Treatment of hemophilia with fitusiran in pediatric patients

Abstract

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

Description

Attorney Reference: 15979-20207.40TREATMENT OF HEMOPHILIA WITH FITUSIRAN IN PEDIATRIC PATIENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 879,538, filed September 10, 2025, U.S. Provisional Application No. 63 / 861,854, filed August 11, 2025, and U.S. Provisional Application No. 63 / 733,966, filed December 13, 2024, the contents of each of which are incorporated herein by reference in their entireties.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (159792020740seqlist.xml; Size: 7,992 bytes; and Date of Creation: November 6, 2025) is herein incorporated by reference in its entirety.FIELD

[0003] The present disclosure relates generally to compositions and methods for treatment of hemophilia, and more specifically to compositions and methods for treatment of hemophilia A or B in pediatric patients.BACKGROUND

[0004] Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders, characterized by deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), leading to a profound defect of thrombin generation with impaired hemostasis and increased risk of bleeding. The development of inhibitors is a major complication in children treated with factor replacement (Peyvandi et al., Haemophilia. (2017) 23(Suppl 1):4- 13). Approximately 30% of children with hemophilia A and 2% to 5% of children with hemophilia B develop inhibitory antibodies to FVIII and FIX, respectively (Gouw et al., V Engl J Med. (2013) 368(3):231-9. ; Puetz et al., Haemophilia. (2014) 20(l):25-31).

[0005] For pediatric patients with hemophilia, the treatment of both inhibitor and noninhibitor populations is further complicated by challenges of venous access and caregiver burden (Santagostino et al., Blood Transfus. (2008) 6(Suppl 2):s 12-6). For noninhibitor pediatric patients, more frequent infusions may be required due to a shorter half-life of factor replacement therapies than in adults (Bjdrkman et al., Blood. (2012) 119(2):612-8.). In the1MF-364681141Attorney Reference: 15979-20207.40 case of inhibitor patients, prophylactic BPA therapy or ITI regimens may require daily or every other day infusions (Ewing et al., Haemophilia. (2015) 21(3):358-64).

[0006] Thus, there remains a need for alternative treatments for pediatric patients having hemophilia A or B.BRIEF SUMMARY

[0007] The present disclosure provides methods of prophylactically treating hemophilia A or B with or without inhibitors with fitusiran to prevent or reduce the frequency of bleeding episodes in pediatric patients, and provides fitusiran for use in these methods.

[0008] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15- 35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0009] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0010] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the2MF-364681141Attorney Reference: 15979-20207.40AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0011] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0012] In some embodiments of any of the above aspects, step (c)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (c)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments, the more than one measurements in step (c)(iii) are within 12 months. In some embodiments of any of the above aspects, the method comprises, after step (c)(ii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (c)(iii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps: (I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient3MF-364681141Attorney Reference: 15979-20207.40 fitusiran at a dose of 1.25 mg every month or every four weeks, (II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or (III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (c)(iii)(I), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps: (A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment, (B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or (C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (c)(iii)(III), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps: (A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, (B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or (C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks. In some embodiments of any of the above aspects, if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement. In some embodiments of any of the above aspects, the method further comprises subcutaneously administering fitusiran to the patient at their latest dose amount and dosing frequency so long as the patient maintains an AT level at 15-35%. In some embodiments of any of the above aspects, each AT level measurement is obtained after the patient has received at least two doses of fitusiran at a given dose amount. In some embodiments of any of the above aspects, the method further comprises after step (c): (d) if4MF-364681141Attorney Reference: 15979-20207.40 the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (c) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (c) dose amount, subcutaneously administering to the patient a higher dose amount of fitusiran than the step (c) dose amount. In some embodiments of any of the above aspects, step (c)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0013] In some embodiments of any of the above aspects, the method further comprises obtaining a measurement of the AT level in the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months. In some embodiments of any of the above aspects, the method further comprises obtaining a measurement of the AT level in the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.

[0014] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

[0015] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg5MF-364681141Attorney Reference: 15979-20207.40 every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

[0016] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

[0017] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

[0018] In some embodiments of any of the above aspects, step (b)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (b)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments, the more than one measurements in step (b)(iii) are within6MF-364681141Attorney Reference: 15979-20207.4012 months. In some embodiments of any of the above aspects, the method comprises, after step (b)(ii), if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (b)(iii), performing one of the following steps: (I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, (II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or (III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (b)(iii)(I), performing one of the following steps: (A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment, (B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or (C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks. In some embodiments of any of the above aspects, the method comprises, after step (b)(iii)(III), performing one of the following steps: (A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, (B) if the AT level is 15- 35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or (C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks. In some embodiments of any of the above aspects, if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement. In some embodiments of any of the above aspects, the method further comprises subcutaneously administering fitusiran to the patient at their latest dose amount7MF-364681141Attorney Reference: 15979-20207.40 and dosing frequency so long as the patient maintains an AT level at 15-35%. In some embodiments of any of the above aspects, each AT level measurement is obtained after the patient has received at least two doses of fitusiran at a given dose amount. In some embodiments of any of the above aspects, the method further comprises after step (b): (c) if the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (b) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (b) dose amount, subcutaneously administering to the patient a higher dose amount of fitusiran than the step (b) dose amount. In some embodiments of any of the above aspects, step (b)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0019] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0020] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0021] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of <15%, the patient having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0022] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0023] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method8MF-364681141Attorney Reference: 15979-20207.40 comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0024] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0025] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0026] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0027] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0028] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0029] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising:9MF-364681141Attorney Reference: 15979-20207.40 subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0030] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0031] In some embodiments of any of the above aspects, fitusiran administration is first paused, optionally until an AT level in the patient is >15%, optionally >22%, before subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of any of the above aspects, a measurement of the AT level in the patient has been obtained every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months. In some embodiments of any of the above aspects, a measurement of the AT level has been obtained at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.

[0032] In some embodiments of any of the above aspects, the body weight of the patient is 8 kg or greater. In some embodiments of any of the above aspects, the body weight of the patient is less than 45 kg. In some embodiments of any of the above aspects, the body weight of the patient is less than 22 kg. In some embodiments of any of the above aspects, the body weight of the patient is between about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg. In some embodiments of any of the above aspects, the AT levels are at steady state. In some embodiments of any of the above aspects, the patient is 1 year of age or older. In some embodiments of any of the above aspects, the patient is less than 12 years of age. In some embodiments of any of the above aspects, the patient is between 1 year of age and 12 years of age. In some embodiments of any of the above aspects, the patient continues a previous non-fitusiran prophylactic treatment for one week after the first dose of fitusiran, optionally wherein the previous non-fitusiran prophylactic treatment is a clotting factor concentrate treatment, a replacement factor treatment, or a bypassing agent treatment.10MF-364681141Attorney Reference: 15979-20207.40

[0033] In some embodiments of any of the above aspects, the patient has hemophilia A or B with inhibitors. In some embodiments of any of the above aspects, the method further comprises treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a bypassing agent (BPA), wherein the effective amount of the BPA is reduced as compared to the recommended effective amount of the BPA. In some embodiments of any of the above aspects, the patient has an AT level of <60%, optionally wherein the patient has an AT level of <60% before administration of fitusiran. In some embodiments of any of the above aspects, the bypassing agent is activated prothrombin complex concentrate (aPCC) and a single dose of aPCC is no more than 50 U / kg and is optionally 30 U / kg, optionally wherein the aPCC administration is repeated, if needed, in no less than 24 hours. In some embodiments of any of the above aspects, the bypassing agent is recombinant factor Vila (rFVIIa) and a single dose of rFVIIa is no more than 45 pg / kg, optionally wherein the rFVIIa administration is repeated, if needed, in no less than two hours. In some embodiments of any of the above aspects, the bypassing agent is efanesoctocog alfa and a single dose of efanesoctocog alfa is no more than 45 pg / kg, optionally wherein the efanesoctocog alfa administration is repeated, if needed, in no less than 72 hours. In some embodiments of any of the above aspects, the patient has hemophilia A or B without inhibitors. In some embodiments of any of the above aspects, the method further comprises treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a replacement factor, wherein the effective amount of the replacement factor is reduced as compared to the recommended effective amount of the replacement factor. In some embodiments of any of the above aspects, the replacement factor is Factor VIII and a single dose of the replacement factor is no more than 20 lU / kg and optionally is 10 lU / kg, optionally wherein the Factor VIII administration is repeated, if needed, in no less than 24 hours. In some embodiments of any of the above aspects, the replacement factor is Sevenfact, and wherein the reduction compared to the recommended effective amount of Sevenfact is half the standard dose with standard treatment frequency. In some embodiments of any of the above aspects, the replacement factor is Factor IX and a single dose of the replacement factor is 30 lU / kg and optionally is 20 lU / kg, optionally wherein the Factor IX administration is repeated, if need, in no less than 24 hours for standard half-life Factor IX or in no less than 5-7 days for extended half-life Factor IX.11MF-364681141Attorney Reference: 15979-20207.40

[0034] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 1.25 mg of fitusiran every month or every four weeks.

[0035] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 2.5 mg of fitusiran every month or every four weeks.

[0036] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 5 mg of fitusiran every month or every four weeks.

[0037] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 7.5 mg of fitusiran every month or every four weeks.

[0038] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 10 mg of fitusiran every month or every four weeks.

[0039] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 20 mg of fitusiran every month or every four weeks.

[0040] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising12MF-364681141Attorney Reference: 15979-20207.40 subcutaneously administering to the patient in need thereof 30 mg of fitusiran every month or every four weeks.

[0041] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 50 mg of fitusiran every month or every four weeks.

[0042] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 20 mg of fitusiran every month or every four weeks, wherein the body weight of the patient is 8 kg to < 22 kg.

[0043] In some embodiments of any of the above aspects, the method further comprises monitoring the AT level of the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every twelve months. In some embodiments of any of the above aspects, the patient is aged 1 year to <12 years old. In some embodiments of any of the above aspects, the patient has a body weight of less than 45 kg. In some embodiments of any of the above aspects, the patient has a body weight of about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg.

[0044] In some embodiments of any of the above aspects, the method further comprises after subcutaneous administration of fitusiran, monitoring the AT levels of the patient periodically, optionally every one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks, or every one month, two months, three months, four months, five months, or six months. In some embodiments of any of the above aspects, obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a kinetic or chromogenic assay. In some embodiments of any of the above aspects, obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of an excess of factor Xa by AT. In some embodiments of any of the above aspects, obtaining a measurement of an antithrombin (AT) level in the patient comprises use of an INNOVANCE™ Antithrombin assay.

[0045] In one aspect, the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: (a)13MF-364681141Attorney Reference: 15979-20207.40 subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In one aspect, the present disclosure provides a method of prophylactic treatment of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

[0046] In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In one aspect, the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

[0047] In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In one aspect, the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

[0048] In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In one aspect, the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate14MF-364681141Attorney Reference: 15979-20207.40(AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

[0049] In some embodiments of any of the above aspects, the method further comprises (c) adjusting the dose amount or dose frequency of fitusiran being subcutaneously administered to the patient in order to maintain an AT level of 15-35%. In some embodiments of any of the above aspects, liver function test results are obtained within 7 days prior to each dose of fitusiran, optionally wherein the liver function test results are reviewed prior to each dose of fitusiran. In some embodiments of any of the above aspects, fitusiran is provided in a phosphate-buffered saline (PBS) at 1-200 mg / mL, optionally 6.25 mg / mL, 12.5 mg / mL or 100 mg / mL. In some embodiments of any of the above aspects, fitusiran is provided in formulation 1 or formulation 2 shown below.frequency of bleeding episodes in the patients, e.g., reducing their annual bleed rates (ABR), annual spontaneous bleeding rates (AsBR), and / or annual joint bleeding rates (AjBR). The method may also reduce thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors.

[0051] In another aspect, the present disclosure provides a series of methods of treating hemophilia A or B in a pediatric patient with or without inhibitors using a pre-determined amount of fitusiran (e.g., 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, or 50 mg) at a pre-determined frequency (e.g., every two months, every eight weeks, every month, or every four weeks).15MF-364681141Attorney Reference: 15979-20207.40

[0052] In another aspect, the present disclosure provides fitusiran formulations suitable for the methods herein. In some embodiments, the fitusiran formulation is an aqueous fitusiran composition comprising: about 12.5 mg / mL fitusiran, about 0.388 mg / mL Naf PO^ffcO, about 0.586 mg / mL Na2HPO4*7H2O, and about 8.7 mg / mL NaCl, with a pH of about 7.0-7.1.

[0053] In another aspect, the present disclosure provides fitusiran for use in a method of any one of the above embodiments.

[0054] In another aspect, the present disclosure provides use of fitusiran for the manufacture of a medicament to treat hemophilia A or B with or without inhibitors in the method of any one of the above embodiments.

[0055] In another aspect, the present disclosure provides a pharmaceutical composition comprising fitusiran for use in a method of any one of the above embodiments.

[0056] In another aspect, the present disclosure provides an article of manufacture for use in a method of any one of the above embodiments, optionally wherein the article of manufacture is a kit. In some embodiments, the article of manufacture is a container, optionally a vial, containing one or more doses of fitusiran, each dose being 30 mg, 20 mg, 10 mg, 5 mg, 2.5 mg, or 1.25 mg. In some embodiments, the container is a vial containing 2.5 mg of fitusiran.

[0057] Also provided herein are fitusiran and articles of manufacture for use in the present treatment methods, use of fitusiran for the manufacture of a medicament for treating hemophilia A or B in a pediatric patient with or without inhibitors in the present methods, and a pharmaceutical composition comprising fitusiran for use in the present treatment methods.

[0058] Other features, objectives, and advantages of the invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating embodiments and aspects of the invention, is given by way of illustration only, not limitation. Various changes and modification within the scope of the invention will become apparent to those skilled in the art from the detailed description.DESCRIPTION OF THE FIGURES

[0059] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0060] FIGS. 1A-1B show the expanded structural formula, chemical formula, and molecular mass of fitusiran (sodium form). FIG. 1A shows the expanded structural formula and chemical16MF-364681141Attorney Reference: 15979-20207.40 formula of fitusiran, and discloses the sense strand (A-l 16858, SEQ ID NO: 1) and the antisense strand (A-l 16861, SEQ ID NO: 2). FIG. IB shows the molecular mass of fitusiran (sodium form).

[0061] FIG. 2 shows the overview of the study design described in Example 1 for fitusiran treatment in pediatric patients with or without inhibitory antibodies to Factors VIII or IX. Subjects from two arms are treated in this study: 1) a roll-over arm of patients from a prior fitusiran study (top) and 2) a fitusiran-naive arm (bottom). Patients in the fitusiran-naive arm undergo screening and a standard of care period prior to fitusiran treatment period (160 weeks), and subjects in the roll-over arm continue fitusiran treatment (60 weeks). Both arms have an antithrombin (AT) follow up period in which AT activity levels are monitored monthly until AT levels are measured at approximately 60%, or per Investigator discretion in consultation with the study Medical Manager.

[0062] FIG. 3 shows a flow chart depicting the fitusiran escalation / de-escalation scheme for patients, as described in Example 1. All subjects initiate / resume fitusiran with a once monthly (QM) 10 mg dose. Dosing escalation or de-scalation is determined based on antithrombin (AT) levels. AT = antithrombin; QM = once monthly. *: At steady state; **: Start of dosing after de-escalation from higher dose to occur only after centrally measured AT activity levels >22%. Note: Dose escalation based on clinical criteria may also be considered.DETAILED DESCRIPTION

[0063] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0064] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Generally, nomenclature used in connection with, and techniques of hematology, medicine, medicinal and pharmaceutical chemistry, and cell biology described herein are those well-known and commonly used in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.17MF-364681141Attorney Reference: 15979-20207.40

[0065] Throughout this specification and aspects, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated element or group of elements but not the exclusion of any other element or group of elements.

[0066] All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0067] As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain aspects, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

[0068] Further, headers herein are created for ease of organization and are not intended to limit the scope of the claimed invention in any manner.

[0069] Fitusiran is an N-acetylgalactosamine (GalNAc) small interfering ribonucleic acid (siRNA) conjugate that reduces production of antithrombin (AT), leading to lower plasma AT activity levels. By reducing plasma AT, fitusiran is designed to improve thrombin generation and hemostasis in individuals with hemophilia, regardless of hemophilia type or presence of inhibitory antibodies to coagulation factor VIII (FVIII) or factor IX (FIX). Fitusiran is being developed for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, including patients with inhibitory antibodies to FVIII or FIX.

[0070] A subcutaneous (SC) therapy that can effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, including those with inhibitors, may reduce treatment burden, improve clinical outcomes, and enhance quality of life, especially for the pediatric patient population.

[0071] The present disclosure provides a method that aims to maintain a favorable benefitrisk balance for pediatric patients with hemophilia A or B with or without inhibitors who are treated with fitusiran. Fitusiran is intended for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in pediatric patients (e.g., 1 to < 12 year(s) old), with hemophilia A or hemophilia B, including patients with inhibitory antibodies (inhibitors) or without inhibitory antibodies. Some aspects of the present treatment methods carefully calibrate the therapy based on the patient’s antithrombin (AT) levels so as to minimize the18MF-364681141Attorney Reference: 15979-20207.40 risk of vascular thrombotic events that may result from low AT levels (e.g., AT levels < 10%).

[0072] As used herein, a pediatric patient refers to a human pediatric patient.

[0073] As used herein, “hemophilia A or B with or without inhibitors” refers to hemophilia A with or without inhibitors, or hemophilia B with or without inhibitors.

[0074] As used herein, “a hemophilia A or B patient with inhibitors” refers to a patient who has developed alloantibodies to the factor they have previously received (z.e., factor VIII for hemophilia A patients or factor IX for hemophilia B patients). A hemophilia A or B patient with inhibitors may become refractory to replacement coagulation factor therapies. As used herein, “a hemophilia A or B patient without inhibitors” refers to a patient who does not have alloantibodies to FVIII or factor FIX. The present treatment methods may be beneficial for hemophilia A patients with or without inhibitors, as well as for hemophilia B patients with or without inhibitors.

[0075] As used herein, AT levels at steady state (SS) refers to AT levels that have stabilized (<10% variability among consecutive measures) after a change in the treatment dose amount or treatment dose frequency administered to the patient. SS is typically reached after two or three doses of fitusiran.I. Fitusiran Pharmaceutical Compositions

[0076] Hemophilia results in a profound defect in thrombin generation, and hemophilia severity is correlated with the inability to generate thrombin. Without being bound by theory, it is believed that fitusiran-mediated lowering of antithrombin (AT) levels will increase thrombin generation and thus improve hemostasis in patients with hemophilia. Antithrombin is encoded by the SERPINC1 (serine (or cysteine) peptidase inhibitor, clade C, member 1) gene.

[0077] Fitusiran, whose structure is provided herein, is a synthetic, chemically modified double-stranded small interfering RNA (siRNA) oligonucleotide covalently linked to a tri- antennary N-acetyl-galactosamine (GalNAc) ligand targeting the AT3 mRNA in the liver, thereby suppressing the synthesis of antithrombin. The nucleosides in each strand of fitusiran are connected through either 3’-5’ phosphodiester or phosphorothioate linkages, thus forming the sugar-phosphate backbone of the oligonucleotide. The sense strand and the antisense strand of fitusiran contain 21 and 23 nucleotides, respectively. The 3’ end of the sense strand is conjugated to the GalNAc containing moiety (referred to as L96) through a phosphodiester linkage. The sense strand contains two consecutive phosphorothioate linkages at its 5’ end.19MF-364681141Attorney Reference: 15979-20207.40The antisense strand contains four phosphorothioate linkages, two at the 3’ end and two at the 5’ end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs and a two-base overhang at the 3’-end of the antisense strand. See also U.S. Pat. 9,127,274, U.S. Pat. 11 ,091 ,759, and WO 2019 / 014187.

[0078] 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), whereinAf = 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-methyladenosineCm = 2’-O-methylcytidineGm = 2’-O-methylguanosineUm = 2’-O-methyluridine(hyphen) = 3 ’-5’ phosphodiester linkage sodium salt“-ps-” = 3 ’-5’ phosphorothioate linkage sodium salt and wherein L96 has the following formula:(I).

[0079] The expanded structural formula, molecular formula, and molecular weight of fitusiran are shown in FIGS. 1A-1B. As used herein, the term 2’-fluoroadenosine is used interchangeably with the term 2’-deoxy-2’-fluoroadenosine; the term 2 ’-fluorocytidine is20MF-364681141Attorney Reference: 15979-20207.40 used interchangeably with the term 2’-deoxy-2’-fluorocytidine; the term 2’ -fluoroguanosine is used interchangeably with the term 2’-deoxy-2’-fluoroguanosine, and the term 2’- fluorouridine is used interchangeably with the term 2’ -deoxy-2’ -fluorouridine.

[0080] The structure of fitusiran can also be described using the following diagram, wherein the X is O:

[0081] For use in the present treatment methods, fitusiran may be provided in a pharmaceutical composition comprising it and a pharmaceutically acceptable excipient. In certain embodiments, the dsRNA compound is in sodium salt form.

[0082] In some embodiments, fitusiran is provided in an aqueous solution at a concentration of 1 to 200 mg / mL (e.g., 50 to 150 mg / mL, 80 to 110 mg / mL, or 90 to 110 mg / mL, or 5 to 25 mg / mL, 7.5 to 20 mg / mL, or 10 to 15 mg / mL). As used herein, values intermediate to recited ranges and values are also intended to be part of this disclosure. In addition, ranges of values using a combination of any of recited values as upper and / or lower limits are intended to be included. In further embodiments, the pharmaceutical composition comprises fitusiran at a concentration of 5 mg / mL, 10 mg / mL, 12.5 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, or 200 mg / mL. In certain embodiments, fitusiran is provided at a concentration of 100 mg / mL in an aqueous solution. In certain embodiments, fitusiran is provided at a concentration of 12.5 mg / mL in an aqueous solution. In certain embodiments, fitusiran is provided at a concentration of 6.25 mg / mL in an aqueous solution.21MF-364681141Attorney Reference: 15979-20207.40

[0083] Unless otherwise indicated, a fitusiran weight recited in the present disclosure is the weight of fitusiran free acid (the active moiety), even though fitusiran is injected to patients subcutaneously in its sodium form (in an aqueous solution). For example, 100 mg / mL fitusiran means 100 mg of fitusiran free acid (equivalent to 106 mg fitusiran sodium, the drug substance) per mL.

