Feltsilan for use in treatment of hemophilia A and hemophilia B in pediatric patients

Abstract

The present disclosure provides methods and compositions for treating paediatric patients with or without inhibitors having hemophilia A or hemophilia B. The present disclosure provides methods and compositions for treating paediatric patients with or without inhibitors.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 63 / 350,382 filed on June 8, 2022 and U.S. Application No. 63 / 381,499 filed on October 28, 2022. 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 022548WO089.xml and is 8,045 bytes in size. Background Art

[0003] Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders characterized by a lack of coagulation factor VIII (FVIII) or factor IX (FIX), resulting in severe defects in thrombin generation, impaired hemostasis and increased risk of bleeding. Factor replacement concentrates are currently the standard of care for hemophilia patients who do not have inhibitory antibodies (i.e., inhibitors) to FVIII or FIX, but the frequency of intravenous (IV) administration (2 to 3 times per week or more) to prophylactically maintain hemostasis causes it to remain a treatment with a high burden of treatment. In addition, the development of inhibitors is a major complication in children treated with factor replacement. Approximately 30% of previously untreated hemophilia A patients and 2% to 5% of previously untreated hemophilia B patients develop inhibitory antibodies to FVIII and FIX, respectively (Gouw et al., N Engl J Med. (2013) 368(3):231-9; and Puetz et al., Haemophilia. (2014) 20(1):25-31).

[0004] Treatment of patients with inhibitors may involve immune tolerance induction (ITI) therapy in an attempt to eradicate the inhibitor and / or require the use of bypass agents (BPA) such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa). However, the failure rate of various ITI approaches is high, especially for patients with hemophilia B, and inhibitor recurrence may occur later after ITI. Compared with factor replacement therapy used in non-inhibitor patients, inhibitor patients using BPA show higher annual bleeding rates and increased treatment burden (Antunes et al., Haemophilia. [Hemophilia] (2014) 20 (1): 65-72; Konkle et al., J Thromb Haemost. [Journal of Thrombosis and Hemostasis] (2007) 5 (9): 1904-13).

[0005] Another potential option for patients with hemophilia A who have inhibitors to FVIII is the recently approved bispecific antibody emicizumab that mimics FVIII function. Although emicizumab has shown promise in this population, thrombotic clinical events requiring risk mitigation strategies and an accompanying black box warning have been observed when emicizumab is used in combination with specific BPAs.

[0006] For pediatric patients with hemophilia, challenges with intravenous access and caregiver burden further complicate treatment for both inhibitor and non-inhibitor populations. For non-inhibitor pediatric patients, more frequent infusions may be required because factor replacement therapy has a shorter half-life than that of adults. In the case of inhibitor patients, prophylactic BPA therapy or ITI regimens may require daily or every other day infusions.

[0007] Therefore, there remains a need for alternative treatments for pediatric patients with hemophilia A or hemophilia B. Summary of the invention

[0008] The present disclosure provides methods for prophylactic treatment of hemophilia A or hemophilia B with or without inhibitors with fetucillin in pediatric patients aged 1 year to less than 12 years to prevent or reduce the frequency of bleeding episodes, and provides fetucillin for use in these methods.

[0009] In one aspect, the present disclosure provides a method for treating hemophilia A or hemophilia B in a pediatric patient with or without inhibitors, the method comprising: (a) administering fetucillin subcutaneously to a patient in need thereof at a starting dose and at a selected dosing frequency; (b) obtaining a measurement of the patient's antithrombin (AT) level; and (c) performing one of the following steps: (i) repeating step (a) if the AT level is 15%-35%, (ii) administering fetucillin subcutaneously to the patient at a higher dose and at a selected dosing frequency or at a starting dose and at a higher dosing frequency if the AT level is >35%, or (iii) administering fetucillin subcutaneously to the patient at a lower dose and at a selected dosing frequency or at a starting dose and at a lower dosing frequency if the AT level is <15%, optionally wherein step (c)(iii) is performed after administration of fetucillin is suspended and after the patient's AT level recovers to ≥15%, optionally ≥22%.

[0010] In some embodiments, the method reduces the frequency of bleeding episodes in a patient, such as reducing their annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR), and / or annual joint bleeding rate (AjBR). The method can also reduce the risk of thrombosis in pediatric patients with or without inhibitors who are receiving fetocillin for prophylactic treatment of hemophilia A or hemophilia B.

[0011] In another aspect, the disclosure provides a series of methods for treating hemophilia A or hemophilia B in pediatric patients with or without inhibitors using a predetermined amount of fetocillin (e.g., 1.25, 2.5, 5, 7.5, 10, 20, 30 or 50 mg) at a predetermined frequency (e.g., every two months, every eight weeks, every month or every four weeks).

[0012] In another aspect, the disclosure provides a non-tocillin formulation suitable for use in the methods herein. In some embodiments, the non-tocillin formulation is an aqueous non-tocillin composition comprising: about 12.5 mg / mL of non-tocillin, about 0.388 mg / mL of NaH2PO4*H2O, about 0.586 mg / mL of Na2HPO4*7H2O, and about 8.7 mg / mL of NaCl, pH about 7.0-7.1.

[0013] Also provided herein are fetocillin and preparations for use in the methods of treatment of the invention, the use of fetocillin for the manufacture of a medicament for treating hemophilia A or hemophilia B in a pediatric patient with or without inhibitors in the methods of the invention, and pharmaceutical compositions comprising fetocillin for use in the methods of treatment of the invention.

[0014] 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

[0015] Figure 1 The expanded structural formula, chemical formula and molecular mass of fetosilan (sodium form) are shown. The figure discloses SEQ ID NOs: 1 and 2, respectively, in the order of appearance.

[0016] Figure 2 is a diagram illustrating the study design described in Example 1. AT (Antithrombin) Follow-up: Antithrombin activity levels were monitored at monthly intervals for participants who did not continue to receive fentanyl until AT activity levels recovered to approximately 60% according to the central laboratory or at the discretion of the Investigator and in consultation with the Study Medical Manager.

[0017] Figure 3Flowchart describing the fetucillin step-up / step-down protocol for patients in Cohort 1 (patients weighing 22 kg to <45 kg). Participants will start / resume receiving fetucillin at a dose of 10 mg every 4 weeks. AT: antithrombin activity; QM=monthly; SS=steady state. *: over a 12-month period; **: dosing initiated after step-down from a higher dose, which will occur only after centrally measured AT activity levels are ≥22%.

[0018] Figure 4 is a flow chart describing the fetucillin step-up / step-down protocol for Cohort 2 patients (patients weighing 8 kg to <22 kg). Participants will begin receiving fetucillin at a dose of 5 mg every 4 weeks. Abbreviations and symbols are the same as above for Figure 3 Same as explained.

[0019] Figure 5 is a schematic diagram depicting the pharmacokinetic / pharmacodynamic (PK / PD) model used to simulate the kinetics of plasma AT activity in patients treated with fetocillin. A : absorption rate; F: bioavailability and dose effect on bioavailability; V2: volume of liver central compartment; V3: volume of liver peripheral compartment; CL: clearance rate from liver central compartment; CL2: clearance rate between liver compartments; Q: clearance rate into RISC compartment; RV: RISC volume; CL R : Clearance rate outside the RISC area; K in : AT generation rate; K out : AT elimination rate; I max : Maximum AT generation inhibition; IC 50 : RISC concentration at which the maximum AT production inhibition is 50%.

[0020] Figure 6 is a table showing computer modeling data of simulated trough and peak AT activity profiles for the pediatric cohort for various dosing regimens. WT: Body weight. Min.: Minimum. Max.: Maximum.

[0021] Fig. 7A and Figure 7B is a graph showing the distribution of calculated predicted AT levels for Cohort 1 patients treated monthly with a starting dose of 10 mg of fetucillin. Fig. 7A A step-down schedule is shown for the 26% of patients predicted to have AT values ​​< 15% after treatment with a starting dose of 10 mg QM. Figure 7B The step-up schedule for the predicted 10% of patients (AT value > 35%) after treatment with a starting dose of 10 mg QM is shown.

[0022] Fig. 8A and Figure 8Bis a graph showing the distribution of calculated predicted AT levels for Cohort 2 patients treated monthly with a starting dose of 5 mg of fetucillin. Fig. 8A A step-down schedule is shown for the predicted 21% of patients (AT values ​​< 15%) after treatment with a starting dose of 5 mg QM. Figure 8B A step-up schedule is shown for the 19% of patients predicted to have AT values ​​> 35% after treatment with a starting dose of 5 mg QM. DETAILED DESCRIPTION

[0023] Fetosilan is an N-acetylgalactosamine (GalNAc) small interfering RNA (siRNA) conjugate that reduces the generation of antithrombin (AT), thereby reducing plasma AT activity levels. By reducing plasma AT, Fetosilan is designed to improve thrombin generation and hemostasis in individuals with hemophilia, regardless of the type of hemophilia or the presence of inhibitory antibodies to FVIII or FIX. Fetosilan is being developed for routine prevention to prevent bleeding episodes or reduce their frequency in hemophilia A or hemophilia B patients (including patients with inhibitory antibodies to FVIII or FIX).

[0024] Subcutaneous (SC) therapies that can effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or hemophilia B, including those with inhibitors, could reduce treatment burden, improve clinical outcomes, and enhance quality of life, particularly in the pediatric patient population.

[0025] The present disclosure provides a method that is intended to maintain a favorable benefit-risk balance for pediatric patients with hemophilia A or hemophilia B with or without inhibitors treated with fetocillin. Fetocillin is intended for routine prevention to prevent or reduce the frequency of bleeding episodes in pediatric patients with hemophilia A or hemophilia B (i.e., aged 1 to <12 years old), including patients with inhibitory antibodies (inhibitors). The treatment methods of the present invention carefully adjust therapy based on the patient's AT level in order to minimize the risk of vascular thrombotic events that may be caused by low AT levels (e.g., AT levels <10%).

[0026] A hemophilia A or hemophilia B patient with an inhibitor is a patient who has developed alloantibodies to a factor he / she has previously received (e.g., factor VIII for a hemophilia A patient or factor IX for a hemophilia B patient). Hemophilia A or hemophilia B patients with inhibitors may become refractory to alternative coagulation factor therapy. A patient without an inhibitor is a patient who does not have such alloantibodies. The treatment methods of the present invention may be beneficial to hemophilia A patients with or without inhibitors, and hemophilia B patients with or without inhibitors. As used herein, "hemophilia A or hemophilia B with or without inhibitors" refers to hemophilia A with or without inhibitors, or hemophilia B with or without inhibitors. As used herein, a patient refers to a human pediatric patient aged 1 to less than 12 years old. I. Fetocilan pharmaceutical composition

[0027] Hemophilia leads to 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 hemophiliacs. Antithrombin is encoded by the SERPINC1 gene.

