Fitusiran for the Treatment of Hemophilia A and B in Pediatric Patients

Abstract

The present disclosure provides methods and compositions for treating pediatric patients with inhibitor-naïve or inhibitor-bearing hemophilia A or B.

Description

【Technical Field】 【0001】 Cross - reference to Related Applications This application claims the benefit of priority to U.S. Patent Application No. 63 / 350,382, filed on June 8, 2022, and U.S. Patent Application No. 63 / 381,499, filed on October 28, 2022. The contents of these priority applications are hereby incorporated by reference in their entirety. 【0002】 Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety. The XML copy (created on June 2, 2023) has the name 022548WO089.xml and a size of 8,045 bytes. 【Background Art】 【0003】 Hemophilia A and hemophilia B are X - linked recessive hereditary bleeding disorders characterized by a deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), resulting in a significant defect in thrombin generation associated with hemostatic disorders and an increased risk of bleeding. Factor replacement concentrates are the current standard treatment for hemophilia patients without inhibitory antibodies against FVIII or FIX, but remain associated with a high treatment burden due to the frequency of intravenous (IV) administration (more than 2 - 3 times per week) required to prophylactically maintain hemostasis. In addition, the development of inhibitors is a major complication in children treated with factor replacement. Approximately 30% of previously untreated patients with hemophilia A and 2% - 5% of previously untreated patients with hemophilia B develop inhibitory antibodies against 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 inhibitor patients may include immune tolerance induction (ITI) therapy in attempts to eradicate inhibitors and / or may require the use of bypassing agents (BPAs) such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa). However, the failure rates of various ITI approaches are high, especially for patients with hemophilia B, and later inhibitor recurrence can occur after ITI. Inhibitor patients using BPAs have shown a higher annual bleeding rate and increased treatment burden compared to factor replacement therapy used by non-inhibitor patients (Antunes et al., Haemophilia. (2014) 20(1):65-72; Konkle et al., J Thromb Haemost. (2007) 5(9):1904-13). 【0005】 As another potential option for patients with hemophilia A and inhibitors to FVIII, emicizumab, a bispecific antibody that mimics the function of FVIII, has recently been approved. Emicizumab has shown promise in this population, but clinical events of thrombosis have been observed when emicizumab is used in combination with certain BPAs that require risk mitigation strategies and accompanying black box warnings. 【0006】 For pediatric patients with hemophilia, treatment of both the inhibitor and non-inhibitor populations is further complicated by issues of venous access and caregiver burden. For non-inhibitor pediatric patients, more frequent infusions may be required due to the shorter half-life of factor replacement therapy compared to adults. In the case of inhibitor patients, prophylactic BPA therapy or ITI regimens may require infusions daily or every other day. 【0007】 Therefore, alternative treatments for pediatric patients with hemophilia A or B are still needed. Summary of the Invention Means for Solving the Problems 【0008】 The present disclosure provides a method for prophylactically treating inhibitor-bearing or inhibitor-naive hemophilia A or B with fitusiran to prevent or reduce the frequency of bleeding episodes in pediatric patients from 1 year to less than 12 years of age, and provides fitusiran used in the method. 【0009】 In one aspect, the present disclosure is a method for treating hemophilia A or B in inhibitor-bearing or inhibitor-naive pediatric patients, comprising: (a) subcutaneously administering an initial dose amount of fitusiran to a patient in need of treatment for hemophilia A or B at a selected dosing frequency; (b) obtaining a measured value of the antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35%, repeating step (a); (ii) if the AT level is >35%, subcutaneously administering to the patient a higher dose amount of fitusiran at the selected dosing frequency or the initial dose amount at a higher dosing frequency; or (iii) if the AT level is <15%, subcutaneously administering to the patient a lower dose amount of fitusiran at the selected dosing frequency or the initial dose amount at a lower dosing frequency, optionally, step (c)(iii) is performed after a temporary cessation of fitusiran administration and after the patient's AT level has returned to ≧15%, optionally ≧22%. 【0010】 In some embodiments, the method reduces the frequency of bleeding episodes in the patient, e.g., reduces the annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR), and / or annual joint bleeding rate (AjBR). The method may also reduce the risk of thrombosis in pediatric patients receiving fitusiran for prophylactic treatment of inhibitor-bearing or inhibitor-naive hemophilia A or B. 【0011】 In another aspect, the present disclosure provides a series of methods for treating hemophilia A or B in inhibitor-bearing or inhibitor-naive pediatric patients using a predetermined amount of fitusiran (e.g., 1.25, 2.5, 5, 7.5, 10, 20, 30, or 50 mg) at a predetermined frequency (e.g., every 2 months, every 8 weeks, monthly, or every 4 weeks). 【0012】 In another aspect, the present disclosure provides a fitusiran formulation suitable for the methods herein. In some embodiments, the fitusiran formulation is an aqueous fitusiran composition having a pH of about 7.0 - 7.1 and comprising: about 12.5 mg / mL of fitusiran, about 0.388 mg / mL of NaH2PO4·H2O, about 0.586 mg / mL of Na2HPO4·7H2O, and about 8.7 mg / mL of NaCl. 【0013】 Also provided herein is the use of fitusiran for the manufacture of a medicament for treating hemophilia A or B in inhibitor-naive or inhibitor-bearing pediatric patients using the fitusiran and products used in the present treatment method, as well as a pharmaceutical composition comprising fitusiran used in the present treatment method. 【0014】 Other features, objects, and advantages of the invention will become apparent in the detailed description that follows. It should, however, be understood that the detailed description is provided by way of illustration only and not limitation, showing embodiments and aspects of the invention. From this detailed description, various changes and modifications within the scope of the invention will become apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS 【0015】 【Figure 1】 Shows the extended structural formula, chemical formula, and molecular mass of fitusiran (sodium form). This figure discloses SEQ ID NOs: 1 and 2 in the order of appearance, respectively. 【Figure 1-1】 Continuation of Figure 1. 【Figure 2】 A diagram showing the study design described in Example 1. AT (antithrombin) follow-up: Antithrombin activity levels are monitored at monthly intervals in participants who discontinue fitusiran treatment until the AT activity level returns to approximately 60% per central laboratory, or at the discretion of the investigator in consultation with the study medical manager. 【Figure 3】It is a flowchart showing the fittinglan escalation / de-escalation scheme for patients in Cohort 1 (patients weighing 22 kg to <45 kg). Participants start / resume fittinglan at a dose of 10 mg every 4 weeks. AT: Antithrombin activity; QM = once a month; SS = steady state. *: within a 12-month period; **: Initiation of dosing after de-escalation from a higher dose is only done after the AT activity level measured centrally is ≧22%. 【Figure 4】 It is a flowchart showing the fittinglan escalation / de-escalation scheme for patients in Cohort 2 (patients weighing 8 kg to <22 kg). Participants start fittinglan at a dose of 5 mg every 4 weeks. Abbreviations and symbols are the same as those described for Figure 3 above. 【Figure 5】 It is a schematic diagram showing the pharmacokinetic / pharmacodynamic (PK / PD) model used to simulate the dynamics of AT activity in the plasma of patients treated with fittinglan. KA: Absorption rate; F: Bioavailability due to dose effect on bioavailability; V2: Liver-centered compartment volume; V3: Liver-peripheral compartment volume; CL: Clearance from the liver-centered compartment; CL2: Clearance between liver compartments; Q: Clearance to the RISC compartment; RV: RISC volume; CLR: Clearance from the RISC compartment; Kin: AT production rate; KOUT: AT removal rate; Imax: Maximum inhibition of AT production; IC50: RISC concentration for 50% of the maximum inhibition of AT production. 【Figure 6】 It is a table showing computer modeling data on the distribution of trough and peak simulated AT activity for the pediatric cohort for various dosing regimens. WT: Weight. Min.: Minimum. Max.: Maximum. 【Figure 7A】 It is a diagram showing the computationally predicted distribution of AT levels in Cohort 1 patients treated with an initial dose of 10 mg of fittinglan once a month. Figure 7A shows the de-escalation scheme for the predicted 26% of patients with AT values <15% after treatment with an initial dose of 10 mg QM. 【Figure 7B】Figure showing the computationally predicted distribution of AT levels in cohort 1 patients treated with an initial dose of 10 mg fitusiran once monthly. Figure 7B shows the escalating scheme for the predicted 10% of patients with AT values > 35% after treatment with an initial dose of 10 mg QM. 【Figure 8A】 Figure showing the computationally predicted distribution of AT levels in cohort 2 patients treated with an initial dose of 5 mg fitusiran once monthly. Figure 8A shows the de-escalating scheme for the predicted 21% of patients with AT values < 15% after treatment with an initial dose of 5 mg QM. 【Figure 8B】 Figure showing the computationally predicted distribution of AT levels in cohort 2 patients treated with an initial dose of 5 mg fitusiran once monthly. Figure 8B shows the escalating scheme for the predicted 19% of patients with AT values > 35% after treatment with an initial dose of 5 mg QM. 【DETAILED DESCRIPTION OF THE INVENTION】 【0016】 Fitusiran is an N-acetylgalactosamine (GalNAc) small interfering ribonucleic acid (siRNA) conjugate that reduces the production of antithrombin (AT) and decreases plasma AT activity levels. By reducing plasma AT, fitusiran is designed to improve thrombin generation and hemostasis in individuals with hemophilia, regardless of the type of hemophilia or the presence of inhibitory antibodies against FVIII or FIX. Fitusiran is expressed for the prophylactic prevention of bleeding episodes or reduction in the frequency of such bleeding episodes in patients with hemophilia A or B, including patients with inhibitory antibodies against FVIII or FIX. 【0017】 A subcutaneous (SC) therapy that can effectively and safely prevent bleeding episodes or reduce the frequency of such bleeding episodes in patients with hemophilia A or B, including patients with inhibitors, can reduce the treatment burden, improve clinical outcomes, and enhance quality of life, particularly for the pediatric patient population. 【0018】 The present disclosure provides a method for maintaining an advantageous benefit - risk balance for pediatric patients with inhibitor - positive or inhibitor - negative hemophilia A or B being treated with fitusiran. Fitusiran is intended for the prophylaxis of bleeding episodes or for routine prophylaxis to reduce the frequency of bleeding episodes in pediatric patients (i.e., 1 to <12 years old) with hemophilia A or B, including patients with inhibitory antibodies (inhibitors). This treatment method carefully calibrates the treatment based on the patient's antithrombin (AT) level so as to minimize the risk of vascular thromboembolic events that may be caused by low AT levels (e.g., AT level <10%). 【0019】 Hemophilia A or B patients with inhibitors refer to patients who have expressed alloantibodies against a factor (e.g., factor VIII for hemophilia A patients or factor IX for hemophilia B patients) that the patient has previously received. Hemophilia A or B patients with inhibitors may become refractory to coagulation factor replacement therapy. Patients without inhibitors refer to patients who do not have such alloantibodies. This treatment method may be beneficial for inhibitor - positive or inhibitor - negative hemophilia A patients and inhibitor - positive or inhibitor - negative hemophilia B patients. As used herein, "inhibitor - positive or inhibitor - negative hemophilia A or B" refers to inhibitor - positive or inhibitor - negative hemophilia A or inhibitor - positive or inhibitor - negative hemophilia B. The patients referred to herein are human pediatric patients from 1 year to less than 12 years old. 【0020】 I. Fitusiran Pharmaceutical Composition Hemophilia results in a severe deficiency in thrombin production, and furthermore, the severity of hemophilia correlates with the inability to produce thrombin. Without being bound by theory, it is thought that the fitusiran - mediated decrease in antithrombin (AT) levels will improve hemostasis in hemophilia patients by increasing thrombin production. Antithrombin is encoded by the SERPINC1 gene. 