[0084] In some embodiments, the pharmaceutical compositions comprise fitusiran in a phophate-buffered saline. The phosphate concentration in the solution may be 1 to 10 mM (e.g., 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, or 9 mM), with a pH of 6.0-8.0. In some embodiments, the pharmaceutical compositions herein include a preservative such as EDTA. In other embodiments, the pharmaceutical compositions are preservative-free.

[0085] In some embodiments, the fitusiran pharmaceutical composition is preservative- free and comprises, consists of, or consists essentially of 100 mg of fitusiran per mL of a 5 mM phosphate buffered saline (PBS) solution. The PBS solution is composed of sodium chloride, dibasic sodium phosphate (heptahydrate), and monobasic sodium phosphate (monohydrate). Sodium hydroxide solution and diluted phosphoric acid may be used to adjust the pH of the composition to about 7.0.

[0086] In some embodiments, the fitusiran pharmaceutical composition is preservative- free and comprises, consists of, or consists essentially of 12.5 mg of fitusiran per mL of a 5 mM phosphate buffered saline (PBS) solution. The PBS solution is composed of sodium chloride, dibasic sodium phosphate (heptahydrate), and monobasic sodium phosphate (monohydrate). Sodium hydroxide solution and diluted phosphoric acid may be used to adjust the pH of the composition to about 7.0.

[0087] The pharmaceutical composition may be provided in a container (e.g., a vial or a syringe). The container may contain single or multiple doses. In some embodiments, the solution is administered to patients through subcutaneous injection. The solution can be stored at 2 to 30°C (e.g., 2 to 8°C). In some embodiments, the pharmaceutical composition is provided in a pre-filled, single-dose syringe. In some embodiments, the pre-filled, singledose syringe comprises 20-50 mg (e.g., about 20 mg or about 30 mg) of fitusiran. In some embodiments, the vials are type I glass single-use vials; in further embodiments, the vials comprise at least 0.2 mL of the aqueous solution comprising fitusiran.

[0088] In some embodiments, fitusiran is provided in 30 mg vials (e.g., at 100 mg / mL), which may also be pooled to achieve a higher dose amount. These vials can also be used in half (half a vial) to achieve a dose amount of 15 mg.22MF-364681141Attorney Reference: 15979-20207.40

[0089] In some embodiments, fitusiran is provided in 20 mg vials (e.g., at 100 mg / mL), which may also be pooed to achieve a high dose amount. These vials can also be used in half (half a vial) to achieve a dose amount of 10 mg.

[0090] In some embodiments, fitusiran is provided in 2.5 mg vials (e.g., at 12.5 mg / mL), which may be pooled to achieve a dose amount of, e.g., 5 mg, 7.5 mg, 10 mg, 20 mg, 30 mg, or 50 mg. These vials can also be used in half (half a vial) to achieve a dose amount of 1.25 mg.

[0091] In some embodiments, fitusiran is provided in 1.25 mg vials (e.g., at 12.5 mg / mL), which may be pooled to achieve a dose amount of, e.g., 2.5 mg, 5 mg, 7.5 mg, or 10 mg. In some embodiments, fitusiran is provided in 1.25 mg vials (e.g., at 6.25 mg / mL), which may be pooled to achieve a dose amount of, e.g., 2.5 mg, 5 mg, 7.5 mg, or 10 mg.

[0092] In one embodiment, 80 mg of fitusiran is delivered in 0.8 mL (100 mg fitusiran / mL). In one embodiment, 50 mg of fitusiran is delivered in 0.5 mL (100 mg fitusiran / mL). In one embodiment, 20 mg of fitusiran is delivered in 0.5 mL (40 mg fitusiran / mL). In one embodiment, 30 mg of fitusiran is delivered in 0.5 mL (60 mg fitusiran / mL). In one embodiment, 10 mg of fitusiran is delivered in 0.5 mL (20 mg fitusiran / mL). In one embodiment, 7.5 mg of fitusiran is delivered in 0.5 mL (15 mg fitusiran / mL). In one embodiment, 5 mg of fitusiran is delivered in 0.5 mL (10 mg fitusiran / mL). In one embodiment, 2.5 mg of fitusiran is delivered in 0.5 mL (5 mg fitusiran / mL). In one embodiment, 1.25 mg of fitusiran is delivered in 0.5 mL (2.5 mg fitusiran / mL).

[0093] In some embodiments, the fitusiran composition for subcutaneous injection contains fitusiran in a 5 mM phosphate buffered saline having 0.64 mM NalfcPC , 4.36 mM Na2HPO4, and 84 mM NaCl at pH 7.0 or 7.1. In certain embodiments, the composition of fitusiran solution for subcutaneous injection is shown in Table 1 below.Table 1. Fitusiran Formulation23MF-364681141Attorney Reference: 15979-20207.40q.s.: quantum satis.

[0094] In certain embodiments, the composition of fitusiran solution for subcutaneous injection is shown in Table 2 below.Table 2. Fitusiran Formulations

[0095] While the fitusiran dosage weight described herein refers to the weight of fitusiran free acid (active moiety), administration of fitusiran to patients herein refers to administration of fitusiran sodium (drug substance) provided in a pharmaceutically suitable aqueous solution (e.g., a phosphate buffered saline at a physiological pH).II. Therapeutic Use of Fitusiran

[0096] Fitusiran can suppress liver production of antithrombin (AT). In its role as an anticoagulant, AT regulates 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). Fitusiran may be used to treat those who have impaired hemostasis. The present disclosure provides uses of fitusiran as routine prophylaxis to treat hemophilia A or B (congenital factor VIII or factor IX deficiency) in, or to prevent or reduce the frequency of bleeding episodes in, a pediatric patient with or without inhibitors. In some embodiments, the pediatric patient is 1 to <12 year(s) of age. In some embodiments, the age of the patient is between about 1 year and 12 years, between about 1 year and about 10 years, between about 1 year and about 8 years, between about 1 year and about 6 years, between about 1 year and about 4 years, between about 1 year and about 3 years, between24MF-364681141Attorney Reference: 15979-20207.40 about 1 year and about 2 years, between about 2 years and about 12 years, between about 3 years and about 12 years, between about 4 years and about 12 years, between about 6 years and about 12 years, between about 8 years and about 12 years, or between about 10 years and about 10 years. In some embodiments, the age of the patient is about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, or about 12 years. In some embodiments, the pediatric patient weighs 8 kg or more. In some embodiments, the pediatric patient weighs less than 45 kg. In some embodiments, the pediatric patient weighs less than 22 kg.

[0097] The present methods include administering to the hemophilia patient (e.g., a hemophilia A or B patient) in need thereof a therapeutically effective amount of fitusiran. “Therapeutically effective amount” refers to the amount of fitusiran that helps the patient to achieve a desired clinical endpoint. A desired clinical endpoint may be, for example, reduction of annual bleeding rates (ABR) to no more than 3, no more than 2, no more than 1, or zero. A desired clinical endpoint may also be, for example, reduction of annual spontaneous bleeding rate (AsBR) to no more than 1, and preferably zero.

[0098] The present treatment methods are based in part on the discovery that the risk of vascular thrombotic events in patients exposed to fitusiran may increase with lower AT levels. AT measurements can be performed by well-established methods, including both kinetic and chromogenic assays. One commonly used method is the INNOV ANCE™ 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 an excess of factor Xa by AT. The assay may be performed by using an automated coagulation instrument (e.g., Siemens BCS® XP, Sysmex® CA-600 and CS Systems, or Atellica® COAG 360 System), and may be calibrated using Siemens standard human plasma (SHP) with a defined value of AT activity calibrated against World Health Organization (WHO) reference plasma. An equivalent assay is the Dade Behring Berichrom® Antithrombin III assay (Dade Behring Marburg GmbH, Marburg, Germany; U.S. FDA 510(k) # K933125). Each measurement may be controlled by two independent controls (low and normal value) also calibrated against the WHO standard. In some embodiments, one or more measurements of an AT level in the patient are obtained or have been obtained by a lab or technician, using any well-established method for obtaining AT measurements (e.g., the INNOVANCE™ Antithrombin assay or the Dade Behring Berichrom® Antithrombin III assay as described herein). The AT activity (%) in a plasma25MF-364681141Attorney Reference: 15979-20207.40 sample is calculated against the WHO reference plasma. 100% AT level is defined as 1 unit of antithrombin activity in 1 mL of reference plasma sample. The limit of detection of the INNOVANCE™ assay is 6.0% based on the assay’s U.S. FDA 510(k) decision summary. AT levels range from about 80% to about 120% in the general population.

[0099] It has been observed that the risk of arterial thrombotic events among patients receiving fitusiran may increase with AT levels <10%. Thus, the patient’s AT levels may be monitored and if necessary, the dose amounts of fitusiran may be adjusted. In some embodiments, the adjusted dose amounts of fitusiran are determined by a prescribing physician in response to one or more measurements of an AT level in the patient.

[0100] In some embodiments, the patient has a steady state AT level within the desired range (e.g., 15-35%) but still has suboptimal bleeding control (e.g., having two or more treated bleeds within a 12-week period starting with the third fitusiran injection at the current dose), such that fitusiran will be dosed at the next higher dose amount or at the next higher dose frequency (e.g., going from every two months or every eight weeks to every month or every four weeks). This dosing adjustment may be adjusted until the patient has no more than two treated bleeds within a 12-week period starting with the third fitusiran injection at the current dose while maintaining a steady state AT range of 15-35%.

[0101] An aspect of the present disclosure includes a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15- 35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional, step (b) is performed by a lab or technician, and step (c) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0102] Another aspect of the present disclosure includes a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, the method26MF-364681141Attorney Reference: 15979-20207.40 comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements, wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification. In some embodiments of this aspect, steps (a) and (b) are performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0103] Another aspect of the present disclosure includes method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional, step (b) is performed by a lab or technician, and step (c) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0104] Another aspect of the present disclosure includes method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b)27MF-364681141Attorney Reference: 15979-20207.40 performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements, wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification. In some embodiments of this aspect, steps (a) and (b) are performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0105] Another aspect of the present disclosure includes method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional, step (b) is performed by a lab or technician, and step (c) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0106] Another aspect of the present disclosure includes method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg28MF-364681141Attorney Reference: 15979-20207.40 every month or every four weeks if an AT level is >35% in one or more measurements, or (iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements, wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification. In some embodiments of this aspect, steps (a) and (b) are performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0107] Another aspect of the present disclosure includes method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and (c) performing one of the following steps: (i) if the AT level is 15-35% in one or more measurements, repeating step (a), (ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or (iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional, step (b) is performed by a lab or technician, and step (c) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level.

[0108] Another aspect of the present disclosure includes method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; (b) performing one of the following steps: (i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements, (ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or29MF-364681141Attorney Reference: 15979-20207.40(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements, wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification. In some embodiments of this aspect, steps (a) and (b) are performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, a prescribing physician determines the dosage amounts of fitusiran in the patient in response to the obtained one or more measurements of AT level. In some embodiments of any of the preceding aspects where an AT level is <15% in one or more measurements, fitusiran administration may first be paused, optionally until an AT level in the patient is >15%, optionally >22%.

[0109] Another aspect of the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, step (b) is performed by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0110] Another aspect of the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained. In some embodiments of this aspect, the patient, a caregiver, or a healthcare professional administers the fitusiran. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0111] Another aspect of the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining30MF-364681141Attorney Reference: 15979-20207.40 one or more measurements of an antithrombin (AT) level in the patient. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, step (b) is performed by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0112] Another aspect of the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained. In some embodiments of this aspect, the patient, a caregiver, or a healthcare professional administers the fitusiran. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0113] Another aspect of the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, step (b) is performed by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0114] Another aspect of the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained. In some embodiments of this aspect, the patient, a caregiver, or a healthcare professional administers the fitusiran. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.31MF-364681141Attorney Reference: 15979-20207.40

[0115] Another aspect of the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: (a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and (b) obtaining one or more measurements of an antithrombin (AT) level in the patient. In some embodiments of this aspect, step (a) is performed by the patient, a caregiver, or a healthcare professional. In some embodiments of this aspect, step (b) is performed by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0116] Another aspect of the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained. In some embodiments of this aspect, the patient, a caregiver, or a healthcare professional administers the fitusiran. In some embodiments of this aspect, the one or more measurements of AT level in the patient are or have been obtained by a lab or technician. In some embodiments of this aspect, the dosage amount of fitusiran is determined by a prescribing physician.

[0117] Another aspect of the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0118] Another aspect of the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0119] Another aspect of the present disclosure provides a method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of <15%, the patient having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.32MF-364681141Attorney Reference: 15979-20207.40

[0120] Another aspect of the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0121] Another aspect of the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0122] Another aspect of the present disclosure provides a method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

[0123] Another aspect of the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0124] Another aspect of the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0125] Another aspect of the present disclosure provides a method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.33MF-364681141Attorney Reference: 15979-20207.40

[0126] Another aspect of the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

[0127] Another aspect of the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

[0128] Another aspect of the present disclosure provides a method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks. In some embodiments of any of the preceding aspects where an AT level is <15% in one or more measurements, fitusiran administration may first be paused, optionally until an AT level in the patient is >15%, optionally >22%.

[0129] In some embodiments of any of the preceding aspects, a measurement of the AT level in the patient is or has been obtained every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months. In some embodiments of any of the preceding aspects, a measurement of the AT level is or has been obtained at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.

[0130] In some embodiments, fitusiran is subcutaneously administered to the patient at a range of 1 mg to 50 mg. In further embodiments, fitusiran is subcutaneously administered to the patient at a range of 1 mg to 30 mg. In further embodiments, fitusiran is subcutaneously administered to the patient at a range of 1 mg to 20 mg. In further embodiments, fitusiran is subcutaneously administered to the patient at a range of 1 mg to 10 mg. In further34MF-364681141Attorney Reference: 15979-20207.40 embodiments, fitusiran is subcutaneously administered to the patient at a range of 1 mg to 5 mg. In certain embodiments, fitusiran is subcutaneously administered to the patient at 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 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 subcutaneously administered every other month or every eight weeks, or every month or every four weeks, at, e.g., one of the aforementioned dosages.

[0131] In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 1.25 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 1.25 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 2.5 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 2.5 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 5 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 5 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 7.5 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 7.5 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 10 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 10 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 20 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 20 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 30 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 30 mg. In some embodiments, fitusiran is subcutaneously administered every other month or every eight weeks at 50 mg. In some embodiments, fitusiran is subcutaneously administered every month or every four weeks at 50 mg. Exemplary treatment protocols are further described below.

[0132] Pediatric patients (e.g., aged 1 to less than 12 year(s) of age) with a body weight of 8 kg to < 45 kg may begin with a starting dose of 10 mg fitusiran every month (or every four35MF-364681141Attorney Reference: 15979-20207.40 weeks). In some embodiments, the body weight of the patient is between about 8 kg and about 45 kg. In some embodiments, the body weight of the patient is between about 8 kg and about 22 kg. In some embodiments, the body weight of the patient is between about 8 kg and about 20 kg, between about 8 kg and about 18 kg, between about 8 kg and about 16 kg, between about 8 kg and about 14 kg, between about 8 kg and about 12 kg, between about 8 kg and about 10 kg, between about 10 kg and about 22 kg, between about 12 kg and about 22 kg, between about 14 kg and about 22 kg, between about 16 kg and about 22 kg, between about 18 kg and about 22 kg, or between about 20 kg and about 22 kg. In some embodiments, the body weight of the patient is about 8 kg, about 9 kg, about 10 kg, about 11 kg, about 12 kg, about 13 kg, about 14 kg, about 15 kg, about 16 kg, about 17 kg, about 18 kg, about 19 kg, about 20 kg, about 21 kg, or about 22 kg. The patient’s AT level may be monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, AT levels are tested quarterly. In some embodiments, the frequency of monitoring of the patient’s AT level is increased after a change in fitusiran dose amount or dose frequency. In some embodiments, the patient’s AT level is monitored every month after a change in fitusiran dose amount or dose frequency. An exemplary escalation and de-escalation scheme for patients is illustrated in FIG. 3.

[0133] In some embodiments, patients treated with a starting dose of 10 mg fitusiran every month (or every four weeks) de-escalate their fitusiran dose regimen. In some embodiments, upon the first AT level <15%, the patient has another AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is <15%, this is considered the second AT <15%. Patients receiving fitusiran at a dose of 10 mg QM with more than 1 (e.g., 2) AT activity levels <15% will de-escalate to a dose of 5 mg fitusiran every month (or every four weeks). In some embodiments, the patient may pause treatment, and initiate treatment with the lower dose of fitusiran after their AT levels have returned to above 15%, e.g., >22%.

[0134] After de-escalating to a dose of 5 mg fitusiran every month, the patient’s AT level may be again monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, upon the first AT level <15%, the patient has another AT activity level sample drawn within a month (e.g., within36MF-364681141Attorney Reference: 15979-20207.40 one or two weeks). If this result is <15%, this is considered the second AT <15%. Patients receiving fitusiran at a dose of 5 mg QM with more than 1 (e.g., 2) AT activity levels <15% will de-escalate to a dose of 1.25 mg fitusiran every month (or every four weeks). In some embodiments, the patient may pause treatment, and initiate treatment with the lower dose of fitusiran after their AT levels have returned to above 15%, e.g., >22%.

[0135] After de-escalating to a dose of 1.25 mg fitusiran every month, the patient’s AT level may be again monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, upon the first AT level <15%, the patient has another AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is <15%, this is considered the second AT <15%. Patients receiving fitusiran at a dose of 1.25 mg QM with more than 1 (e.g., 2) AT activity levels <15% may discontinue or pause fitusiran treatment.

[0136] In some embodiments, after de-escalating to a dose of 5 mg fitusiran every month, the patient’s AT level is again monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, upon the first steady state AT level >35%, the patient has another AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is >35%, this is considered the second steady state AT >35%. Patients receiving fitusiran at a dose of 5 mg QM with more than 1 (e.g., 2) steady state AT activity levels >35% may escalate to a dose of 7.5 mg fitusiran once a month (or every four weeks).

[0137] In some embodiments, after de-escalating to a dose of 1.25 mg fitusiran every month, the patient’s AT level is again monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, upon the first steady state AT level >35%, the patient has another AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is >35%, this is considered the second steady state AT >35%. Patients receiving fitusiran at a dose of 1.2537MF-364681141Attorney Reference: 15979-20207.40 mg QM with more than 1 (e.g., 2) steady state AT activity levels >35% may escalate to a dose of 2.5 mg fitusiran once a month (or every four weeks).

[0138] In other embodiments, patients treated with a starting dose of 10 mg fitusiran every month (or every four weeks) may escalate their dose of fitusiran. The patient’s AT level may be monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, or every six months). In some embodiments, upon the first steady state AT level >35%, the patient has another steady state AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is >35%, this is considered the second steady state AT >35%. Patients receiving fitusiran at a dose of 10 mg QM with more than 1 (e.g., 2) steady state AT activity levels >35% may escalate to a dose of 20 mg fitusiran every month (or every four weeks).

[0139] In some embodiments, after escalating to a dose of 20 mg fitusiran every month, the patient’s AT level may be again monitored periodically (e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or every twelve months). In some embodiments, upon the first steady state AT level >35%, the patient has another steady state AT activity level sample drawn within a month (e.g., within one or two weeks). If this result is >35%, this is considered the second steady state AT >35%. Patients receiving fitusiran at a dose of 20 mg QM with more than 1 (e.g., 2) steady state AT activity levels >35% may escalate to a dose of 50 mg fitusiran once a month (or every four weeks).

[0140] In some embodiments, escalation is performed after AT activity levels at steady state remain >35% (see, e.g., FIG. 3).

[0141] In some embodiments, AT activity levels used for deciding whether to escalate a fitusiran dose amount or frequency are those measured at steady state (SS), i.e., once the patient’s AT levels have been stabilized after fitusiran treatment. The SS is typically reached after two or three doses of fitusiran. AT measurements for dosing determination are taken at an appropriate interval (e.g., every four weeks or every eight weeks).

[0142] An AT level of 10-35% (e.g., 10-25%, 15-35%, or 15-25%) is targeted to mitigate the risk of vascular thrombotic events while aiming to maintain a favorable benefit-risk38MF-364681141Attorney Reference: 15979-20207.40 balance for patients on fitusiran. Thus, so long as the patient reaches this targeted steady state AT level, there is no need for the patient to receive a higher fitusiran dosage or more frequent dosing except as otherwise discussed herein (e.g., patients having bleeding events more often than a pre-set threshold). That is, the patient may remain on the current treatment regimen (z.e., maintenance regimen). For example, once the desired AT level is reached, the patient may be treated with a subcutaneous dose of fitusiran (e.g., 1.25-30 mg per dose) at an interval of, e.g., every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks, or every one month, every two months, every three months, or every four months. In some embodiments, if the patient has two AT measurements of no greater than 35% while receiving 10 mg QM, they will maintain this dosing regimen, with no need to further escalate the dosage or dosing frequency. In some embodiments, the exceptions may be that when the patients bleed more often than a pre-set threshold, they escalate the fitusiran dosage despite having a within-range (15-35%) AT activity level. As another example, if the patient has two AT measurements of no greater than 35% while receiving 5 mg QM, they will remain on this dosing regimen, with no need to further escalate the dosage or dosing frequency (to, e.g., 10 mg QM or 20 mg QM). However, fitusiran treatment should be dose de-escalated (or discontinued if already de-escalated to the lowest permissible dose) if a patient has more than 1 (e.g., 2) AT measurements <15% (e.g., < 10%) as a risk mitigation measure for vascular thrombotic events. In some embodiments, a patient on a maintenance regimen has their AT level monitored every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or every twelve months.

[0143] A pediatric patient with hemophilia A or B with or without inhibitors may be treated with a subcutaneous maintenance dose of fitusiran at 1-50 mg per dose every month (or every four weeks). In some embodiments of maintenance regimens, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 50 mg per dose every month (or every four weeks). In some embodiments of maintenance regimens, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 30 mg per dose every month (or every four weeks). In other embodiments, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 20 mg every month (or every four weeks). In other embodiments, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran 10 mg every month (or every four weeks). In some39MF-364681141Attorney Reference: 15979-20207.40 embodiments of maintenance regimens, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 7.5 mg per dose every month (or every four weeks). In other embodiments, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 5 mg every month (or every four weeks). In other embodiments, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 2.5 mg every month (or every four weeks). In other embodiments, a patient with hemophilia A or B with or without inhibitors is treated with a subcutaneous dose of fitusiran at 1.25 mg every month (or every four weeks).

[0144] In some embodiments, patients may receive periodic (e.g., monthly or every four weeks) AT monitoring for 12 months following a change in fitusiran dosing regimen.