[0028] The structure of the fetosilan provided herein is a synthetic chemically modified double-stranded small interfering RNA (siRNA) oligonucleotide, which is covalently linked to a triantennary N-acetyl-galactosamine (GalNAc) ligand targeting the AT3 mRNA in the liver, thereby inhibiting the synthesis of antithrombin. The nucleosides in each chain of fetosilan are connected by 3'-5' phosphodiester or thiophosphate linkages, thereby forming the sugar-phosphate backbone of the oligonucleotide. The sense strand and antisense strand of fetosilan contain 21 and 23 nucleotides respectively. The 3' end of the sense strand is conjugated to a part (called L96) containing GalNAc by phosphodiester linkages. 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, thereby forming 21 nucleotide base pairs and a two-base overhang 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.

[0029] 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:

[0030] The expanded structural formula, molecular formula and molecular weight of fetosilan 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.

[0031] The structure of fetosilan can also be described by the following diagram, where X is O:

[0032] For use in the therapeutic methods of the invention, fetocillin may be provided in a pharmaceutical composition comprising fetocillin and a pharmaceutically acceptable excipient. In certain embodiments, the dsRNA compound is in the form of a sodium salt.

[0033] In some embodiments, fetucillin is provided in an aqueous solution at a concentration of 1 to 200 mg / mL (e.g., 50 to 150 mg / mL, 80 to 110 mg / mL, or 90 to 110 mg / mL, or 5 to 25 mg / mL, 7.5 to 20 mg / mL, or 10 to 15 mg / mL). As used herein, values ​​between the ranges and values ​​are also intended to be part of the present disclosure. In addition, it is intended to include a range of values ​​using a combination of any of the values ​​as upper and / or lower limits. In further embodiments, the pharmaceutical composition comprises fetucillin at a concentration of 5, 10, 12.5, 50, 75, 100, 125, 150 or 200 mg / mL. In certain embodiments, fetucillin is provided in the form of an aqueous solution at a concentration of 100 mg / mL. In certain embodiments, fetucillin is provided in the form of an aqueous solution at a concentration of 12.5 mg / mL. In certain embodiments, fetucillin is provided in the form of an aqueous solution at a concentration of 6.25 mg / mL.

[0034] Unless otherwise specified, the weight of fetocillin described in this disclosure is the weight of fetocillin free acid (active moiety), even if fetocillin is injected subcutaneously into a patient in its sodium form (in aqueous solution). For example, 100 mg / mL of fetocillin means that each mL contains 100 mg of fetocillin free acid (equivalent to 106 mg of fetocillin sodium, the drug substance).

[0035] In some embodiments, the pharmaceutical composition comprises fetosilan in phosphate buffered saline. The phosphate concentration in the solution may be 1 to 10 mM (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 mM) with a pH of 6.0-8.0. The pharmaceutical composition herein may include a preservative, such as EDTA. Alternatively, the pharmaceutical composition does not contain a preservative.

[0036] In certain embodiments, the fetocillin pharmaceutical composition is preservative-free and comprises, consists of, or consists essentially of 100 mg of fetocillin per mL of 5 mM phosphate buffered saline (PBS) solution. The PBS solution consists of sodium chloride, disodium hydrogen phosphate (heptahydrate), and sodium dihydrogen phosphate (monohydrate). The pH of the composition can be adjusted to about 7.0 using sodium hydroxide solution and diluted phosphoric acid.

[0037] In certain embodiments, the fetocillin pharmaceutical composition is preservative-free and comprises, consists of, or consists essentially of 12.5 mg fetocillin per mL of 5 mM phosphate buffered saline (PBS) solution. The PBS solution consists of sodium chloride, disodium hydrogen phosphate (heptahydrate), and sodium dihydrogen phosphate (monohydrate). The pH of the composition can be adjusted to about 7.0 (e.g., 7.1) using sodium hydroxide solution and diluted phosphoric acid.

[0038] 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 solution is administered to the patient by subcutaneous injection. The solution can be stored at 2°C to 30°C (e.g., 2°C to 8°C). In some embodiments, the pharmaceutical composition is provided in a pre-filled single-dose syringe. In some embodiments, the pre-filled single-dose syringe contains 20-50 mg (e.g., about 20 mg or about 30 mg) of fetuxilan. In some embodiments, the vial is a type I glass single-use vial; in other embodiments, the vial contains at least 0.2 mL of an aqueous solution containing fetuxilan.

[0039] In some embodiments, fetocillin is provided in 30 mg vials (e.g., at 100 mg / mL), which can also be combined to obtain higher doses. These vials can also be used in halves (half vials) to obtain a dose of 15 mg.

[0040] In some embodiments, fetocillin is provided in 20 mg vials (e.g., at 100 mg / mL), which can also be combined to obtain a high dose. These vials can also be used in half (half a vial) to obtain a dose of 10 mg.

[0041] In some embodiments, fetosilan is provided in 2.5 mg vials (e.g., at 12.5 mg / mL), which can be combined to obtain, for example, a dose of 5, 7.5, 10, 20, 30, or 50 mg. These vials can also be used in halves (half vials) to obtain a dose of 1.25 mg.

[0042] In some embodiments, fetocillin is provided in 1.25 mg vials (e.g., at 12.5 mg / mL), which can be combined to obtain, for example, a dose of 2.5, 5, 7.5, or 10 mg. In some embodiments, fetocillin is provided in 1.25 mg vials (e.g., at 6.25 mg / mL), which can be combined to obtain, for example, a dose of 2.5, 5, 7.5, or 10 mg.

[0043] In one embodiment, 80 mg of fetocillin is delivered in 0.8 mL (100 mg of fetocillin / mL). In one embodiment, 50 mg of fetocillin is delivered in 0.5 mL (100 mg of fetocillin / mL). In one embodiment, 20 mg of fetocillin is delivered in 0.5 mL (40 mg of fetocillin / mL). In one embodiment, 30 mg of fetocillin is delivered in 0.5 mL (60 mg of fetocillin / mL). In one embodiment, 10 mg of fetocillin is delivered in 0.5 mL (20 mg of fetocillin / mL). In one embodiment, 7.5 mg of fetocillin is delivered in 0.5 mL (15 mg of fetocillin / mL). In one embodiment, 5 mg of fetocillin is delivered in 0.5 mL (10 mg of fetocillin / mL). In one embodiment, 2.5 mg of fetocillin is delivered in 0.5 mL (5 mg of fetocillin / mL). In one embodiment, 1.25 mg of fetocillin is delivered in 0.5 mL (2.5 mg fetocillin / mL).

[0044] In certain embodiments, the fetocillin composition for subcutaneous injection contains fetocillin in 5 mM phosphate buffered saline at pH 7.0 or 7.1, the phosphate buffered saline having 0.64 mM NaH2PO4, 4.36 mM Na2HPO4 and 84 mM NaCl. In certain embodiments, the composition of the fetocillin solution for subcutaneous injection is shown in Table 1A below. Table 1A. Non-toxicillin formulations qs: appropriate amount.

[0045] In certain embodiments, the composition of the fetocillin solution for subcutaneous injection is shown in Table 1B below. Table 1B. Non-toxilan formulations

[0046] 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

[0047] 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 generation 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 as a routine prevention to treat hemophilia A or hemophilia B in pediatric patients with or without inhibitors, or to prevent bleeding episodes or reduce their frequency. In a specific embodiment, fetosilan is used to treat pediatric patients (i.e., patients aged 1 year old to <12 years old) with inhibitors or without inhibitors for hemophilia A or hemophilia B (congenital factor VIII or factor IX deficiency).

[0048] The method of the present invention comprises administering a therapeutically effective amount of fetucillin to a hemophilia patient (e.g., hemophilia A or hemophilia B patient) in need thereof. "Therapeutically effective amount" refers to an amount of fetucillin that helps the patient reach a desired clinical endpoint. The desired clinical endpoint may be, for example, a reduction in the annualized bleeding rate (ABR) to no more than 3, no more than 2, no more than 1, or zero. The desired clinical endpoint may also be, for example, a reduction in the annualized spontaneous bleeding rate (AsBR) to no more than 1, and preferably zero.

[0049] The therapeutic methods of the present invention are based in part on the discovery that the risk of vascular thrombotic events in patients exposed to fetocillin increases as AT levels decrease. AT can be measured by recognized methods including both kinetic and chromogenic assays. One commonly used method is INNOVANCE TM Antithrombin assay (Siemens Healthineers, Malvern, PA; US Food and Drug Administration 510(k) No. K081769). INNOVANCE TM The AT-X is a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of excess factor Xa by AT. XP, CA-600 and CS system or COAG 360 system) and can be calibrated using Siemens standard human plasma (SHP), where the definition of AT activity is calibrated against the World Health Organization (WHO) reference plasma. An equivalent assay is the Berichrom TMAntithrombin III assay (Dade Behring Marburg GmbH, Marburg, Germany; US FDA 510(k) No. K933125). Each measurement can be controlled by two independent control values ​​(low value and normal value), also calibrated according to WHO standards. AT activity (%) in plasma samples was calculated based on WHO reference plasma. 100% AT level was defined as the presence of 1 unit of antithrombin activity in 1 mL of reference plasma sample. Based on INNOVANCE TM The FDA 510(k) decision summary for the assay states that the limit of detection for the assay is 6.0%. AT levels range from about 80% to about 120% in the general population.

[0050] It has been observed that the risk of arterial thrombotic events in patients receiving fetucillin may increase with AT levels <10%. Therefore, the patient's AT level can be monitored and the dose of fetucillin can be adjusted if necessary.

[0051] In some embodiments, the patient has a steady-state AT level within a desired range (e.g., 15%-35%), but bleeding control is still suboptimal (e.g., two or more treated bleeds within a 12-week period from the third injection of fetocillin at the current dose, fetocillin will be administered at a higher level or at a higher frequency (e.g., from every two months or every eight weeks to every month or every four weeks)). The dosing regimen adjustment can be adjusted until the patient has no more than two treated bleeds within a 12-week period from the third injection of fetocillin at the current dose, while maintaining a steady-state AT range of 15%-35%.

[0052] In some embodiments, a range of 1 mg to 50 mg of fetucillin is administered subcutaneously to a patient. In further embodiments, a range of 1 mg to 30 mg of fetucillin is administered subcutaneously to a patient. In further embodiments, a range of 1 mg to 20 mg of fetucillin is administered subcutaneously to a patient. In further embodiments, a range of 1 mg to 10 mg of fetucillin is administered subcutaneously to a patient. In further embodiments, a range of 1 mg to 5 mg of fetucillin is administered subcutaneously to a patient. In certain embodiments, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg are administered subcutaneously to a patient. , 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg of fetuxilan. In certain embodiments, fetuxilan, for example, one of the above weight doses, is administered subcutaneously every other month or every eight weeks, or every month or every four weeks.