【0021】 Fitusiran (its structure is described herein) is a synthetically chemically modified double-stranded small interfering RNA (siRNA) oligonucleotide that suppresses the synthesis of antithrombin by covalently binding to a 3-antennary N-acetyl-galactosamine (GalNAc) ligand that targets AT3 mRNA in the liver. The nucleosides in each strand of fitusiran are linked by either 3'-5' phosphodiester or phosphorothioate bonds to form the sugar-phosphate backbone of the oligonucleotide. The sense and antisense strands of fitusiran contain 21 and 23 nucleotides, respectively. The 3' end of the sense strand is conjugated to a GalNAc-containing moiety (also called L96) via a phosphodiester bond. The sense strand contains two consecutive phosphorothioate bonds at its 5' end. The antisense strand contains four phosphorothioate bonds, two at the 3' end and two at the 5' end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand to form 21 nucleotide base pairs and a 2-base overhang at the 3' end of the antisense strand. See also U.S. Patent No. 9,127,274, U.S. Patent No. 11,091,759, and International Publication No. 2019 / 014187 pamphlet. 【0022】 The two nucleotide strands of fitusiran are shown below: Sense strand: 5’Gf-ps-Gm-ps-Uf-Um-Af-Am-Cf-Am-Cf-Cf-Af-Um-Uf-Um-Af-Cm-Uf-Um-Cf-Am-Af-L96 3’ (SEQ ID NO: 1), and Antisense strand: 5’Um-ps-Uf-ps-Gm-Af-Am-Gf-Um-Af-Am-Af-Um-Gm-Gm-Uf-Gm-Uf-Um-Af-Am-Cf-Cm-ps-Am-ps-Gm 3’ (SEQ ID NO: 2) wherein, Af = 2'-fluoroadenosine (i.e., 2'-deoxy-2'-fluoroadenosine) Cf = 2'-fluorocytidine (i.e., 2'-deoxy-2'-fluorocytidine) Gf = 2'-fluoroguanosine (i.e., 2'-deoxy-2'-fluoroguanosine) Uf = 2'-fluorouridine (i.e., 2'-deoxy-2'-fluorouridine) Am = 2'-O-methyladenosine Cm = 2'-O-methylcytidine Gm = 2'-O-methylguanosine Um = 2'-O-methyluridine "-" (hyphen) = sodium salt of 3'-5' phosphodiester bond "-ps-" = sodium salt of 3'-5' phosphorothioate bond and L96 has the following formula: 【Chemical formula】 and has 【0023】 The extended structural formula, molecular formula, and molecular weight of ficollan are shown in Figure 1. The term 2'-fluoroadenosine used in this specification can be used interchangeably with the term 2'-deoxy-2'-fluoroadenosine; the term 2'-fluorocytidine can be used interchangeably with the term 2'-deoxy-2'-fluorocytidine; the term 2'-fluoroguanosine can be used interchangeably with the term 2'-deoxy-2'-2'-fluoroadenosine; the term fluorouridine can be used interchangeably with the term 2'-deoxy-2'-fluorouridine. 【0024】 Also, the structure of ficollan can be described using the following diagram: 【Chemical formula】 where X is O. 【0025】 For use in the present treatment method, ficiran may be provided by a pharmaceutical composition comprising ficiran and a pharmaceutically acceptable excipient. In certain embodiments, the dsRNA compound is in the sodium salt form. 【0026】 In some embodiments, ficiran is provided by an aqueous solution at a concentration of 1 to 200 mg / mL (e.g., 50 to 150 mg / mL, 80 to 110 mg / mL, 90 to 110 mg / mL, 5 to 25 mg / mL, 7.5 to 20 mg / mL, or 10 to 15 mg / mL). Intermediate values within the described ranges and values used herein are also intended to be part of the present disclosure. Additionally, ranges of values using any combination of the described values as upper and / or lower limits are intended to be included. In further embodiments, the pharmaceutical composition comprises ficiran at a concentration of 5, 10, 12.5, 50, 75, 100, 125, 150, or 200 mg / mL. In certain embodiments, ficiran is provided at a concentration of 100 mg / mL in an aqueous solution. In certain embodiments, ficiran is provided at a concentration of 12.5 mg / mL in an aqueous solution. In certain embodiments, ficiran is provided at a concentration of 6.25 mg / mL in an aqueous solution. 【0027】 Unless otherwise stated, the ficiran weight described in the present disclosure is the weight of the ficiran free acid (active moiety), even if ficiran is subcutaneously injected into a patient in its sodium form (by an aqueous solution). For example, 100 mg / mL of ficiran means 100 mg of ficiran free acid per mL (equivalent to 106 mg of the ficiran sodium drug substance). 【0028】 In some embodiments, the pharmaceutical composition comprises ficiran in phosphate buffered saline. The phosphate concentration in the solution can be 1 to 10 mM (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 mM) at pH 6.0 to 8.0. The pharmaceutical compositions herein may contain a preservative such as EDTA. Alternatively, the pharmaceutical composition may be preservative-free. 【0029】 In certain embodiments, the fusiran pharmaceutical composition does not contain a preservative and comprises, consists of, or consists essentially of 100 mg of fusiran per 1 mL of 5 mM phosphate buffered saline (PBS) solution. The PBS solution is composed of sodium chloride, disodium phosphate (heptahydrate), and monosodium phosphate (monohydrate). Sodium hydroxide solution and dilute phosphoric acid can be used to adjust the pH of the composition to about 7.0. 【0030】 In certain embodiments, the fusiran pharmaceutical composition does not contain a preservative and comprises, consists of, or consists essentially of 12.5 mg of fusiran per 1 mL of 5 mM phosphate buffered saline (PBS) solution. The PBS solution is composed of sodium chloride, disodium phosphate (heptahydrate), and monosodium phosphate (monohydrate). Sodium hydroxide solution and dilute phosphoric acid can be used to adjust the pH of the composition to about 7.0 (e.g., 7.1). 【0031】 The pharmaceutical composition can be provided in a container (e.g., a vial or syringe). The container can contain a single or multiple doses. In some embodiments, the solution is administered to a patient by subcutaneous injection. The solution can be stored at 2 - 30 °C (e.g., 2 - 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 fusiran. In some embodiments, the vial is a type I glass single-use vial, and in a further embodiment, the vial contains at least 0.2 mL of an aqueous solution containing fusiran. 【0032】 In some embodiments, fusiran is provided in a 30 mg vial (e.g., at 100 mg / mL), which can also be pooled to achieve higher dose amounts. Also, these vials can be used in half (half of the vial) to achieve a 15 mg dose amount. 【0033】 In some embodiments, ficirulan is provided in 20 mg vials (e.g., at 100 mg / mL), which can also be pooled to achieve higher dose amounts. Also, half of these vials (half of the vial) can be used to achieve a dose amount of 10 mg. 【0034】 In some embodiments, ficirulan is provided in 2.5 mg vials (e.g., at 12.5 mg / mL), which can be pooled to achieve dose amounts of, for example, 5, 7.5, 10, 20, 30, or 50 mg. Also, half of these vials (half of the vial) can be used to achieve a dose amount of 1.25 mg. 【0035】 In some embodiments, ficirulan is provided in 1.25 mg vials (e.g., at 12.5 mg / mL), which can be pooled to achieve dose amounts of, for example, 2.5, 5, 7.5, or 10 mg. In some embodiments, ficirulan is provided in 1.25 mg vials (e.g., at 6.25 mg / mL), which can be pooled to achieve dose amounts of, for example, 2.5, 5, 7.5, or 10 mg. 【0036】 In one embodiment, 80 mg of ficiran is delivered by 0.8 mL (100 mg of ficiran / mL). In one embodiment, 50 mg of ficiran is delivered by 0.5 mL (100 mg of ficiran / mL). In one embodiment, 20 mg of ficiran is delivered by 0.5 mL (40 mg of ficiran / mL). In one embodiment, 30 mg of ficiran is delivered by 0.5 mL (60 mg of ficiran / mL). In one embodiment, 10 mg of ficiran is delivered by 0.5 mL (20 mg of ficiran / mL). In one embodiment, 7.5 mg of ficiran is delivered by 0.5 mL (15 mg of ficiran / mL). In one embodiment, 5 mg of ficiran is delivered by 0.5 mL (10 mg of ficiran / mL). In one embodiment, 2.5 mg of ficiran is delivered by 0.5 mL (5 mg of ficiran / mL). In one embodiment, 1.25 mg of ficiran is delivered by 0.5 mL (2.5 mg of ficiran / mL). 【0037】 In certain embodiments, the subcutaneous ficiran composition contains ficiran in 5 mM phosphate buffered saline at pH 7.0 or 7.1 having 0.64 mM NaH2PO4, 4.36 mM Na2HPO4, and 84 mM NaCl. In certain embodiments, the composition of the subcutaneous ficiran solution is shown in Table 1A below. 【0038】 [Table 1] 【0039】 In certain embodiments, the composition of the subcutaneous ficiran solution is shown in Table 1B below. 【0040】 [Table 2] 【0041】 The FIX product dosing weights described herein refer to the weight of FIX free acid (the active moiety), but administration of FIX to a patient herein refers to administration of sodium FIX (the drug substance) provided in a pharmaceutically suitable aqueous solution (e.g., phosphate buffered saline at physiological pH). 【0042】 II. Therapeutic Use of FIX FIX can suppress the hepatic production of antithrombin (AT). In its role as an anticoagulant, AT modulates hemostasis by directly targeting thrombin production or by inactivating uncomplexed FXa, which in turn reduces thrombin production (Quinsey et al., Int J Biochem Cell Biol. (2004) 36(3):386-9). FIX can be used to treat individuals with a hemostatic disorder. For example, FIX can be used to treat hemophilia A or B in inhibitor-bearing or non-bearing pediatric patients, or as routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In certain embodiments, FIX is used to treat pediatric patients (i.e., patients 1-<12 years of age) with inhibitor-bearing or non-bearing hemophilia A or B (congenital factor VIII or factor IX deficiency). 【0043】 The method comprises administering to a hemophilia patient (e.g., a hemophilia A or B patient) in need thereof a therapeutically effective amount of FIX. "Therapeutically effective amount" refers to the amount of FIX that aids a patient in achieving a desired clinical endpoint. Desired clinical endpoints can be, for example, a reduction in annual bleeding rate (ABR) to 3 or less, 2 or less, 1 or less, or zero. Also, desired clinical endpoints can be, for example, a reduction in annual spontaneous bleeding rate (AsBR) to 1 or less, preferably zero. 【0044】 This treatment method is based in part on the finding that the risk of vascular thromboembolic events in patients exposed to unfractionated heparin may increase as the AT level decreases. AT measurement can be performed by well-established methods, including both kinetic assays and chromogenic assays. As one commonly used method, there is the INNOVANCE™ Antithrombin Assay (Siemens Healthineers, Malvern, PA; U.S. FDA 510(k) #K081769). INNOVANCE™ is a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of excess factor Xa by AT. The assay can be performed by using an automated coagulation device (e.g., Siemens BCS® XP, Sysmex® CA-600 and CS Systems, or Atellica® COAG 360 System), and can be calibrated with a defined value of AT activity calibrated against World Health Organization (WHO) reference plasma using Siemens Standard Human Plasma (SHP). As an equivalent assay, there is the Dade Behring Berichrom™ Antithrombin III Assay (Dade Behring Marburg GmbH, Marburg, Germany; U.S. FDA 510(k) #K933125). Each measurement can be controlled by two independent controls (low and normal values) that are also calibrated against the WHO standard. The AT activity (%) in the plasma sample is calculated against the WHO reference plasma. An AT level of 100% is defined as 1 unit of antithrombin activity in 1 mL of reference plasma sample. The detection limit of the INNOVANCE™ assay is 6.0% based on the U.S. FDA 510(k) determination summary of the assay. AT levels range from approximately 80% to approximately 120% in the general population. 【0045】 The risk of arterial thromboembolic events among patients receiving unfractionated heparin has been observed to increase when the AT level is <10%. Therefore, the patient's AT level can be monitored and, if necessary, the unfractionated heparin dosage can be adjusted. 【0046】 In some embodiments, the patient has a steady-state AT level within the desired range (e.g., 15-35%), but still does not have optimal bleeding control (e.g., if bleeding is treated more than twice within 12 weeks starting from the third injection of fitusiran at the current dose, fitusiran will be dosed at the next higher level or the next higher frequency (e.g., from every two months or every eight weeks to monthly or every four weeks). This dosing adjustment can be made until the patient's bleeding treatment is less than twice within a 12-week period starting from the third injection of fitusiran at the current dose while maintaining the steady-state AT range of 15-35%. 【0047】 In some embodiments, fitusiran is administered subcutaneously to the patient in the range of 1 mg to 50 mg. In a further embodiment, fitusiran is administered subcutaneously to the patient in the range of 1 mg to 30 mg. In a further embodiment, fitusiran is administered subcutaneously to the patient in the range of 1 mg to 20 mg. In a further embodiment, fitusiran is administered subcutaneously to the patient in the range of 1 mg to 10 mg. In a further embodiment, fitusiran is administered subcutaneously to the patient in the range of 1 mg to 5 mg. In certain embodiments, fitusiran is administered subcutaneously to the patient at 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, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg. In certain embodiments, fitusiran is administered subcutaneously, for example, at one of the aforementioned weight dosages, every other month or every eight weeks, or monthly or every four weeks. 