[0145] In some embodiments, once a patient stays 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 level may be monitored every month, every two months, every three months, every four months, semi-annually, annually, or every two years.III. Patient Management

[0146] Patients on fitusiran are monitored for hemostasis parameters, e.g., coagulation parameters (D-dimer, prothrombin fragment 1+2, and fibrinogen) and for signs and symptoms of vascular thrombotic events. Such signs and symptoms may include, but are not limited to, severe or persistent headache, headache with nausea and vomiting, chest pain and / or tightness, coughing up blood, trouble breathing, abdominal pain, fainting or loss of consciousness, swelling or pain in the arms or legs, vision problems, weakness and / or sensory deficits, and changes in speech. An evaluation of signs and symptoms potentially consistent with vascular thrombosis should include appropriate imaging studies as applicable. For the diagnosis of cerebral venous sinus thrombosis magnetic resonance imaging venogram (MRV) or computed tomography venogram (CTV) is recommended.

[0147] If a patient develops thrombosis while on fitusiran, AT reversal may be administered in combination with a replacement factor or BPA and appropriate anticoagulation. AT reversal should follow labeled product recommendations for the prevention of perioperative thrombosis in patients with AT deficiency, and individualize patient doses to target 80-120% AT activity. The use of plasma derived AT may be preferable to recombinant AT, given its longer half-life.40MF-364681141Attorney Reference: 15979-20207.40IV. Bleeding Episodes and Bleed Management

[0148] Bleeding events in patients on fitusiran may be managed by on-demand administration of a replacement factor (recombinant or plasma-derived Factor VIII or Factor IX) or a BPA (e.g., fresh-frozen plasma (FFP); rFVIIa; and aPCC). The amount of the factor or BPA may be reduced in patients on fitusiran to prevent vascular thrombosis. See, e.g., WO 2019 / 014187. Management of bleeding episodes in pediatric patients who are on prophylactic fitusiran treatment is described in further detail in Example 1. See, e.g., Table 7, infra.

[0149] The present methods include methods of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, methods of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, methods of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors. The present methods also include methods of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors.

[0150] Certain aspects of the present disclosure relate to the bleeding rates and bleeding episodes and their management. A bleeding episode can be defined as any occurrence of hemorrhage that requires administration of CFCs or BPAs, e.g., hemoarthrosis, muscle, or mucosal bleeding. The start time of a bleeding episode can be considered the time at which symptoms of a bleeding episode first develop. A spontaneous bleeding episode can be a bleeding episode that occurs for no apparent or known reason, particularly into the joints, muscles, and soft tissues. A joint bleeding episode can be characterized by an unusual sensation in the joint (“aura”) in combination with 1) increasing swelling or warmth over the skin over the joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline. A muscle bleed can be characterized by pain, swelling, and loss of movement over the affected muscle group. A target joint can be defined as a joint where 3 or more spontaneous bleeding episodes in a single joint within a consecutive 6-month period has occurred; where there have been <2 bleeding episodes in the joint within a consecutive 12-month period, the joint is no longer considered a target joint. A traumatic bleeding episode can be one that is caused by a known injury or trauma.41MF-364681141Attorney Reference: 15979-20207.40EXEMPLARY EMBODIMENTS

[0151] Exemplary embodiments of the methods, uses, and compositions described herein include:1. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.2. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.3. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;42MF-364681141Attorney Reference: 15979-20207.40(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.4. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.5. The method of any one of embodiments 1-4, wherein step (c)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (c)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.43MF-364681141Attorney Reference: 15979-20207.406. The method of embodiment 5, wherein the more than one measurements in step (c)(iii) are within 12 months.7. The method of embodiment 5, comprising, after step (c)(ii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks.8. The method of any one of embodiments 1-7, comprising, after step (c)(iii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks,(II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or(III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks.9. The method of embodiment 8, comprising, after step (c)(iii)(I), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks.44MF-364681141Attorney Reference: 15979-20207.4010. The method of embodiment 8, comprising, after step (c)(iii)(III), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks.11. The method of any one of embodiments 5-10, wherein if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement.12. The method of any one of embodiments 1-11, further comprising subcutaneously administering fitusiran to the patient at their latest dose amount and dosing frequency so long as the patient maintains an AT level at 15-35%.13. The method of any one of embodiments 1-12, wherein each AT level measurement is obtained after the patient has received at least two doses of fitusiran at a given dose amount.14. The method of any one of embodiments 1-13, further comprising after step (c):(d) if the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (c) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (c) dose amount,45MF-364681141Attorney Reference: 15979-20207.40 subcutaneously administering to the patient a higher dose amount of fitusiran than the step (c) dose amount.15. The method of any one of embodiments 1-14, wherein step (c)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.16. The method of any one of embodiments 1-15, further comprising obtaining a measurement of the AT level in the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.17. The method of any one of embodiments 1-15, further comprising obtaining a measurement of the AT level at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.18. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.46MF-364681141Attorney Reference: 15979-20207.4019. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.20. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.21. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising:47MF-364681141Attorney Reference: 15979-20207.40(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.22. The method of any one of embodiments 18-21, wherein step (b)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (b)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.23. The method of embodiment 22, wherein the more than one measurements in step (b)(iii) are within 12 months.24. The method of embodiment 22, comprising, after step (b)(ii), if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks.25. The method of any one of embodiments 18-24, comprising, after step (b)(iii), performing one of the following steps:48MF-364681141Attorney Reference: 15979-20207.40(I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks,(II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or(III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks.26. The method of embodiment 25, comprising, after step (b)(iii)(I), performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks.27. The method of embodiment 25, comprising, after step (b)(iii)(III), performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks.49MF-364681141Attorney Reference: 15979-20207.4028. The method of any one of embodiments 22-27, wherein if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement.29. The method of any one of embodiments 18-28, further comprising subcutaneously administering fitusiran to the patient at their latest dose amount and dosing frequency so long as the patient maintains an AT level at 15-35%.30. The method of any one of embodiments 18-29, wherein each AT level measurement is or has been obtained after the patient has received at least two doses of fitusiran at a given dose amount.31. The method of any one of embodiments 18-30, further comprising after step (b):(c) if the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (b) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (b) dose amount, subcutaneously administering to the patient a higher dose amount of fitusiran than the step (b) dose amount.32. The method of any one of embodiments 18-31, wherein step (b)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.33. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.50MF-364681141Attorney Reference: 15979-20207.4034. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.35. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of <15%, the patient having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.36. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.37. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.38. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.51MF-364681141Attorney Reference: 15979-20207.4039. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.40. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.41. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.42. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.43. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.52MF-364681141Attorney Reference: 15979-20207.4044. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.45. The method of any one of embodiments 35, 38, 41, and 44, wherein fitusiran administration is first paused, optionally until an AT level in the patient is >15%, optionally >22%, before subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.46. The method of any one of embodiments 18-45, wherein a measurement of the AT level in the patient has been obtained every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.47. The method of any one of embodiments 18-45, wherein a measurement of the AT level has been obtained at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.48. The method of any one of embodiments 1-47, wherein the body weight of the patient is 8 kg or greater.49. The method of any one of embodiments 1-48, wherein the body weight of the patient is less than 45 kg.50. The method of any one of embodiments 1-48, wherein the body weight of the patient is less than 22 kg.51. The method of any one of embodiments 1-49, wherein the body weight of the patient is between about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg.53MF-364681141Attorney Reference: 15979-20207.4052. The method of any one of embodiments 1-51, wherein the AT levels are at steady state.53. The method of any one of embodiments 1-52, wherein the patient is 1 year of age or older.54. The method of any one of embodiments 1-53, wherein the patient is less than 12 years of age.55. The method of any one of embodiments 1-54, wherein the patient is between 1 year of age and 12 years of age.56. The method of any one of embodiments 1-55, wherein the patient continues a previous non-fitusiran prophylactic treatment for one week after the first dose of fitusiran, optionally wherein the previous non-fitusiran prophylactic treatment is a clotting factor concentrate treatment, a replacement factor treatment, or a bypassing agent treatment.57. The method of any one of embodiments 1-56, wherein the patient has hemophilia A or B with inhibitors.58. The method of embodiment 57, further comprising treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a bypassing agent (BPA), wherein the effective amount of the BPA is reduced as compared to the recommended effective amount of the BPA.59. The method of embodiment 58, wherein the patient has an AT level of <60%, optionally wherein the patient has an AT level of <60% before administration of fitusiran.60. The method of embodiment 58 or embodiment 59, wherein the bypassing agent is activated prothrombin complex concentrate (aPCC) and a single dose of aPCC is no more than 50 U / kg and is optionally 30 U / kg, optionally wherein the aPCC administration is repeated, if needed, in no less than 24 hours.54MF-364681141Attorney Reference: 15979-20207.4061. The method of embodiment 58 or embodiment 59, wherein the bypassing agent is recombinant factor Vila (rFVIIa) and a single dose of rFVIIa is no more than 45 pg / kg, optionally wherein the rFVIIa administration is repeated, if needed, in no less than two hours.62. The method of embodiment 58 or embodiment 59, wherein the bypassing agent is efanesoctocog alfa and a single dose of efanesoctocog alfa is no more than 45 pg / kg, optionally wherein the efanesoctocog alfa administration is repeated, if needed, in no less than 72 hours.63. The method of any one of embodiments 1-56, wherein the patient has hemophilia A or B without inhibitors.64. The method of embodiment 63, further comprising treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a replacement factor, wherein the effective amount of the replacement factor is reduced as compared to the recommended effective amount of the replacement factor.65. The method of embodiment 63 or embodiment 64, wherein the replacement factor is Factor VIII and a single dose of the replacement factor is no more than 20 lU / kg and optionally is 10 lU / kg, optionally wherein the Factor VIII administration is repeated, if needed, in no less than 24 hours.66. The method of embodiment 63 or embodiment 64, wherein the replacement factor is Sevenfact, and wherein the reduction compared to the recommended effective amount of Sevenfact is half the standard dose with standard treatment frequency.67. The method of embodiment 63 or embodiment 64, wherein the replacement factor is Factor IX and a single dose of the replacement factor is 30 lU / kg and optionally is 20 lU / kg, optionally wherein the Factor IX administration is repeated, if need, in no less than 24 hours for standard half-life Factor IX or in no less than 5-7 days for extended half-life Factor IX.55MF-364681141Attorney Reference: 15979-20207.4068. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 1.25 mg of fitusiran every month or every four weeks.69. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 2.5 mg of fitusiran every month or every four weeks.70. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 5 mg of fitusiran every month or every four weeks.71. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 7.5 mg of fitusiran every month or every four weeks.72. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 10 mg of fitusiran every month or every four weeks.73. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 20 mg of fitusiran every month or every four weeks.74. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or56MF-364681141Attorney Reference: 15979-20207.40 the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 30 mg of fitusiran every month or every four weeks.75. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 50 mg of fitusiran every month or every four weeks.76. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 10 mg of fitusiran every month or every four weeks, wherein the body weight of the patient is < 22 kg.77. The method of any one of embodiments 68-76, further comprising monitoring the AT level of the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every twelve months.78. The method of any one of embodiments 68-77, wherein the patient is aged 1 year to <12 years old.79. The method of any one of embodiments 68-78, wherein the patient has a body weight of less than 45 kg.80. The method of embodiment 78, wherein the patient has a body weight of about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg.81. The method of any one of embodiments 1-80, further comprising, after subcutaneous administration of fitusiran, monitoring the AT levels of the patient periodically, optionally every one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks, or every one month, two months, three months, four months, five months, or six months.57MF-364681141Attorney Reference: 15979-20207.4082. The method of any one of embodiments 1-81, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a kinetic or chromogenic assay.83. The method of embodiment 82, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of an excess of factor Xa by AT.84. The method of embodiment 82, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of an INNOV ANCE™ Antithrombin assay.85. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.86. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.87. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.88. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.58MF-364681141Attorney Reference: 15979-20207.4089. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.90. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.91. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.92. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.93. The method of any one of embodiments 85-92, further comprising adjusting the dose amount or dose frequency of fitusiran being subcutaneously administered to the patient in order to maintain an AT level of 15-35%.59MF-364681141Attorney Reference: 15979-20207.4094. The method of any one of embodiments 1-93, wherein liver function test results are obtained within 7 days prior to each dose of fitusiran, optionally wherein the liver function test results are reviewed prior to each dose of fitusiran.95. The method of any one of embodiments 1-94, wherein fitusiran is provided in a phosphate-buffered saline (PBS) at 1-200 mg / mL, optionally 6.25 mg / mL, 12.5 mg / mL or 100 mg / mL.96. The method of embodiment 95, wherein fitusiran is provided in formulation 1 or formulation 2 shown below.97. Fitusiran for use in a method of any one of embodiments 1-96.98. Use of fitusiran for the manufacture of a medicament to treat hemophilia A or B with or without inhibitors in the method of any one of embodiments 1-96.99. A pharmaceutical composition comprising fitusiran for use in a method of any one of embodiments 1-96.100. An article of manufacture for use in a method of any one of embodiments 1-96, optionally wherein the article of manufacture is a kit.60MF-364681141Attorney Reference: 15979-20207.40101. The article of manufacture of embodiment 100, wherein the article of manufacture is a container, optionally a vial, containing one or more doses of fitusiran, each dose being 30 mg, 20 mg, 10 mg, 5 mg, 2.5 mg, or 1.25 mg.102. The article of manufacture of embodiment 101, wherein the container is a vial containing 2.5 mg of fitusiran.

[0152] Additional definitions of terminology and exemplary embodiments are described in the Examples.

[0153] Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure.

[0154] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.EXAMPLES

[0155] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0156] LIST OF ABBREVIATIONSABR: annualized bleeding rateAE: adverse eventAjBR: annualized joint bleeding rateALT: alanine aminotransferase aPCC: activated prothrombin complex concentrateAPRI: aspartate transaminase to platelet ratio indexAsBR: annualized spontaneous bleeding rateAST: aspartate aminotransferaseAT: antithrombinAxMP: Auxiliary medicinal productBPA: bypassing agentBU: Bethesda unitCFC: clotting factor concentrate61MF-364681141Attorney Reference: 15979-20207.40CRF: case report formDMC: data monitoring committee eDiary: electronic DiaryEOS: end of studyEOT: end of treatmentEQ-5D-Y : EuroQoL-5 dimensions-youthFAS: full analysis setFEIBA: Factor VIII inhibitor bypassing activityFIX: factor IXFVIII: factor VIIIGalNAc: N-AcetylgalactosamineHBsAg: hepatitis B surface antigenHIV : human immunodeficiency virusHJHS: Hemophilia joint health scoreIB: Investigator’s BrochureICF: informed consent formIMP: investigational medicinal product, Investigational medicinal productINR: International normalized ratioISR: injection site reactionISTH: International Society on Thrombosis and HemostasisITI: immune tolerance inductionIV: intravenous (ly)EFT: liver function testPD: pharmacodynamicsPK: pharmacokineticsPKAS: pharmacokinetic analysis setPPS: per protocol setPROMIS: Patient- Reported Outcomes Measurement Information SystemQM: once monthlyQoE: quality of life rFVIIa: recombinant activated factor VIISAE: serious adverse event62MF-364681141Attorney Reference: 15979-20207.40SAP: statistical analysis planSAS: safety analysis setSC: subcutaneous (ly) siRNA: small interfering ribonucleic acidSOC: standard of careTG: thrombin generationULN: upper limit of normalExample 1: Clinical Trial Protocol for an Open-Label Study to Investigate the Efficacy and Safety of Fitusiran Prophylaxis in Male Participants Aged 1 to Less Than 12 Years with Hemophilia A or B

[0157] This Example describes the protocol for an open-label, multinational, single-group, Phase 3, two-arm study that investigates the efficacy and safety of fitusiran prophylaxis in male participants aged 1 to less than 12 years with hemophilia A or B with or without inhibitory antibodies to Factors VIII or IX. Treatment of both inhibitor and non-inhibitor populations remains associated with high treatment burden due to the frequency of IV administration to prophylactically maintain hemostasis and is further complicated by challenges of venous access and caregiver burden.Introduction

[0158] Fitusiran is an N-Acetylgalactosamine (GalNAc) small interfering ribonucleic acid (siRNA) conjugate that reduces production of AT, leading to lower plasma AT activity levels. By reducing plasma AT, fitusiran is designed to improve thrombin generation and hemostasis in individuals with hemophilia, regardless of hemophilia type or presence of inhibitory antibodies to FVIII or FIX. Fitusiran is being developed for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, including patients with inhibitory antibodies to exogenous FVIII or FIX substitution. Because of the durability of the pharmacodynamic effect of fitusiran demonstrated in previous studies in non-pediatric patients, the SC administration required is notably less frequent than current IV standard of care with CFCs or BPAs, representing potentially improved quality of life and lowered treatment burden for participants with hemophilia.

[0159] For pediatric patients with hemophilia, the treatment of both inhibitor and noninhibitor populations remains associated with high treatment burden due to the frequency of IV administration to prophylactically maintain hemostasis and is further complicated by63MF-364681141Attorney Reference: 15979-20207.40 challenges of venous access and caregiver burden. A SC therapy that can effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, with or without inhibitors, may reduce treatment burden, improve clinical outcomes, and enhance quality of life, especially in the pediatric patient population.

[0160] Fitusiran has been investigated in the pediatric population in a previous study, which enrolled male participants aged 1 to <12 years with hemophilia A or B with inhibitors. The purpose of the previous study was to confirm the appropriate pediatric dosing regimen as well as to examine the safety and tolerability of fitusiran in the pediatric population. The purpose of the present study is to investigate the efficacy and safety of fitusiran in male participants aged 1 to <12 years, with hemophilia A or B, with or without inhibitors. The study population consists of participants who have never been exposed to fitusiran (fitusiran-naive arm), as well as participants who rolled over from the previous study (roll-over arm). The primary analysis will only include fitusiran-naive participants and will be conducted once all these participants have completed Week 60 of the study.

[0161] Identified risks of fitusiran include thrombotic events, transaminase elevations, and acute and recurrent gallbladder disease. In addition, serious hypersensitivity reactions, including injection site reactions (ISRs), are considered a potential risk of fitusiran. The risk of thrombotic events is thought to be elevated in participants receiving fitusiran with AT activity levels <10%. In addition, the concomitant treatment of breakthrough bleeding episodes with factor or BPA, at doses higher than recommended in the protocol, may confer an increased risk of thrombotic events.

[0162] This protocol has exclusion criteria intended to minimize the risk of thrombosis, transaminase elevations, and serious ISRs. With respect to the risk of thrombosis, the protocol includes an AT-based dose regimen targeting AT levels between 15% and 35%, detailed guidance and oversight on treatment of breakthrough bleeding episodes with reduced factor and / or BPA dosing, and monitoring for symptoms and signs of thrombosis. The protocol also excludes participants with evidence of liver disease (including active viral hepatitis), stipulates ongoing monitoring for elevated transaminases and gallbladder disease, and provides instruction for the potential discontinuation of fitusiran.64MF-364681141Attorney Reference: 15979-20207.40Objectives and EndpointsPrimary Objective• To evaluate treatment efficacy during fitusiran prophylaxis and standard of care (SOC) periods in the fitusiran-naive arm.Primary Endpoint• Annualized treated bleeding rate (ABR) in the fitusiran primary efficacy period (Day 85 to Day 421) and in the SOC period (Week -24 to Day -1) o A bleeding episode is defined as any occurrence of hemorrhage that requires administration of CFCs or BPAsSecondary Objectives• To characterize the following during the fitusiran prophylaxis and SOC periods in the fitusiran-naive arm: o The frequency of treated spontaneous and bleeding episodes o The frequency of treated joint bleeding episodes• To characterize the frequency of treated bleeding episodes during the fitusiran treatment period in both arms• To characterize the effect of fitusiran prophylaxis on health-related quality of life (HRQoL) outcomes in the fitusiran-naive arm• To characterize the safety of fitusiran in both arms• To characterize the effect of fitusiran prophylaxis on joint health outcomes in the fitusiran-naive arm.Secondary Endpoints• Annualized spontaneous bleeding rate (AsBR) in the fitusiran primary efficacy period (Day 85 to Day 421) and in the SOC period (Week -24 to Day -1) o A spontaneous bleeding episode is a bleeding event that occurs for no apparent or known reason, particularly into the joints, muscles, and soft tissues• Annualized joint bleeding rate (AjBR) in the fitusiran primary efficacy period (Day85 to Day 421) and in the SOC period (Week -24 to Day -1) o A joint bleeding episode is characterized by an unusual sensation in the joint (“aura”) in combination with 1) increasing swelling or warmth over the skin65MF-364681141Attorney Reference: 15979-20207.40 over the joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline• ABR in the fitusiran treatment period (160 weeks) for fitusiran-naive participants (Day 1 to Day 1121) o A bleeding episode is defined as any occurrence of hemorrhage that requires administration of CFCs or BPAs• ABR in the fitusiran treatment period (60 weeks) for rolled-over participants (Day 1 to Day 421) o A bleeding episode is defined as any occurrence of hemorrhage that requires administration of CFCs or BPAs• Changes in PROMIS-SF Physical Activity from Day 1 to Day 421, and from Week - 24 to Day -1, as measured via the PROMIS Pediatric Short Form vl.O - Physical Activity 4a (>8 years old) and via the PROMIS Parent Proxy Short Form vl.O - Physical Activity 4a (>5 years old)• Changes in PROMIS Pain Intensity from Day 1 to Day 421, and from Week -24 to Day -1, as measured via the PROMIS Numeric Rating Scale vl.O - Pediatric Pain Intensity la (>8 years old) and via the PROMIS Numeric Rating Scale vl.O - Parent Proxy Pain Intensity la (>5 years old)• Changes in HRQoL, as measured by the EQ-5D-Y-3L Proxy version 1 (>4 years old): o From Day 1 to Day 421 o From Week -24 to Day - 1• Incidence, severity, seriousness, and relatedness of adverse events (AEs) o All AEs are collected from the signing of the informed consent form (ICF) until last AT follow-up visit o Date of signed ICF (Day -228 to Day -169) until last AT follow-up visit (Day 1121 + approximately 24 weeks)• Change from Day 1 to Day 421, and from Week -24 to Day -1, in total score and domain scores (e.g., swelling and strength) assessed by the Hemophilia Joint Health Score• Target joints resolution at Day 421 per ISTH criteria66MF-364681141Attorney Reference: 15979-20207.40Tertiary Objectives• To determine fitusiran plasma concentrations at selected timepoints (e.g., fitusiran plasma levels)• To characterize the pharmacodynamic (PD) effect and immunogenicity of fitusiran in both arms (e.g., antithrombin (AT) activity level over time, thrombin generation (TG) over time, incidence and titer of antidrug antibodies to fitusiran)• To assess the impact of fitusiran treatment on health-related quality of life outcomes in the fitusiran-naive arm (e.g., changes in PROMIS-SF Physical Activity during the fitusiran treatment period, changes in PROMIS Pain Intensity during the fitusiran treatment period, changes in EuroQoL 5-dimension Youth (EQ-5D-Y) (>8 years old) and via EQ-5D-Y Proxy version 1 (4-7 years old) during SOC period and during the fitusiran treatment period)• To assess caregiver- and / or patient-reported clinical outcome assessment measurements, and health resource utilization (e.g., caregiver interviews at EOT (or subsequent poststudy follow-up visit), description of healthcare resource utilization and child / caregiver productivity).Tertiary Endpoints• Fitusiran plasma levels• Antithrombin (AT) activity level over time• Thrombin generation (TG) over time• Changes in PROMIS-SF Physical Activity during the fitusiran treatment period• Changes in EuroQoL 5-dimension Youth (EQ-5D-Y) (>8 years old) and via EQ-5D-Y Proxy version 1 (4-7 years old) during SOC period and during the fitusiran treatment period• Caregiver interviews at EOT (or subsequence post-study follow-up visit)• Description of healthcare resource utilization and child / caregiver productivityTrial Periods, Duration, Schedules

[0163] Participants will be enrolled into 1 of 2 arms:1) Fitusiran-naive: these participants have not previously received fitusiran, and they will undergo screening and study eligibility assessments. Once enrolled, they will go through a 24-week SOC period before starting fitusiran prophylaxis. The fitusiran treatment period67MF-364681141Attorney Reference: 15979-20207.40 will include a dose adjustment period. See FIG. 2. If a fitusiran dose adjustment is needed during the study, participants will follow a specific dosing regimen as per study protocol. Fitusiran-naive arm participants will undergo screening and study eligibility assessments. Enrolled participants will continue their standard of care treatment for up to 24 weeks before starting fitusiran therapy. AT Follow up: In participants who do not continue fitusiran treatment, antithrombin activity levels will be monitored at monthly intervals until AT activity levels return to approximately 60% per the central laboratory, or per Investigator discretion in consultation with the study Medical Manager).2) Roll-over participants from the previous study: only participants who are still on active treatment in the previous study and consenting to the present study will be eligible to roll over into the present study. They will not need to undergo screening or further eligibility assessments. They will enroll directly into the fitusiran treatment period and continue treatment on their current fitusiran dose. See FIG. 2. Any future dose adjustments, if needed, will follow a specific dosing regimen as per study protocol. AT Follow up: In participants who do not continue fitusiran treatment, antithrombin activity levels will be monitored at monthly intervals until AT activity levels return to approximately 60% per the central laboratory, or per Investigator discretion in consultation with the study Medical Manager).