[0053] In some embodiments, 1.25 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0054] In some embodiments, 1.25 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0055] In some embodiments, 2.5 mg of fetocilan is administered subcutaneously every other month or every eight weeks.

[0056] In some embodiments, 2.5 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0057] In some embodiments, 5 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0058] In some embodiments, 5 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0059] In some embodiments, 7.5 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0060] In some embodiments, 7.5 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0061] In some embodiments, 10 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0062] In some embodiments, 10 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0063] In some embodiments, 20 mg of fetocilan is administered subcutaneously every other month or every eight weeks.

[0064] In some embodiments, 20 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0065] In some embodiments, 30 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0066] In some embodiments, 30 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0067] In some embodiments, 50 mg of fetocillin is administered subcutaneously every other month or every eight weeks.

[0068] In some embodiments, 50 mg of fetocilan is administered subcutaneously every month or every four weeks.

[0069] Exemplary treatment regimens are described further below. Higher weight pediatric patients

[0070] Patients weighing 22 kg to <45 kg can start with a starting dose of 10 mg of fetocillin every month (or every four weeks). Patients' AT levels can be monitored regularly (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months). An exemplary step-up and step-down schedule for patients in Cohort 1 is shown in Figure 3 middle.

[0071] In some embodiments, patients treated with a starting dose of 10 mg of fetucillin per month (or every four weeks) gradually reduce their fetucillin dosage regimen. In some embodiments, when the first AT level is <15%, another AT activity level sample is drawn from the patient within one month (e.g., within one or two weeks). If this result is <15%, this is considered the second AT <15%. Patients who receive fetucillin at a dose of 10 mg QM and have more than 1 (e.g., 2) AT activity levels <15% will be gradually reduced to a dose of 2.5 mg of fetucillin per month (or every four weeks). After their AT level returns to above 15% (e.g., ≥22%), the patient can start treatment with a lower dose of fetucillin.

[0072] After gradually reducing the dose of 2.5 mg of fetucillin per month, the patient's AT level can be monitored again regularly (e.g., every one, two, three, four, five, six, seven or eight weeks, or every one, two, three, four, five or six months). In some embodiments, when the first AT level is <15%, another AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is <15%, this is considered to be the second AT <15%. Patients who receive fetucillin at a dose of 2.5 mg QM and have more than 1 (e.g., 2) AT activity levels <15% can discontinue or suspend fetucillin treatment.

[0073] Alternatively, after gradually decreasing to a monthly dose of 2.5 mg fetucillin, the patient's AT level is monitored again regularly (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months). In some embodiments, when the first steady-state AT level is >35%, another AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 2.5 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 5 mg fetucillin once a month (or once every four weeks).

[0074] In other embodiments, patients treated with a starting dose of 10 mg of fetucillin per month (or every four weeks) can gradually increase their fetucillin dose. Patients' AT levels can be monitored regularly (e.g., every week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks, or every month, two months, three months, four months, five months, or six months). In some embodiments, when the first steady-state AT level is >35%, another steady-state AT activity level sample of the patient is drawn within one month (e.g., within one week or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 10 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 20 mg fetucillin per month (or every four weeks).

[0075] After gradually increasing to a monthly dose of 20 mg fetucillin, the patient's AT level can be monitored again regularly (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months). In some embodiments, when the first steady-state AT level is >35%, another steady-state AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 20 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 30 mg fetucillin once a month (or once every four weeks).

[0076] In some embodiments, the AT activity level at steady state remains >35% before the stepwise increase (see e.g. Figure 3 ). Lower-weight pediatric patients

[0077] Patients weighing 8 kg to <22 kg (Cohort 2) can start with a starting dose of 5 mg of fetucillin every month (or every four weeks). The step-up and step-down schedule for patients in Cohort 2 is shown in Figure 4 The patient's AT level can be monitored regularly (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months).

[0078] In some embodiments, patients treated with a starting dose of 5 mg of fetucillin per month (or every four weeks) can have their fetucillin dose gradually reduced. In some embodiments, when the first AT level is <15%, another AT activity level sample is drawn from the patient within one month (e.g., within one or two weeks). If this result is <15%, this is considered the second AT <15%. Patients who receive fetucillin at a dose of 5 mg QM and have more than 1 (e.g., 2) AT activity levels <15% can be gradually reduced to a dose of 1.25 mg of fetucillin per month (or every four weeks). After their AT level returns to above 15% (e.g., ≥22%), the patient can start at a lower dose of fetucillin.

[0079] After gradually reducing the dose of 1.25 mg of fetucillin per month, the patient's AT level can be monitored again regularly (e.g., every one, two, three, four, five, six, seven or eight weeks, or every one, two, three, four, five or six months). In some embodiments, when the first AT level is <15%, another AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is <15%, this is considered to be the second AT <15%. Patients who receive fetucillin at a dose of 1.25 mg QM and have more than 1 (e.g., 2) AT activity levels <15% can discontinue or suspend fetucillin treatment.

[0080] Alternatively, after gradually decreasing to a monthly dose of 1.25 mg fetucillin, the patient's AT level may be monitored again on a regular basis (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months). In some embodiments, when the first steady-state AT level is >35%, another steady-state AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 1.25 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 2.5 mg fetucillin once a month (or once every four weeks).

[0081] In other embodiments, patients treated with a starting dose of 5 mg of fetucillin per month (or every four weeks) can gradually increase their fetucillin dose. Patients' AT levels can be monitored regularly (e.g., every week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks, or every month, two months, three months, four months, five months, or six months). In some embodiments, when the first steady-state AT level is >35%, another steady-state AT activity level sample of the patient is drawn within one month (e.g., within one week or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 5 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 10 mg of fetucillin per month (or every four weeks).

[0082] After gradually increasing to a monthly dose of 10 mg fetucillin, the patient's AT level can be monitored again regularly (e.g., every one, two, three, four, five, six, seven, or eight weeks, or every one, two, three, four, five, or six months). In some embodiments, when the first steady-state AT level is >35%, another steady-state AT activity level sample of the patient is drawn within one month (e.g., within one or two weeks). If this result is >35%, this is considered to be the second steady-state AT>35%. Patients who receive fetucillin at a dose of 10 mg QM and have more than 1 (e.g., 2) steady-state AT activity levels>35% can be gradually increased to a dose of 20 mg fetucillin once a month (or once every four weeks).

[0083] In some embodiments, the AT activity level at steady state remains >35% before the stepwise increase (see e.g. Figure 4 ).

[0084] In some embodiments, the AT activity level used to decide whether to gradually increase the dose or frequency of fetucillin is the AT activity level measured at steady state (SS) (i.e., once the patient's AT level stabilizes after fetucillin treatment). SS is usually achieved after two or three doses of fetucillin. AT measurements used to determine dosing are taken at appropriate intervals (e.g., every four weeks or every eight weeks).

[0085] In the above dosage determination scheme, the starting dose of 10 mg fetucillin QM or 5 mg fetucillin QM is discussed as an illustrative example. For example, the starting dose of fetucillin can be 20 mg QM, 10 mg Q2M, 7.5 mg Q2M, 5 mg Q2M or 2.5 mg QM. Then, the dose can be gradually increased and gradually decreased accordingly starting from each starting dose. For example, the starting dose of 2.5 mg QM fetucillin can be gradually increased to 5 mg QM, 10 mg QM, 20 mg QM, 30 mg QM or 50 mg QM, optionally gradually increased in this order, or gradually decreased to 2.5 mg Q2M or 1.25 QM.

[0086] 10%-35% (e.g., 10%-25%, 15%-35% or 15%-25%) AT levels are intended to mitigate the risk of vascular thrombotic events, while maintaining a favorable benefit-risk balance for patients receiving fetocillin. Therefore, unless otherwise discussed herein (e.g., the patient's bleeding events are more frequent than a preset threshold), as long as the patient reaches the target AT level, the patient does not need to receive a higher dose of fetocillin or more frequent dosing. In other words, the patient can maintain the current treatment regimen (i.e., maintenance regimen). For example, once the desired AT level is reached, the patient can be treated with a subcutaneous dose of fetocillin (e.g., 1.25-30 mg per dose) at intervals of, for example, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks or eight weeks or one month, two months, three months or four months. In some embodiments, if the patient has two AT measurements of no more than 35% when receiving 10 mg QM, the patient will maintain this dosing regimen without further stepwise increase in dosage or dosing frequency. As another example, if a patient has two AT measurements of no greater than 35% while receiving 5 mg QM, the patient will remain on this dosing regimen without further step-up in dose or dosing frequency (e.g., step-up to 10 mg QM or 20 mg QM). However, if the patient has more than 1 (e.g., 2) AT measurements <15% (e.g., <10%), then as a risk mitigation measure for vascular thrombotic events, fetucillin therapy should be gradually reduced in dose (or discontinued if already gradually reduced to the lowest allowed dose). In some embodiments, an exception may be when a patient bleeds more frequently than a preset threshold, even though the AT activity level is within range (15%-35%), the patient also steps up the fetucillin dose.

[0087] Pediatric patients with hemophilia A or hemophilia B with or without inhibitors can be treated with a subcutaneous maintenance dose of 1-50 mg of fetucillin per dose per month (or every four weeks). In some embodiments of the maintenance regimen, patients with or without inhibitors of hemophilia A or hemophilia B are treated with a subcutaneous dose of 50 mg of fetucillin per dose per month (or every four weeks). In some embodiments of the maintenance regimen, patients with or without inhibitors of hemophilia A or hemophilia B are treated with a subcutaneous dose of 30 mg of fetucillin per dose per month (or every four weeks). In other embodiments, patients with or without inhibitors of hemophilia A or hemophilia B are treated with a subcutaneous dose of 20 mg of fetucillin per month (or every four weeks). In other embodiments, patients with or without inhibitors of hemophilia A or hemophilia B are treated with a subcutaneous dose of 10 mg of fetucillin per month (or every four weeks). In some embodiments of the maintenance regimen, patients with hemophilia A or hemophilia B with or without inhibitors are treated with a subcutaneous dose of 7.5 mg of fetucillin per dose every month (or every four weeks). In other embodiments, patients with hemophilia A or hemophilia B with or without inhibitors are treated with a subcutaneous dose of 5 mg of fetucillin per month (or every four weeks). In other embodiments, patients with hemophilia A or hemophilia B with or without inhibitors are treated with a subcutaneous dose of 2.5 mg of fetucillin per month (or every four weeks). In other embodiments, patients with hemophilia A or hemophilia B with or without inhibitors are treated with a subcutaneous dose of 1.25 mg of fetucillin per month (or every four weeks).

[0088] In some embodiments, patients may receive regular (eg, monthly or every four weeks) AT monitoring for 12 months following the change in the fetucillin dosing regimen.