【0048】 In some embodiments, ficiran is administered subcutaneously at 1.25 mg every other month or every 8 weeks. 【0049】 In some embodiments, ficiran is administered subcutaneously at 1.25 mg monthly or every 4 weeks. 【0050】 In some embodiments, ficiran is administered subcutaneously at 2.5 mg every other month or every 8 weeks. 【0051】 In some embodiments, ficiran is administered subcutaneously at 2.5 mg monthly or every 4 weeks. 【0052】 In some embodiments, ficiran is administered subcutaneously at 5 mg every other month or every 8 weeks. 【0053】 In some embodiments, ficiran is administered subcutaneously at 5 mg monthly or every 4 weeks. 【0054】 In some embodiments, ficiran is administered subcutaneously at 7.5 mg every other month or every 8 weeks. 【0055】 In some embodiments, ficiran is administered subcutaneously at 7.5 mg monthly or every 4 weeks. 【0056】 In some embodiments, ficiran is administered subcutaneously at 10 mg every other month or every 8 weeks. 【0057】 In some embodiments, ficiran is administered subcutaneously at 10 mg monthly or every 4 weeks. 【0058】 In some embodiments, ficiran is administered subcutaneously at 20 mg every other month or every 8 weeks. 【0059】 In some embodiments, ficiran is administered subcutaneously at 20 mg monthly or every 4 weeks. 【0060】 In some embodiments, ficiran is administered subcutaneously at 30 mg every other month or every 8 weeks. 【0061】 In some embodiments, ficiran is administered subcutaneously at 30 mg monthly or every 4 weeks. 【0062】 In some embodiments, ficiran is administered subcutaneously at 50 mg every other month or every 8 weeks. 【0063】 In some embodiments, ficiran is administered subcutaneously at 50 mg monthly or every 4 weeks. 【0064】 Exemplary treatment protocols are further described below. 【0065】 Pediatric patients with higher body weights Patients weighing 22 kg to <45 kg may start with an initial dose of 10 mg of ficiran monthly (or every 4 weeks). The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). An exemplary escalation and de-escalation scheme for patients in cohort 1 is shown in Figure 3. 【0066】 In some embodiments, patients treated with an initial dose of 10 mg of ficiran monthly (or every 4 weeks) taper the ficiran dosage regimen. In some embodiments, when the first AT level is <15%, the patient has another AT activity level sample taken within 1 month (e.g., within 1 or 2 weeks). If this result is <15%, this is considered the second AT being <15%. Patients receiving ficiran at a dose of 10 mg QM with two or more (e.g., 2) AT activity levels <15% will taper to a dose of 2.5 mg of ficiran monthly (or every 4 weeks). After the patient's AT level returns above 15%, e.g., ≧22%, treatment with a lower dose of ficiran may be initiated. 【0067】 After tapering to a monthly dose of 2.5 mg of ficiran, the patient's AT level can be monitored again regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first AT level is < 15%, within one month (e.g., within 1 or 2 weeks), another AT activity level sample is taken from the patient. If this result is < 15%, this is considered the second AT < 15%. Patients receiving ficiran at a dose of 2.5 mg QM with two or more (e.g., 2) AT activity levels < 15% may discontinue or pause ficiran treatment. 【0068】 In addition, after tapering to a monthly dose of 2.5 mg of ficiran, the patient's AT level is monitored again regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level > 35%, within one month (e.g., within 1 or 2 weeks), another AT activity level sample is taken from the patient. If this result is > 35%, this is considered the second steady-state AT > 35%. Patients receiving ficiran at a dose of 2.5 mg QM with two or more (e.g., 2) steady-state AT activity levels > 35% may increase the dose of ficiran to 5 mg once a month (or every 4 weeks). 【0069】 In other embodiments, patients treated with a starting dose of 10 mg of ficiran monthly (or every 4 weeks) may increase the dose of ficiran. The patient's AT level can be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level > 35%, within one month (e.g., within 1 or 2 weeks), another steady-state AT activity level sample is taken from the patient. If this result is > 35%, this is considered the second steady-state AT > 35%. Patients receiving ficiran at a dose of 10 mg QM with two or more (e.g., 2) steady-state AT activity levels > 35% may increase the dose of ficiran to 20 mg monthly (or every 4 weeks). 【0070】 After the dose of ficirnase is gradually increased to 20 mg per month, the patient's AT level can be monitored again regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level > 35%, within one month (e.g., within 1 or 2 weeks) of the patient, another steady-state AT activity level sample is taken. If this result is > 35%, this is considered that the second steady-state AT is > 35%. Patients receiving ficirnase at a dose of 20 mg QM with two or more (e.g., 2) steady-state AT activity levels > 35% can have their dose gradually increased to 30 mg of ficirnase once a month (or every 4 weeks). 【0071】 In some embodiments, the escalation is performed after the steady-state AT activity level remains > 35% (see, e.g., Figure 3). 【0072】 Pediatric patients with lower body weight Patients with a body weight of 8 kg to < 22 kg (cohort 2) can start from an initial dose of 5 mg of ficirnase monthly (or every 4 weeks). The escalation and de-escalation schemes for cohort 2 patients are shown in Figure 4. The patient's AT level can be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). 【0073】 In some embodiments, patients treated with an initial dose of 5 mg of ficilitran monthly (or every 4 weeks) may have their dose of ficilitran tapered. In some embodiments, when the first AT level is < 15%, within one month (e.g., within 1 or 2 weeks) another AT activity level sample is taken from the patient. If this result is < 15%, this is considered the second AT being < 15%. Patients receiving ficilitran at a dose of 5 mg QM with two or more (e.g., 2) AT activity levels < 15% may have their dose tapered to 1.25 mg of ficilitran monthly (or every 4 weeks). After the AT level has returned above 15%, e.g., ≥ 22%, the patient may start with a lower dose of ficilitran. 【0074】 After tapering to a dose of 1.25 mg of ficilitran monthly, the patient's AT level may be monitored again regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first AT level is < 15%, within one month (e.g., within 1 or 2 weeks) another AT activity level sample is taken from the patient. If this result is < 15%, this is considered the second AT being < 15%. Patients receiving ficilitran at a dose of 1.25 mg QM with two or more (e.g., 2) AT activity levels < 15% may discontinue or pause ficilitran treatment. 【0075】 Alternatively, after tapering to a dose of 1.25 mg of ficilitran monthly, the patient's AT level may be monitored again regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady state AT level > 35%, within one month (e.g., within 1 or 2 weeks) another steady state AT activity level sample is taken from the patient. If this result is > 35%, this is considered the second steady state AT being > 35%. Patients receiving ficilitran at a dose of 1.25 mg QM with two or more (e.g., 2) steady state AT activity levels > 35% may have their dose increased to 2.5 mg of ficilitran once a month (or every 4 weeks). 【0076】 In other embodiments, patients treated with an initial dose of 5 mg of ficilitran monthly (or every 4 weeks) may have their dose of ficilitran titrated up. The patient's AT level may be monitored periodically (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level > 35%, within 1 month (e.g., within 1 or 2 weeks) another steady-state AT activity level sample is taken from the patient. If this result is > 35%, this is considered the second steady-state AT > 35%. Patients receiving ficilitran at a dose of 5 mg QM with two or more (e.g., 2) steady-state AT activity levels > 35% may have their dose titrated up to 10 mg of ficilitran monthly (or every 4 weeks). 【0077】 After titrating up to a dose of 10 mg of ficilitran monthly, the patient's AT level may again be monitored periodically (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level > 35%, within 1 month (e.g., within 1 or 2 weeks) another steady-state AT activity level sample is taken from the patient. If this result is > 35%, this is considered the second steady-state AT > 35%. Patients receiving ficilitran at a dose of 10 mg QM with two or more (e.g., 2) steady-state AT activity levels > 35% may have their dose titrated up to 20 mg of ficilitran once monthly (or every 4 weeks). 【0078】 In some embodiments, the titration is carried out after the steady-state AT activity level has remained > 35% (see, e.g., Figure 4). 【0079】 In some embodiments, the activity level used to determine whether to increase the dose amount or frequency of ficiran is that measured at steady state (SS), i.e., when the patient's AT level is measured to be stable after ficiran treatment. SS is typically reached after two or three doses of ficiran. AT measurements for dosing decisions are taken at appropriate intervals (e.g., every 4 weeks or every 8 weeks). 【0080】 In the dosing regimens described above, starting doses of 10 mg ficiran QM or 5 mg ficiran QM are considered as illustrative examples. For example, the starting dose of ficiran can be 20 mg QM, 10 mg Q2M, 7.5 mg Q2M, 5 mg Q2M, or 2.5 mg QM. Thereafter, dose increases and decreases can be carried out as appropriate from each starting dose. For example, a starting dose of 2.5 mg QM ficiran can be incrementally increased, optionally in that order, to 5 mg QM, 10 mg QM, 20 mg QM, 30 mg QM, or 50 mg QM, or decreased to 2.5 mg Q2M or 1.25 QM. 【0081】 An AT level of 10 - 35% (e.g., 10 - 25%, 15 - 35%, or 15 - 25%) is intended to maintain a favorable benefit - risk balance for patients who regularly use factor Xa inhibitor, while aiming to reduce the risk of venous thromboembolic events. Thus, as long as the patient reaches this target AT level, except as otherwise considered herein (e.g., patients with bleeding events more frequent than a preset threshold), the patient does not need to receive a higher factor Xa inhibitor dosage or more frequent dosing. That is, the patient can remain on the current treatment regimen (i.e., maintenance regimen). For example, upon reaching the desired AT level, the patient can be treated with a subcutaneous dose of factor Xa inhibitor (e.g., 1.25 - 30 mg per dose) at intervals of, for example, every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, or 4 months. In some embodiments, if two AT measurements are 35% or less while the patient is receiving 10 mg QM, the dosing regimen can be maintained without the need to further increase the dosage or dosing frequency. As another example, if two AT measurements are 35% or less while the patient is receiving 5 mg QM, the patient can remain on this dosing regimen without the need to further increase (e.g., to 10 mg QM or 20 mg QM) the dosage or dosing frequency. However, factor Xa inhibitor treatment should result in a dose reduction (or discontinuation if already tapered to the lowest allowable dose) if two or more (e.g., 2) AT measurements of the patient are < 15% (e.g., < 10%) as a risk reduction measure for venous thromboembolic events. In some embodiments, an exception can be that if the patient bleeds more frequently than a preset threshold, the factor Xa inhibitor dosage can be increased even though the AT activity level is within the range of 15 - 35%. 【0082】 Pediatric patients with inhibitor - positive or inhibitor - negative hemophilia A or B can be treated with subcutaneous maintenance doses of FEIBA at 1 - 50 mg per dose, monthly (or every 4 weeks). In some embodiments of the maintenance regimen, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 50 mg per dose, monthly (or every 4 weeks). In some embodiments of the maintenance regimen, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 30 mg per dose, monthly (or every 4 weeks). In other embodiments, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 20 mg per dose, monthly (or every 4 weeks). In other embodiments, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 10 mg per dose, monthly (or every 4 weeks). In some embodiments of the maintenance regimen, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 7.5 mg per dose, monthly (or every 4 weeks). In other embodiments, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 5 mg per dose, monthly (or every 4 weeks). In other embodiments, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 2.5 mg per dose, monthly (or every 4 weeks). In other embodiments, patients with inhibitor - positive or inhibitor - negative hemophilia A or B are treated with subcutaneous doses of FEIBA at 1.25 mg per dose, monthly (or every 4 weeks). 