[0164] The duration of fitusiran treatment will be up to 160 weeks for the fitusiran-naive arm and up to 60 weeks for the roll-over arm.

[0165] Fitusiran-naive participants are eligible for enrollment if they met all inclusion criteria and none of the exclusion criteria. These study participants enter a screening period followed by a 24- week SOC period during which they continue receiving their prior on- demand or prophylaxis regimen with CFCs or BPAs. This is followed by a fitusiran treatment period, as described below. During the 40-month (i.e., 160- week) fitusiran treatment period, fitusiran-naive participants receive the fitusiran starting dose, administered subcutaneously every 4 weeks. Participants who experience more than 1 AT activity level <15% (within a 12- month period) are de-escalated to lower fitusiran doses. If participants on the lowest fitusiran dose experience more than 1 AT activity level <15% (within a 12-month period), they permanently discontinue fitusiran. If a participant’ s steady state AT activity levels remain >35% while on the starting dose, the participant is escalated to a higher dose. An additional escalation to a higher fitusiran dose is required if the participant’s steady state AT activity levels remained >35% on the first escalation dose. See FIG. 3. The fitusiran dose can68MF-364681141Attorney Reference: 15979-20207.40 also be escalated in cases of suboptimal bleed control, as judged by the Investigator, despite an AT activity level <35%.

[0166] Throughout the study, participants in both arms may receive on-demand treatment for breakthrough bleeding episodes with CFCs or BPAs, as appropriate. During the fitusiran treatment period and AT follow-up visits, participants follow the specific bleed management guidelines provided in section Management of bleeding episodes.

[0167] Bleeding events and doses of CFCs or BPAs administered after enrollment will be recorded in an eDiary. Safety, QoL, PD, and PK data will also be collected.

[0168] After completion or premature permanent discontinuation of fitusiran prophylaxis, AT activity level will be monitored during the AT follow-up period at approximately monthly intervals following the final fitusiran dose until AT activity levels return to at least 60% as per the central laboratory. If applicable, for participants continuing fitusiran prophylaxis directly after the trial, the AT follow-up visits are not required.Fitusiran-Ndive Arm

[0169] Fitusiran-naive participants have not previously received fitusiran, and they will undergo screening and study eligibility assessments. The fitusiran treatment period will include a dose adjustment period. See FIG. 3.

[0170] Study participants will enter a screening period followed by a 24-week standard of care (SOC) period during which they will continue receiving their prior on-demand or prophylaxis regimen with CFCs or BPAs. This will be followed by a fitusiran treatment period, as described below.

[0171] During the 40-month (i.e., 160- week) fitusiran treatment period, fitusiran-naive participants will receive the fitusiran starting dose of 10 mg, administered subcutaneously every 4 weeks. AT levels will be assessed regularly as provided in Table 3B. Participants who experience more than 1 AT activity level <15% (within a 12-month period) will be deescalated to lower fitusiran doses. If participants on the lowest fitusiran dose experience more than 1 AT activity level <15% (within a 12-month period), they must permanently discontinue fitusiran. If a participant’s steady state AT activity levels remain >35% while on the starting dose, the participant will be escalated to a higher dose. An additional escalation to a higher fitusiran dose is required if the participant’s steady state AT activity levels remain >35% on the first escalation dose.

[0172] The total study duration in the fitusiran-naive arm will be up to approximately 216 weeks (Tables 3A-3C), and will include:69MF-364681141Attorney Reference: 15979-20207.40A screening period up to 8 weeksA standard of care (SOC) treatment period of approximately 24 weeksA fitusiran treatment period of approximately 160 weeks, consisting of the following: o A dose adjustment period of approximately 12 weeks o A primary efficacy period of approximately 48 weeks o An extension period of approximately 100 weeks An AT follow-up period of approximately 24 weeks.

[0173] Fitusiran-naive participants will undergo two site visits during the SOC period. The frequency of site visits for fitusiran-naive participants will be approximately every 4 weeks during the first 24 weeks of fitusiran treatment, and then approximately every 12 weeks until Week 84, and then approximately every 24 weeks thereafter. The frequency of telephone visits for all participants will be approximately every 2 weeks (±4 days) between site visits. If applicable, home or remote visits may be conducted during the study, where permitted by national and local regulations.Table 3A. Schedule of Activities (SoA) (fitusiran-naive arm) - SOC Period70MF-364681141Attorney Reference: 15979-20207.4071MF-364681141Attorney Reference: 15979-20207.40Table 3B. Schedule of Activities (fitusiran-naive arm) - Fitusiran Treatment Perioda72MF-364681141Attorney Reference: 15979-20207.4073MF-364681141Attorney Reference: 15979-20207.40Abbreviations: ADA = antidrug antibody; AE = adverse event; APRI = AST to platelet ratio index; AT = antithrombin; BPA = bypassing agent; eDiary = electronic diary; EOS = End of Study; EOT = End of Treatment; EQ-5D-Y = EuroQoL-5 dimensions-youth; ET = Early Termination; FVIII = factor VIII; FIX = factor IX; FU = follow-up; HJHS = Hemophilia joint health score; LFT = liver function test; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; SAE = serious adverse event, ULN = upper limit of normal, TG=thrombin generation.Notes:• In exceptional circumstances, screening for new participants may be extended beyond the 8 weeks window after consultation with the Sponsor. In case it was needed, some assessments performed at the beginning of screening may have to be repeated.• Rescreening of new participants is permitted after consultation with the Medical Monitoring Team.• When scheduled at the same time points, vital signs will be performed before the physical examinations and blood sample collections.• Unless otherwise specified, assessments on dosing days are pre-dose.• Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of 3% of total blood volume over a 4- week period. Sampling is prioritized for safety laboratory tests (LFT, AT, hematology, biochemistry), ADA, and then PK. a. Fitusiran as prophylaxis treatment and permitted on-demand use of CFC or BPAs for treatment of breakthrough bleeding episodes. New participants may continue their routine CFC or BPA regimen (prophylaxis or on-demand) for up to the first 7 days following the first injection of fitusiran starting dose. Beginning at Day 8, CFC and BPA treatments for bleeding episode management should follow bleeding management guidelines. b. The Site / Home visit option (“S / H”) refers to the option for participants to complete the study visit at home or at the study site, when permitted by local regulations. Mandatory site visits are indicated with “S”. If participants opt to conduct the visit at home, they must follow the guidelines for IMP administration via home injection.74MF-364681141Attorney Reference: 15979-20207.40Any requirement for AT / LFT sample collection for central laboratory assessment must be maintained. In case of any fitusiran dose change, the participant must receive the first injection of that dose at the study site. c. Complete medical history / disease history (ie, including bleeding episode and treatment history in the previous 6 months) to be recorded at screening. d. eDiary training may be repeated during the study if deemed necessary by the investigator or designee. e. SC administration of fitusiran as per the Pharmacy Manual and will continue every 28 days ±7 days when study site visits and assessments occur quarterly. Training on home injection will occur at the study site. Home injection may occur as per conditions and instructions provided herein. f. A complete physical examination will be performed at screening only; a directed physical examination will be performed at all other specified visits. g. Height and weight will be recorded at all specified visits. h. Hepatitis C virus antibody positive participants only. FibroScan where available, otherwise FibroTest and APRI. i. Samples drawn from central lines may be excluded from TG analysis. j. AT levels are tested monthly during the fitusiran treatment period up to Week 60. After Week 60 visit, quarterly AT testing can be implemented. Participants on quarterly AT testing will need to resume monthly AT testing for at least 6 months every time there is a change in the fitusiran dose. Quarterly AT testing can be resumed afterward if the participant’s AT levels are between 15% and 35%. At each dose level, upon the first AT level <15%, the participant must have another AT activity level sample drawn within 1 week of site receipt of the results. If this second result is <15%, this will be considered the second AT activity level <15%. k. On fitusiran dosing days, pre-dose samples will be collected within 4 hours prior to dosing. l. LFT results may be obtained up to 7 days before the study site visit on which fitusiran dosing is scheduled. LFTs performed within 7 days of Day 1 will only be used to inform dosing on Day 1 and do not need to be used to confirm eligibility. LFTs can be analyzed locally, but if a local assessment is performed, a serum chemistry sample must also be collected for analysis at the central laboratory. LFT results will be obtained prior to receiving monthly fitusiran dosing. Monthly pre-dose LFT testing is not required after Week 60 for participants who have met the criteria for quarterly pre-dose LFT monitoring described as follows:- Did not have any alanine transaminase elevation >3 x ULN persisting for >2 months at any time during fitusiran treatment- Must not have had any fitusiran doses held due to LFT elevations during the first 12 months of fitusiran treatment- Did not have any escalation of fitusiran dose in the last 6 months m. Blood samples for PK analysis will be collected at the time points listed in Table 4. n. PROMIS-SF: the forms used are PROMIS Pediatric Short Form vl.O - Physical Activity 4a (>8 years old) and via PROMIS Parent Proxy Short Form vl.O - Physical Activity 4a (>5 years old). o. PROMIS Pain: the forms used are PROMIS Numeric Rating Scale vl.O - Pediatric Pain Intensity la (>8 years old) and via the PROMIS Numeric Rating Scale vl.O - Parent Proxy Pain Intensity la (>5 years old). p. EQ-5D-Y : the forms used are EQ-5D-Y (>8 years old) and EQ-5D- Y Proxy version 1 (4-7 years old).75MF-364681141Attorney Reference: 15979-20207.40 q. These questionnaires can be completed earlier in case of early withdrawal / termination as long as participants have completed at least up to Week 32 in the study. r. Caregiver interviews will take place within 14 days of Week 60 visit date. s. Bleed management review: Will include review of entries, (symptoms of bleeding episodes, bleeding causality, bleeding location, reason for dosing, bleed severity, doses of CFC or BPAs), whether appropriate study site contact occurred regarding treatment of bleeding episodes, and review of participant bleed management plan and recommendations and requirements for study site contact regarding dosing. t. It is strongly preferred that details of doses of CFC or BPAs administered and bleeding episodes are entered in the eDiary immediately or within 24 hours. u. AEs and SAEs will be monitored and recorded from date of signed informed consent / assent until the EOS visit or until the last AT follow-up visit, whichever occurs later. Signs and symptoms of thrombosis will be evaluated at every visit. v. In addition to recording concomitant medications, documented history of prior medications will be collected during screening.Table 3C. Schedule of Activities (fitusiran-naive arm) - treatment Week 84 through AT follow-up76MF-364681141Attorney Reference: 15979-20207.4077MF-364681141Attorney Reference: 15979-20207.40Abbreviations: ADA = antidrug antibody; AE = adverse event; APRI = AST to platelet ratio index; AT = antithrombin; BPA = bypassing agent; CFC = clotting factor concentrate; eDiary = electronic diary; EOS = End of Study; EOT = End of Treatment; EQ-5D-Y-3L = EuroQoL-5 dimensions-youth 3-level; ET = Early Termination; FVIII = factor VIII; FIX = factor IX; FU = follow-up; HJHS = Hemophilia joint health score; IMP=investigational medicinal product; LFT = liver function test; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; S = mandatory site visit; S / H = site or home visit option; SAE = serious adverse event; ULN = upper limit of normal.Notes:• In exceptional circumstances, screening for new participants may be extended beyond the 8 weeks window after consultation with the Sponsor. In case it was needed, some assessments performed at the beginning of screening may have to be repeated.• Rescreening of new participants is permitted after consultation with the Medical Monitoring Team.• When scheduled at the same time points, vital signs will be performed before the physical examinations and blood sample collections.• Unless otherwise specified, assessments on dosing days are predose.• Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of 3% of total blood volume over a 4- weeks period. Sampling is prioritized for LFT, AT, hematology, biochemistry, ADA, and then PK. a Fitusiran as prophylaxis treatment and permitted on-demand use of CFCs or BPAs for treatment of breakthrough bleeding episodes. New participants may continue their routine CFC or BPA regimen (prophylaxis or on-demand) for up to the first 7 days following the first injection of fitusiran starting dose. Beginning at Day 8, CFC and BPA treatments for bleeding episode management should follow bleeding78MF-364681141Attorney Reference: 15979-20207.40 management guidelines. b Participants who discontinue fitusiran dosing for any reason will need to complete the EOS / ET visit and the AT F / U visits. They may receive treatment consistent with bleed management guidelines until their AT activity level returns to at least 60%, per the central laboratory, or per Investigator discretion in consultation with the Medical Monitoring Team. c The Site / Home visit option (“S / H”) refers to the option for participants to complete the study visit at home or at the study site, when permitted by local regulations. Mandatory site visits are indicated with “S”. If participants opt to conduct the visit at home, they must follow the guidelines for IMP administration via home injection. Any requirement for AT / LFT sample collection for central laboratory assessment must be maintained. In case of any fitusiran dose change, the participant must receive the first injection of that dose at the study site. d SC administration of fitusiran as per the Pharmacy Manual and will continue every 28 days ±7 days, even when study site visits and assessments occur quarterly. Training on home injection will occur at the study site. Home injection may occur as per conditions and instructions provided herein (in case of a fitusiran dose change while the participant in receiving home injections, see also footnote c). e A complete physical examination will be performed at screening only; a directed physical examination will be performed at all other specified visits. f Height and weight will be recorded at all specified visits. g AT levels are tested monthly during the fitusiran treatment period up to Week 60. After the Week 60 visit, quarterly AT testing can be implemented. Participants on quarterly AT testing will need to resume monthly AT testing for at least 6 months every time there is a change in the fitusiran dose. Quarterly AT testing can be resumed afterward if the participant’s AT levels are between 15% to 35%. At each dose level, upon the first AT level <15%, the participant must have another AT activity level sample drawn within 1 week of site receipt of the results. If this second result is <15%, this will be considered the second AT activity level <15%. h On fitusiran dosing days, predose samples will be collected within 4 hours prior to dosing. i LFT results may be obtained up to 7 days before the study visit on which fitusiran dosing is scheduled. LFTs performed within 7 days of Day 1 will only be used to inform dosing on Day 1 and do not need to be used to confirm eligibility. LFTs can be analyzed locally, but if a local assessment is performed, a serum chemistry sample must also be collected for analysis at the central laboratory. LFT results will be obtained prior to receiving monthly fitusiran dosing. Monthly predose LFT testing is not required after Week 60 for participants who have met the criteria for quarterly predose LFT monitoring described as follows:Did not have any alanine transaminase elevation >3 x ULN persisting for >2 months at any time during fitusiran treatmentMust not have had any fitusiran doses held due to LFT elevations during the previous 12 months of fitusiran treatmentDid not have any escalation of fitusiran dose in the last 6 months j Blood samples for PK and ADA analysis will be collected. k PROMIS-SF: the form used is the PROMIS Parent Proxy Short Form vl.O - Physical Activity 4a (>5 years old). / PROMIS Pain: the form used is the PROMIS Numeric Rating Scale vl.O - Parent Proxy Pain Intensity la (>5 years old).79MF-364681141Attorney Reference: 15979-20207.40 m EQ-5D-Y-3L: the form used is the EQ-5D-Y-3L Proxy version 1 (>4 years old). n Bleed management review: will include review of entries, (symptoms of bleeding episodes, bleeding causality, bleeding location, reason for dosing, bleed severity, doses of CFCs or BPAs), whether appropriate study site contact occurred regarding treatment of bleeding episodes, and review of participant bleed management plan and recommendations and requirements for study site contact regarding dosing. o It is strongly preferred that details of doses of CFCs or BPAs administered and bleeding episodes are entered in the eDiary immediately or within 24 hours. p AEs and SAEs will be monitored and recorded from date of signed informed consent / assent until the EOS visit or until the last AT follow-up visit, whichever occurs later. Signs and symptoms of thrombosis will be evaluated at every visit. q In addition to recording concomitant medications, documented history of prior medications will be collected during screening.Table 4. Plasma Pharmacokinetic and ADA timepoints for fitusiran-naive participantsAbbreviations: ADA = antidrug antibody; PK = pharmacokinetics.aThese two additional samples are optional and will be needed from approximately 10 participants. These examples can be collected at the participant’s home via home nursing, if permitted by local regulations.Roll-Over Arm

[0174] Participants who enrolled in the previous dose confirmation study at age <12 years and who are still on active fitusiran treatment in the previous study will be eligible to roll80MF-364681141Attorney Reference: 15979-20207.40 over to this study and continue their current fitusiran treatment for an additional 60 weeks as soon as the study protocol is approved at their respective clinical site. If fitusiran dose adjustment is needed while participating in the previous study, roll-over participants will need to follow the dosing instructions in section Dosing Regimen.

[0175] Roll-over participants will not need to undergo screening or further eligibility assessments (but will need to provide consent before rolling over to the present study) and will enroll directly into the fitusiran treatment period and continue treatment on their current fitusiran dose. See FIG. 2.

[0176] The total study duration in the fitusiran roll-over arm will be up to approximately 84 weeks, and will include:A fitusiran treatment period of approximately 60 weeks An AT follow-up period of approximately 24 weeks.

[0177] The frequency of site visits for participants rolling over from the previous study will be approximately every 24 weeks. The frequency of telephone visits for all participants will be approximately every 2 weeks (±4 days) between site visits. If applicable, home or remote visits may be conducted during the study, where permitted by national and local regulations frequency.