[0089] In some embodiments, once the patient maintains a maintenance regimen (e.g., 1.25 mg QM or Q4W, 2.5 mg QM or Q4W, 5 mg QM or Q4W, 7.5 mg QM or Q4W, 10 mg QM or Q4W, 20 mg QM or Q4W, 30 mg QM or Q4W, or 50 mg QM or Q4W), the patient may receive less frequent AT monitoring. For example, the patient's AT level may be monitored every month, every two months, every three months, every four months, every six months, every year, or every two years. III. Patient Management

[0090] Monitor the hemostatic parameters such as coagulation parameters (D-dimer, prothrombin fragment 1+2 and fibrinogen) of the patient who receives fetoxilan, and monitor the signs and symptoms of its vascular thrombosis events. Such signs and symptoms may include but are not limited to severe or persistent headache, headache with nausea and vomiting, chest pain and / or chest tightness, hemoptysis, dyspnea, abdominal pain, fainting or loss of consciousness, swelling or pain in arms or legs, vision problems, weakness and / or sensory deficits and speech changes. Evaluation of the signs and symptoms that are potentially consistent with vascular thrombosis should include appropriate imaging studies when applicable. For the diagnosis of cerebral venous sinus thrombosis, magnetic resonance imaging venography (MRV) or computed tomography venography (CTV) are recommended.

[0091] If patients develop thrombosis while receiving fetocillin, AT reversal can be administered in combination with replacement factors or BPA and appropriate anticoagulation. AT reversal should follow the labeled product recommendations for the prevention of perioperative thrombosis in patients with AT deficiency, and the patient dose should be individualized to target 80%-120% AT activity. Given the longer half-life of plasma-derived AT, its use may be preferred over recombinant AT.

[0092] Bleeding episodes in patients receiving fetocillin can be managed by administering replacement factors (recombinant or plasma-derived factor VIII or factor IX) or BPA (e.g., fresh frozen plasma (FFP); rFVIIa; and aPCC) as needed. The amount of factor or BPA must be reduced in patients receiving fetocillin to prevent vascular thrombosis. See, e.g., WO 2019 / 014187. Management of bleeding episodes in pediatric patients receiving prophylactic fetocillin therapy is described in further detail in Example 1. See, e.g., Table 4 below.

[0093] Additional definitions of terms and exemplary embodiments are described in the Examples and are incorporated herein by reference.

[0094] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present disclosure, exemplary methods and materials are described below. In the event of a conflict, the present specification including the definitions shall prevail. Typically, the nomenclature and techniques used in conjunction with the 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 shall include pluralities, and plural terms shall include singularities. Throughout the present specification and aspects, the words "have" and "include / comprise" or variations (such as "has, having", "comprises or comprising") shall be understood to mean including the stated integer or integer group, but not excluding any other integer or integer group. 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 of these documents constitute part of the common general knowledge in the art. As used herein, the term "about" or "approximately" when applied to one or more target values ​​refers to a value similar to the reference value. In certain aspects, unless otherwise specified or otherwise clear from the context, the term refers to a range of values ​​that fall within (greater or less than) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the reference value.

[0095] 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.

[0096] 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. Examples Example 1: Clinical Trial Protocol for an Open-Label Study of Non-Tocillin Prophylaxis in Male Pediatric Subjects Aged 1 to Less Than 12 Years with Hemophilia A or Hemophilia B

[0097] This example describes an open-label, multinational study protocol for non-tocillin prophylaxis in male pediatric participants aged 1 year to <12 years with severe hemophilia A or hemophilia B who have inhibitory antibodies to FVIII or FIX. Persons diagnosed with severe hemophilia A or hemophilia B with inhibitory antibodies were eligible for enrollment as long as they met all inclusion criteria and did not meet exclusion criteria.

[0098] The objectives of the study are to determine the appropriate starting, step-up, and step-down doses of fetucillin when administered to male pediatric participants (age 1 year to <12 years on Day 1). The study consists of a screening period of up to 60 days (which may be extended in exceptional circumstances after consultation with the sponsor), followed by a fetucillin treatment period during which participants will receive a starting dose of fetucillin administered subcutaneously every 4 weeks.

[0099] Participants who experience more than one antithrombin activity level less than 15% will be allowed to step down to a lower dose of fetucillin. Participants who have more than 1 antithrombin activity level less than 15% while receiving this lower dose must permanently discontinue fetucillin. Participants will be allowed to step up to a higher dose of fetucillin if their steady-state antithrombin activity level remains greater than 35% while receiving the starting dose. The study protocol is described in Figure 2 The dose administered will be based on 2 weight-based groups (Cohort 1 and Cohort 2), as further described below.

[0100] Throughout the study, participants could receive treatment for breakthrough bleeding episodes with BPA as needed according to bleeding management guidelines, as further described below.

[0101] Approximately 32 pediatric participants with severe hemophilia A or hemophilia B who have inhibitory antibodies to FVIII or FIX and are receiving on-demand or prophylactic treatment with BPA will be enrolled in the study (approximately 12 participants in Cohort 1 and approximately 20 participants in Cohort 2). In Cohort 2, approximately half of the participants should weigh 8 kg to <16 kg.

[0102] Once all participants in the 22kg to <45kg weight group (Group 1) have received 3 consecutive injections of the starting dose of fetucillin every 4 weeks, the independent data monitoring committee (DMC) will review the available safety and PD data from the first group until at least 4 weeks after the last dose. The DMC's approval to proceed will trigger the enrollment of participants with a weight of 8kg to <22kg. Once all participants in the 8kg to <22kg weight group (Group 2) have received 3 consecutive injections of fetucillin every 4 weeks, the DMC will review the available safety and PD data from both groups until at least 4 weeks after the last dose of the second group. Once all participants in the relevant groups have received injections of their respective doses, the DMC will also review the available safety and PD data of the step-up and step-down doses of fetucillin, as well as the available PK data for the starting dose.

[0103] Participants who complete 12 weeks of treatment with the starting, step-up or step-down dose may be eligible to continue treatment with fetocillin every 4 weeks as part of this study, or as a participant in an open label extension (OLE) study when available. Participants who remain on fetocillin will remain on study until all dosing groups are completed and until pediatric dosing is completed. If the participant and / or caregiver completes training and meets eligibility requirements, it may be possible to begin home injections of fetocillin at week 56, if permitted by national and local regulations.

[0104] For participants who are experiencing clinical benefit and remain on treatment, their estimated time in the study is up to 160 weeks. If the OLE study is feasible before 160 weeks, the participant is eligible, and the caregiver chooses to switch the participant to the OLE study, the duration of the study may be shorter.

[0105] Participants who discontinue fetuxiram treatment will need to be monitored until their AT activity level has recovered to approximately 60% as determined by the central laboratory or at the discretion of the investigator in consultation with the study medical administrator. This may take up to 24 weeks.

[0106] During the study, pharmacodynamic (PD) and pharmacokinetic (PK) data as well as safety / tolerability data will be collected. The blood sampling times for PD are shown in Table 2. Table 2. Timeline of activities Abbreviations: ADA = antidrug antibodies; AE = adverse event; APRI = AST to platelet ratio index; AT = antithrombin; BPA = bypassing agent; eDiary = electronic diary; EOS = end of study; EOT = end of treatment; ET = early termination; FVIII = factor VIII; FIX = factor IX; F / U = follow-up; LFT = liver function test; PK = pharmacokinetics; SAE = severe adverse event, ULN = upper limit of normal; TG = thrombin generation. Note: In exceptional circumstances, screening may be extended beyond the 60-day window in consultation with the sponsor. In such cases, some assessments performed at the start of screening may have to be repeated. Rescreening of participants is permitted after consultation with the study medical administrator. Participants in Cohort 1 who received fetucillin prior to dose maintenance will receive a new participant number and will resume dosing at fetucillin 10 mg SC every 4 weeks starting at the baseline visit. · When scheduled at the same time point, vital signs will be taken before the physical examination and blood sample collection. Unless otherwise stated, assessments on dosing days are prior to dosing. Blood samples will be obtained as blood volume permits and not exceed a blood volume collection limit of 2 mL / kg for any given 24-hour period and 7 mL / kg over an 8-week period. Sampling is prioritized for safety lab tests (LFTs, hematology, biochemistry), AT, ADA, then PK. aFetocillin is used as prophylactic therapy, and BPA is permitted as needed to treat breakthrough bleeding episodes. Participants may continue their regular BPA regimen (including BPA prophylaxis for participants on prophylaxis) for up to the first 7 days after the first starting dose of fetocillin. Beginning on day 8, BPA treatment for management of bleeding episodes should follow bleeding management guidelines. bParticipants who discontinue fetucillin for any reason will need to complete the EOS / ET visit and the AT F / U visit. They may receive treatment consistent with bleeding management guidelines until their AT activity level recovers to approximately 60%. c Participants who do not continue fetucillin therapy in this study or are not enrolled in the OLE study will complete assessments via AT F / U visits at monthly intervals after the last fetucillin dose until AT activity levels recover to approximately 60% as determined by the central laboratory or at the discretion of the investigator and in consultation with the study medical administrator. d Complete medical / medical history (ie, including bleeding episodes and treatment history in the previous 6 months) was recorded at Screening. e eDiary training will be completed at the screening clinic. Refresher training should also be provided at the baseline visit fAdminister fetocillin SC according to the Pharmacy Manual and continue every 28 days ± 7 days when the study site visits and assessments are performed quarterly and every 6 months. Home injection training will be conducted at the study site. Home injections can be performed according to conditions and instructions, but no earlier than Week 56. gA complete physical examination will be performed at Screening only; at all other visits, a straightforward physical examination will be performed. hHeight and weight will be recorded at all visits. i HCV antibody-positive participants only. FibroScan when available, FibroTest and APRI otherwise. jAfter the Week 52 visit, monthly AT testing will need to be resumed for at least 12 months each time a change in the fentanyl dose is made. At each dose level, at the first AT level <15%, participants must draw another AT activity level sample within 1 week of receiving the result at the site. If this result is <15%, this will be considered a second AT activity level <15%. kAfter the specified analysis is performed, residual samples (excluding ADA and PK samples) may be stored for up to 25 years from the completion of the clinical study report and used to further study biomarkers related to hemophilia and related conditions, study emerging safety issues, or develop fetocillin. PK and ADA samples will be disposed of after the CSR is completed unless data indicate that additional analysis that can be performed at a later time may be required. Samples drawn from the central line may be excluded from TG analysis. On days of fetucilan administration, a pre-dose sample will be collected within 4 hours prior to dosing. mLFT results may be obtained up to 7 days prior to the study site visit for scheduled dosing of fetucillin. LFTs performed within 7 days of Day 1 will only be used to inform dosing on Day 1 and are not required to confirm eligibility. LFTs may be analyzed locally, but if a local assessment is performed, a serum chemistry sample must also be collected for analysis at the central laboratory. LFT results will be obtained prior to receiving the monthly fetucillin dose. Monthly pre-dose LFT testing is not required after Week 52 for participants who have met the criteria for quarterly pre-dose LFT monitoring as described below: - No alanine aminotransferase elevation >3×ULN for ≥2 months at any time during fetucilan treatment; and - During the first 12 months of the study, any non-tocillin dose must not be maintained due to elevated LFTs.