【0083】 In some embodiments, patients may receive regular (e.g., monthly or every 4 - week) AT monitoring for 12 months after a change in the FEIBA dosing regimen. 【0084】 In some embodiments, when a patient remains on 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, AT levels may be monitored monthly, every two months, every three months, every four months, every six months, annually, or every two years. 【0085】 III. Patient Management Patients on long-term use of Fitsiran are monitored for hemostasis parameters such as coagulation parameters (D-dimer, prothrombin fragment 1+2, and fibrinogen), and signs and symptoms of vascular thromboembolic events. Such signs and symptoms may include, but are not limited to, severe or persistent headache, headache accompanied by nausea and vomiting, chest pain and / or tightness, hemoptysis, dyspnea, abdominal pain, syncope or loss of consciousness, swelling or pain in the arm or leg, vision problems, weakness and / or sensory disturbances, and changes in speech. Evaluation of signs and symptoms potentially consistent with vascular thrombosis should, where appropriate, include appropriate imaging studies. Magnetic resonance venogram (MRV) or computed tomography venogram (CTV) is recommended for the diagnosis of cerebral venous sinus thrombosis. 【0086】 If a patient develops thrombosis while on long-term use of Fitsiran, AT reversal can be performed 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. The use of plasma-derived AT may be preferred over recombinant AT considering its longer half-life. 【0087】 Bleeding events in patients using FIX can be managed by on-demand administration of replacement factors (recombinant or plasma-derived factor VIII or factor IX) or BPA (e.g., fresh frozen plasma (FFP); rFVIIa; and aPCC). The amount of factor or BPA must be reduced in patients using FIX to prevent vascular thrombosis. See, for example, WO 2019 / 014187. The management of bleeding episodes in pediatric patients using prophylactic FIX treatment is described in more detail in Example 1. See, for example, Table 4 below. 【0088】 Additional definitions of terms and exemplary embodiments are described in the Examples and are incorporated herein by reference. 【0089】 Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by one of ordinary skill in the art. Exemplary methods and materials are described below, but methods and materials similar to or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. In general, the nomenclature and techniques used in connection with hematology, medicine, pharmaceuticals and pharmaceutical chemistry, and cell biology described herein are well known and commonly used in the art. Further, unless the context requires otherwise, singular terms shall include the plural, and plural terms shall include the singular. Throughout this specification and the claims, the words “have” and “comprise” or variations thereof, such as “has,” “having,” “comprises,” or “comprising,” are to be understood to mean including the recited integer or group of integers but not excluding any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety. Although some of these references are cited herein, such citation does not constitute an admission that any of these references form part of the common general knowledge in the art. The term “about” or “approximately” as used herein, when used in connection with one or more values of interest, refers to a value similar to the recited reference value. In certain embodiments, the term refers to a range of values that fall within (greater than or less than) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the recited reference value in either direction, unless otherwise stated or otherwise apparent from the context. 【0090】 According to the present disclosure, a back-reference in a dependent claim means a shorthand notation for a direct and explicit disclosure of any combination of claims indicated by the back-reference. Further, the headings in this specification are created to facilitate organization and are not intended to limit the scope of the invention claimed in any way. 【0091】 To better understand the present invention, the following examples are described. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way. 【Example】 【0092】 Example 1: A clinical trial protocol for a non-blind study of prophylaxis with fitusiran in male pediatric subjects aged 1 to less than 12 years with hemophilia A or B This example describes a protocol for a non-blind multinational study of prophylaxis with fitusiran in male pediatric participants aged 1 to <12 years with severe hemophilia A or hemophilia B who have inhibitory antibodies against FVIII or FIX. People diagnosed with severe hemophilia A or hemophilia B with inhibitory antibodies are eligible for enrollment as long as they meet all inclusion criteria and none of the exclusion criteria. 【0093】 The purpose of this study is to confirm the appropriate starting dose, escalating dose, and de-escalating dose of fitusiran when administered to male pediatric participants (1 year to <12 years on Day 1). This study consists of a screening period of up to 60 days (which may be extended after consultation with the sponsor in exceptional circumstances), followed by a fitusiran treatment period during which participants will receive a starting dose of fitusiran administered subcutaneously every 4 weeks. 【0094】 Participants who experience antithrombin activity levels of less than 15% on two or more occasions are permitted to taper to lower doses of factor VIII inhibitor bypassing activity (FEIBA). Participants who routinely take such lower doses and have antithrombin activity levels of less than 15% on two or more occasions must permanently discontinue FEIBA. If a participant's steady-state antithrombin activity level while taking the starting dose remains above 35%, the participant is permitted to titrate to higher doses of FEIBA. The study protocol is shown in Figure 2. The doses administered are based on two weight-based groups, cohort 1 and cohort 2, as further explained below. 【0095】 Throughout the study, participants may receive on-demand treatment for breakthrough bleeding episodes with BPA according to bleeding management guidelines as further explained below. 【0096】 Approximately 32 pediatric participants with severe hemophilia A or B who have inhibitory antibodies to FVIII or FIX and are receiving either 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 between 8 kg and <16 kg. 【0097】 If all participants within the 22 kg to <45 kg weight cohort (Cohort 1) receive three consecutive injections of the starting dose of Fitsiran administered every four weeks, the Independent Data Monitoring Committee (DMC) reviews the safety and PD data available from this first cohort until at least four weeks after the final dose. If approved by the DMC to continue, the enrollment of participants weighing 8 kg to <22 kg is triggered. If all participants in the 8 kg to <22 kg weight cohort (Cohort 2) receive three consecutive injections of Fitsiran administered every four weeks, the DMC reviews the safety and PD data available from both cohorts until at least four weeks after the last dose in the second cohort. Additionally, the DMC reviews the safety and PD data available for the escalating and de-escalating doses of Fitsiran, and the PK data available for the starting dose, when all participants in the relevant cohort receive the injection of each dose. 【0098】 Participants who have completed 12 weeks of treatment using the starting dose, escalating dose, or de-escalating dose may be eligible to continue treatment with Fitsiran administered every four weeks as part of this study or, if available, as participants in an open-label extension (OLE) study. Participants who remain on Fitsiran continue the study until completion of all dosing cohorts and until pediatric dosing is complete. Home injection of Fitsiran may be initiated at week 56 if the participant and / or caregiver have completed training and meet the eligibility requirements and if permitted by national and regional regulations. 【0099】 For participants who derive a clinical benefit and continue treatment, the estimated time in the study is up to 160 weeks. If an OLE study is available before 160 weeks, the participant is eligible, and the caregiver chooses to roll the participant over into the OLE study, the duration of the study may be shortened. 【0100】 Participants who discontinue the Ficiran treatment need to be monitored until the AT activity level returns to approximately 60% per central laboratory, or according to the discretion of the investigator in consultation with the study medical manager. This may take up to 24 weeks. 【0101】 During the study, pharmacodynamics (PD) and pharmacokinetics (PK) data, as well as safety / tolerability data, are collected. The blood sampling times for PD are shown in Table 2. 【0102】 [Table 3] 【0103】 [Table 4] 【0104】 [Table 5] 【0105】 [Table 6] 【0106】 [Table 7] 【0107】 The blood sampling times for PK are shown in Table 3. 【0108】 [Table 8] 【0109】 Throughout the study, participants can receive on-demand treatment for breakthrough bleeding episodes with BPA according to the bleeding management guidelines described further below. The investigator will establish an individual bleeding management plan for each participant based on the guidelines in Table 4 and provide instructions regarding this. 【0110】 【Table 9】 【0111】 Record details of bleeding episodes and the dose of BPA administered during the conduct of the study in an electronic diary (eDiary). 【0112】 Scientific basis In patients with hemophilia A or B, including those with inhibitors, a subcutaneous therapy that can effectively and safely prevent bleeding episodes or reduce the frequency of such bleeding episodes can reduce the treatment burden, improve clinical outcomes, and improve quality of life, especially in the pediatric patient population. In this patient category, patients with inhibitors appear to have the highest unmet treatment needs, so enrollment in this dose confirmation study is limited to patients with hemophilia A or B who have inhibitors. 【0113】 This study intends to confirm the appropriate dose of fitusiran for pediatric participants aged 1 to <12 years within two weight categories of 22 kg to <45 kg and 8 kg to <22 kg. This is based on the level of AT activity and safety and tolerability data. 【0114】 Using modeling and simulation, the dose at which participants within a specific weight cohort can maintain an AT activity level of ≧15% was identified. The model was created considering preclinical data and based on adult dosing data, simulating approximately 1000 and 2000 pediatric participants for the weight categories of 22 kg to <45 kg and 8 kg to <22 kg, respectively. To optimize the safety of participants in this confirmation study, the heaviest (22 kg to <45 kg) participants are initially dosed with a starting dose of 10 mg. The DMC will dose the next weight cohort only if it evaluates the data available from the largest cohort and considers it appropriate. 【0115】 Basis for dose The selection of pediatric doses for specific weight ranges is based on population PK / PD modeling. To account for pediatric participants 1 to <12 years of lower weight, adult PK models were updated using non-human primate AT decline response data, and then the updated models were used to predict doses for pediatric studies. 【0116】 Following changes in the dose and regimen of fitusiran in adult / young studies introduced as a risk reduction measure for vascular thromboembolic events, an update of fitusiran dosing was implemented in this study. Since the risk of vascular thromboembolic events is considered to increase at low AT activity levels, starting doses of 10 mg (cohort 1) or 5 mg (cohort 2) administered SC once every 4 weeks were selected to minimize the occurrence of AT activity levels of less than 10%. At these starting doses, if two or more AT levels of the participant are <15% (within a 12-month period), the participant can be tapered to a lower dose. At that lower dose, if two or more AT levels of the participant are <15% (within a 12-month period), the participant needs to permanently discontinue fitusiran. Based on modeling and simulation, less than 1% of participants are expected to discontinue fitusiran treatment based on AT activity levels at this lower dose. The starting doses of 10 mg and 5 mg were predicted by modeling and simulation to result in antithrombin levels of ≥15% to ≤35% in the majority of participants in both cohorts 1 and 2. If the two steady-state AT levels of the starting dose of the participant are above 35%, the participant's dose is escalated to 20 mg (cohort 1) or 10 mg (cohort 2) administered SC once every 4 weeks. The escalated doses of 20 mg and 10 mg are predicted to result in antithrombin levels of ≥15% or more to ≤35% in the majority of participants with AT values >35% at the starting doses of 10 mg and 5 mg. Further escalation to 30 mg (cohort 1) and 20 mg (cohort 2) administered SC once every 4 weeks is permitted if such escalation is necessary. 