[0178] The duration of fitusiran treatment will be up to 60 weeks for the roll-over arm, as provided in Table 5.Table 5. Schedule of Activities (Roll-Over) - Fitusiran Treatment Perioda81MF-364681141Attorney Reference: 15979-20207.4082MF-364681141Attorney Reference: 15979-20207.40Abbreviations: ADA = antidrug antibody; AE = adverse event; APRI = AST to platelet ratio index; AT = antithrombin; BPA = bypassing agent; CFC = clotting factor concentrate; eDiary = electronic diary; EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FVIII = factor VIII; FIX = factor IX; FU = follow-up; HJHS = Hemophilia joint health score; IMP=investigational medicinal product; LFT = liver function test; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; S = mandatory site visit; S / H = site or home visit option; SAE = serious adverse event, TG=thrombin generation; ULN = upper limit of normal.Notes:• Participants from the previous study will continue on their current fitusiran dose and will follow the dosing regimen of this study. Baseline visit in this study will be scheduled on the same date of the EOS visit in the previous study.• When scheduled at the same time points, vital signs will be performed before the physical examinations and blood sample collections.• Unless otherwise specified, assessments on dosing days are predose.• Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of 3% of total blood volume over a 4- weeks period. Sampling is prioritized for LFT, AT, hematology, biochemistry, ADA, and then PK. a Fitusiran as prophylaxis treatment and permitted on-demand use of CFCs or BPAs83MF-364681141Attorney Reference: 15979-20207.40 for treatment of breakthrough bleeding episodes. CFC and BPA treatments for bleeding episode management should follow bleeding management guidelines. b Participants who discontinue fitusiran dosing for any reason will need to complete the EOS / ET visit and the AT F / U visits. They may receive treatment consistent with bleed management guidelines until their AT activity level returns to at least 60%, per the central laboratory, or per Investigator discretion in consultation with the Medical Monitoring Team. c The baseline visit for this study should occur in the same day of the completion of the EOS visit for the previous study. The EOS visit tests and assessments in the previous study will be utilized as baseline results for this study. TG and PK testing (which are not part of the EOS assessment of the previous study) will be performed at Day 1 in this study. d The Site / Home visit option (“S / H”) refers to the option for participants to complete the study visit at home or at the study site, when permitted by local regulations. Mandatory site visits are indicated with “S”. If participants opt to conduct the visit at home, they must follow the guidelines for IMP administration via home injection. Any requirement for AT / LFT sample collection for central laboratory assessment must be maintained. In case of any fitusiran dose change, the participant must receive the first injection of that dose at the study site. e The ICF for this study should be signed after all the tests and assessments of the previous study End of Study (EOS) visit are performed. f Ongoing AEs from the previous study will be recorded as medical history at baseline. g Refresher eDiary training should be provided at the Baseline visit. h SC administration of fitusiran as per the Pharmacy Manual and will continue every 28 days ±7 days, even when study site visits and assessments occur quarterly. If needed, training on home injection will occur at the study site. Home injection may occur as per conditions and instructions provided herein (in case of a fitusiran dose change while the participant in receiving home injections, see also footnote d). Participants who are already on home injection will be allowed to continue as per instructions. i A directed physical examination will be performed at all specified site visits. j Height and weight will be recorded at all specified site visits. k Samples drawn from central lines may be excluded from TG analysis. / Participants on quarterly AT testing will need to resume monthly AT testing for at least 6 months every time there is a change in the fitusiran dose. Participants already on quarterly AT testing in the previous study can continue the same testing frequency in this study but monthly AT testing will need to be resumed if there is a change in the fitusiran dose. At each dose level, upon the first AT level <15%, the participant must have another AT activity level sample drawn within 1 week of site receipt of the results. If this second result is <15%, this will be considered the second AT activity level <15%. m On fitusiran dosing days, predose samples will be collected within 4 hours prior to dosing. n LFT results may be obtained up to 7 days before the study visit on which fitusiran dosing is scheduled. LFTs performed within 7 days of Day 1 will only be used to inform dosing on Day 1 and do not need to be used to confirm eligibility. LFTs can be analyzed locally, but if a local assessment is performed, a serum chemistry sample must also be collected for analysis at the central laboratory. LFT results will be obtained prior to receiving monthly fitusiran dosing. Monthly predose LFT testing is not required for rolled-over participants who have met the criteria for quarterly predose84MF-364681141Attorney Reference: 15979-20207.40LFT monitoring described as follows:Did not have any alanine transaminase elevation >3 x ULN persisting for >2 months at any time during fitusiran treatmentMust not have had any fitusiran doses held due to LFT elevations during the previous 12 months of fitusiran treatmentDid not have any escalation of fitusiran dose in the last 6 months o Blood samples for PK and ADA analysis will be collected. p Bleed management review: Will include review of entries, (symptoms of bleeding episodes, bleeding causality, bleeding location, reason for dosing, bleed severity, doses of CFCs or BPAs), whether appropriate study site contact occurred regarding treatment of bleeding episodes, and review of participant bleed management plan and recommendations and requirements for study site contact regarding dosing. q It is strongly preferred that details of doses of CFCs or BPAs administered and bleeding episodes are entered in the eDiary immediately or within 24 hours. r AEs and SAEs will be monitored and recorded from date of signed informed consent / assent until the EOS visit or until the last AT follow-up visit, whichever occurs later. Signs and symptoms of thrombosis will be evaluated at every visit. s Including concomitant medications which are ongoing at baseline visit.Table 6. Plasma Pharmacokinetic and ADA in participants who previously received fitusiran in the previous studyAbbreviations: ADA = antidrug antibody; EOT = End of Treatment; PK = pharmacokinetic s .Study DesignOverall Design

[0179] This is an open-label, multinational study of fitusiran prophylaxis in male participants aged 1 to <12 years with severe hemophilia A or B with or without inhibitory antibodies to factors VIII (FVIII) or IX (FIX). The primary objective of this study is to evaluate the treatment efficacy during the fitusiran prophylaxis and SOC periods in fitusiran- naive male participants, aged 1 to <12 years, with hemophilia A or B with or without inhibitory antibodies to FVIII or FIX.

[0180] Children diagnosed with severe hemophilia A or B with or without inhibitory antibodies are eligible for enrollment, irrespective of previous exposure to fitusiran.85MF-364681141Attorney Reference: 15979-20207.40Participants will be enrolled in one of two arms, one arm for fitusiran-naive participants and another arm for participants rolling over from the previous study. The primary analysis will only include fitusiran-naive participants and will be conducted once all these participants have completed Week 60 of the study.Fitusiran-Naive Participants

[0181] Participants who have not been previously exposed to fitusiran will be eligible for enrollment if they meet all inclusion criteria and none of the exclusion criteria.

[0182] These study participants will enter a screening period followed by a 24- week SOC period during which they will continue receiving their prior on-demand or prophylaxis regimen with CFCs or BPAs. This will be followed by a fitusiran treatment period, as described below.

[0183] During the 40-month (ie, 160- week) fitusiran treatment period, fitusiran-naive participants will receive fitusiran starting dose, administered SC QM. Participants who experience more than 1 AT activity level <15% (within a 12-month period) will be deescalated to lower fitusiran doses. If participants on the lowest fitusiran dose experience more than 1 AT activity level <15% (within a 12-month period), they must permanently discontinue fitusiran. If a participant’s steady state AT activity levels remain >35% while on the starting dose, the participant will be escalated to a higher dose. An additional escalation to a higher fitusiran dose would be required if the participant’s steady state AT activity levels remain >35% on the first escalation dose. The fitusiran dose can also be increased in cases of suboptimal bleed control, as judged by Investigator, despite an AT activity level <35%.Roll-Over Participants

[0184] Participants who enrolled in the previous study at age <12 years and who are still on active fitusiran treatment in the previous study will be eligible to roll over to this study and continue their current fitusiran treatment for an additional 60 weeks as soon as the study protocol is approved at their respective clinical site. They will not need to undergo screening or further eligibility assessments. If fitusiran dose adjustment is needed while participating in the previous study 5, roll-over participants will need to follow the dosing instructions provided herein.

[0185] Throughout the study, participants in both arms may receive on-demand treatment for breakthrough bleeding episodes with CFCs or BPAs, as appropriate. During the fitusiran86MF-364681141Attorney Reference: 15979-20207.40 treatment period and AT follow-up visits, participants must follow the specific bleed management guidelines provided herein.

[0186] Bleeding events and doses of CFCs or BPAs administered after enrollment will be recorded in an eDiary. Safety, QoL, PD, and PK data will also be collected.

[0187] After completion or premature permanent discontinuation of fitusiran prophylaxis, AT activity level will be monitored during the AT follow-up period at approximately monthly intervals following the final fitusiran dose until AT activity levels return to at least 60% as per the central laboratory. If applicable, for participants continuing fitusiran prophylaxis directly after the trial, the AT follow-up visits are not required.

[0188] Study details include:Fitusiran-naive arm• The total study duration in the fitusiran-naive arm will be up to approximately 216 weeks, and will include:A screening period of up to 8 weeksA standard of care (SOC) treatment period of approximately 24 weeks A fitusiran treatment period of approximately 160 weeks, consisting of the following:A dose adjustment period of approximately 12 weeks A primary efficacy period of approximately 48 weeks An extension period of approximately 100 weeks An AT follow-up period of approximately 24 weeks.Previous study roll-over arm• The total study duration for participants rolling over from the previous study will be up to approximately 84 weeks, and will include:A fitusiran treatment period of approximately 60 weeks. An AT follow-up period of approximately 24 weeks.

[0189] Fitusiran-naive participants will undergo two site visits during the SOC period. The frequency of site visits during the fitusiran treatment period will be approximately every 4 weeks during the first 24 weeks of fitusiran treatment, then approximately every 12 weeks until Week 84, and then approximately every 24 weeks thereafter. The frequency of site visits for participants rolling over from the previous study will be approximately every 24 weeks.The frequency of telephone visits for all participants will be approximately every 2 weeks (±487MF-364681141Attorney Reference: 15979-20207.40 days) between site visits. If applicable, home or remote visits may be conducted during the study, where permitted by national and local regulations.Scientific Rationale for Study Design

[0190] This study is a two-arm, Phase 3, multicenter, multinational, open-label study designed to demonstrate the efficacy and safety of fitusiran prophylaxis in male participants aged 1 to <12 years with severe hemophilia A or B, with or without inhibitory antibodies to factor VIII or IX, who are currently treated with prophylactic or on-demand regimens of CFCs / BPAs or who are rolling over from the previous study.

[0191] The primary objective is to characterize the frequency of treated bleeding episodes in fitusiran- naive participants receiving fitusiran prophylaxis. The crossover design in the fitusiran-naive arm of this study allows for intra-patient control to enable examination of the effect of the two treatment methods on the ABR during the CFC / BPA SOC period and the ABR when receiving fitusiran prophylaxis, while limiting confounding effects of different participant bleeding phenotypes and therapy variability. Given that the study design is a two- arm design, with a crossover from prophylaxis or on-demand SOC to fitusiran in the fitusiran- naive arm, the study is not blinded.

[0192] The primary endpoint of the study is ABR during the fitusiran primary efficacy period (Day 85 to Day 421) and in the SOC period. ABR is a well-established endpoint that has been used as the primary endpoint in global approvals of all hemophilia treatments. Secondary analyses evaluate annualized treated spontaneous (AsBR) and treated joint bleeding rates (AjBR) during the fitusiran primary efficacy period (Day 85 to Day 421) compared to the SOC period. Other secondary endpoints include ABR during the fitusiran treatment period for both arms, changes in PROMIS physical activity and pain scores, the safety and tolerability of fitusiran, and joint health outcomes. Characterization of bleeding episodes is clinically relevant to assess overall bleeding episode protection. Joint bleeding episodes result in pain and hemarthrosis, leading to progressive joint destruction, and hence are important to assess. The Euro-QoL is a hemophilia-specific health-related quality of life (HRQOL) survey instrument, has been used in other hemophilia clinical trials, has been validated, reviewed by clinicians, and is considered the most appropriate HRQOL tool available for use in the study.88MF-364681141Attorney Reference: 15979-20207.40End-of-Study Definition

[0193] A participant is considered to have completed the study if the participant has completed all periods of the study including the End of Study (EOS) visit. Following administration of the final fitusiran dose in the study, AT activity levels will be monitored at monthly intervals in participants who do not continue fitusiran treatment until activity levels return to at least 60% per the central laboratory, or per Investigator discretion in consultation with the Medical Monitoring Team. The end of the study is defined as the date of the last visit / last contact of the last participant in the study.Study Population

[0194] Male pediatric subjects (aged 1 to less than 12 years) diagnosed with severe hemophilia A or B with or without inhibitory antibodies are eligible for enrollment. Pediatric subjects previously treated with fitusiran in the previous study are also eligible and form the roll-over arm of the study. The present study population consists of participants who have never been exposed to fitusiran (fitusiran-naive arm), as well as participants who rolled over from the previous study (roll-over arm).

[0195] Approximately 60 fitusiran-naive participants with severe hemophilia A or B, with or without inhibitors (fitusiran-naive arm), and approximately 25 participants with severe hemophilia A or B with inhibitors rolling over from the previous dose confirmation study (roll-over arm) are enrolled in this study.Inclusion Criteria

[0196] Participants not previously exposed to fitusiran are eligible to be included in the study only if all of the following criteria apply:Age101. Participant must be 1 to <12 years of age at the time of signing the informed consent.Type of participant and disease characteristicsI 02. Participants must have severe hemophilia A or B (FVIII <1% or FIX <2%) as evidenced by a central laboratory measurement at screening or documented medical record evidence.I 03. Participants must meet inhibitor or non-inhibitor status as defined below:Inhibitor:89MF-364681141Attorney Reference: 15979-20207.40Requiring use of BPA for prophylaxis or BPA as on-demand therapy for any bleeding episodes for at least the last 3 months prior to screening, and meet one of the following Nijmegen-modified Bethesda assay results criteria:- Inhibitor titer of >0.6 BU / mL at screening, OR- Inhibitor titer of <0.6 BU / mL at screening with medical record evidence of 2 consecutive titers >0.6 BU / mL, OR- Inhibitor titer of <0.6 BU / mL at screening with medical record evidence of 1 inhibitor titer >0.6 BU / mL and a history of anamnestic response or severe allergic reaction (e.g. anaphylaxis) or nephrotic syndrome.Non-inhibitor:Requiring use of CFC for prophylaxis or CFC as on-demand therapy for any bleeding episodes for at least the last 3 months prior to screening, and meet each of the following criterion:- Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU / mL at screening, AND- No use of BPA to treat bleeding episodes for at least the last 3 months prior to screening.104. Participants must have adequate peripheral venous access, as determined by the Investigator, to allow the blood draws required by the study protocol.WeightNot applicable.Sex, contraceptive / barrier method and pregnancy testing requirements / breastfeeding105. MaleThere are no contraceptive requirements for this study except where required by local regulations.Informed ConsentI 06. Capable of giving signed informed consent / assent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. A signed written informed consent must be obtained from parent(s) / legal guardian (hereafter referred to as the “parent”), as well as a written or oral assent obtained from participant, per local and national requirements.90MF-364681141Attorney Reference: 15979-20207.40Exclusion Criteria

[0197] Participants not previously exposed to fitusiran are excluded from the study if any of the following criteria apply:Medical conditionsE 01. Known co-existing bleeding disorders other than hemophilia A or B, e.g., von Willebrand disease, additional factor deficiencies, or platelet disorders.E 02. Presence of clinically significant liver disease, or as indicated by any of the conditions below: a) International normalized ratio (INR) >1.2; b) Alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) >2 x ULN reference range; c) Total bilirubin >ULN (>2 x ULN in participants with Gilbert’s syndrome); d) History of portal hypertension, esophageal varices, or hepatic encephalopathy; e) Presence of ascites by physical examination.E 03. History of antiphospholipid antibody syndrome.E 04. History of arterial or venous thromboembolism, unrelated to an indwelling venous access.E 05. Any condition (e.g., medical concern), which in the opinion of the Investigator, would make the participant unsuitable for dosing or which could interfere with the study compliance, the participant’ s safety and / or the participant’ s participation in the completion of the treatment period of the study. This includes significant cardiovascular, neurologic, gastrointestinal, endocrine, renal (e.g., inadequate renal function), or psychiatric disorders unrelated to hemophilia identified by key laboratory abnormalities or medical history.E 06. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.E 07. Subjects with a central or peripheral indwelling catheter, with a history of venous access complications (such as infections, thrombosis) leading to hospitalization and / or systemic anticoagulation therapy in the last 12 months. (Note: Heparin flushing of a catheter is not to be considered systemic anticoagulation.) E 08. At screening, anticipated need of surgery during the study or planned surgery scheduled to occur during the study.91MF-364681141Attorney Reference: 15979-20207.40E 09. Completion of a surgical procedure within 14 days prior to screening, or currently receiving additional BPA infusion for postoperative hemostasis.E 10. History of intolerance to SC injection(s).Prior / concomitant therapyE l l. Current participation in ITI therapy.E 12. The use of emicizumab (Hemlibra®) or any non-factor bleed management treatment within 6 months prior to screening.E 13. Prior gene therapy.Prior / concurrent clinical study experienceE 14. Current or future participation in another clinical study, scheduled to occur during this study, involving an investigational product other than fitusiran or an investigational device; in order to participate in this study, participant must discontinue the investigational product or investigational device at least 30 days (or 5 x the investigational product half-life, whichever is longer) prior to dosing (Day 1).Diagnostic assessmentsE 15. AT activity <60% at screening, as determined by central laboratory analysis. E 16. Co-existing thrombophilic disorder, as determined by presence of any of the below as identified at central laboratory: a) Factor V Leiden mutation (homozygous or heterozygous), b) Protein S deficiency, c) Protein C deficiency, or d) Prothrombin mutation (G20210A; homozygous and heterozygous).E 17. Hepatitis C virus antibody positive, except participants with a history of HCV infection who meet both of the following conditions: a) Completed curative treatment at least 12 weeks prior to enrollment and attained sustained virologic response as documented by a negative HCV ribonucleic acid (RNA) at screening, or they have spontaneously cleared the infection as documented by negative HCV RNA at screening. b) No evidence of cirrhosis according to one of the following assessments:- FibroScan <9 kPa (where available), or- FibroTest score <0.36 and AST to platelet ratio index (APRI) <1 (if FibroScan unavailable) (Tokuhara et al., PLoS One. (2016) 11(1 l):e016668315; de Ledinghen et al., J Pediatr Gastroenterol Nutr. (2007) 45(4):443-50)92MF-364681141Attorney Reference: 15979-20207.40E 18. Presence of acute hepatitis, i.e., hepatitis A, hepatitis E.E 19. Presence of acute or chronic hepatitis B infection (IgM antibody to hepatitis B core antigen [anti-HBc IgM] positive or hepatitis B surface antigen [HBsAg] positive)*.* As confirmed by central laboratory assessment of HBsAg, anti-HBc IgM and Total hepatitis B core antibody (Total anti-HBc).E 20. Platelet count <100, 000 / pL.E 21. Presence of acute infection at screening, not including minor viral syndromes at the discretion of the Investigator in consultation with the study Medical Manager. E 22. Known to be human immunodeficiency virus (HIV) positive with cluster of differentiation (CD) 4 count <400 cells / pL.E 23. Estimated glomerular filtration rate <45 mL / min / 1.73 m2(using the Schwartz formula).Other exclusion criteriaE 24. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.E 25. Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.E 26. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with Section 1.61 of the ICH-GCP Ordinance E6).E 27. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.E 28. Any country-related specific regulation that would prevent the participant from entering the study.Screen Failures

[0198] A screen failure occurs when a participant who consents to participate in the clinical study is not subsequently enrolled in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the CONSORT publishing requirements and to respond to queries from regulatory93MF-364681141Attorney Reference: 15979-20207.40 authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, and any SAE.

[0199] Individuals who do not meet the criteria for participation in this study (screen failure) due to reasons expected to change at rescreening may be rescreened once.Participants who are rescreened are required to sign a new informed consent form, and should be assigned a new study participant number, and all the screening procedures should be repeated and entered in the screening visit pages.Study Interventions and Concomitant TherapyInvestigational medicinal product (IMP)

[0200] Participants will receive fitusiran as the investigational medicinal product (Table 15).Table 15. Investigational medicinal product administeredAbbreviations: AT=antithrombin; GalNAc=N-acetylgalactosamine; PBS=phosphate buffered saline; SC=subcutaneous; siRNA=small interfering RNA; QM=once monthly.• Formulation: fitusiran is formulated as 100 mg / mL and 12.5 mg / mL solutions for injection in phosphate buffered saline (PBS) (see FIGS. 1A-1B).• Route of administration: SC injection.• Dose regimen:94MF-364681141Attorney Reference: 15979-20207.40 o A starting dose of 10 mg QM in all fitusiran-naive participants, with possible escalation to 20 mg QM or 50 mg QM; and a possible de-escalation to 7.5 mg QM, 5 mg QM, 2.5 mg QM or 1.25 mg QM (FIG. 3). o Participants rolling over from the previous study will continue their current fitusiran dose. If dose adjustment is needed, they will follow the same dosing scheme as above.Auxiliary medicinal products (AxMPs)

[0201] Auxiliary medicinal products are described in Table 11 below.Table 11. Auxiliary medicinal product administeredAbbreviations: AT=antithrombin; ATC=Anatomical Therapeutic Chemical;ATIIIC=Antithrombin concentrate; BPA=bypassing agent; CFC=Clotting factor concentrate;IV=intravenous; SOC=standard of care.aFollowing local label requirement.

[0202] Participants may use on-demand CFC or BPA as auxiliary medicinal products (AxMPs) for treatment of breakthrough bleeding episodes, as described in Table 7 below.95MF-364681141Attorney Reference: 15979-20207.40• Formulation: CFCs, BPAs, and antithrombin concentrate are formulated as solutions for injection.• Route of administration: IV injection.• Dose regimen: following local label requirements during the SOC period and as per Bleed Management Recommendations during the fitusiran treatment period.

[0203] For the first 7 days after the start of fitusiran treatment, fitusiran-naive arm participants will continue their pre-study CFC or BPA therapies for hemophilia (prophylaxis or on-demand) on a regimen consistent with their pre-study regimen, within the general recommendation of the approved prescribing information, and per Investigator discretion. Bleeding episodes management should be per the local standard practice for on-demand use of CFCs or BPAs and as per Investigator discretion. After the first 7 days of fitusiran starting dose, participants must discontinue CFC or BPA prophylaxis. Breakthrough bleeding episodes may be treated with on-demand CFC or BPA therapy as necessary per the bleed management dosing guidelines.

[0204] Antithrombin concentrates (ATIIIC) can be used as AxMP in case reversal medication is needed. Details of the reversal medication (Antithrombin concentrate) are provided in section Reversal Medication.Study Arms

[0205] The arms for this study are described in Table 10.Table 10. Study arms96MF-364681141Attorney Reference: 15979-20207.40Abbreviations: AT=antithrombin; ATIIIC=antithrombin concentrate; BPA=bypassing agent; CFC=clotting factor concentrate; QM=once monthly.

[0206] The CFCs and BPAs may be supplied at the site or from the PPsite / Sponsor to the participant via a Sponsor-approved courier company where allowed by local regulations and agreed upon by the participant.

[0207] Post-trial access to study medication will be offered to study participants in line with local regulations and guidelines, as applicable.

[0208] The duration of study intervention for the fitusiran-naive arm will be up to 24 weeks for the SOC period and up to 160 weeks for the fitusiran treatment period. The duration of study intervention for the roll-over arm will be up to 60 weeks.Preparation, Handling, Storage, Accountability, Packaging, Labeling

[0209] The Investigator or designee must confirm appropriate conditions (eg, temperature) have been maintained during transit for all study intervention received and any discrepancies are reported and resolved before use of the study intervention.

[0210] Only participants enrolled in the study may receive study intervention and only authorized site staff may supply, prepare, or administer study intervention.

[0211] All study intervention must be stored in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the Investigator and authorized site staff.

[0212] The Investigator or authorized site staff is responsible for study intervention accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records).

[0213] Any quality issue noticed with the receipt or use of an IMP / AxMP (deficiency in condition, appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. Some deficiencies may be recorded through a complaint procedure

[0214] A potential defect in the quality of IMP / AxMP may be subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for promptly97MF-364681141Attorney Reference: 15979-20207.40 addressing any request made by the Sponsor, in order to recall the IMP / AxMP and eliminate potential hazards.

[0215] Under no circumstances will the Investigator supply IMP / AxMP to a third party (except for DTP shipment, for which a courier company has been approved by the Sponsor), allow the IMP / AxMP to be used other than as directed by this clinical trial protocol, or dispose of IMP / AxMP in any other manner.

[0216] All packaging, labeling, and production of the study drug will be in compliance with current Good Manufacturing Practice (GMP), or local applicable regulations, where necessary. Investigational medicinal product labels and external packaging will include all appropriate information as per local labeling requirements. Additional details will be available in the Pharmacy Manual.Home Injection

[0217] Home injection of fitusiran may be possible where permitted by national and local regulations. Participants must meet the eligibility requirements outlined below. In addition, the Investigator and the Sponsor must agree that home injection of fitusiran is appropriate for a given participant. The participant’s underlying comorbidities and ability to adhere to the requirements of the study must be taken into account when evaluating participants for eligibility to receive fitusiran using home injection. Any identified risk of noncompliance with study requirements or potential for loss to follow up should lead to a participant not being eligible to receive fitusiran using home injection. Home injection should begin no earlier than Week 28 for participants in the fitusiran-naive arm. Participants in the rollover arm who are already receiving home injections can continue doing so in this study.