[0107] The blood sampling times for PK are shown in Table 3. Table 3. Pharmacokinetic Time Points in Pediatric Participants a The 4-hour time point corresponds to the median time to maximum concentration in adults. b Predose time point corresponds to the minimum concentration after the third dose. Note: Time 00:00 is the time of drug administration.

[0108] Throughout the study, participants can receive treatment for breakthrough bleeding episodes with BPA as needed according to bleeding management guidelines, as described further below. The investigator will establish an individualized bleeding management plan for each participant and provide instructions based on the guidelines in Table 4. Table 4. Dosing Guidelines for Bleeding Management by Specific Products

[0109] Details of bleeding episodes and BPA doses administered during the study will be recorded in an electronic diary (eDiary). Scientific Basics

[0110] A subcutaneous therapy that can effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or hemophilia B, including those with inhibitors, could reduce treatment burden, improve clinical outcomes, and enhance quality of life, particularly in the pediatric patient population. Within this patient category, patients with inhibitors appear to have the highest unmet therapeutic need, and accordingly, enrollment in this dose-finding study will be limited to patients with hemophilia A or hemophilia B with inhibitors.

[0111] The current study aims to confirm the appropriate dosing of fetucillin in pediatric participants aged 1 year to <12 years in two weight categories, 22 kg to <45 kg and 8 kg to <22 kg. This will be based on AT activity levels as well as safety and tolerability data.

[0112] Modeling and simulation were used to identify participants within a specific weight group who would be able to maintain a dose of AT activity level ≥ 15%. The model was created with consideration of preclinical data and was based on adult dosing data, and approximately 1000 and 2000 pediatric participants with weight categories of 22kg to <45kg and 8kg to <22kg were simulated, respectively. In order to optimize the safety of participants in this confirmatory study, the heaviest (22kg to <45kg) participants will first be administered with a starting dose of 10mg. Only when the DMC has evaluated the available data from the largest group and deemed it appropriate will the next weight group be administered. Dosage justification

[0113] The selection of pediatric doses for specific weight ranges was based on population PK / PD modeling. To account for the lower weight of pediatric participants aged 1 year to <12 years, the adult PK model was updated using nonhuman primate AT lowering response data, and the updated model was then used to predict doses for pediatric studies.

[0114] Following the introduction of a dose and regimen change of fetucillin as a risk mitigation measure for vascular thrombotic events in the adult / adolescent study, an updated regimen for fetucillin administration was implemented in this study. Since the risk of vascular thrombotic events is believed to increase with low AT activity levels, a starting dose of 10 mg (cohort 1) or 5 mg (cohort 2) administered SC once every 4 weeks was selected to minimize the occurrence of AT activity levels below 10%. At these starting doses, if a participant has more than 1 AT level <15% (within a 12-month period), the participant can be gradually reduced to a lower dose. If a participant has more than 1 AT level <15% (within a 12-month period) when receiving this lower dose, it will require permanent discontinuation of fetucillin. Based on modeling and simulation, based on the participant's AT activity level at this lower dose, it is expected that less than 1% of the participants will discontinue fetucillin treatment. Modeling and simulation predict that starting doses of 10 mg and 5 mg will result in antithrombin levels of ≥15% to ≤35% for more than half of the participants in both cohorts 1 and 2. If the participant has 2 steady-state AT levels above 35% at the starting dose, the participant's dose will be gradually increased to 20 mg (group 1) or 10 mg (group 2) once every 4 weeks SC. At the starting dose of 10 mg and 5 mg, it is expected that the step-up dose of 20 mg and 10 mg will result in the antithrombin level of most participants with AT values>35% being ≥15% to ≤35%. If such a step-up is required, a further step-up will be allowed to be applied to 30 mg (group 1) and 20 mg (group 2) once every 4 weeks SC.

[0115] In addition to the above, dose escalation will be permitted based on clinical criteria with the goal of achieving adequate efficacy while maintaining AT levels above 15%. Goals and End Points

[0116] The primary objective of the study was to confirm the appropriate dose level of fetucillin when administered to male pediatric participants (ages 1 to <12 years) with severe hemophilia A or hemophilia B. The primary endpoint was to characterize AT activity at the optimal therapeutic dose.

[0117] Secondary objectives were to characterize safety and tolerability and to determine plasma concentrations of fetuxiram at selected time points. Secondary endpoints were the incidence, severity, severity, and relevance of adverse events (AEs); and plasma concentrations in samples collected 4 h after dosing on Day 1 (corresponding to the median time to maximum concentration in adults) and before dosing on Day 85 (corresponding to the minimum concentration after the third dose).

[0118] Tertiary / exploratory objectives were to characterize the frequency of bleeding episodes while receiving fetucillin and to characterize immunogenicity. Tertiary / exploratory endpoints were the annualized bleeding rate (ABR) at the best therapeutic dose from day 1 until the AT analysis time point, from the AT analysis time point until the end of study (EOS) visit at week 160, and for the overall treatment period; and the incidence and titer of anti-drug antibodies. Enrollment

[0119] Enrollment will be staggered in two weight-based groups. Participants weighing 22kg to <45kg (Group 1) will first be enrolled to receive 3 doses of 10mg of fetucillin every 4 weeks, and secondly, participants weighing 8kg to <22kg (Group 2) will be enrolled to receive 3 doses of 5mg of fetucillin every 4 weeks. For participants with 2 steady-state AT values ​​greater than 35%, the fetucillin dose will be gradually increased to 20mg (for Group 1) or 10mg (for Group 2) every 4 weeks. Participants with 2 steady-state AT values ​​greater than 35% when receiving the first step-up dose can be further gradually increased to 30mg (for Group 1) and 20mg (for Group 2) every 4 weeks. Study Group

[0120] Participants were eligible for inclusion in the study only if they met all of the following criteria: age I.01. Participants must be aged 1 to <12 years at the time of enrollment. Types of participants and disease characteristics I.02 Severe hemophilia A or hemophilia B (FVIII <1% or FIX ≤2%) I.03 Participants must have inhibitory antibodies to FVIII or FIX and must meet one of the following Nijmegen modified Bethesda assay result criteria: - Inhibitor titer ≥ 0.6 BU / mL at screening, or - Inhibitor titer <0.6BU / mL at screening and medical records showing titer ≥0.6BU / mL for 2 consecutive times, or -Inhibitor titer <0.6 BU / mL at screening, medical documentation of 1 inhibitor titer ≥0.6 BU / mL, and history of anamnestic response or severe allergic reaction (anaphylaxis or nephrotic syndrome). I.04 Adequate peripheral venous access as determined by the Investigator to allow blood draws as required by the study protocol. weight I.05 Weight requirements for entry: a) Group 1: Weight 22 to <45kg b) Group 2: Weight 8 to <22kg gender I.06Male There was no contraception requirement for this study unless required by local regulations.

[0121] Participants were excluded from the study if any of the following criteria applied: Medical conditions E.01 Known coexisting bleeding disorder other than hemophilia A or hemophilia B, i.e. von Willebrand disease, another factor deficiency or platelet disorder. E.02 AT activity <60% at screening as determined by central laboratory analysis. E.03 Presence of clinically significant liver disease or as indicated by any of the following: a) International normalized ratio (INR)>1.2; b) Alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 2×ULN reference range; c) total bilirubin >ULN (>2×ULN in participants with Gilbert's syndrome); d) history of portal hypertension, esophageal varices or hepatic encephalopathy; e) Physical examination revealed the presence of ascites. E.04 Hepatitis C virus antibody positive, except for participants with a history of HCV infection and who meet both of the following conditions: a) Completed curative therapy at least 12 weeks prior to enrollment and achieved a sustained virological response as evidenced by negative HCV ribonucleic acid (RNA) at screening, or they had spontaneously cleared the infection as evidenced by negative HCV RNA at screening. b) No evidence of cirrhosis based on one of the following assessments: -FibroScan < 9kPa (where available), or -FibroTest score <0.36 and AST to platelet ratio index (APRI) <1 (if FibroScan is not available) (Tokuhara et al., PLoS One. (2016) 11(11):e016668315; de Lédinghen et al., J Pediatr Gastroenterol Nutr. (2007) 45(4):443-50) E.05 There is acute hepatitis, namely hepatitis A and hepatitis E. E.06 Presence of acute or chronic hepatitis B infection (positive IgM antibody to hepatitis B core antigen [anti-HBc IgM] or positive hepatitis B surface antigen [HBsAg])*. *As confirmed by central laboratory assessment of HBsAg, anti-HBc IgM, and total hepatitis B core antibody (total anti-HBc). E.07 Platelet count ≤100,000 / μL. E.08 Presence of acute infection at screening, excluding minor viral syndromes at the discretion of the investigator and in consultation with the study medical administrator. E.09 is known to be human immunodeficiency virus (HIV) positive with a cluster of differentiation (CD) 4 count of <400 cells / μL. E.10 Estimated glomerular filtration rate ≤ 45 mL / min / 1.73 m 2 (Using Schwartz's formula). E.11 Coexistent thrombophilic disorder confirmed by central laboratory identification of any of the following: a) Factor V Leiden mutation (homozygous or heterozygous), b) Protein S deficiency, c) Protein C deficiency, and d) Prothrombin mutation (G20210A; homozygous and heterozygous). E.12 History of antiphospholipid antibody syndrome. E.13 History of arterial or venous thromboembolism not related to indwelling venous access. E.14 Any condition (e.g., medical problem) that the investigator believes would make the participant unsuitable for dosing on Day 1 or that could interfere with study compliance, the participant's safety, and / or the participant's participation in the treatment period to complete the study. This includes significant cardiovascular, neurological, gastrointestinal, endocrine, renal, or psychiatric disorders not related to hemophilia identified by key laboratory abnormalities or medical history. E.15 At Screening, surgery is anticipated to be required during the study or is planned to be performed during the study. E.16 Completed a surgical procedure within 14 days prior to screening, or is currently receiving additional BPA infusion for postoperative hemostasis. E.17 History of multiple drug allergies or allergic reactions to oligonucleotides or GalNAc. E.18 Subjects with central or peripherally indwelling catheters who have a history of venous access complications (e.g., infection, thrombosis) leading to hospitalization and / or systemic anticoagulation therapy within the last 12 months. (Note: Heparin-flushed catheters are not considered systemic anticoagulation.) E.19 History of SC injection intolerance. Prior / concomitant therapy E.20. Currently participating in ITI therapy. E.21 Use of emicizumab within 6 months before screening Previous / concurrent clinical research experience E.22 Currently or in the future participating in another clinical study, planned to be conducted during this study, involving an investigational product or investigational device other than fetocillin; in order to participate in this study, participants must have discontinued the investigational product or investigational device for at least 30 days (or 5 times the half-life of the investigational product, whichever is longer) prior to dosing (Day 1). Study Intervention

[0122] Study interventions were defined as any one or more investigational interventions, one or more marketed products, placebo, or one or more medical devices that were intended to be administered to study participants according to the study protocol. Fetocilan was administered every 4 weeks as shown in Table 5 below. Table 5. Summary of administered fetocilan

[0123] Based on the safety and PD data observed for the previous group, the dose of fetucillin can be reduced or increased relative to the dose initially planned for the next group. The decision to modify the dose of fetucillin will be based on the level of AT activity; changes in the planned dose can only occur after consultation between the DMC and the sponsor. After 12 weeks of treatment with the initial, step-up or step-down preventive dose of fetucillin, participants who remain receiving fetucillin will continue to study until the treatment period of all dosing groups is completed and pediatric dosing has been completed. If the growth of the participant leads to inclusion in a higher weight group and as indicated clinically according to the judgment of the investigator and in consultation with the research medical management personnel, the dose can be considered to be increased to the next dose based on weight based on individual participants.