【0117】 In addition to the above, a gradual increase in dosage is allowed based on clinical criteria with the goal of achieving appropriate efficacy while maintaining the AT level above 15%. 【0118】 Objectives and Evaluation Items The primary objective of this study is to confirm the appropriate dosage level of fitusiran when administered to male pediatric participants (1 year to <12 years) with severe hemophilia A or B. The primary evaluation item is to characterize the AT activity at the optimal treatment dosage. 【0119】 The second objective is to characterize safety and tolerability and to determine the fitusiran plasma concentration at selected time points. Secondary evaluation items are the incidence, severity, significance, and relevance of adverse events (AEs); and the plasma concentration in samples collected 4 hours after the dose on day 1 (corresponding to the median time to maximum concentration in adults) and before the dose on day 85 (corresponding to the minimum concentration after the third dose). 【0120】 The third / exploratory objective is to characterize the frequency of bleeding episodes during fitusiran treatment and to characterize immunogenicity. The third / exploratory evaluation items are the annual bleeding rate (ABR) from day 1 to the AT analysis time point, from the AT analysis time point to week 160 of the end of study (EOS) visit, and over the entire treatment period at the optimal treatment dosage; and the incidence and titer of anti-drug antibodies. 【0121】 Registration Enrollment is staggered by two weight-based cohorts. Participants weighing 22 kg to < 45 kg (cohort 1) are enrolled first and receive three doses of 10 mg of fitsiran administered every four weeks, and participants weighing 8 kg to < 22 kg (cohort 2) are enrolled second and receive three doses of 5 mg of fitsiran administered every four weeks. The fitsiran dose is escalated to 20 mg administered every four weeks (for cohort 1) or 10 mg administered every four weeks (for cohort 2) for participants whose two steady-state AT values exceed 35%. Participants whose two steady-state AT values exceed 35% at the first escalation dose may be further escalated to 30 mg every four weeks (for cohort 1) and 20 mg every four weeks (for cohort 2). 【0122】 Study population Participants are eligible for inclusion in the study only if all of the following criteria are met. Age I.01. Participants must be 1 to < 12 years of age at the time of enrollment. Participant type and disease characteristics I.02 Severe hemophilia A or B (FVIII < 1% or FIX ≤ 2%) I.03 Participants must not have inhibitory antibodies to FVIII or FIX and must meet one of the following Nijmegen modified Bethesda assay result criteria: - Inhibitor titer at screening ≥ 0.6 BU / mL, or - Inhibitor titer at screening < 0.6 BU / mL and there is evidence in the medical record of two consecutive titers ≥ 0.6 BU / mL, or - Inhibitor titer at screening < 0.6 BU / mL, there is evidence in the medical record of one inhibitor titer ≥ 0.6 BU / mL, and a history of previous response or severe allergic reaction (anaphylaxis or nephrotic syndrome). I.04 Appropriate peripheral venous access to enable blood sampling required by the study protocol as determined by the investigator. Weight I.05 Body weight requirements at the time of registration: a) Cohort 1: Body weight 22 - <45 kg b) Cohort 2: Body weight 8 - <22 kg Gender I.06 Males Except when required by regional regulations, there are no contraceptive requirements for this study. 【0123】 Participants will be excluded from the study if any of the following criteria apply: Medical conditions E.01 Known co - existing bleeding disorders other than hemophilia A or B, i.e., von Willebrand disease, additional factor deficiencies, or platelet disorders. E.02 AT activity at screening <60% as determined by central laboratory analysis. E.03 Presence of liver disease that is clinically significant or indicated by any of the following conditions: 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 for participants with Dubin - Johnson syndrome); d) History of portal hypertension, esophageal varices, or hepatic encephalopathy; e) Presence of ascites by physical examination. HCV antibody positive, excluding patients with a history of HCV infection who meet both of the following conditions: a) Completed a therapeutic treatment at least 12 weeks prior to registration and achieved a sustained virological response demonstrated by negative HCV ribonucleic acid (RNA) at screening, or spontaneously cleared the infection demonstrated by negative HCV RNA at screening. b) No evidence of cirrhosis according to one of the following evaluations: - FibroScan <9 kPa (if available), or - FibroTest score < 0.36 and AST-to-platelet ratio index (APRI) < 1 (when FibroScan is not available) (Tokuhara et al., PLoS One. (2016) 11(11):e016668315; de Ledinghen et al., J Pediatr Gastroenterol Nutr. (2007) 45(4):443-50) E.05 Presence of acute hepatitis, i.e., hepatitis A, hepatitis E. E.06 Presence of acute or chronic hepatitis B infection (positive for hepatitis B core antigen [anti-HBc IgM] or IgM antibody against hepatitis B surface antigen [HBsAg])*. * Confirmed by central laboratory evaluation 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 the time of screening (excluding minor viral syndromes at the discretion of the investigator in consultation with the study medical manager). E.09 Known to be positive for human immunodeficiency virus (HIV) with a CD4 count < 400 cells / μL. E.10 Estimated glomerular filtration rate ≤ 45 mL / min / 1.73m 2 (using the Schwartz formula). E.11 Coexisting thrombotic disorder determined by the presence of any of the following identified by the central laboratory: 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 unrelated to indwelling venous access. E.14 In the opinion of the investigator, any condition that may make the participant ineligible for dosing on Day 1 or that may interfere with study compliance, participant safety, and / or participant participation at the end of the study treatment period (e.g., medical concerns). This includes serious cardiovascular, neurological, gastrointestinal, endocrine, renal, or psychiatric disorders unrelated to hemophilia that are identified by significant laboratory abnormalities or medical history. E.15 The need for surgery anticipated during the study or planned scheduled surgery to be performed during the study at the time of screening. E.16 Completion of surgery within 14 days prior to screening or currently receiving additional BPA infusion for hemostasis after surgery. E.17 History of multi-drug allergy or history of allergic reaction to oligonucleotides or GalNAc. E.18 Subjects with a central or peripheral indwelling catheter and a history of venous access complications (infections, thrombosis, etc.) leading to hospitalization and / or systemic anticoagulation therapy in the past 12 months. (Note: Heparin flushing of the catheter should not be considered systemic anticoagulation.) E.19 History of intolerance to SC injection. Previous therapy / combination therapy E.20 Current participation in ITI therapy. E.21 Use of emicizumab (Hemlibra®) within 6 months prior to screening. Previous / concurrent clinical research experience E.22 Current or future participation in another clinical study planned during this study that includes an investigational drug other than fitusiran or an investigational device; for a participant to participate in this study, the investigational drug or investigational device must be discontinued at least 30 days (or 5 times the half-life of the investigational drug, whichever is longer) prior to dosing (Day 1). 【0124】 Study intervention Study intervention is defined as any investigational intervention, marketed product, placebo, or medical device that is intended to be administered to study participants according to the study protocol. Fitusiran is administered every 4 weeks as shown in Table 5 below. 【0125】 【Table 10】 【0126】 Based on the safety and PD data observed in previous cohorts, the fitusiran dose may be decreased or increased from that initially planned for the next cohort. The decision to modify the fitusiran dose is based on the AT activity level; changes to the planned dose can only be made after consultation between the DMC and the sponsor. After 12 weeks of treatment with fitusiran starting, escalating, or prophylactically decreasing doses, participants who remain on fitusiran continue in the study until the end of the treatment period in all dosing cohorts and until pediatric dosing is complete. As participants grow and would be included in a higher weight group, dose increases up to the next weight-based dose, as clinically indicated and at the discretion of the investigator in consultation with the study medical manager, may be considered on an individual participant basis. 【0127】 During the first 7 days of the fitusiran starting dose initiation period, participants continue pre-study BPA therapy (prophylaxis or on-demand) for hemophilia according to a regimen consistent with the pre-study regimen, within the general recommended range of the approved prescribing information and at the discretion of the investigator. Management of bleeding episodes should be carried out according to the regional standard practice for on-demand use of BPA and at the discretion of the investigator; however, dose reduction is recommended if possible. After the first 7 days of the fitusiran starting dose, participants discontinue BPA prophylaxis if applicable, and all participants treat breakthrough bleeding episodes with on-demand BPA therapy as needed, according to the bleeding episode management guidelines of this protocol. 【0128】 Combination Therapy Any medications or vaccines that participants receive at the time of registration or during the study (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) must be recorded. As the regional standard of care for hemophilia, intravenous (IV) infusion of BPA (e.g., recombinant activated factor VII (rFVIIa; NovoSeven®) and activated prothrombin complex concentrate (aPCC; FEIBA®)) is considered, but not limited to, these. The use of these agents is described as follows and the details must be recorded in the participant's eDiary: - The use of prothrombin complex concentrate for bleeding episode management is not permitted; - The use of emicizumab (Hemlibra®) during the study is not permitted; and - Antifibrinolytics can be used as a single agent but cannot be used in combination with BPA. The use of FEIBA® and NovoSeven® as combination therapy is not recommended. 【0129】 AT activity Blood samples are collected for the assessment of AT activity levels according to Table 2. On the day of fitusiran dosing, the sample is collected within 4 hours before dosing (pre-dose). Antithrombin levels are determined by a validated assay. The results are collected and interpreted by the central laboratory. 【0130】 After administration of the final fitusiran dose, AT activity levels are monitored at monthly (or approximately every 4 weeks) intervals or at the discretion of the investigator in consultation with the study medical manager until they return to approximately 60% (per central laboratory) of the activity level. 【0131】 The optimal therapeutic dose for each participant is defined as the dose that brings the participant's steady-state AT within the target range of 15 - 35% and does not meet the criteria for clinically based titration. Steady state is considered to be achieved after the third injection of fitusiran dose. This is because modeling and simulation have shown that the majority of patients are in a steady state at this point. 【0132】 Management of bleeding episodes The occurrence of bleeding episodes is a typical feature of hemophilia; bleeding episodes are recorded as an assessment of the effectiveness of factor VIII, and are not considered AEs unless the criteria for SAE are met. Investigators are required to establish an individual bleeding management plan for each participant based on the guidelines in Table 4 and provide instructions regarding this. Most participants are expected to enter the OLE study immediately after completing the factor VIII study. However, considering that participants may have various periods of gaps between studies and that the AT activity levels at study entry may vary, the approach to bleeding management is described below based on the AT activity levels at study entry. 【0133】 Definition of bleeding episodes A bleeding episode is defined as any occurrence of bleeding that requires administration of BPA, such as joint bleeding, muscle bleeding, or mucosal bleeding. The definitions of the bleeding episode types described below are based on the consensus opinion of the International Society on Thrombosis and Haemostasis (ISTH) as reflected in recent publications (22). 【0134】 The start time of a bleeding episode is considered to be the time when the symptoms of the bleeding episode first occur. Bleeding or any symptoms of bleeding at the same location that occur within 72 hours of the last injection used to treat the bleeding episode at that location are considered part of the original bleeding episode and counted as one bleeding episode for ABR. Any bleeding symptoms that start more than 72 hours after the last injection used to treat the bleeding episode at that location constitute a new bleeding episode. 