[0218] Home injection of fitusiran may be performed by a healthcare professional or a caregiver (a caregiver can be a parent or legal guardian if they provide care), contingent upon completion of training. The Investigator can decide to stop home injections at any time if the requirements for home injection are no longer fulfilled. The DTP supply of IMP via courier could be used if allowed by local regulations and agreed upon by the participant.

[0219] The following criteria must be documented in the participant’s medical record:• The participant must be able to provide blood samples for central laboratory AT testing and any other tests.• The Investigator must document that home injection is appropriate for the participant98MF-364681141Attorney Reference: 15979-20207.40• The participant and participant's caregiver must be willing and able to comply with home injection procedures.• The participant’s caregiver has been trained on home injection process.• The participant must, in the Investigator’s (or designee’s) opinion, have been clinically stable with no history of moderate or severe IAR for at least 6 months.• The participant must have no ongoing (not yet recovered) SAEs that, in the opinion of the Investigator, may affect the participant’s ability to tolerate the injection.• Home injection infrastructure, resources, and procedures must be established and available according to applicable regional regulations.• The participant has not experienced a severe AE or SAE considered related to fitusiran within the past 12 weeks.• Participants who experience an ISR or an IAR (moderate or severe) while being injected at home will return to the study site for their following injection and will continue to receive injections at the study site until no such events are present for at least 12 weeks.• For participants receiving fitusiran injections at home as administered by a healthcare professional (where available), the healthcare professional will collect and review safety assessments (AEs, concomitant medications), confirm administration of the fitusiran dose, and review bleeding episode information in the eDiary.• For participants receiving fitusiran by a caregiver, the Investigator or delegate, via telephone, will collect and review safety assessments (AEs, concomitant medications), confirm administration of the fitusiran dose, and review bleeding episode information in the eDiary.• In the event of an IMP presentation or manufacturing change, the participant will be required to receive the first injection at the site. All criteria for the return to home injection of fitusiran will apply.• The first injection under a new dose level must be administered at the clinical site.• Prior to beginning home injection of fitusiran, training will be provided to the participant’ s caregiver by the Investigator or a qualified healthcare99MF-364681141Attorney Reference: 15979-20207.40 professional according to the protocol dosing requirements and the Instruction For Use Manual. Training of the participant’s caregiver will be tracked in the participant’ s file.Study Intervention Compliance

[0220] When participants are dosed at the site, they will receive study intervention directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of study intervention and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study intervention.

[0221] When participants receive the study intervention(s) at home, compliance with study intervention will be assessed at each visit. Compliance will be assessed by direct questioning during the telephone visit, by return of used vials and empty boxes / medical devices during the site visits and documented in the source documents and relevant form. Deviation(s) from the prescribed dosage regimen should be recorded.

[0222] A record of the quantity of IMP dispensed to and administered by each participant must be maintained and reconciled with study intervention and compliance records.Intervention start and stop dates, including dates for intervention delays and / or dose reductions will also be recorded.Dosing Regimen and Modification

[0223] Fitusiran-naive participants will start on fitusiran 10 mg SC every 4 weeks (FIG. 3). Participants rolling over from the previous study will continue receiving the fitusiran dose they were receiving in that study. The decision to modify the fitusiran doses during this study will be mainly based on the AT activity level. Specific clinical criteria can be assessed by the Investigator as basis for dose modification, upon consultation with the Medical Monitoring Team.Dose Escalation

[0224] Participants on the 10 mg fitusiran dose will be escalated to 20 mg every 4 weeks (QM) if they have more than 1 steady state AT value >35% (as per central laboratory), starting with the third fitusiran injection at the 10 mg dose.100MF-364681141Attorney Reference: 15979-20207.40

[0225] Participants receiving the 20 mg dose will be further escalated to 50 mg every 4 weeks (QM) if they have more than 1 AT value >35% (as per central laboratory), starting with the AT measurement at their third fitusiran injection at the 20 mg dose.

[0226] If a participant has more than 1 AT activity level <15% (within a 12-month period) after escalation to 20 mg or 50 mg, the Investigator will consult with the study Medical Manager regarding further treatment with fitusiran.Dose De-Escalation

[0227] Participants receiving fitusiran at the starting dose of 10 mg will be de-escalated to 5 mg every 4 weeks (QM) if participants have more than 1 AT activity level <15% (within a 12-month period) while on the 10 mg starting dose. The dose of 5 mg QM should only start once the participant’s AT activity level reaches >22%.

[0228] Participants with more than 1 AT level <15% on the 5 mg dose (within a 12-month period) will be further deescalated to 1.25 mg every 4 weeks (QM). The dose of 1.25 mg QM should only start once the participant’s AT activity level reaches >22%.

[0229] Participants with more than 1 AT level <15% on the 1.25 mg dose (within a 12- month period) must permanently discontinue fitusiran.

[0230] Participants de-escalated to 5 mg will be up titrated to 7.5 mg QM if they have 2 steady state AT values >35 on the 5 mg dose. Further escalation to the 10 mg dose (in case of 2 steady AT values >35% on the 7.5 mg dose) or de-escalation to the 5 mg dose (in case of more than 1 AT value <15% on the 7.5 mg dose) can be considered, after discussion with the medical monitoring team.

[0231] Participants de-escalated to 1.25 mg will be up titrated to 2.5 mg QM if they have 2 steady state AT values >35. Further escalation to the 5 mg dose (in case of 2 steady AT values >35% on the 2.5 mg dose) or de-escalation to the 1.25 mg dose (in case of more than 1 AT value <15% on the 2.5 mg dose) can be considered, after discussion with the medical monitoring team.

[0232] At each dose level, upon the first AT activity level <15%, the participant must have another AT measurement within 1 week of site receipt of the results. If the second result is <15%, this will be considered the second AT activity level <15%. Participants with 1 AT activity level <15% must not receive fitusiran at their current dose regimen until the AT activity level from the second measurement is available to guide management.

[0233] The Investigator may request approval from the study Medical Manager to escalate to a higher dose of fitusiran, despite an AT activity level <35%, if:101MF-364681141Attorney Reference: 15979-20207.40• At least 2 doses of fitusiran at the current dose level have been administered, and• The Investigator judges suboptimal bleeding control at the current dose level, which is defined as 2 or more treated bleeds within a 12- week period starting with the third fitusiran injection at the current dose.

[0234] Participants rolling over from the previous study will continue receiving the same fitusiran dose they were receiving in the previous study. If there is a need to escalate or de- escalate their dose, they will follow the same escalation and de-escalation requirements mentioned above.

[0235] AT levels and additional clinical data, as applicable, will be considered in the dose escalation of individual participants.

[0236] If the Investigator believes that a specific participant warrants dose escalation based on a different reason, they may discuss the case with the Medical Monitoring Team.Liver Function Test criteria for withholding, monitoring and stopping fitusiran dosing

[0237] Liver function test (LFT) results are to be obtained within 7 days prior to dosing and results are to be reviewed prior to each dose of fitusiran (or on quarterly basis for participants satisfying the quarterly LFT testing requirements). Central laboratory test results are preferable. If not available, local laboratory test results may be used; however, if a local assessment is performed, a serum chemistry sample must also be collected for analysis at the central laboratory.

[0238] For any ALT or AST elevation >3 x ULN central laboratory test results should be used to guide subsequent monitoring as detailed in Table 12.

[0239] For any ALT or AST elevation >3 x ULN:• Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but no later than 7 days• Perform assessments per Table 13 and Table 14.• If an alternative cause is found, provide appropriate care

[0240] For any ALT or AST elevation >3 x ULN without alternative cause that is accompanied by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant abdominal pain, jaundice) or elevated bilirubin to >2 x ULN or INR >1.5, permanently discontinue dosing with fitusiran.102MF-364681141Attorney Reference: 15979-20207.40

[0241] For confirmed ALT or AST elevations >3 x ULN without alternative cause and not accompanied by symptoms or elevated bilirubin >2 x ULN or INR >1.5, see Table 12.Table 12. Monitoring and dosing rules for asymptomatic participants with confirmed isolated elevations of ALT and / or AST >3 x ULN, with no alternative cause identifiedAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFT = liver function test; ULN = upper limit of normal. Note: In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, as appropriate.Table 13. Protocol-required laboratory tests103MF-364681141Attorney Reference: 15979-20207.40Table 14. Hepatic assessments in participants who experience LFT elevationsAbbreviations: CT = computed tomography; HAV = hepatitis A virus; HBc = hepatitis B core; HBsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; HEV = hepatitis E virus; HHV-6 = human herpes virus 6; HIV = human immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; LFT=liver function test; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; RNA = ribonucleic acid.Note: All assessments will be analyzed in a central laboratory. The full panel of assessments should only be performed once (based on the clinical context); individual assessments may be repeated, as needed.aHepatitis tests will be mandatory, whereas the remaining tests are optional and should be requested based on the clinical context, and as per Investigator assessment.bHIV testing will not be performed where prohibited by local regulations.104MF-364681141Attorney Reference: 15979-20207.40Continued Access to Intervention After the End of the Study[ 2A2\ Local standard treatment of hemophilia will be considered after the end of the study, when the AT activity levels will have returned to at least 60% (per the central laboratory).

[0243] Depending on the participant’ s medical need, the availability of alternative therapies, and an assessment of what is known about the benefits and risks of fitusiran, posttrial access to study medication may be offered to participants who have completed their participation in this clinical trial. For participants continuing fitusiran prophylaxis directly after the trial, the AT follow-up visits will not be required.

[0244] The Investigator / treating physician will determine if access to fitusiran is the best medical option for the participant and will then submit a request to Sanofi. Post-trial access to fitusiran will be in compliance with all applicable national and local laws and regulations, including safety reporting obligations.

[0245] A patient will not be eligible for post-trial access if their participation in the trial is terminated prematurely.Treatment of Overdose

[0246] An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or spontaneously notified by the participant and defined as at least twice the intended dose within the planned therapeutic interval. The minimal therapeutic interval in this study is 14 days.

[0247] The Sponsor does not recommend specific treatment for an overdose. Administration of AT may be used in case of overdose, after discussion between the Investigator and the Medical Monitoring Team.

[0248] In the event of an overdose, the Investigator should:• Closely monitor the participant for any AE / SAE and laboratory abnormalities.• Document appropriately in the CRF.

[0249] Decisions regarding dose interruptions or modifications will be made by the Investigator in consultation with the Medical Monitoring Team based on the clinical evaluation of the participant.105MF-364681141Attorney Reference: 15979-20207.40Prior and Concomitant Therapy

[0250] Any medication or vaccine (including over the counter or prescription medicines, vitamins, and / or herbal supplements) that the participant is receiving at the time of enrollment or receives during the study must be recorded along with the following:• Reason for use• Dates of administration including start and end dates• Dosage information including dose and frequency.

[0251] Participants must consult with the Investigator before taking any prescription or nonprescription drugs within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study drug and up until completion of the last follow up visit.Prohibited medication / therapies during the study• Use of prothrombin complex concentrates for bleeding episode management is not permitted.• Antifibrinolytics may be used as single agents but may not be used in combination with CFCs or BPAs.• Use of aPCC and rFVIIa as combination therapy is not recommended.• Use of emicizumab (Hemlibra®) or anti-tissue factor pathway inhibitors during the study is not permitted.• Gene therapy is not permitted.• Use of >75 mg / kg acetaminophen / paracetamol per day is not permitted.• Any investigational medication / therapy other than fitusiran is not permitted.Concomitant hemophilia medication during the study

[0252] CFCs and BPAs such as rFVIIa (NovoSeven®), and aPCC (FEIBA®) are considered to be AxMP in this study. Use of these agents administered after enrollment will be captured in the participant’s eDiary. Other concomitant medications may be considered on a case by case basis by the Investigator in consultation with the study Medical Manager if required.Prophylaxis or on-demand therapy during the SOC period

[0253] Fitusiran-naive participants previously receiving CFC or BPA prophylaxis will continue to receive their pre-study prophylaxis regimen during the SOC period. The regimen106MF-364681141Attorney Reference: 15979-20207.40 should allow for adjustment to individual participant response, and should be designed to decrease spontaneous bleeding, especially joint bleeding. CFC or BPA doses and frequency should follow the local prescribing information.

[0254] The CFC or BPA prophylaxis regimen used during this SOC period must have a minimum frequency of administration as presented in Table 16.Table 16. CFC or BPA prophylaxis requirementsAbbreviation: aPCC= activated prothrombin complex concentrates; BPA=bypassing agent; CFC=clotting factor concentrate; FVIII = Factor VIII; FIX = Factor IX; rFVIIa=recombinant Factor Vila.Management of CFC or BPA prophylaxis during the transition tofitusiran treatment period

[0255] Fitusiran-naive participants who were on a prophylaxis regimen during the SOC period will continue CFC or BPA prophylaxis with a minimum frequency as in Table 16, for the first 7 days of the fitusiran onset period. Subsequent to Day 7 of the fitusiran treatment period, CFCs or BPAs should be administered only for bleeding episodes or if needed in advance of invasive medical procedures.

[0256] Use of CFCs / BPAs from Day 8 to Week 160 as prophylaxis for bleed prevention is not permitted.Other concomitant medications

[0257] Treatment for HIV is permitted and must be recorded as concomitant medication.

[0258] Standard vitamins and topical medications are permitted. However, topical steroids must not be applied anywhere near the injection site(s) unless medically indicated.

[0259] Any concomitant medication that is required for the participant's welfare may be prescribed by the Investigator. However, it is the responsibility of the Investigator to ensure that details regarding the medication are recorded on the eCRF. Concomitant medication will be coded using World Health Organization (WHO) Drug Dictionary.107MF-364681141Attorney Reference: 15979-20207.40Management of bleeding episodes

[0260] The occurrence of bleeding episodes is a typical characteristic of hemophilia; bleeding episodes will be recorded as efficacy assessments of fitusiran and will not be considered as AEs unlessassociated with an injection of fitusiran (eg, bleeding or bruising at the injection site) or the criteria for SAEs are met. Bleeding episodes will be recorded in the eDiary. For bleeding episodes in which there were no CFC or BPA infusions or other type of intervention employed, the reason the bleeding episodes were untreated will be recorded in the eDiary.

[0261] Investigators are required to establish and provide instructions for an individualized bleed management plan based on the guidelines in Table 7 for each participant.

[0262] The bleed management plan and all data recorded by the participant in the eDiary should be reviewed by the Investigator or designee with the participant at least every 2 weeks (+ / - 4 days) via telephone visits and at each study site visit.During the SOC period (participants not receiving fitusiran)

[0263] During the SOC period, all participants should receive bleed management therapy with factor VIII or factor IX concentrates (CFCs) or BPAs as prior to study and as approved locally.

[0264] Where clinical circumstances allow, it is recommended that the participants contact the Investigator or designee for all events that may be suspected to be or are characteristic of a bleeding episode. If adequate hemostasis does not occur after two doses of factor or BPA, the participant should contact the site for further instructions.

[0265] If the participant feels the need to administer doses higher than the participant’s bleeding episode management plan recommends, or at a higher frequency, it is recommended that the participant contact the site.During the fitusiran treatment period

[0266] Since it is expected that participants may have varying AT activity levels at study entry, depending whether they were previously exposed or naive to fitusiran, approaches to bleed management are described below based on AT activity levels at study entry.Participants with AT activity level of >60% (per central laboratory) at study entry108MF-364681141Attorney Reference: 15979-20207.40

[0267] After Day 1 of fitusiran dosing when the AT activity level is >60%, it is recommended that participants and / or their caregiver call the Investigator prior to dosing with CFC or BPA.

[0268] As quickly as 7 days after the initial fitusiran dose, the majority of participants may have AT activity levels at or below 60% activity. By 14 days after the first fitusiran dose, it is expected that most participants will have reached a clinically meaningful reduction in AT level. Based on these AT activity kinetics, it is recommended that participants continue with their standard CFC or BPA regimens for the first week following initiation of fitusiran dosing, with institution of the protocol specific bleed management guidelines with reduced CFC or BPA starting the second week after initiation or re-initiation of fitusiran dosing, as described below and in Table 7.Day 1 to Day 7 (fitusiran-naive arm only)

[0269] Participants should be instructed to call the site prior to administering CFCs or BPAs for the management of bleeding episodes. Participants may continue with their standard CFC or BPA regimens including their previous prophylaxis or on-demand treatment, as applicable.Day 1 (roll-over arm) or Day 8 (fitusiran-naive arm) until end of fitusiran treatment

[0270] When a participant experiences symptoms that may be consistent with bleeding episodes, the following steps should be followed:1. The participant and / or their caregiver should be instructed to call the study site to discuss symptoms to determine whether or not they are consistent with a bleeding episode and to discuss the appropriate CFC or BPA dose to use. This interaction between participant and / or their caregiver and Investigator is recommended prior to the administration of each dose of CFC or BPA. Confirmation of bleeding episodes at the study site prior to treatment may be considered.2. If a determination is made that symptoms require treatment, the recommended treatment algorithm for bleeding episodes is described below: a) A single dose can be administered according to the guidelines in Table 7. b) The participant and / or their caregiver should be instructed to re-evaluate symptoms in 24 hours for bleeding episodes treated with FVIII, FIX, or aPCC and in 2 to 3 hours for bleeding episodes treated with rFVIIa. Administration of FIX extended half-life should not be more frequent than every 5-7 days.109MF-364681141Attorney Reference: 15979-20207.403. If a second dose (in the case of FVIII, FIX, or aPCC) or a third dose (in the case of rFVIIa) is needed, the participant and / or their caregiver must call the study site before dosing. a) Consider evaluation and treatment of the participant at the study site and confirmation of bleeding episodes when repeated doses are needed. b) If more than 2 doses of FVIII, FIX, or aPCC or 3 doses of rFVIIa are needed, the participant should be seen at the study site within 48 to 72 hours, if required as per Investigator’s judgement.4. Doses should not be administered at less than 24-hour intervals (except rFVIIa as indicated in Table 7).5. Doses should not exceed the protocol recommended maximum dose indicated in Table 7.6. Consultation with the study Medical Manager and Clinical Advisor should be considered for the following clinical circumstances: a) Doses of CFC or BPA higher than those recommended in Table 7. b) Dosing of CFC or BPA at decreased intervals than those recommended in Table 7. c) Multiple or repeat doses of CFC or BPA.7. Antifibrinolytics may not be used in combination with CFC or BPA.Table 7. Bleed management dosing guidelines by specific product110MF-364681141Attorney Reference: 15979-20207.40Abbreviations: aPCC = activated prothrombin complex concentrate; BPA = bypassing agentaShould not repeat in less than 72 hours if efanesoctocog alfa (Altuviiio / Altuvoct) is used.bFor Sevenfact, use half the standard dose with standard treatment frequency.Bleeding episode management following discontinuation of fitusiran

[0271] Participants who opt to discontinue fitusiran may resume standard prophylaxis or on-demand dosing with CFCs or BPAs when their AT activity level returns to approximately 60% (per the central laboratory). An earlier restart of standard treatment may be considered in conjunction with consultation from the study Medical Manager, if a strong medical need arises (e.g., increased frequency of bleeding). If full doses of CFCs or BPAs are required to achieve hemostasis prior to full AT recovery (approximately 60% AT activity per the central laboratory), AT replacement could be considered, if needed.Monitoring and Management of Thrombotic Events

[0272] As serious vascular (arterial and venous) thrombotic events have been reported in patients exposed to fitusiran, Investigators should diligently evaluate signs and symptoms potentially consistent with these diagnoses. Signs and symptoms of vascular thrombotic events may include, but are not limited to, severe or persistent headache, headache with nausea and vomiting, chest pain and / or tightness, coughing up blood, trouble breathing, abdominal pain, fainting or loss of consciousness, swelling or pain in the arms or legs, vision problems, weakness and / or sensory deficits, and changes in speech.

[0273] An evaluation of signs and symptoms potentially consistent with vascular thrombosis should include appropriate imaging studies as applicable. Copies of radiographic images and imaging reports should be submitted to the Sponsor (or representative).

[0274] If a participant develops thrombosis while on fitusiran, AT reversal could be considered, if needed, in combination with factor or BPA replacement and appropriate anticoagulation. Antithrombin reversal should follow labeled product recommendations for the prevention of perioperative thrombosis in participants with AT deficiency, and participant doses individualized to target 80% to 120% AT activity level. The use of plasma derived AT111MF-364681141Attorney Reference: 15979-20207.40 may be preferable to recombinant AT, given its longer half-life. It is recommended that cases of thrombosis are discussed with the Medical Monitoring Team.Management of Surgery

[0275] Participants with planned or anticipated surgical procedures should not be enrolled into this study before completing the surgical procedure. However, if a need for surgery arises during the study period, the Medical Monitoring Team should be informed, and the perioperative hemostatic treatment plan should be communicated to the Team prior to the procedure unless clinical circumstances do not allow.

[0276] Minor surgery is defined as any invasive operative procedure in which only skin, mucous membranes, or superficial connective tissue is manipulated and does not meet the criteria for major surgery (eg, dental extraction of <3 nonmolar teeth). Minor surgical procedures may be performed at a local health care provider institution.

[0277] Major surgery is defined as any invasive operative procedure that requires any of the following:• Opening into a major body cavity (eg, abdomen, thorax, skull)• Operation on a joint• Removal of an organ• Dental extraction of any molar teeth or >3 nonmolar teeth• Operative alteration of normal anatomy• Crossing of a mesenchymal barrier (eg, pleura, peritoneum, dura)

[0278] It is recommended that any elective nondental major surgery be performed at a study site, when possible.

[0279] In participants who will undergo major a surgical procedure, a written perioperative treatment plan will be reviewed with the Medical Monitoring Team before conducting the procedure, unless clinical circumstances do not allow. The perioperative treatment plan should be developed using the same principles as bleed management described herein and the following guidelines:

[0280] If the clinical circumstance is such that the recommended doses and / or dose intervals in Table 7 are deemed insufficient for hemostasis, consider AT replacement and manage thrombotic risk as per Investigator practice for a hemophilia participant undergoing that particular surgical procedure.112MF-364681141Attorney Reference: 15979-20207.40

[0281] Nonpharmacologic methods of thromboprophylaxis should also be employed as clinically indicated.Fitusiran treatment during the perioperative evaluation period

[0282] For minor operative procedures, dosing with fitusiran may continue uninterrupted.