[0124] For the first 7 days of the fetucillin initiation period, participants will continue their pre-study BPA therapy for hemophilia (prophylaxis or as needed) within the general recommendations of the approved prescribing information and at the investigator's discretion on a regimen consistent with their pre-study regimen. Bleeding episode management should be performed in accordance with local standard practices for BPA episodic use and at the investigator's discretion; however, reduced dosing is recommended when possible. After the first 7 days of fetucillin initiation, participants will discontinue BPA prophylaxis where applicable, and all participants will treat breakthrough bleeding episodes with on-demand BPA therapy as needed according to the bleeding episode management guidelines in this protocol. Concomitant therapy

[0125] Any medications or vaccines that the participant was taking at enrollment or received during the study (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) must be recorded. The local standard of care for hemophilia is considered to be, but not limited to, intravenous (IV) infusion of BPA (e.g., recombinant activated factor VII (rFVIIa; ) and activated prothrombin complex concentrate (aPCC; ). The use of these agents is described below and the details must be recorded in the participant's eDiary: - The use of prothrombin complex concentrate for the management of bleeding episodes is not permitted; - Use of emicizumab during the study is not permitted as well as -Antifibrinolytic drugs can be used as single agents but not in combination with BPA; not recommended and As a combination therapy. AT activity

[0126] Blood samples will be collected for assessment of AT activity levels according to Table 2. On days of fetucillin administration, samples will be collected within 4 hours prior to dosing (pre-dose). Antithrombin levels will be determined by a validated assay. Results will be collected and interpreted by a central laboratory.

[0127] Following administration of the final fetocilan dose, AT activity levels were monitored at monthly (or approximately every 4 weeks) intervals until recovery to approximately 60% of the activity level (according to the central laboratory) or at the discretion of the Investigator and in consultation with the Study Medical Administrator.

[0128] The optimal therapeutic dose for each participant was defined as the dose that resulted in that participant's steady-state AT within the target range of 15%-35% and that did not meet clinically based step-up criteria. Steady-state was considered to have been achieved after the third dose of fetucillin, as modeling and simulations had indicated that most patients would be in steady-state at this time. Management of bleeding episodes

[0129] The occurrence of bleeding episodes is a typical feature of hemophilia; bleeding episodes will be recorded as an efficacy assessment of fetucillin and will not be considered an AE unless the criteria for an SAE are met. The investigator is required to establish an individualized bleeding management plan for each participant based on the guidelines in Table 4 and provide instructions. It is expected that most participants will enter the OLE study shortly after completing the fetucillin study. However, given that it is possible that participants may have intervals of different durations between studies and therefore have different AT activity levels at the time of study entry, the following describes the approach to bleeding management based on the AT activity level at study entry. Bleeding episode definition

[0130] A bleeding episode was defined as the occurrence of any bleeding requiring administration of BPA infusion, such as joint bleeds, muscle or mucosal bleeds. The definitions of the types of bleeding episodes described below are based on the consensus of the International Society on Thrombosis and Haemostasis (ISTH) as reflected in a recent publication (22).

[0131] The time of onset of a bleeding episode will be considered 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 will be considered part of the original bleeding episode and counted as 1 bleeding episode for the ABR. Any bleeding symptoms that begin more than 72 hours after the last injection for a bleeding episode at the treatment site will constitute a new bleeding episode.

[0132] Spontaneous bleeding episodes are episodes of bleeding without an obvious or known cause, particularly into joints, muscles, and soft tissues.

[0133] An episode of joint bleeding is characterized by an abnormal sensation in the joint ("aura") and is 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 with baseline.

[0134] Muscle bleeds may be characterized by pain, swelling, and loss of motion in the affected muscle group.

[0135] A target joint was defined as a joint with three or more spontaneous bleeding episodes in a single joint within a 6-month consecutive period; a joint was no longer considered a target joint if there were ≤2 bleeding episodes in the joint within a 12-month consecutive period.

[0136] Traumatic bleeding episodes are bleeding episodes caused by a known injury or trauma. Bleeding episodes sustained during sports and recreation will be counted as traumatic bleeding episodes. Bleeding Management Guidelines for Participants with AT Activity Levels ≥60% (Based on Central Laboratory) at Study Entry

[0137] After dosing with fetocillin on day 1, when AT activity levels were ≥60%, participants and / or their caregivers were advised to call the investigator prior to dosing with BPA.

[0138] As soon as 7 days after the initial fentanyl dose, most participants will have AT activity levels at or below 60% activity. By 14 days after the first fentanyl dose, most participants are expected to have a >50% reduction in AT activity. Based on these AT activity kinetics, participants are advised to continue their standard BPA regimen during the first week after initiation of fentanyl administration, and to begin reducing BPA in the second week after initiation or reinitiation of fentanyl administration, in accordance with established regimen-specific bleeding management guidelines, as described below and in Table 4. Guidelines for the Management of Bleeding at Week 2 and Thereafter for Participants with AT Activity Levels <60% (Based on Central Laboratory) at Study Entry

[0139] When participants experienced symptoms that might be consistent with a bleeding episode, the following steps were followed: 1. Participants and / or their caregivers should be instructed to call the study site to discuss symptoms to determine if they are consistent with a bleeding episode and to discuss the appropriate dose of BPA to be used. This interaction between the participant and / or their caregiver and the investigator is recommended prior to administration of each dose of BPA. Confirmation of bleeding episodes at the study site prior to treatment may be considered. 2. If symptoms are determined to require treatment, the suggested treatment algorithm for a bleeding episode is described below: a) A single dose may be administered according to the guidelines in Table 4. b) Participants and / or their caregivers should be instructed to re-evaluate symptoms of bleeding episodes treated with aPCC within 24 hours and within 2 to 3 hours for bleeding episodes treated with rFVIIa. 3. If a second dose (in the case of aPCC) or a third dose (in the case of rFVIIa) is required, the participant and / or their caregiver must call the study site prior to dosing. a) Consider evaluating and treating participants at the study site and confirming bleeding episodes if any repeat doses are needed. b) If more than 2 doses of aPCC or 3 doses of rFVIIa are required, the participant should be observed at the study site for 48 to 72 hours. 4. Doses should not be administered at intervals of less than 24 hours (except for rFVIIa as shown in Table 4). 5. The dose should not exceed the maximum dose recommended by the regimen shown in Table 4. 6. Consultation with the study medical administrator and clinical advisor should be considered for the following clinical situations that may require AT substitution: a) The dose of BPA was higher than that recommended in Table 4. b) administering BPA at intervals less frequent than those recommended in Table 4. c) Multiple or repeated doses of BPA. 7. Antifibrinolytic drugs should not be used in combination with BPA. Management of bleeding episodes after discontinuation of fetucilan

[0140] Participants who choose to discontinue fetocilan may resume standard prophylaxis or on-demand dosing with BPA when their AT activity level recovers to approximately 60% (according to central laboratories). If a strong medical need arises (e.g., increased frequency of bleeding), early restart of standard therapy may be considered in consultation with the study medical administrator. If a full dose of BPA is required to achieve hemostasis before adequate AT recovery (approximately 60% AT activity according to central laboratories), AT substitution should be considered. Surgical management

[0141] Perioperative care planning should be developed using the same principles as described above for bleeding management and the following guidelines: - For participants with hemophilia undergoing this specific surgical procedure, if the clinical situation is such that the recommended doses and / or dosing intervals in Table 4 are considered inadequate for hemostasis, consider AT substitution and manage thrombotic risk according to the investigator's practice. -Non-pharmacological methods of thromboprophylaxis should also be employed as clinically indicated.

[0142] Fetocillin treatment during the perioperative evaluation period is as follows. If the need for major surgery arises during the study and the procedure is not emergent or urgent, it is recommended that the procedure be postponed until after the study is completed. For minor surgical procedures, fetocillin administration may be continued without interruption.

[0143] If the need for sudden or emergency major surgery arises during the study, participants should be medically managed according to the above guidelines. If a dose of fetucillin is scheduled on or very close to the day of surgery or at any time during the perioperative period, that dose should be withheld. The perioperative evaluation period is defined as the day of surgery until the last day of supplemental hemostatic or antithrombotic therapy administered as part of the perioperative care plan. At the discretion of the investigator, fetucillin administration may be resumed at the next scheduled visit after the perioperative evaluation period.

[0144] Minor surgery was defined as any invasive surgical procedure in which only the skin, mucosa, or superficial connective tissue was manipulated and did not meet the criteria for major surgery (eg, extraction of <3 non-molar teeth). Minor surgical procedures could be performed at a local healthcare facility.

[0145] Major surgery was defined as any invasive surgical procedure requiring any of the following: -Opening into a major body cavity (eg, abdomen, thorax, skull). - Joint surgery, - removal of organs, - Extraction of any molar or ≥ 3 non-molar teeth, - Surgery that alters normal anatomy, and -Cross mesenchymal barriers (e.g., pleura, peritoneum, dura mater). Rescue medication

[0146] The following rescue medications may be used: Antithrombin concentrate. Antithrombin reversal should follow the labeled product recommendations for prevention of perioperative thrombosis in participants with AT deficiency and individualize participant dosing to target 80% to 120% AT activity levels. Dose Modifications

[0147] In each study group, subcutaneous therapy of fetucillin will be used for administration. Based on the observed safety and PD data, the dose of fetucillin can be reduced or increased from the dose of fetucillin initially planned for the next group, but will not exceed 30 mg. The decision to modify the dose of fetucillin will be based on the level of AT activity; changes in the planned dose can only occur after consultation between the DMC and the sponsor. Participants who remain receiving fetucillin will continue to be in the study until the treatment period of all dosing groups is completed and pediatric dosing and the regimen have been completed. If the growth of the participant leads to inclusion in a higher weight group and as indicated clinically according to the judgment of the investigator and in consultation with the research medical management personnel, the dose may be considered to be increased to the next dose based on weight. Antithrombin level criteria for dose adjustment in cohort 1

[0148] For Cohort 1, participants will initiate or resume fetuxilam at a dose of 10 mg every 4 weeks. Figure 3 As shown, if participants receiving a 10 mg dose of fetucillin every 4 weeks had 2 steady-state (SS) AT values ​​greater than 35%, they could be titrated up to a stepwise increase of 20 mg every 4 weeks: - assessed using pre-dose AT values ​​at Weeks 8 and 12; and - If the escalation rules are met, participants will receive fetuxiram 20 mg every 4 weeks starting at Week 16.