【0135】 Spontaneous bleeding episodes are bleeding episodes that occur, without any obvious or known reason, particularly in joints, muscles, and soft tissues. 【0136】 An articular bleeding episode is characterized by 1) swelling or increased warmth of the skin covering the joint, 2) increased pain, or 3) abnormal sensation ("aura") in the joint combined with a progressive loss of range of motion of the limb or difficulty in using the limb compared to baseline. 【0137】 Muscle bleeding can be characterized by pain, swelling, and loss of movement across the affected muscle group. 【0138】 A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred in a single joint within a consecutive six - month period; if a joint has ≤ 2 bleeding episodes within a consecutive twelve - month period, that joint is no longer considered a target joint. 【0139】 Traumatic bleeding episodes are those caused by a known injury or trauma. Bleeding episodes that persist during sports and recreation are counted as traumatic bleeding episodes. 【0140】 Bleeding management guidelines for participants with an AT activity level ≥ 60% (per central laboratory) at study entry After the first day of fitusiran dosing, when the AT activity level is ≥ 60%, participants and / or their caregivers are recommended to call the investigator before BPA dosing. 【0141】 As early as 7 days after the first fitusiran dose, most participants will have an AT activity level of 60% or less. By 14 days after the first fitusiran dose, most participants are expected to have an AT activity decrease of > 50%. Based on these AT activity dynamics, participants continue the standard BPA regimen during the first week after the start of fitusiran dosing as follows and as described in Table 4, and facilities following protocol - specific bleeding management guidelines are recommended to initiate BPA reduction at week 2 after the start or restart of fitusiran dosing. 【0142】 Bleeding management guidelines for participants starting from the second week onwards and for those with AT activity levels < 60% (per central laboratory) at study entry If a participant experiences symptoms that may be consistent with a bleeding episode, the following steps should be followed: 1. The participant and / or their caregiver should be instructed to call the study site to discuss the symptoms, determine whether the symptoms are consistent with a bleeding episode, and discuss the appropriate BPA dose to use. This dialogue between the participant and / or their caregiver and the investigator is recommended prior to administration of each dose of BPA. Confirmation of the bleeding episode at the study site prior to treatment may be considered. 2. If the symptoms are determined to require treatment, the recommended treatment algorithm for the bleeding episode is described below. a) A single dose can be administered according to the guidelines in Table 4. b) The participant and / or their caregiver should be instructed to re-evaluate the symptoms at 24 hours for bleeding episodes treated with aPCC and at 2 - 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 before dosing. a) Consider participant evaluation and treatment at the study site and confirmation of the bleeding episode if any repeat dose is required. b) If more than 2 doses of aPCC or 3 doses of rFVIIa are required, the participant should be examined at the study site within 48 - 72 hours. 4. Doses should not be administered at intervals of less than 24 hours (except for rFVIIa as shown in Table 4). 5. Doses should not exceed the maximum protocol-recommended dose shown in Table 4. 6. Consultation with the study medical manager and clinical advisor should be considered for the following clinical situations that may warrant AT supplementation: a) Higher BPA doses than those recommended in Table 4. b) Administration of BPA at intervals shorter than those recommended in Table 4. c) Multiple or repeated doses of BPA. 7. Antifibrinolytics cannot be used in combination with BPA. 【0143】 Management of bleeding episodes after discontinuation of fitusiran Participants who have chosen to discontinue fitusiran may resume standard prophylaxis or on-demand dosing with BPA when the AT activity level returns to approximately 60% (per central laboratory). If a strong medical need (e.g., increased bleeding frequency) arises, early resumption of standard treatment may be considered in conjunction with consultation from the study medical management team. If the full dose of BPA is required to achieve hemostasis before complete AT recovery (approximately 60% AT activity per central laboratory), AT supplementation should be considered. 【0144】 Management of surgery The perioperative treatment plan should be created using the same principles as the bleeding management described above and the following guidelines: - If the clinical situation is such that the recommended doses and / or dosing intervals in Table 4 are considered insufficient for hemostasis, AT supplementation should be considered and the risk of thrombosis managed in accordance with the investigator's implementation for hemophilia participants undergoing that specific surgical procedure. - Non-pharmacological methods of thrombo-prophylaxis should also be used as clinically indicated. 【0145】 Fitusiran treatment during the perioperative evaluation period is as follows. If the need for major surgery arises during the study and the surgery is not urgent or emergency, it is recommended to postpone the surgery until after the study is completed. For minor surgery, dosing with fitusiran can continue without interruption. 【0146】 If the need for emergency or major surgery arises during the study, the participant should be medically managed according to the previous guidelines. If the fitusiran dose is scheduled to occur on or near the surgical day, or at any time during the perioperative period, the dose should be withheld. The perioperative evaluation period is defined as the surgical day up to the last day on which adjunctive hemostatic or antithrombotic treatment is administered as part of the perioperative treatment plan. Fitusiran dosing may be resumed at the discretion of the investigator at the next scheduled visit after the perioperative evaluation period. 【0147】 Minor surgery is defined as any invasive procedure in which only the skin, mucous membranes, or superficial connective tissue is manipulated and which does not meet the criteria for major surgery (e.g., extraction of < 3 non-molar teeth). Minor surgery may be performed at a local healthcare facility. 【0148】 Major surgery is defined as any invasive procedure that requires any of the following: - An opening into a major body cavity (e.g., abdomen, chest, skull). - Surgery of a joint, - Removal of an organ, - Extraction of any molar or ≥ 3 non-molar teeth, - Surgical alteration of normal anatomical structures, and - Transection of a mesenchymal barrier (e.g., pleura, peritoneum, dura). 【0149】 Rescue medications The following rescue medications may be used: Antithrombin concentrate. Antithrombin reversal should follow the recommendations of the labeled product for the prevention of perioperative thrombosis in participants with AT deficiency, and the participant dose should be individualized to target an AT activity level of 80% - 120%. 【0150】 Dose modification Use subcutaneous therapy with fitusiran for dosing in each study cohort. Based on the safety and PD data observed, the fitusiran dose can be decreased or increased from what was initially planned for the next cohort, but not exceed 30 mg. The decision to modify the fitusiran dose is based on AT activity levels; changes to the planned dose can only be made after consultation between the DMC and the sponsor. Participants who remain on fitusiran continue in the study until the end of the treatment period in all dosing cohorts and until the pediatric dose and regimen are completed. If a participant grows into a higher weight group, an increase in dose up to the next weight-based dose, clinically indicated at the discretion of the investigator in consultation with the study medical manager, may be considered. 【0151】 Antithrombin level criteria for dose adjustment for Cohort 1 For Cohort 1, participants start or restart fitusiran at a dose of 10 mg every 4 weeks. As shown in Figure 3, participants receiving fitusiran at a dose of 10 mg every 4 weeks can be titrated up to a titrated dose of 20 mg every 4 weeks if their 2 steady-state (SS) AT values exceed 35%: - The pre-dose AT values at Week 8 and Week 12 are used for assessment; and - If the titration rules are met, participants receive 20 mg of fitusiran every 4 weeks starting at Week 16. 【0152】 As shown in Figure 3, participants receiving a titrated dose of 20 mg can be further titrated up to a titrated dose of 30 mg every 4 weeks if their 2 steady-state AT values exceed 35%: - The pre-dose AT values at Week 24 and Week 28 are used for assessment. - If the titration rules are met, participants receive 30 mg of fitusiran every 4 weeks starting at Week 32. 【0153】 In the rare situation where a participant does not meet the titration criteria at the above time points but later does, the investigator consults with the study medical manager before any titration. 【0154】 In the unlikely event that the AT activity levels of two or more participants are less than 15% after increasing incrementally to 20 mg or 30 mg every four weeks (within a 12 - month period), the investigator will consult with the study medical manager regarding further treatment with ficiran. 【0155】 Participants who are receiving ficiran at an initial dose of 10 mg every four weeks and have two or more AT activity levels less than 15% at this dose (within a 12 - month period) may have their ficiran dose tapered by 2.5 mg every four weeks. This lower ficiran dose should only be administered after the participant's AT activity level has reached ≥22%. Participants with two or more AT levels less than 15% at this lower dose (within a 12 - month period) must discontinue ficiran permanently. 【0156】 Participants in Cohort 1 who had to discontinue ficiran prior to this protocol amendment due to AT activity levels <15% may resume ficiran dosing at the lower dose of 2.5 mg administered every four weeks. This lower ficiran dose should only be administered after the participant's AT activity level has reached ≥22%. 【0157】 Participants receiving a tapered ficiran dose of 2.5 mg every four weeks may have their dose increased incrementally to 5 mg of ficiran every four weeks if their two steady - state AT values exceed 35%. 【0158】 At each dose level, when the first AT activity level is <15%, the participant must have another AT measurement within one week of the location where the results are received. If the result is <15%, it is considered the second AT activity level <15%. Participants with an AT activity level <15% must not receive ficiran at the current dosing regimen until the AT activity level from the second measurement is available for guiding management. 【0159】 Antithrombin level criteria for dose adjustment for Cohort 2 For Cohort 2, participants initiate or resume ficlatuzumab at a dose of 5 mg every 4 weeks. As shown in Figure 4, participants receiving ficlatuzumab at a dose of 5 mg every 4 weeks may have their dose escalated to a titrating dose of 10 mg every 4 weeks if their two steady-state AT values exceed 35%: - The pre-dose AT values at Week 8 and Week 12 are used for evaluation. - If the titration rule is met, participants receive 10 mg of ficlatuzumab every 4 weeks starting from Week 16. 【0160】 As shown in Figure 4, participants receiving a titrating dose of 10 mg may have their dose further escalated to a titrating dose of 20 mg every 4 weeks if their two steady-state AT values exceed 35%: - The pre-dose AT values at Week 24 and Week 28 are used for evaluation. - If the titration rule is met, participants receive 20 mg of ficlatuzumab every 4 weeks starting from Week 32. 【0161】 In the rare situation where a participant does not meet the titration criteria at the above time points but later meets the criteria, the investigator consults with the study medical manager before any titration. 【0162】 In the unlikely situation where two or more AT activity levels of a participant are less than 15% (within a 12-month period) after escalating to 10 mg or 20 mg every 4 weeks, the investigator consults with the study medical manager regarding further treatment with ficlatuzumab. 【0163】 Participants receiving ficlatuzumab at a starting dose of 5 mg every 4 weeks and having two or more AT activity levels less than 15% at this dose (within a 12-month period) may have their ficlatuzumab dose tapered to 1.25 mg every 4 weeks. This lower ficlatuzumab dose should only be administered after the participant's AT activity level reaches ≥22%. Participants having two or more AT levels less than 15% at this lower dose (within a 12-month period) must permanently discontinue ficlatuzumab. 