[0283] If the need for major surgery arises during the study, the participant should be managed medically according to the guidelines provided in this section. If a fitusiran dose is scheduled to occur on or in close proximity to the day of surgery, or anytime during the perioperative period, the dose should be withheld.

[0284] The Perioperative Evaluation Period is defined as the day of the surgery through the final day on which supplemental hemostatic or antithrombotic treatments are administered as part of the perioperative treatment plan. Fitusiran dosing may be resumed at the next scheduled dosing visit following the Perioperative Evaluation Period at the discretion of the Investigator. If multiple consecutive doses of fitusiran are withheld, the Investigator will consult with the Medical Monitoring Team, who will determine if the participant may continue in the study.Perioperative assessments of safety and hemostatic efficacy in participants who undergo major operative procedures

[0285] In participants who undergo major operative procedures during the treatment period, safety and hemostatic efficacy assessments will be performed according to the Perioperative SoA (described below and outlined in Table 17), where possible.

[0286] After a review of medical and surgery history has been completed, participants will have the following assessed as specified in the Perioperative SoA (Table 17): directed physical examination and assessment of vital sign measurements; clinical laboratory assessments including hematology (complete blood count, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelets); serum chemistry, coagulation (activated partial thromboplastin time [APTT], prothrombin time [PT], INR, fibrinogen, D-dimer); hepatic assessments [LFTs]; and hemostatic efficacy assessments (perioperative questionnaire based on ISTH Scientific and Standardization Committee [SSC] definitions).Table 17. Perioperative schedule of assessments in participants undergoing major operative proceduresPerioperative Evaluation Period61113MF-364681141Attorney Reference: 15979-20207.40Abbreviations: AT = antithrombin; BPA = bypassing agent; LFT = liver function test; SDay = surgery day; SoA = schedule of activities. Note: Any operative procedure dates (SDay -3 to SDay 28) may overlap with the study SoA. a During the Perioperative Evaluation Period, AEs and concomitant medications will be collected continuously per the study protocol SoA. b Assessments to be completed within 24 hours (±12 hours) from the time of end of the surgical procedure. c Visit may occur anytime between SDay 2 to SDay 14, postoperatively, on a day to be determined by the Investigator. If multiple visits are planned between Days 2 and 14 after the surgical procedure, the perioperative questionnaire for Postoperative Visit 2 should be completed on the day of the last visit. d Directed physical examination. e Vital signs will be the same as conducted per the study protocol SoA. f Clinical laboratory assessments will include hematology, serum chemistry, LFTs, and coagulation (Table 13). g If the procedure is not performed at a study site, then these assessments are recommended, but not required. If the assessments are performed, they must be performed on the day of the procedure before the operation and after CFC or BPA administration. h Hemostatic efficacy is to be assessed intraoperatively with the perioperative questionnaire on the day of the procedure (SDay 0); assessment may be completed up to 8 hours postoperatively. The perioperative assessment (by using perioperative questionnaire) will also be completed at Postoperative Visit 1 and Visit 2. i This postoperative assessment is required if the procedure is performed at a study site. j The date and time of when perioperative hemostatic treatment and thromboprophylaxis (if applicable) coverage was completed will be captured. If completed at postoperative Visit 2, the date / time of completion should be recorded114MF-364681141Attorney Reference: 15979-20207.40 and the postoperative visit 3 (SDay 28) is not required.Reversal Medication

[0287] The supply of reversal medications will be specified at the country level. The following reversal medications may be used:• Antithrombin concentrate.

[0288] Antithrombin reversal should follow labeled product recommendations for the prevention of perioperative thrombosis in participants with AT deficiency, and participant doses individualized to target 80% to 120% AT activity level.

[0289] The date and time of reversal medication administration as well as the name and dosage regimen of the reversal medication must be recorded.Efficacy Assessments

[0290] Planned timepoints for all efficacy assessments are provided in the Objectives and Endpoints section.Bleeding Episodes

[0291] A bleeding episode is defined as any occurrence of hemorrhage that requires administration of CFCs or BPAs, eg, hemarthrosis, muscle, or mucosal bleeding. As bleeding episodes are to be recorded as an efficacy assessment of fitusiran, bleeding episodes will not be treated as AEs unless they meet any of the SAE criteria provided herein.

[0292] The definition of bleeding episode types described below is based on consensus opinion of International Society on Thrombosis and Hemostasis (ISTH).

[0293] The start time of a bleeding episode will be considered the time at which symptoms of a bleeding episode first develop. Bleeding or any symptoms of bleeding at the same location that occur within 72 hours of the last injection used to treat a bleeding episode at that location will be considered a part of the original bleeding episode, and will count as 1 bleeding event towards the ABR. Any bleeding symptoms that begin more than 72 hours after the last injection used to treat a bleeding episode at that location will constitute a new bleeding event.

[0294] A spontaneous bleeding episode is a bleeding episode that occurs for no apparent or known reason, particularly into the joints, muscles, and soft tissues.

[0295] A joint bleeding episode is characterized by an unusual sensation in the joint (“aura”) in combination with 1) increasing swelling or warmth over the skin over the joint, 2)115MF-364681141Attorney Reference: 15979-20207.40 increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline.

[0296] A muscle bleed may be characterized by pain, swelling, and loss of movement over the affected muscle group.

[0297] A target joint is defined as a joint where 3 or more spontaneous bleeding episodes in a single joint within a consecutive 6-month period has occurred; where there have been <2 bleeding episodes in the joint within a consecutive 12-month period, the joint is no longer considered a target joint.

[0298] A traumatic bleeding episode is one that is caused by a known injury or trauma. Bleeding episodes sustained during sports and recreation will be counted as traumatic bleeding episodes, but participants will be asked to indicate in the eDiary that the event occurred during such activities. Training will be provided on recording details of traumatic bleeding episodes and other aspects of eDiary use. eDiary

[0299] Participants will be supplied with an electronic diary (eDiary) to record all bleeding episodes, and all doses of CFCs or BPAs administered during the conduct of the study. Entries are to be made in a timely manner, and it is preferred that details of bleeding episodes and CFC / BPA doses are entered immediately upon occurrence / administration or within 24 hours.

[0300] An eDiary training will be completed at the study site at Week -24 visit. The eDiary training may be repeated during the study if needed. Training of participants and / or caregiver should be documented in the appropriate source record.

[0301] Participants and caregivers will be prompted to enter:• bleeding location• severity• causality (spontaneous or traumatic)• doses of CFCs or BPAs• symptoms of bleeding episodes, and• reasons for dosing (prophylaxis, treatment of a bleed)

[0302] The Sponsor or a delegate will review eDiary entries for data quality to identify issues such as participants who may need retraining on eDiary use and timely entry of bleeding episode information.116MF-364681141Attorney Reference: 15979-20207.40

[0303] Data recorded by the participant and / or caregiver in the eDiary will be reviewed by the Investigator or designee (and by Sponsor representatives) continuously for the study duration. The study site will contact the participant at a minimum interval of every 2 weeks (±4 days) between visits per the SoA to review eDiary records and ensure that the participant is following the bleeding episode management plan recommendations.

[0304] Sites will be notified when participants enter details of initial treatments for bleeding episodes into their eDiaries. If the dose amount exceeds the recommended dose according to the bleeding episode management plan, or if there are any other discrepancies or issues noted with the eDiary data, the participant must be contacted as soon as possible, preferably within 24 to 48 hours of receiving the alert.

[0305] At the time of contact, the participant’s clinical condition will be reviewed along with the dose and efficacy of the treatment given, and the Investigator will provide appropriate guidance regarding further management of the bleeding episode. The study site will also receive an alert, and must make contact with the participant as soon as possible if a third dose of product is administered for a single bleed, to review clinical condition, the need for further therapy, and appropriate ongoing management of the bleeding episode required to achieve hemostasis.

[0306] In addition, participants and / or caregivers will be instructed to contact the study site if they feel they need to administer CFCs or BPAs at a higher dose level or higher frequency than their bleeding episode management plan recommends, or if more than two doses are required to achieve hemostasis.

[0307] Complete instructions for use and review of the eDiary will be provided in the eDiary Manual.Clinical Outcome Assessment Measures (fitusiran-naive arm only)

[0308] Clinical outcome assessments (COAs) will be utilized in this study where available to assess participant health-related quality of life (HRQoL), physical activity, pain, and joint health. All completed questionnaires or instrument forms for the COAs described below will be collected, entered into a database, and archived.

[0309] The Sponsor or designee will provide the translations for all instruments: sites must not translate any instruments themselves.

[0310] Participants and their caregivers will complete several COA measures during this study. These will only be completed by participants’ caregivers (the Observer Reported Outcome [ObsRO] measures, sometimes referred to as “proxy measures”), and one will be 117MF-364681141Attorney Reference: 15979-20207.40 completed by clinicians (the Clinician Reported Outcome [ClinRO] measure). The COA measures are described in further detail below.

[0311] The COA measures should be completed by caregivers prior to any study-related activities during site visits. The measures will be administered at the timepoints specified in the schedules herein.Participant / Caregiver Completed MeasuresPROMIS Parent Proxy Short Form yl.O - Physical Activity 4a

[0312] The PROMIS (Patient-Reported Outcomes Measurement Information System) is a system of reliable and precise measures of participant- reported heath status.

[0313] The PROMIS Physical Activity instruments assess a child’s capability in engaging in physical activities over the past 7 days. The PROMIS Pediatric Short Form vl.O - Physical Activity 4a instrument included in this study (parent proxy report version) comprises 4 items that ask patients to report on how many days of physical activity they completed with a recall period of 7 days.

[0314] The sum of each items is used to calculate a total raw score out of 20, which is then translated into a T-score. Lower scores indicate lower impact on physical activity (ie, higher HRQoL), while higher scores indicate a higher impact on physical activity (ie, lower HRQoL).PROMIS Numeric Rating Scale yl.O - Parent Proxy Pain Intensity la

[0315] The PROMIS Pain Intensity la is a single item assessing average pain intensity. The item asks participants / caregivers to rate their / their child’s average pain on a 0 to 10-point numeric rating scale ranging from “No pain” to “Worst pain you can think of’ and utilizes a recall period of 7 days. Low scores indicate a better symptom outcome and high scores a worse symptom outcome.EQ-5D-Y-3L Proxy version 1

[0316] The EQ-5D-Y-3L is a child friendly version of the generic, self-complete health status instrument to measure the health-related quality of life (HRQoL) of children and adolescents developed by the European quality of life (EuroQol) Group. The EQ-5D-Y-3L is the youth version of the adult HRQoL measure the EQ-5D-3L, and its design is based on this, with its dimensions, description of the visual analog scale (EQ VAS), and question layout adapted to be age-appropriate. It is comprised of five dimensions: walking about (the118MF-364681141Attorney Reference: 15979-20207.40 equivalent of ‘mobility’ in the adult version), looking after myself (‘self-care’), doing usual activities (‘usual activities’), having pain or discomfort (‘pain / discomfort’), and feeling worried, sad or unhappy (‘anxiety / depression’), each with a 3-point Likert scale.

[0317] The EQ-VAS is numbered from 0 to 100, where 0 indicates the worst imaginable health and 100 indicates best imaginable health.Productivity Questionnaire

[0318] The Productivity Questionnaire quantifies the productivity impact on caregivers dedicated to patient care during the previous six-month period.Patient Treatment Preference Questionnaire

[0319] The Patient Treatment Preference Questionnaire evaluates hemophilia treatment satisfaction using 5-point Likert scales (l=extremely unsatisfied to 5=extremely satisfied) for both patient and caregiver assessments, comparing pre- and post-study responses.Additionally, caregivers rate their treatment preference reasons on a 3-point scale (l=not important, 2=important, 3=very important).Clinician Completed MeasuresHemophilia Joint Health Score (HJHS)

[0320] The Hemophilia Joint Health Score (HJHS) is a clinical outcome assessment tool for the evaluation of joint health in participants with hemophilia. HJHS assesses impairment in six joints (right and left elbows, knees, and ankles) and includes a global gait score assessed by a trained physician or trained healthcare professional using a 9-item score (swelling, duration of swelling, muscle atrophy, crepitus, flexion loss, extension loss, joint pain, gait, and strength).

[0321] Axial alignment is measured but not scored.

[0322] Total scores range from 0 to 124, with lower scores denoting less functional limitations (reduced impairment). Joint health status will be assessed via the HJHS, as administered by a healthcare professional trained in the use of anthropometric measures, as specified in the SoA. Completed HJHS score forms will be collected and archived.Treatment experience interviews (fitusiran-naive arm only)

[0323] Treatment experience interviews will be conducted with caregivers at Week 60, or earlier in the case of early withdrawal / termination (participants should have completed at least up to Week 32 in the study). These structured qualitative interviews will be conducted to119MF-364681141Attorney Reference: 15979-20207.40 gain a more comprehensive and holistic understanding of participant experiences with fitusiran treatment than is captured by traditional clinical outcome assessments. Interviews will be conducted by an external research partner and are designed to capture the following information:• Experience of living with hemophilia (signs and symptoms, daily life impacts and disease management)• Experience with hemophilia treatments prior to fitusiran• Expectations for the trial and new treatment• Experience with the trial and fitusiran treatment during the trial (benefits and challenges), including any behavioral changesWeight-adjusted consumption of CFC and BP A

[0324] All CFC or BPA doses administered during the study will be recorded by the participant in the eDiary and reviewed by the Investigator or designee. This includes CFC or BPA doses administered for prophylaxis or on-demand treatment during the SOC period as well as CFC or BPA doses administered during the fitusiran treatment period to treat bleeding episodes.Safety AssessmentsPhysical examinations

[0325] A complete physical examination will be performed at screening visit, and it will include, at a minimum, assessments of the following: general appearance, head, eyes, ears, nose and throat; cardiovascular, respiratory, gastrointestinal, musculoskeletal and dermatological systems, thyroid, lymph nodes, and neurological systems. Height and weight will also be measured and recorded. Height will be measured in centimeters and body weight will be measured in kilograms. Height and body weight measurements will be collected as specified in the SoA and will be recorded in the eCRF.

[0326] A directed physical examination will be performed at all other visits, and it will include, at a minimum, assessments of the following systems with attention to evaluation for signs and symptoms of thrombosis, bleeding and arthropathy: neurologic, respiratory, cardiovascular, dermatological, gastrointestinal / liver, and musculoskeletal / extremities.

[0327] Investigators should pay special attention to clinical signs related to previous serious illnesses.120MF-364681141Attorney Reference: 15979-20207.40

[0328] For participants with a central or peripheral indwelling venous access, the physical examination should include an assessment of catheters and ports for signs of inflammation and swelling.

[0329] Any new finding or worsening of previous finding should be reported as a new AE.

[0330] In participants who will undergo a major surgical procedure, a directed physical examination will also be performed.Vital signs

[0331] Oral, tympanic, axillary, or temporal temperature (in degrees Celsius), heart rate, respiratory rate, and blood pressure will be recorded (before blood collection for laboratory tests).

[0332] Blood pressure and pulse measurements will be assessed in the seated or supine position with a completely automated device. Manual techniques will be used only if an automated device is not available.

[0333] Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (eg, television, cell phones).

[0334] For blood pressure measurements, 3 consecutive blood pressure readings will be recorded at intervals of at least 1 minute. The average of the 3 blood pressure readings will be recorded on the eCRF.Clinical safety laboratory tests

[0335] The Investigator must review the laboratory results, document this review, and record any clinically significant changes occurring during the study as an AE. The laboratory results must be retained with source documents. Abnormal laboratory findings associated with the underlying disease are not considered clinically significant, unless judged by the Investigator to be more severe than expected for the participant’s condition.

[0336] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 1 month after the last dose of study intervention should be repeated until the values return to normal or baseline or are no longer considered clinically significant by the Investigator.

[0337] If clinically significant values do not return to normal / baseline within a period of time judged reasonable by the Investigator, the etiology should be identified and the Sponsor notified.121MF-364681141Attorney Reference: 15979-20207.40

[0338] All protocol-required laboratory tests must be conducted in accordance with the laboratory manual and the SoA.

[0339] If laboratory values from non-protocol specified laboratory tests performed at the institution’s local laboratory require a change in participant management or are considered clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results must be recorded.Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting

[0340] The Investigator and any qualified designees are responsible for detecting, documenting, and recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative) that meet the definition of an AE or SAE and remain responsible for following up AEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study.Time period and frequency for collecting AE and SAE information

[0341] All AEs (serious or nonserious) will be collected from the signing of the ICF until the last follow- up visit at the timepoints specified in the SoA.

[0342] All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and under no circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available.

[0343] Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of the study participation. However, if the Investigator learns of any SAE, including a death, at any time after a participant has been discharged from the study, and the Investigator considers the event to be reasonably related to the study intervention or study participation, the Investigator must promptly notify the Sponsor.Method of detecting AEs and SAEs

[0344] Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open- ended and nonleading verbal questioning of the participant is the preferred method to inquire about AE occurrences.Follow-up of AEs and SAEs

[0345] After the initial AE / AESVSAE report, the Investigator is required to proactively follow each participant at subsequent visits / contacts. At the pre-specified study end-date, all122MF-364681141Attorney Reference: 15979-20207.40SAEs and AESIs, will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up.Regulatory reporting requirements for SAEs and other safety reporting

[0346] Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met.

[0347] The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. The Sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRB / IEC, and Investigators.

[0348] Serious adverse events that are considered expected will be specified in the reference safety information (IB).

[0349] Investigator safety reports must be prepared for suspected unexpected serious adverse reactions (SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.

[0350] An Investigator who receives an Investigator safety report describing an SAE, SUS AR or any other specific safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it along with the IB and will notify the IRB / IEC, if appropriate according to local requirements. It is the responsibility of the Sponsor to assess whether an event meets the criteria for a SUS AR, and therefore, is expedited to regulatory authorities.Pregnancy

[0351] Details of all pregnancies in female partners of male participants will be collected after the start of study intervention and until 1 month after the last fitusiran dose.

[0352] If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy of the female partner of male participant (after obtaining the necessary signed informed consent from the female partner).

[0353] Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.123MF-364681141Attorney Reference: 15979-20207.40

[0354] The pregnant female partner will be followed to determine the outcome of the pregnancy. The Investigator will collect follow-up information on the pregnant female partner and the neonate and the information will be forwarded to the Sponsor.

[0355] Any post-study pregnancy-related SAE considered reasonably related to the study intervention by the Investigator will be reported to the Sponsor as described in

[0356] While the Investigator is not obligated to actively seek this information in former pregnant female partner, he or she may leam of an SAE through spontaneous reporting.Recording ofISRs

[0357] For all ISRs, the Investigator, or delegate, should submit a complementary ISR eCRF, recording additional information (eg, descriptions, onset and resolution date, severity, treatment given, event outcome). An ISR is defined as a local reaction at or near the site of injection. “At or near” the injection site includes reactions at the injection site, adjacent to the injection site, or a reaction which may shift slightly away from the injection site due to gravity (eg, as may occur with swelling or hematoma). Reactions with onset and resolution within 4 hours of the injection (eg, transient pain / buming at injection site) do not meet the study definition of ISRs, unless immediate treatment is required. A systemic reaction which includes the injection site, eg, generalized urticaria, other distinct entities or conditions like lymphadenopathy that may be near the injection site is not considered an ISR.Death events

[0358] Death is an outcome of an event. The event that resulted in death should be recorded and reported on the appropriate eCRF. All causes of death must be reported as SAEs within 24 hours of the site becoming aware of the event. The term death should be reported as an SAE only if the cause of death is not known and cannot be determined.Disease-related events and / or disease-related outcomes not qualifying as AEs or SAEs

[0359] The following disease related events (DREs) are common in participants with hemophilia and can be serious / life threatening:• Bleeding episodes

[0360] Because these events are typically associated with the disease under study, they will not be recorded as AEs unless the events are associated with an injection of fitusiran (eg, bleeding or bruising at the injection site) or meet the definition of a SAE.124MF-364681141Attorney Reference: 15979-20207.40Adverse events of special interest

[0361] An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor is required. Such events may require further investigation in order to characterize and understand them. Adverse events of special interest may be added, modified or removed during a study by protocol amendment.• Pregnancy occurring in a female partner of a male participant entered in a study with IMP / AxMPPregnancy occurring in a female participant entered in the clinical trial or in a female partner of a male participant entered in the clinical trial. It will be qualified as an SAE only if it fulfills one of the seriousness criteria.Follow-up of the pregnancy in a female partner of a male participant is mandatory until the outcome has been determined.• Symptomatic overdose (serious or nonserious) with IMP / AxMP• Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) >3xULN• Other project specific AESI(s)Suspected or confirmed thrombosisSevere or serious ISRs, ISRs that are associated with a recall phenomenon (reaction at the site of a prior injection with subsequent injections), or those that lead to temporary dose interruption or permanent discontinuation of fitusiranSystemic IARS, defined as hypersensitivity reactions which are related or possibly related to IMPCholecystitisCholelithiasisMedication errors or misuses of medicinal product

[0362] All reports of medication error or misuse in relation to the IMP with or without an AE must be recorded on the corresponding page(s) of the CRF and transmitted to the Sponsor’s representative following standard processes.

[0363] A medication error is an unintended failure in the drug treatment process (ie, mistake in the process of prescribing, storing, dispensing, preparing, or administering medicinal products in clinical practice) that leads to, or has the potential to lead to harm to the participant. This includes situations in which a participant was involved or not (eg, even if the error was recognized and intercepted before the participant received or used the product), and whether it resulted in harm to the participant or not.125MF-364681141Attorney Reference: 15979-20207.40

[0364] A misuse refers to situations where the medicinal product is intentionally and inappropriately used, ie, not in accordance with the terms of the marketing authorization or outside what is foreseen in the protocol, by the participant for a therapeutic purpose.

[0365] Of note, if a medication error or misuse meets the protocol definition of an overdose, it will be recorded in the overdose page of the CRF.Guidelines for reporting product complaints

[0366] Any defect in the IMP / AxMP must be reported as soon as possible by the Investigator to the monitoring team that will complete a product complaint form within required timelines.

[0367] Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to product identification and to the potential deficiencies may need to be gathered. The Investigator will assess whether or not the quality issue has to be reported together with an AE or SAE.Pharmacokinetics

[0368] Plasma samples will be collected for measurement of plasma concentrations of fitusiran as specified in the SoA. Instructions for the collection and handling of biological samples will be provided by the Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.

