIa) and a single dose of rFVIIa does not exceed 45 μg / kg, optionally wherein the rFVIIa is administered repeatedly within no less than two hours if necessary.

33. The method of any one of claims 1-28, wherein the subject is an inhibitor-free hemophilia A patient or an inhibitor-free hemophilia B patient.

34. The method of claim 33, comprising administering an effective amount of a replacement factor to treat a bleeding episode, wherein the effective amount of the replacement factor is reduced compared to the recommended effective amount of the replacement factor.

35. The method of claim 34, wherein the replacement factor is Factor VIII (FVIII), and a single dose of FVIII does not exceed 20 IU / kg and optionally is 10 IU / kg, optionally wherein the FVIII is administered repeatedly in no less than 24 hours if necessary.

36. The method of claim 34, wherein the replacement factor is Factor IX (FIX) and a single dose of FIX does not exceed 30 IU / kg and optionally is 20 IU / kg, optionally wherein the Factor IX is repeated if necessary within no less than 24 hours for standard half-life FIX or within no less than 5-7 days for extended half-life FIX.

37. The method of any one of claims 1-36, wherein the subcutaneous administering step comprises administering fetucillin at about 50 mg about every two months or about every eight weeks.

38. The method of claim 37, further comprising: Obtaining a measurement of the patient's steady-state antithrombin (AT) level; and Do one of the following: (i) if the AT level is between 15% and 35%, repeat administration of fetuxilan at about 50 mg; (ii) if the AT level is >35%, administering fetocillin subcutaneously to the patient at about 80 mg about every two months or about every eight weeks, or about 50 mg about every month or about every four weeks, or (iii) If the AT level is <15%, discontinue or suspend fetuxiram treatment.

39. The method of any one of claims 1-36, wherein the subcutaneous administering step comprises administering fetucillin at about 80 mg about every two months or about every eight weeks.

40. The method of any one of claims 1-36, wherein the subcutaneous administering step comprises administering fetucillin at about 50 mg about monthly or about every four weeks.

41. The method of any one of claims 1-36, wherein the subcutaneous administering step comprises administering fetucillin at about 80 mg about monthly or about every four weeks.

42. The method of any one of claims 1-41, wherein the patient has no (i) clinically significant liver disease, (ii) ALT>1.5×upper limit of normal reference range (ULN), (iii) AST>1.5×upper limit of normal reference range (ULN), (iv) Hepatitis C, (v) Hepatitis A, (vi) Hepatitis E, and / or (vii) Hepatitis B.

43. The method of any one of claims 1-42, wherein the patient is an adult or adolescent patient 12 years or older with hemophilia A or B, with or without inhibitors.

44. The method of any one of claims 1-43, wherein the method reduces the patient's annualized weight-adjusted replacement factor or BPA consumption.

45. The method of any one of claims 1-44, wherein the method reduces (i) the number of breakthrough bleeding episodes requiring treatment in that patient during a given time period; (ii) the patient's total weight-adjusted replacement factor / BPA dose during a given period, (iii) the average replacement factor / BPA consumption for that patient during a given period of time, or (iv) The number of injections of replacement factor / BPA required to treat breakthrough bleeding in this patient.

46. ​​Fetocilan for use in the method of any one of claims 1 to 45.

47. Use of fetocilan in the manufacture of a medicament for use in the method of any one of claims 1 to 45.

48. A pharmaceutical composition comprising fetocilan for use in a method as claimed in any one of claims 1 to 45.

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