【0164】 Participants receiving a tapered dose of 1.25 mg of fitusiran every 4 weeks may have their dose of fitusiran increased to 2.5 mg every 4 weeks if their two steady-state AT values exceed 35%. 【0165】 At each dose level, when the first AT activity level is < 15%, the participant must have another AT measurement within 1 week of the site where the result was received. If the result is < 15%, it is considered a second AT activity level < 15%. Participants with an AT activity level < 15% must not receive fitusiran at the current dosing regimen until the AT activity level from the second measurement is available to guide management. 【0166】 Clinical-based criteria for dose adjustment The investigator may request permission from the study medical manager to increase the study participant to a higher dose of fitusiran if, despite an AT activity level ≤ 35%, the following apply. - At least two doses of fitusiran have been administered at the current dose level, and - The investigator determines suboptimal bleeding control at the current dose level, defined as bleeding that occurred more than twice within a 12-week period starting from the third fitusiran injection at the current dose. 【0167】 The AT activity level, and, if applicable, additional clinical data, are considered in the dose escalation for each individual participant. 【0168】 If the investigator believes that a particular participant warrants a dose escalation based on different reasons, the investigator may discuss the case with the study medical manager. 【0169】 Evaluation of treatment response Recommendations from the International Society on Thrombosis and Hemostasis are described in Table 6 below for the evaluation of treatment response. 【0170】 [Table 11] 【0171】 Example 2: Calculation and Prediction of AT Levels in Pediatric Patients The pediatric patient population was separated into two groups: Cohort 1 (22 kg to < 45 kg) and Cohort 2 (8 kg to < 22 kg). The dosing escalation and de-escalation schemes for Cohorts 1 and 2 are described in the previous Example 1. 【0172】 To minimize the risk of vascular thrombosis while maintaining efficacy, a target AT tolerance period (window) of 15% to 35% was selected. Thus, all PK / PD modeling described below was performed with the aim of finding dosing regimens that could maintain 15% to 35% AT activity. 【0173】 The pharmacokinetic / pharmacodynamic (PK / PD) model shown in Figure 5 (showing the dynamics of plasma AT activity in patients treated with fitusiran) was developed using AT activity data from 274 participants from adult and adolescent Phase 1, Phase 2, and Phase 3 studies (Phase 3 data included patients on 80 mg QM and 50 mg Q2M). 【0174】 The pediatric PK / PD model used to select dosing regimens was based on an adult PK / PD base model scaled to the pediatric population using body weight-based allometry. Table 7 shows the parameter estimates of the adult PK / PD base model and the body weight allometric exponent for scaling the model to the pediatric population. 【0175】 [Table 12] 【0176】 Using the pediatric PK / PD model with parameter estimated values shown in Table 7, steady-state AT activity was simulated for different dosing scenarios in a virtual population of pediatric patients. The distribution of AT activity for multiple dosing regimens for both pediatric cohorts is shown in Figure 6. The modeled dosing regimens were 1.25, 2.5, 5, 10, 20, or 30 mg Q4W for Cohort 1 and Cohort 2. 【0177】 Based on the simulated dosing regimens shown in Figure 6, for Cohort 1 receiving 10 mg QM ficlatuzumab: a) Approximately 64% of the patients were predicted to have AT activity levels within the range of 15% ≤ AT ≤ 35%; b) Approximately 26% of the patients were predicted to have AT activity values < 15%, so these patients require a lower ficlatuzumab dose to maintain AT activity within the range of 15% ≤ AT ≤ 35%; a tapered dose of 2.5 mg QM for these patients helped 95% of the tapered patients achieve AT activity within the range of 15% ≤ AT ≤ 35% (Figure 7A); and c) Approximately 10% of the patients were predicted to have AT activity values > 35%, so these patients require a higher dose to maintain AT activity within the range of 15% ≤ AT ≤ 35%; a dose escalation to 20 mg QM was supported by pediatric PK / PD model simulations and, if required, further escalation to 30 mg QM was maintained (Figure 7B). 【0178】 Based on the simulated dosing regimens shown in Figure 6, for Cohort 2 receiving 5 mg QM ficlatuzumab: a) Approximately 60% of the patients were predicted to have AT activity values within the range of 15% ≤ AT ≤ 35%; b) Approximately 21% of the patients were predicted to have an AT activity value < 15%, so these patients required lower doses to maintain AT activity within the range of 15% ≤ AT ≤ 35%; the tapered dose of 1.25 mg QM for these patients then helped 94% of the tapered patients achieve AT activity within the range of 15% ≤ AT ≤ 35% (Figure 8A); and c) Approximately 19% of the patients were predicted to have an AT activity value > 35%, so these patients required higher doses to maintain AT activity within the range of 15% ≤ AT ≤ 35%; pediatric PK / PD model simulations supported (for approximately 76% of the patients in this subpopulation) a dose escalation to 10 mg QM and, if needed, maintained a further escalation to 20 mg QM (for approximately 24% of the patients in this subpopulation) (Figure 8B).

Claims

[Claim 1] A pharmaceutical composition comprising fitsilane for use in a method of prophylactic treatment for hemophilia A or B in pediatric patients with or without inhibitors, The aforementioned method, (a) Subcutaneous administration of a starting dose of fitsiran at a selected dosage frequency to the patient requiring prophylactic treatment for hemophilia A or B; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; (c) The following steps: (i) If the AT activity level is 15-35%, repeat step (a). (ii) If the AT activity level is >35%, administer a higher dose of fitsiran to the patient at the selected dosing frequency, or administer the initial dose of fitsiran at a higher dosing frequency, or (iii) If the AT activity level is <15%, administer a lower dose of fitsiran to the patient at the selected dosing frequency, or the initial dose at a lower dosing frequency. To perform one of the following actions, A pharmaceutical composition containing the following: [Claim 2] A pharmaceutical composition comprising fitiran for use in a method of reducing the risk of thrombosis in pediatric patients receiving fitiran for prophylactic treatment of hemophilia A or B with or without inhibitors, The aforementioned method, (a) Subcutaneous administration of a starting dose of fitsiran at a selected dosage frequency to the patient requiring a reduction in the risk of thrombosis; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; (c) The following steps: (i) If the AT activity level is 15-35%, repeat step (a). (ii) If the AT activity level is >35%, administer a higher dose of fitsiran to the patient at the selected dosing frequency, or administer the initial dose of fitsiran at a higher dosing frequency, or (iii) If the AT activity level is <15%, administer a lower dose of fitsiran to the patient at the selected dosing frequency, or the initial dose at a lower dosing frequency. To perform one of the following actions, A pharmaceutical composition containing the following: [Claim 3] A pharmaceutical composition comprising fitsilane for use in a method to reduce the frequency of bleeding episodes in pediatric patients with hemophilia A or B, with or without inhibitors, The aforementioned method, (a) Subcutaneous administration of a starting dose of fitsiran at a selected dosage frequency to the patient requiring a reduction in the frequency of bleeding episodes; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; (c) The following steps: (i) If the AT activity level is 15-35%, repeat step (a). (ii) If the active AT level is >35%, administer a higher dose of fitsiran to the patient at the selected dosing frequency, or administer the initial dose of fitsiran at a higher dosing frequency, or (iii) If the AT activity level is <15%, administer a lower dose of fitsiran to the patient at the selected dosing frequency, or the initial dose at a lower dosing frequency. To perform one of the following actions, A pharmaceutical composition containing the following: [Claim 4] A pharmaceutical composition comprising fitsilane for use in a method of reducing the annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR), and / or annual joint bleeding rate (AjBR) in pediatric patients with hemophilia A or B with or without inhibitors, The aforementioned method, (a) Subcutaneous administration of a starting dose of fitsiran at a selected dosage frequency to the patient requiring reduction of ABR, AsBR, and / or AjBR; (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; (c) The following steps: (i) If the AT activity level is 15-35%, repeat step (a). (ii) If the AT activity level is >35%, administer a higher dose of fitsiran to the patient at the selected dosing frequency, or administer the initial dose of fitsiran at a higher dosing frequency, or (iii) If the AT activity level is <15%, administer a lower dose of fitsiran to the patient at the selected dosing frequency, or the initial dose at a lower dosing frequency. To perform one of the following actions, A pharmaceutical composition containing the following: [Claim 5] Step (c)(iii) is performed after a temporary suspension of fitsilan administration and after the patient's AT activity level has returned to ≥15% or ≥22%, the pharmaceutical composition according to any one of claims 1 to 4. [Claim 6] The pharmaceutical composition according to any one of claims 1 to 4, wherein the initial dose, the higher dose, and the lower dose are all in the range of 1 mg to 50 mg, and 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. [Claim 7] The pharmaceutical composition according to claim 6, wherein one of the above-mentioned starting dose, higher dose, and lower dose is 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, or 50 mg. [Claim 8] The selected medication frequency is every two months or every eight weeks, and a higher medication frequency is every month or every four weeks, or The pharmaceutical composition according to any one of claims 1 to 4, wherein the selected drug administration frequency is monthly or every four weeks, and a lower drug administration frequency is every two months or every eight weeks. [Claim 9] The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient's weight is between 22 kg and <45 kg. [Claim 10] The pharmaceutical composition according to claim 9, wherein the initial dose of physylane is 10 mg. [Claim 11] The pharmaceutical composition according to claim 9, wherein the selected drug administration frequency is monthly (QM) or every four weeks (Q4W). [Claim 12] The initial dose is 10 mg, and the selected dosing frequency is QM or Q4W. Step (c)(ii) is performed if there are two or more measurements of the steady-state AT activity level, and optionally two of these measurements are >35%, or Step (c)(iii) is performed if two or more AT activity levels are optionally equal to <15%, the pharmaceutical composition according to claim 11. [Claim 13] The pharmaceutical composition according to claim 12, wherein step (c)(ii) comprises subcutaneously administering 20 mg QM of fitsilan to the patient. [Claim 14] The pharmaceutical composition according to claim 12, further comprising subcutaneously administering 30 mg QM of fitsilan to the patient after step (c)(ii) if, optionally, according to two measured values, the steady-state AT activity level in the patient after step (c)(ii) is >35%. [Claim 15] After step (c)(iii): (A) Optionally, administer 2.5 mg QM of fitisran subcutaneously to the patient after temporary suspension of fitisran administration and after the patient's AT activity level has returned to ≥22%; (B) The AT activity level of the patient after step (A) is If, according to two or more optional measurements, the result is <15%, discontinue or temporarily suspend the phytosis treatment. If the percentage is between 15% and 35%, repeat process (A), or Selectively, if two or more steady-state measurements indicate a value >35%, administer 5 mg QM of fitsiran subcutaneously to the patient. A pharmaceutical composition according to claim 12, comprising: [Claim 16] The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient's weight is between 8 kg and <22 kg. [Claim 17] The pharmaceutical composition according to claim 16, wherein the initial dose of physylane is 5 mg. [Claim 18] The pharmaceutical composition according to claim 16, wherein the selected drug administration frequency is monthly (QM) or every four weeks (Q4W). [Claim 19] The initial dose is 10 mg, and the selected dosing frequency is QM or Q4W. Step (c)(ii) is performed if two or more measurements of the AT activity level in a steady state are taken, and any two of these measurements are >35%, or Step (c)(iii) is performed if two or more measurements of the AT activity level are taken, and