[0149] like Figure 3 As shown, if participants receiving the 20 mg escalating dose had 2 steady-state AT values ​​greater than 35%, they could be further uptitrated to a 30 mg escalating dose every 4 weeks: - Assessment using pre-dose AT values ​​at Weeks 24 and 28. - If the escalation rules are met, participants will receive fetuxiram 30 mg every 4 weeks starting at Week 32.

[0150] In the rare event that a participant does not meet the step-up criteria at the above time points and later meets those criteria, the investigator will consult with the medical administrator prior to any step-up.

[0151] In the unlikely event that a participant has more than 1 AT activity level less than 15% (over a 12-month period) after titration to 20 mg or 30 mg every 4 weeks, the Investigator will consult with the Study Medical Administrator regarding further treatment with fetocillin.

[0152] Participants who receive fetucilan at a starting dose of 10 mg every 4 weeks and have more than 1 AT activity level less than 15% (during a 12-month period) while receiving this dose will be allowed to step down to a fetucilan dose of 2.5 mg every 4 weeks. This lower fetucilan dose should be administered only after the participant's AT activity level reaches ≥22%. Participants who have more than 1 AT level less than 15% (during a 12-month period) while receiving this lower dose must permanently discontinue fetucilan.

[0153] Participants in Cohort 1 who had to discontinue fetucillin before this protocol modification due to AT activity levels <15% will be able to resume fetucillin dosing at a lower dose of 2.5 mg every 4 weeks. This lower fetucillin dose should be administered only after the participant's AT activity level reaches ≥22%.

[0154] If participants receiving a step-down dose of 2.5 mg of fetucillin every 4 weeks had 2 steady-state AT values ​​greater than 35%, they could be titrated up to a dose of 5 mg of fetucillin every 4 weeks.

[0155] At each dose level, participants must have another AT measurement within 1 week of receiving the result on site when the first AT activity level is <15%. If that result is <15%, this is considered the second AT activity level <15%. Participants with 1 AT activity level <15% must not receive fetufenoxan at their current dose regimen until the AT activity level from the second measurement is available to guide management. Antithrombin level criteria for dose adjustment in cohort 2

[0156] For Cohort 2, participants will initiate or resume fetuxilam at a dose of 5 mg every 4 weeks. Figure 4 As shown, if participants receiving a 5 mg dose of fetucillin every 4 weeks had 2 steady-state AT values ​​greater than 35%, they could be titrated up to a stepwise increase of 10 mg every 4 weeks: - Assessment was performed using pre-dose AT values ​​at Weeks 8 and 12. - If the escalation rules are met, participants will receive fetuxiram 10 mg every 4 weeks starting at Week 16.

[0157] like Figure 4 As shown, if participants receiving the 10 mg escalating dose had 2 steady-state AT values ​​greater than 35%, they could be further titrated up to a 20 mg escalating dose every 4 weeks: - Assessment using pre-dose AT values ​​at Weeks 24 and 28. - If the escalation rules are met, participants will receive fetuxiram 20 mg every 4 weeks starting at Week 32.

[0158] In the rare event that a participant does not meet the step-up criteria at the above time points and later meets those criteria, the investigator will consult with the study medical administrator prior to any step-up.

[0159] In the unlikely event that a participant has more than 1 AT activity level less than 15% (over a 12-month period) after escalation to a dose of 10 mg or 20 mg every 4 weeks, the investigator will consult with the study medical administrator regarding further treatment with fetocillin.

[0160] Participants who receive fetucilan at a starting dose of 5 mg every 4 weeks and have more than 1 AT activity level less than 15% (during a 12-month period) while receiving this dose will be allowed to step down to a fetucilan dose of 1.25 mg every 4 weeks. This lower fetucilan dose should be administered only after the participant's AT activity level reaches ≥22%. Participants who have more than 1 AT level less than 15% (during a 12-month period) while receiving this lower dose must permanently discontinue fetucilan.

[0161] If participants receiving a step-down dose of 1.25 mg of fetucillin every 4 weeks had 2 steady-state AT values ​​greater than 35%, they could be titrated up to a dose of 2.5 mg of fetucillin every 4 weeks.

[0162] At each dose level, participants must have another AT measurement within 1 week of receiving the result on site when the first AT activity level is <15%. If that result is <15%, this is considered the second AT activity level <15%. Participants with 1 AT activity level <15% must not receive fetufenoxan at their current dose regimen until the AT activity level from the second measurement is available to guide management. Clinical basis for dose adjustment

[0163] The investigator may request permission from the study medical administrator to escalate the study participant's fentocillin dose to a higher level even if the AT activity level is ≤35% if: - Have been administered at least 2 doses of fetuxilam at the current dose level, and - Inadequate bleeding control at the current dose level as judged by the investigator, defined as 2 or more treated bleeds within a 12-week period starting from the third injection of fetucillin at the current dose.

[0164] Dose escalation for individual participants will take into account AT activity levels and additional clinical data, if applicable.

[0165] If the investigator believes that a particular participant may be candidates for dose escalation for a variety of reasons, they may discuss this with the study medical administrator. Assessment of treatment response

[0166] The International Society on Thrombosis and Haemostasis recommendations for assessing treatment response are provided in Table 6 below. Table 6. Evaluation of treatment of acute joint / muscle bleeding episodes Example 2: Computational prediction of AT levels in pediatric patients

[0167] The pediatric patient population was divided into two groups: Cohort 1 (22 kg to <45 kg) and Cohort 2 (8 kg to <22 kg). The dose step-up and step-down schedules for Cohort 1 and Cohort 2 are described in Example 1 above.

[0168] The target AT window of 15% to 35% was chosen to minimize the risk of vascular thrombosis while maintaining efficacy. Therefore, the goal of all PK / PD modeling described below was to find a dosing regimen that could maintain AT activity between 15% and 35%.

[0169] The AT activity data from 274 participants in Phase 1, 2, and 3 studies in adults and adolescents (Phase 3 data included patients taking 80 mg QM and 50 mg Q2M) were used to develop the AT activity data. Figure 5Shown is a pharmacokinetic / pharmacodynamic (PK / PD) model demonstrating the kinetics of plasma AT activity in patients treated with fetucillin.

[0170] The pediatric PK / PD model for selecting the dosing regimen is based on the adult PK / PD base model, which is scaled to the pediatric population using weight-based allometric growth. The parameter estimates for the adult PK / PD base model and the weight allometric exponent for scaling the model to the pediatric population are shown in Table 7. Table 7. Pediatric PK / PD Model with Allometric Indices Scaled from Adult Model

[0171] The pediatric PK / PD model with parameter estimates shown in Table 7 was used to simulate the AT activity levels at steady state in the virtual pediatric patient population under different dosing scenarios. The AT activity distributions of the two pediatric cohorts for multiple dosing regimens are shown in Figure 6 For Cohorts 1 and 2, the modeled dosing regimens were 1.25, 2.5, 5, 10, 20, or 30 mg Q4W.

[0172] based on Figure 6 Simulated dosing schedule shown, for Cohort 1 receiving 10 mg QM fetucillin: a) It is predicted that approximately 64% of patients will have AT activity levels within the range of 15% ≤ AT ≤ 35%; b) It is predicted that approximately 26% of patients will have AT activity values ​​< 15%, and therefore these patients will require lower doses of fetucillin to maintain AT activity within the range of 15% ≤ AT ≤ 35%; a step-down dose of 2.5 mg QM for these patients will help 95% of the step-down patients achieve AT activity within the range of 15% ≤ AT ≤ 35% ( Fig. 7A );and c) It is predicted that approximately 10% of patients will have AT activity values ​​> 35%, and therefore these patients will require higher doses to maintain AT activity in the range of 15% ≤ AT ≤ 35%; pediatric PK / PD model simulations support dose escalation to 20 mg QM and maintenance of further escalation to 30 mg QM if needed ( Figure 7B ).

[0173] based on Figure 6 Simulated dosing schedule shown, for Cohort 2 receiving 5 mg QM fetucillin: a) It is predicted that approximately 60% of patients will have AT activity values ​​within the range of 15% ≤ AT ≤ 35%; b) It is predicted that approximately 21% of patients will have AT activity values ​​< 15%, and therefore these patients will require lower doses to maintain AT activity within the range of 15% ≤ AT ≤ 35%; a step-down dose of 1.25 mg QM for these patients will then help 94% of the step-down patients achieve AT activity within the range of 15% ≤ AT ≤ 35% ( Fig. 8A );and c) It is predicted that approximately 19% of patients will have AT activity values ​​> 35%, and therefore these patients will require higher doses to maintain AT activity within the range of 15% ≤ AT ≤ 35%; pediatric PK / PD model simulations support dose escalation to 10 mg QM (for approximately 76% of patients in this subpopulation) and further escalation to 20 mg QM (for approximately 24% of patients in this subpopulation) if necessary ( Figure 8B ).

Claims

1. A method for the prophylactic treatment of hemophilia A or hemophilia B in a pediatric patient with or without an inhibitor, the method comprising: (a) administering subcutaneously fetocillin to a patient in need thereof at a starting dose and at a selected dosing frequency; (b) obtaining a measurement of the patient's antithrombin (AT) level; and (c) Perform one of the following steps: (i) If the AT level is 15%-35%, repeat step (a), (ii) if the AT level is >35%, administering subcutaneous fetucillin to the patient at a higher dose and at a selected dosing frequency or at a starting dose and at a higher dosing frequency, or (iii) if the AT level is <15%, administering subcutaneously fetucillin to the patient at a lower dose and at a selected dosing frequency or at a starting dose and at a lower dosing frequency, optionally wherein step (c)(iii) is performed after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥15%, optionally ≥22%.

2. A method for reducing the risk of thrombosis in a pediatric patient with or without an inhibitor receiving fetocillin for prophylactic treatment of hemophilia A or hemophilia B, the method comprising: (a) administering subcutaneously fetocillin to a patient in need thereof at a starting dose and at a selected dosing frequency; (b) obtaining a measurement of the patient's antithrombin (AT) level; and (c) Perform one of the following steps: (i) If the AT level is 15%-35%, repeat step (a), (ii) if the AT level is >35%, administering subcutaneous fetucillin to the patient at a higher dose and at a selected dosing frequency or at a starting dose and at a higher dosing frequency, or (iii) if the AT level is <15%, administering subcutaneously fetucillin to the patient at a lower dose and at a selected dosing frequency or at a starting dose and at a lower dosing frequency, optionally wherein step (c)(iii) is performed after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥15%, optionally ≥22%.

3. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or hemophilia B with or without inhibitors, the method comprising: (a) administering subcutaneously fetocillin to a patient in need thereof at a starting dose and at a selected dosing frequency; (b) obtaining a measurement of the patient's antithrombin (AT) level; and (c) Perform one of the following steps: (i) If the AT level is 15%-35%, repeat step (a), (ii) if the AT level is >35%, administering subcutaneous fetucillin to the patient at a higher dose and at a selected dosing frequency or at a starting dose and at a higher dosing frequency, or (iii) if the AT level is <15%, administering subcutaneously fetucillin to the patient at a lower dose and at a selected dosing frequency or at a starting dose and at a lower dosing frequency, optionally wherein step (c)(iii) is performed after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥15%, optionally ≥22%.

4. A method of reducing the annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR) and / or annual joint bleed rate (AjBR) in a pediatric patient with hemophilia A or hemophilia B with or without inhibitors, the method comprising: (a) administering subcutaneously fetocillin to a patient in need thereof at a starting dose and at a selected dosing frequency; (b) obtaining a measurement of the patient's antithrombin (AT) level; and (c) Perform one of the following steps: (i) If the AT level is 15%-35%, repeat step (a), (ii) if the AT level is >35%, administering subcutaneous fetucillin to the patient at a higher dose and at a selected dosing frequency or at a starting dose and at a higher dosing frequency, or (iii) if the AT level is <15%, administering subcutaneously fetucillin to the patient at a lower dose and at a selected dosing frequency or at a starting dose and at a lower dosing frequency, optionally wherein step (c)(iii) is performed after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥15%, optionally ≥22%.

5. The method of any one of claims 1-4, wherein all starting doses, upper doses and lower doses are in the range of 1 mg to 50 mg, optionally in the range of 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 10 mg, or 1 mg to 5 mg.

6. The method of claim 5, wherein one of the starting dose, the upper dose, and the lower dose is 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, or 50 mg.

7. The method of any one of claims 1 to 6, wherein the selected dosing frequency is every two months or every eight weeks, and the higher dosing frequency is every month or every four weeks, or The selected dosing frequency is every month or every four weeks, and the less frequent dosing is every two months or every eight weeks.

8. The method of any one of claims 1-7, wherein the patient's body weight is 22 kg to <45 kg.

9. The method of claim 8, wherein the initial dose of fetuxiram is 10 mg.

10. The method of claim 8 or 9, wherein the selected dosing frequency is every month (QM) or every four weeks (Q4W).

11. The method of claim 10, wherein the starting dose is 10 mg, and the selected dosing frequency is QM or Q4W, wherein If more than one, optionally both, of the measured AT levels at steady state are >35%, then proceed to step (c)(ii), or If more than one, optionally two, measurements of the AT level are < 15%, step (c)(iii) is performed.

12. The method of claim 11, wherein step (c)(ii) comprises administering fetucillin subcutaneously to the patient at 20 mg QM.

13. The method of claim 12, comprising administering fetucillin subcutaneously to the patient at 30 mg QM after step (c)(ii) if the patient's AT level at steady state after step (c)(ii) is >35%, optionally based on two measurements.

14. The method of any one of claims 11 to 13, comprising, after step (c)(iii): (A) administering fetucillin 2.5 mg QM subcutaneously to the patient, optionally after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥22%; (B) if after step (A) the patient's AT level is < 15%, optionally based on exceeding the measured value, discontinuing or suspending fetuxiram treatment, 15%-35%, then repeat step (A), or >35%, optionally based on exceeding one measurement at steady state, then administer fetocillin 5 mg QM subcutaneously to the patient.

15. The method of any one of claims 1-7, wherein the patient's body weight is 8 kg to <22 kg.

16. The method of claim 15, wherein the initial dose of fetuxiram is 5 mg.

17. The method of claim 15 or 16, wherein the selected dosing frequency is every month (QM) or every four weeks (Q4W).

18. The method of claim 17, wherein the starting dose is 10 mg, and the selected dosing frequency is QM or Q4W, wherein If more than one, optionally both, of the measured AT levels at steady state are >35%, then proceed to step (c)(ii), or If more than one, optionally two, measurements of the AT level are < 15%, step (c)(iii) is performed.

19. The method of claim 18, wherein step (c)(ii) comprises administering fetucillin subcutaneously to the patient at 10 mg QM.

20. The method of claim 19, comprising administering fetucillin subcutaneously to the patient at 20 mg QM after step (c)(ii) if the patient's AT level at steady state after step (c)(ii) is >35%, optionally based on two measurements.

21. The method of any one of claims 18 to 20, comprising, after step (c)(iii): (A) administering fetucillin 1.25 mg QM subcutaneously to the patient, optionally after administration of fetucillin is suspended and after the patient's AT level has recovered to ≥22%; (B) if after step (A) the patient's AT level is < 15%, optionally based on exceeding the measured value, discontinuing or suspending fetuxiram treatment, 15%-35%, then repeat step (A), or >35%, optionally based on exceeding one measurement at steady state, then administer fetocillin 2.5 mg QM subcutaneously to the patient.

22. The method of any of the preceding claims, further comprising administering subcutaneously fetocillin to the patient at a dose and frequency sufficient to maintain the patient's AT level at 15%-35%, optionally comprising administering subcutaneously fetocillin under the following conditions: 1.25 mg every 4 weeks or every 4 weeks 2.5 mg every 4 weeks or every 4 weeks, 5 mg every 4 weeks or every 3 weeks, 7.5 mg every 4 weeks or every 3 weeks, 10 mg every 4 weeks or every 3 weeks, 20 mg every 4 weeks or every 4 weeks, 30 mg every 4 weeks or every 4 weeks, or 50 mg QM or Q4W.

23. The method of any one of the preceding claims, wherein each AT level measurement is obtained after the patient has received at least two doses of a given dose of fetuxiram.

24. The method of any one of the preceding claims, further comprising: (d) after step (c), if the patient has an AT level of 15%-35% and has had at least two doses of the step (c) dose of fetucillin and has two or more treated bleeds within a 12-week period starting from the third injection of fetucillin at the step (c) dose, subcutaneously administering to the patient a dose of fetucillin that is higher than the step (c) dose.

25. The method of claim 24, wherein the dosage of step (c) and the dosage of step (d) are respectively: 1.25mg and 2.5mg, 2.5mg and 5mg, 5mg and 10mg, 10 mg and 20 mg, or 20mg and 30mg.

26. The method of any one of the preceding claims, wherein the patient continues a previous non-fetocillin prophylactic treatment for only one week after the first dose of fetocillin, optionally wherein the previous non-fetocillin prophylactic treatment was replacement factor therapy or bypassing agent therapy.

27. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering subcutaneously 1.25 mg of fetucillin to a patient in need thereof every month or every four weeks.

28. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering subcutaneously to a patient in need thereof 2.5 mg of fetucillin every month or every four weeks.

29. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering 5 mg of fetucillin subcutaneously to a patient in need thereof every month or every four weeks.

30. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising subcutaneously administering 7.5 mg of fetucillin to a patient in need thereof every month or every four weeks.

31. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering subcutaneously 10 mg of fetucillin to a patient in need thereof every month or every four weeks.

32. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering 20 mg of fetucillin subcutaneously to a patient in need thereof every month or every four weeks.

33. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering 30 mg of fetucillin subcutaneously to a patient in need thereof every month or every four weeks.

34. A method for the prophylactic treatment of hemophilia A or hemophilia B in a patient with or without inhibitors, or for reducing the frequency of bleeding episodes in such a patient, optionally ABR, AsBR or AjBR, the method comprising administering 50 mg of fetucillin subcutaneously to a patient in need thereof every month or every four weeks.

35. The method of any of the preceding claims, comprising obtaining measurements of the patient's AT level every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.

36. The method of any one of claims 1-35, wherein the patient has hemophilia A or hemophilia B with an inhibitor, the method further comprising administering an effective amount of a bypassing agent (BPA) to treat bleeding episodes, wherein the effective amount of BPA is reduced compared to the recommended effective amount of BPA.

37. The method of claim 36, wherein the bypassing agent 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 repeated in no less than 24 hours if necessary.

38. The method of claim 36, wherein the bypassing agent is recombinant Factor VIIa (rFVIIa) and a single dose of rFVIIa does not exceed 45 μg / kg, optionally wherein the rFVIIa is repeated within no less than two hours if necessary.

39. The method of any one of claims 1-35, wherein the patient has hemophilia A or hemophilia B without inhibitors, the method 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 a recommended effective amount of the replacement factor.

40. The method of claim 39, wherein the replacement factor is Factor VIII and a single dose of the replacement factor does not exceed 20 IU / kg and optionally is 10 IU / kg, optionally wherein administration of the Factor VIII is repeated in no less than 24 hours if necessary.

41. The method of claim 39, wherein the replacement factor is Factor IX and a single dose of the replacement factor is 30 IU / kg and optionally 20 IU / kg, optionally wherein if necessary, the Factor IX is repeated within no less than 24 hours for standard half-life FIX or within no less than 5-7 days for extended half-life FIX.

42. The method of any one of the preceding claims, wherein fetucilan is provided in phosphate buffered saline (PBS) at 1-200 mg / mL, optionally 6.25 mg / mL, 12.5 mg / mL or 100 mg / mL.

43. The method of claim 42, wherein fetucillin is provided as Formulation 1 or Formulation 2 as shown below.

44. Fetocilan for use in a method as claimed in any one of claims 1 to 43.

45. Use of fetocilan for the manufacture of a medicament for the treatment of hemophilia A or hemophilia B with or without inhibitors in a method as claimed in any one of claims 1 to 43.

46. ​​A pharmaceutical composition comprising fetucilan for use in the method of any one of claims 1-43.

47. An aqueous non-toxilan composition comprising: 12.5mg / mL fetocillin, 0.388mg / mL NaH2PO4*H2O, 0.586mg / mL Na2HPO4*7H2O, and 8.7mg / mL NaCl, The pH is about 7.0-7.

1.

48. An article comprising the composition of claim 47.

49. An article of manufacture for use in the method of any one of claims 1-43, optionally wherein the article of manufacture is a kit.

50. The article of manufacture of claim 48 or 49, wherein the article of manufacture is a container, optionally a vial, containing one or more doses of fetuxiram, each dose being 30 mg, 20 mg, 10 mg, 5 mg, 2.5 mg or 1.25 mg.

51. The article of manufacture of claim 50, wherein the container is a vial containing 2.5 mg of fetocillin.

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