optionally two of the measurements are <15%. The pharmaceutical composition according to claim 18. [Claim 20] The pharmaceutical composition according to claim 19, wherein step (c)(ii) comprises subcutaneously administering 10 mg QM of fitsilan to the patient. [Claim 21] The pharmaceutical composition according to claim 20, wherein, after step (c)(ii), if the steady-state AT activity level in the patient after step (c)(ii) is >35% according to two optionally measured values, 20 mg QM of fitsilan is administered subcutaneously to the patient. [Claim 22] After step (c)(iii): (A) After selectively suspending the administration of fitsiran and after the patient's AT activity level has returned to ≥22%, administer fitsiran subcutaneously to the patient at a dose of 1.25 mg QM; (B) The AT activity level of the patient after step (A) If, according to two or more optional measurements, the result is <15%, discontinue or temporarily suspend the phytosis treatment. If the percentage is between 15% and 35%, repeat process (A), or Selectively, if two or more steady-state measurements indicate a value >35%, administer 2.5 mg QM of fitsiran subcutaneously to the patient. The pharmaceutical composition according to claim 19, comprising: [Claim 23] The method further comprises subcutaneously administering fitsiran to the patient in a dose and frequency sufficient to maintain the AT activity level in the patient at 15-35%, optionally: 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 A pharmaceutical composition according to any one of claims 1 to 4, comprising subcutaneous administration of phytosisran. [Claim 24] The pharmaceutical composition according to any one of claims 1 to 4, wherein each AT activity level measurement can be obtained after the patient has received at least two doses of fitsilane at a given dose. [Claim 25] (d) If, after step (c), the patient's AT activity level is 15-35%, and the dose in step (c) is at least two doses of fitsiran, and there are two or more procedural bleeding events within 12 weeks starting from the third fitsiran injection at the dose in step (c), then administer a higher dose of fitsiran to the patient subcutaneously. A pharmaceutical composition according to any one of claims 1 to 4, further comprising: [Claim 26] The dosage amounts for step (c) and step (d) are, respectively, 1.25 mg and 2.5 mg, 2.5 mg and 5 mg, 5 mg and 10 mg, 10 mg and 20 mg, or 20 mg and 30 mg The pharmaceutical composition according to claim 25. [Claim 27] The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient continues a prior non-fitsiran prophylaxis for only one week after the first dose of fitsiran, and optionally, the prior non-fitsiran prophylaxis is a replacement factor treatment or a bypass agent treatment. [Claim 28] A pharmaceutical composition comprising fitsilane for use in a method for prophylactically treating hemophilia A or B in pediatric patients with or without inhibitors, or for reducing the frequency of bleeding episodes in said patients, The method described above applies to the patient who requires the above treatment or reduction. (a) 1.25 mg of phytosisran every month (QM) or every four weeks (Q4M) (b) 5 mg QM or Q4 M, (c) 5 mg QM or Q4 M, (d) 7.5 mg QM or Q4M, (e) 10 mg QM or Q4 M, (f) 20 mg QM or Q4M, (g) 50 mg QM or Q4M A pharmaceutical composition comprising subcutaneous administration. [Claim 29] The pharmaceutical composition according to claim 28, wherein the annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR), and / or annual joint bleeding rate (AjBR) in patients are reduced. [Claim 30] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, wherein the age of the patient is between 1 year and less than 12 years. [Claim 31] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, wherein the AT activity level in the patient is measured every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every twelve months. [Claim 32] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, wherein, after administration of the initial dose of fitsilan, or after administration of a modified dose compared to the previous dose, measurements of the patient's AT activity level can be obtained at 4 weeks or 1 month, 12 weeks or 3 months, 20 weeks or 5 months, and 24 weeks or 6 months. [Claim 33] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, further comprising monitoring the patient's AT activity level every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or every eight weeks, or every month, every two months, every three months, every four months, every five months, or every six months after subcutaneous administration of fitsilan. [Claim 34] The pharmaceutical composition according to any one of claims 1 to 4, wherein obtaining a measurement of the patient's antithrombin (AT) activity level includes the use of a kinetic assay or a colorimetric assay. [Claim 35] Obtaining measurements of a patient's antithrombin (AT) activity levels is important for detecting excessive AT activity. A pharmaceutical composition according to any one of claims 1 to 4, comprising the use of a colorimetric assay to quantify functionally active AT in human citrate-treated plasma based on inhibition of factor Xa. [Claim 36] The pharmaceutical composition according to claim 35, wherein obtaining a measurement of antithrombin (AT) activity level in a patient involves using the INNOVANCE® antithrombin assay. [Claim 37] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, further comprising administering an effective amount of a bypass agent (BPA) to treat a bleeding episode, wherein the effective amount of BPA is reduced compared to a recommended effective amount of BPA. [Claim 38] The pharmaceutical composition according to claim 37, wherein the bypass agent is an activated prothrombin complex concentrate (aPCC), the single dose of aPCC is 50 U / kg or less, optionally 30 U / kg, and optionally, the administration of aPCC is repeated over a period of 24 hours or more as needed. [Claim 39] The pharmaceutical composition according to claim 37, wherein the bypass agent is recombinant factor VIIa (rFVIIa), the single dose of rFVIIa is 45 μg / kg or less, and the administration of rFVIIa is optionally repeated within 2 hours or less as needed. [Claim 40] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, wherein the patient has inhibitor-free hemophilia A or B, and the composition comprises 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. [Claim 41] The pharmaceutical composition according to claim 40, wherein the supplementation factor is factor VIII, the single dose of the supplementation factor is 20 IU / kg or less, optionally 10 IU / kg, and optionally, the administration of factor VIII is repeated as needed over a period of 24 hours or more. [Claim 42] The pharmaceutical composition according to claim 40, wherein the supplementation factor is factor IX, the single dose of the supplementation factor is 30 IU / kg, optionally 20 IU / kg, and optionally, the administration of factor IX is repeated as needed for a period of 24 hours or more for a standard half-life FIX, or for 5 to 7 days or more for an extended half-life FIX. [Claim 43] The pharmaceutical composition according to any one of claims 1 to 4 and 28 to 29, wherein phytosislan is provided in phosphate-buffered saline (PBS) at a concentration of 1 to 200 mg / mL, optionally 6.25 mg / mL, 12.5 mg / mL, or 100 mg / mL. [Claim 44] Phytsia japonica is as follows: Table 1 The pharmaceutical composition according to claim 43, provided by formulation 1 or formulation 2 shown. [Claim 45] 12.5 mg / mL of physirane, 0.388 mg / mL NaH 2 PO 4 *H 2 O, 0.586 mg / mL Na 2 HPO 4 *7H 2 O, and 8.7 mg / mL NaCl An aqueous phytosislane composition containing [the specified ingredient], with a pH of approximately 7.0 to 7.

1. [Claim 46] A product comprising the composition described in claim 45. [Claim 47] A product used in the method according to any one of claims 1 to 4 and 28 to 29, which is optionally a kit. [Claim 48] The product according to claim 46 or 47, wherein the product is a container, optionally a vial, containing one or more doses of fitsilane, each dose being 30 mg, 20 mg, 10 mg, 5 mg, 2.5 mg, or 1.25 mg. [Claim 49] The product according to claim 48, wherein the container is a vial containing 2.5 mg of phytsilane. [Claim 50] A method for monitoring the treatment of a pediatric patient administered with fitsilan, comprising measuring the level of antithrombin (AT) activity in the patient, wherein the level of AT activity is measured by a colorimetric method that quantifies functionally active AT in human citrate plasma based on excessive inhibition of factor Xa by AT. [Claim 51] The method according to claim 50, wherein the level of AT activity is measured using the INNOVANCE® antithrombin assay. [Claim 52] A pharmaceutical composition comprising fitsilane for use in the prophylactic treatment of hemophilia A or B in pediatric patients with or without inhibitors, The above method is as follows: （１） (a) The patient is given 10 mg of phytosislan per month (QM) or every four weeks (Q4W) via the skin. Administer as follows: (b) Obtaining a measurement of the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 10 mg of fitsilan subcutaneously as QM or Q4W. (ii) If the patient's AT activity level is >35%, administer 20 mg of fitsilan subcutaneously to the patient in QM or Q4W form, (iii) If the patient's AT activity level is <15%, administer 5 mg of fitsilan subcutaneously to the patient as QM or Q4W. Perform one of the following: （２） (a) The patient shall be given 20 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 20 mg of fitsilan subcutaneously as QM or Q4W. (ii) If the patient's AT activity level is >35%, administer 50 mg of fitsilan subcutaneously as QM or Q4W. Performing one of the following, （３） (a) The patient shall be given 5 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 5 mg of fitsilan subcutaneously to the patient once a month (QM) or every four weeks (Q4W). (ii) If the patient's AT activity level is >35%, administer 7.5 mg of fitsilan subcutaneously as QM or Q4W, or (iii) If the patient's AT activity level is <15%, administer 1.25 mg of fitsilan subcutaneously to the patient in QM or Q4W. Performing one of the following; or （４） (a) The patient shall be given 1.25 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 1.25 mg of fitsilan subcutaneously to the patient every other month (QM) or every four weeks (Q4W). (ii) If the patient's AT activity level is >35%, administer 2.5 mg of fitsilan to the patient subcutaneously as QM or Q4W, or (iii) If the AT activity level of the patient is less than 15%, discontinue administration of fitsilan. Perform one of the following actions A pharmaceutical composition containing the following: [Claim 53] (a) Reduce the risk of thrombosis, (b) Reduce the frequency of bleeding episodes, and / or (c) Reduce the annual bleeding rate (ABR), annual spontaneous bleeding rate (AsBR), and / or annual joint bleeding rate (AjBR) in pediatric patients with hemophilia A or B, with or without inhibitors. A pharmaceutical composition comprising physylane for use in a method, The above method is as follows: （１） (a) Subcutaneously administer 10 mg of fitsilan to the patient every month (QM) or every four weeks (Q4W); (b) to obtain a measurement of the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 10 mg of fitsilan subcutaneously as QM or Q4W. (ii) If the patient's AT activity level is >35%, administer 20 mg of fitsilan subcutaneously to the patient in QM or Q4W form, (iii) If the patient's AT activity level is <15%, administer 5 mg of fitsilan subcutaneously to the patient as QM or Q4W. Perform one of the following: （２） (a) The patient shall be given 20 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 20 mg of fitsilan subcutaneously as QM or Q4W. (ii) If the patient's AT activity level is >35%, administer 50 mg of fitsilan subcutaneously as QM or Q4W. Performing one of the following, （３） (a) The patient shall be given 5 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 5 mg of fitsilan subcutaneously to the patient once a month (QM) or every four weeks (Q4W). (ii) If the patient's AT activity level is >35%, administer 7.5 mg of fitsilan subcutaneously as QM or Q4W, or (iii) If the patient's AT activity level is <15%, administer 1.25 mg of fitsilan subcutaneously to the patient in QM or Q4W. Performing one of the following; or （４） (a) The patient shall be given 1.25 mg of fitsilan subcutaneously every month (QM) or every four weeks (Q4W); (b) Measuring the antithrombin (AT) activity level in the patient; and (c) The following steps: (i) If the patient's AT activity level is 15-35%, administer 1.25 mg of fitsilan subcutaneously to the patient every other month (QM) or every four weeks (Q4W). (ii) If the patient's AT activity level is >35%, administer 2.5 mg of fitsilan to the patient subcutaneously as QM or Q4W, or (iii) If the AT activity level of the patient is less than 15%, discontinue administration of fitsilan. Perform one of the following actions A pharmaceutical composition containing the following:

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