[0369] The timing of sampling may be altered during the course of the study based on newly available data (eg, to obtain data closer to the time of peak plasma concentrations or to reduce PK timepoints during the course of the study based on the updated knowledge of drug behavior, upon notification from the Sponsor) to ensure appropriate monitoring.Pharmacodynamics

[0370] In this study, AT activity level and thrombin generation (TG) data will be collected as measurements of PD effect. These measurements will be collected and analyzed at a central laboratory. As interpretation is uncertain, TG results will not be used to adjust dosing of fitusiran or guide other elements of study conduct or clinical management and will not be shared with sites until after study completion.Antithrombin activity

[0371] Blood samples will be collected for assessment of AT activity levels according to the SoA. On fitusiran dosing days, samples will be collected within 4 hours prior to dosing.126MF-364681141Attorney Reference: 15979-20207.40Antithrombin levels will be determined by a validated assay. Results will be documented and interpreted by a central laboratory.

[0372] Following administration of the final fitusiran dose, AT activity level will be monitored at monthly intervals until returning to an activity level of at least 60% (per the central laboratory) or per Investigator discretion in consultation with the Medical Monitoring Team.Genetics

[0373] During thrombophilia screening, genetic testing for Factor V Leiden and Prothrombin G20210A mutation will be performed if no historical results are available. No other genetics will be evaluated in this study.Immunogenicity Assessments

[0374] Antibodies to fitusiran will be evaluated in serum samples collected from all participants according to the SoA. Additionally, serum samples should also be collected at the final visit from participants who discontinued study intervention or were withdrawn from the study.

[0375] Instructions for the collection and handling of these samples will be provided by the Sponsor in a separate document. These samples will be tested by the Sponsor or Sponsor’s designee using a qualified assay method.

[0376] Samples for immunogenicity analyses and their derivatives may be stored for up to 5 years after the last participant’s last visit for potential re-analyses.

[0377] A 3-tiered approach will be employed to assess the immunogenicity of fitusiran when applicable: samples will be screened and then confirmed for antibodies binding to fitusiran and the titer of confirmed positive samples will be reported. Other analyses may be performed to further characterize the immunogenicity of fitusiran.

[0378] All samples collected for detection of antibodies to fitusiran may also be evaluated for fitusiran serum concentration to enable interpretation of the antibody data.Statistical Considerations

[0379] The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a more technical and detailed description of the statistical analyses described in127MF-364681141Attorney Reference: 15979-20207.40 this section. This section is a summary of the planned statistical analyses of the most important endpoints including primary and secondary endpoints.

[0380] All endpoints will be summarized descriptively. The roll-over arm and the fitusiran-naive arm will be analyzed separately. The evaluation of efficacy of fitusiran will rely on descriptive analyses in the fitusiran-naive arm. The roll-over arm provides supportive data for the evaluation of long-term efficacy and safety.Populations for Analyses

[0381] The primary objective of this study is to characterize the frequency of treated bleeding episodes while receiving fitusiran prophylaxis and standard of care (SOC). The primary analysis is to estimate ABR in the primary efficacy period and SOC period based on data from fitusiran-naive participants who received prophylaxis or on-demand therapy in the SOC period and any dose of fitusiran, i.e., Full Analysis Set 1 (FAS1) (see Table 8).Table 8. Populations for analyses.Statistical AnalysesStudy Period

[0382] The study will consist of the following:Fitusiran-naive arm:• The pre-treatment period is defined as the period up to first dose of fitusiran, including:128MF-364681141Attorney Reference: 15979-20207.40 o A screening period of up to 60 days: from Day -228 to Day -169 which is only applicable for fitusiran-naive arm participants, as roll-over arm participants will be directly enrolled. o A standard of care (SOC) period: From Day -168 to Day -1 (24 weeks) in which participants will continue their prior on-demand or prophylaxis regimen with CFC or BPA.• The treatment-emergent (fitusiran treatment) period is defined as the period from the first dose of fitusiran to the last dose of fitusiran + 28 days (Day 1 to Day 1121), including: o The dose adjustment period: From Day 1 to Day 84 (12 weeks) o The primary efficacy period: From Day 85 to Day 421 (48 weeks) o The extension period: From Day 422 to Day 1121 (100 weeks)).Roll-over arm:• The treatment-emergent period is defined as the period from the first dose of fitusiran to the last dose of fitusiran + 28 days (Day 1 to Day 421).

[0383] The baseline value for the treatment-emergent period is defined as the last nonmissing value on or before the date of first dose of fitusiran in this study for fitusiran-naive arm and for roll-over arm participants.

[0384] The post-treatment period is defined as the period from the end of the treatment- emergent period.Baseline evaluations

[0385] Baseline for fitusiran treatment period is defined as the last non-missing value on or before the date of first dose of fitusiran in this study (Day 1) for fitusiran-naive arm and for roll-over arm participants. Baseline for SOC period is defined as the last non-missing value on or before the enrollment date (Day -168) for fitusiran-naive arm.

[0386] Unless otherwise specified, analyses will be performed by study period (treatment period versus SOC period) for fitusiran-naive arm. Analyses for the roll-over arm (in this study period) will be provided separately. Subgroup analyses, eg, by inhibitor status and other factors, will be detailed in the SAP.129MF-364681141Attorney Reference: 15979-20207.40Primary endpoint(s) analysesDefinition ofendpoint(s)

[0387] The primary endpoint is annualized treated bleeding rate (ABR) in the fitusiran primary efficacy period and SOC period.

[0388] The primary source of bleeding data is the eDiary. Additional bleeding data may be captured from the bleeding diary pages of the case report form (CRF), if not reported in the eDiary. A treated bleeding episode is defined as any occurrence of hemorrhage that requires administration of factor concentrates or BPA infusion, e.g., hemarthrosis, muscle, or mucosal bleeding episodes. The definition of bleeding episode types described below is based on consensus opinion of International Society on Thrombosis and Hemostasis (ISTH) as reflected in Blanchette et al., J Thromb Haemost. (2014) 12(11): 1935-9.

[0389] The start time of a bleeding episode will be considered the time at which symptoms of a bleeding episode first develop. Bleeding or any symptoms of bleeding at the same location that occur within 72 hours of the last injection used to treat a bleeding episode at that location will be considered a part of the original bleeding event, and will count as one bleeding episode towards the ABR. Any bleeding symptoms that begin more than 72 hours from the last injection used to treat a bleeding episode at that location will constitute a new bleeding event.

[0390] A spontaneous bleeding episode is a bleeding event that occurs for no apparent or known reason, particularly into the joints, muscles, and soft tissues.

[0391] A joint bleeding episode is characterized by an unusual sensation in the joint (“aura”) in combination with 1) increasing swelling or warmth over the skin over the joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline.

[0392] A muscle bleed may be characterized by pain, swelling and loss of movement over the affected muscle group.

[0393] A traumatic bleeding episode is one that is caused by a known injury or trauma. Bleeding episodes sustained during sports and recreation will be counted as traumatic bleeding episodes, but participants will be asked to indicate in the eDiary that the event occurred during such activities.130MF-364681141Attorney Reference: 15979-20207.40Main Analytical Approach

[0394] The primary objective of this study is to characterize the frequency of treated bleeding episodes while receiving fitusiran prophylaxis and standard of care (SOC). The primary analysis is to estimate ABR in the primary efficacy period and SOC period based on data from fitusiran-naive participants who received prophylaxis or on-demand therapy in the SOC period and any dose of fitusiran, ie, Full Analysis Set 1 (FAS)l (see Table 8).

[0395] Additionally, efficacy will be further validated by showing consistent efficacy results with the adult and adolescent patients on fitusiran. The decision rules to evaluate the efficacy claim indicating an adequate bleed control in the pediatric population <12 years of age by demonstrating consistency of the following:1. Ratio of ABR during the fitusiran primary efficacy period versus SOC period from this study: the lower bound of 95% CI of the ABR ratio is less than 1.2. Consistency of ABR ratio estimates in this study and in adult / adolescent population by SOC treatment type: a) fitusiran prophylaxis versus SOC on-demand treatment: the 95% CI of the ABR ratio in this study overlaps with the 95% CI of the ABR ratio in adult / adolescent population; b) fitusiran prophylaxis versus SOC prophylaxis treatment: the 95% CI of the ABR ratio in this study overlaps with the 95% CI of the ABR ratio in adult / adolescent population

[0396] Including treated bleeding events in the period of intercurrent events (i.e., permanent discontinuation of fitusiran treatment during dose adjustment period or during primary efficacy period, surgery, antithrombin administration, prohibited medications administrated while in the fitusiran period, etc.) could significantly bias fitusiran effect and make the treatment effect difficult to interpret. Thus, a combination of while- on-treatment and hypothetical strategy (Table 9) will be used to deal with intercurrent events to avoid the confounder of the treatment effect. Accordingly, treated bleeding episode data during the intercurrent events will be excluded or imputed according to the specific intercurrent events from the primary analysis. The FAS1 will be used for the primary analysis to avoid potential selection bias.Table 9. Strategies to address intercurrent events of the estimand of the primary analysis.131MF-364681141Attorney Reference: 15979-20207.40aFor participants who permanently discontinue fitusiran during the dose adjustment period due to low AT level (intercurrent event 1(a)), the unobserved bleeding data during primary efficacy period will be imputed via MI method with MAR assumption based on observed bleeding data from primary efficacy period for participants dosed and with evaluable follow up duration during primary efficacy period.bFor participants who permanently discontinue fitusiran during the dose adjustment period due to other reason (intercurrent event 1(b)), the dose adjustment period will count as primary efficacy period and available bleeding episode data starting from Day 1 visit to end of study will be used.cFor participants who have the corresponding intercurrent events II to IV, on-treatment strategy will be applied and the bleeding events during the defined period of corresponding intercurrent events will be excluded.dFor participants who have prohibited medication administered, any data after the administration is considered as missing. The missing and unobserved bleeding data during primary efficacy period will be imputed via MI method with MAR assumption based on observed bleeding data from primary efficacy period for patients dosed and with evaluable follow up duration during primary efficacy period.

[0397] The primary analysis is to estimate the ABR in the primary efficacy period (Day 85 to Day 421) and SOC period in FAS1. The number of treated bleeding episodes will be analyzed using a repeated measures negative binomial model with study period (primary efficacy period and standard of care [SOC] treatment period) treated as fixed effect and a robust sandwich covariance matrix is constructed to account for the within subject dependence. The logarithm number of days that each participant spends in the period matching the bleeding episode data being analyzed will be included as an offset variable to account for unequal follow-up time due to early withdrawal, surgery or other reasons. The estimated ABR and its two-sided 95% CI in the primary efficacy period will be presented.

[0398] In addition, summary statistics for observed individual level ABR, including the median and interquartile range and maximum and minimum, will be presented, where observed individual level ABR is defined as:Number of treated bleeding episodes during the respective periodABR = x 365.25Total number of days during the respective period132MF-364681141Attorney Reference: 15979-20207.40Sensitivity Analysis

[0399] Sensitivity analyses will be performed to evaluate the impact of missing data under different missing data mechanisms.Supplementary analyses

[0400] A sensitivity analysis on ABR will be performed based on treatment policy strategy by including all treated bleeding episodes collected through the primary efficacy period, only excluding events due to major or minor surgeries on FAS1 as in the primary efficacy analysis.

[0401] Sensitivity analyses to assess the robustness of hypothetical strategy will be performed by imputing the missing data based on different missing data mechanism. The missing part of each pattern-specific distribution is modelled using MAR and Copy Reference (CR) approaches.

[0402] In addition, the primary efficacy analysis may be repeated using the zero-inflated negative binomial model to address the concern of potential excessive zero bleeding events, and the results will be presented if model converges. Details of the sensitivity analyses will be specified in the SAP.Secondary Endpoint(s) Analyses

[0403] Annualized treated spontaneous (AsBR) and joint bleeding rate (AjBR) in the primary efficacy period and SOC period will be analyzed for FAS1 in a similar fashion as the primary endpoint.

[0404] Summary statistics for observed individual level ABR in fitusiran treatment period will be presented for FAS 1 in the fitusiran primary efficacy period and SOC period and for FAS 2 in fitusiran treatment period.

[0405] All safety analyses will be performed on the Safety Analysis Set (SAS1 or SAS2). The incidence, severity, seriousness, and relatedness of adverse events (AEs) will be summarized by system organ class and preferred term.

[0406] Change from Baseline in health-related quality of life outcomes (physical activity / pain intensity as measured via PROMIS-SF and HRQoL as measured by EQ-5D-Y- 3L) and change from baseline in joint health outcomes (total score and domains scores as assessed by HJHS will be summarized descriptively.

[0407] The percentage of participants with resolution of at least 1 target joint and the percentage of total target joints that are resolved at Day 421 will be summarized. A target133MF-364681141Attorney Reference: 15979-20207.40 joint is defined as a major joint (eg, hip, elbow, wrist, shoulder, knee or ankle) into which >3 spontaneous bleeding episodes occurred in a consecutive 6-month period and resolution is achieved when <2 bleeding episodes occur into that joint during 12 months of continuous exposure.Tertiary / exploratory endpoint(s) analyses

[0408] Details of the analyses for the exploratory endpoints will be described in the SAP. A Qualitative Analysis Plan (QAP) will be developed separately to describe how data collected during participants’ interviews will be analyzed.Multiplicity adjustment

[0409] All analyses are descriptive in nature and therefore adjustments for multiplicity will not be applied.Safety analysesAdverse eventsGeneral common rules for adverse events

[0410] The AEs will be analyzed in the following 3 categories:• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre- treatment period.• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent period (ie, the fitusiran treatment period).• Post-treatment AEs: AEs that developed, worsened or became serious during the post- treatment period.

[0411] Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment periods.Analysis of all adverse events

[0412] Extent of exposure will be summarized. Pre-treatment AEs, TEAEs, and posttreatment AEs will be summarized on the Safety Analysis Set 1 (SAS1) for the fitusiran- naive arm. All TEAEs will be summarized on the Safety Analysis Set 2 (SAS2) for the rollover arm. Incidence of AEs, AEs by maximum severity, AEs by relationship to study medication, SAEs and AEs leading to discontinuation of treatment, and AESIs will be presented.134MF-364681141Attorney Reference: 15979-20207.40

[0413] The AE summaries will be generated with number (%) of participants experiencing at least one event.

[0414] Deaths will also be analyzed.Laboratory variables and vital signsQuantitative analyses

[0415] When relevant, for laboratory variables and vital signs, descriptive statistics for results and changes from baseline will be presented by scheduled visit and study period. These analyses will be performed using central measurements for laboratory variables.Analyses according to PCSA

[0416] PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at the time of the database lock.

[0417] Analyses according to PCSA will be performed based on the worst value during the treatment- emergent period, using all measurements either local or central, either scheduled or nonscheduled.

[0418] For laboratory variables and vital signs, the incidence of participants with at least one PCSA during the treatment-emergent period will be summarized regardless of the baseline level and according to the following baseline status categories:• Normal / missing• Abnormal according to PCSA criterion or criteriaInterim Analyses

[0419] An interim analysis is planned to be conducted when all participants in the fitusiran-naive arm have either discontinued or completed the fitusiran primary efficacy period (Day 85 to Day 421 since the first dose of fitusiran). The primary and secondary efficacy assessments concerning the ABR in the fitusiran primary efficacy period results will be considered as final and may serve as the basis for regulatory submissions. No study conduct changes are expected as a result of the primary analysis and the final analysis will be performed at the completion of the study.

[0420] Additional analysis after the primary analysis but before the final analysis may be performed at the Sponsor's discretion (e.g., for purposes of publications or regulatory activities).135MF-364681141Attorney Reference: 15979-20207.40Sample Size Determination

[0421] The overall sample size is approximately 85 participants, including approximately 60 in the fitusiran-naive arm and approximately 25 in the roll-over arm (from the previous study of which the sample size is 32). It is assumed that the dropout rate during this study will be about 20%.

[0422] The proposed sample size is considered clinically adequate to characterize efficacy and safety of fitusiran prophylaxis in this pediatric population.Other Operational ConsiderationsClinical Laboratory Tests

[0423] The tests detailed in, e.g., Table 13 will be performed by the central laboratory. Specific instructions for transaminase elevations and LFT monitoring are provided herein. For any other unexplained clinically relevant abnormal laboratory test result occurring after IMP administration, the test should be repeated and followed up at the discretion of the Investigator until the value has returned to the normal range or stabilized, and / or a diagnosis is made to adequately explain the abnormality. Additional safety laboratory tests and assessments as indicated by the clinical situation may be requested. Clinical laboratory assessments are listed in Table 13 and will be assessed as specified in the SoA.

[0424] While local laboratory test results may be used for urgent clinical decisions on the day of the study site visit assessments, including the use of local laboratory LFT results for dosing decisions, all laboratory assessments specified in Table 13 that are performed at the study site should also be sent in parallel to the central laboratory. In the case of discrepant local and central laboratory test results on samples drawn on the same day, central laboratory test results will be relied upon for clinical and dosing decisions. Local laboratory results used to make either a study intervention decision or response evaluation must be recorded in the CRF.

[0425] Samples for clinical laboratory assessments may be collected at the clinical study site or at home by a trained healthcare professional. It is preferred that samples for clinical laboratory assessments are drawn via peripheral draw (ie, fresh stick); however, in cases where peripheral access is not possible an existing indwelling venous access may be utilized.

[0426] Blood samples will be obtained as blood volume permits and will not exceed the blood volume collection limit of 3% of total blood volume over 4- weeks period. If needed, blood sampling is prioritized for LFT, AT, hematology, biochemistry, ADA, and then PK.136MF-364681141Attorney Reference: 15979-20207.40Also, please note that blood sampling for Screening can take place over more than one day if deemed appropriate by the Investigator.Additional Laboratory Assessments

[0427] For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and consultation may be performed for clinical evaluation as determined necessary by the Investigator or required by local regulations or in consultation with the Medical Monitoring Team; results may be collected and should be included in the clinical database. In case of thrombotic events, copies of radiographic images and imaging reports should be submitted to the Sponsor (or representative).

[0428] For participants undergoing cholecystectomy due to cholecystitis, cholelithiasis or any other biliary pathology, the following should be performed when possible: histopathological evaluation of the resected gallbladder and analyses of gallbladder contents including bile and gallstone composition. If performed, results should be included in the SAE and / or AESI report, as applicable.

[0429] Additional laboratory assessments will be performed in participants who experience any LFT abnormalities. Following the occurrence of elevated liver transaminases or other LFT abnormalities per central laboratory analyses, clinically meaningful assessments from Table 14 will be performed once (hepatitis testing is mandatory, other tests are optional as per Investigator judgement), as well as hematology, serum chemistry, LFT, and coagulation assessments from Table 13, and other assessments or evaluations per Investigator discretion, as appropriate.

[0430] Monthly predose LFT testing is not required after Week 60 for fitusiran-naive participants who have met the criteria for quarterly predose LFT monitoring described as follows:• Did not have any ALT elevation >3 x ULN persisting for >2 months at any time during fitusiran treatment.• Must not have had any fitusiran doses held due to LFT elevations during the previous 12 months of fitusiran treatment.• Did not have any escalation of fitusiran dose in the last 6 months.

[0431] Rolled over participants from the previous study who have met the criteria for quarterly predose LFT monitoring can continue on quarterly LFT testing in this study.137MF-364681141Attorney Reference: 15979-20207.40AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, and ReportingAE Definitions

[0432] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

[0433] NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.

[0434] An unsolicited AE is an AE that was not solicited using a participant diary and that is communicated by a participant / caregiver who has signed the informed consent. Unsolicited AEs include serious and nonserious AEs.

[0435] Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a hospitalization, emergency room visit, or visit to / by a health care provider). The participants / caregiver will be instructed to contact the site as soon as possible to report medically attended event(s), as well as any events that, though not medically attended, are of participant / caregiver concern. Detailed information about reported unsolicited AEs will be collected by qualified site personnel and documented in the participant’s records.

[0436] Unsolicited AEs that are not medically attended nor perceived as a concern by the participant / caregiver will be collected during an interview with the participants / caregiver and by review of available medical records at the next visit.

[0437] Solicited AEs are predefined local and systemic events for which the participant is specifically questioned, and which are noted by the participants in their diary.

[0438] Events meeting the AE definition:• Any abnormal laboratory test results other than antithrombin (hematology, clinical chemistry, or urinalysis) that is:Symptomatic and / orRequiring either corrective treatment or consultation, and / orLeading to IMP discontinuation or modification of dosing, and / orFulfilling a seriousness criterion, and / orDefined as an AESI138MF-364681141Attorney Reference: 15979-20207.40• Any abnormal other safety assessments (eg, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, not related to progression of underlying disease, or more severe than expected for the participant’s condition), eg:Symptomatic and / orRequiring either corrective treatment or consultation, and / orLeading to IMP discontinuation or modification of dosing, and / orFulfilling a seriousness criterion, and / orDefined as an AESI• Exacerbation of ...

Claims

Attorney Reference: 15979-20207.40CLAIMSWhat is claimed is:

1. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

2. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

3. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks;147MF-364681141Attorney Reference: 15979-20207.40(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

4. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) obtaining one or more measurements of an antithrombin (AT) level in the patient; and(c) performing one of the following steps:(i) if the AT level is 15-35% in one or more measurements, repeating step (a),(ii) if the AT level is >35% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, or(iii) if the AT level is <15% in one or more measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

5. The method of any one of claims 1-4, wherein step (c)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (c)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.148MF-364681141Attorney Reference: 15979-20207.

406. The method of claim 5, wherein the more than one measurements in step (c)(iii) are within 12 months.

7. The method of claim 5, comprising, after step (c)(ii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks.

8. The method of any one of claims 1-7, comprising, after step (c)(iii), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks,(II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or(III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks.

9. The method of claim 8, comprising, after step (c)(iii)(I), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks.149MF-364681141Attorney Reference: 15979-20207.4010. The method of claim 8, comprising, after step (c)(iii)(III), obtaining one or more measurements of an antithrombin (AT) level in the patient, and performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks.

11. The method of any one of claims 5-10, wherein if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement.

12. The method of any one of claims 1-11, further comprising subcutaneously administering fitusiran to the patient at their latest dose amount and dosing frequency so long as the patient maintains an AT level at 15-35%.

13. The method of any one of claims 1-12, wherein each AT level measurement is obtained after the patient has received at least two doses of fitusiran at a given dose amount.

14. The method of any one of claims 1-13, further comprising after step (c):(d) if the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (c) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (c) dose amount,150MF-364681141Attorney Reference: 15979-20207.40 subcutaneously administering to the patient a higher dose amount of fitusiran than the step (c) dose amount.

15. The method of any one of claims 1-14, wherein step (c)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

16. The method of any one of claims 1-15, further comprising obtaining a measurement of the AT level in the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.

17. The method of any one of claims 1-15, further comprising obtaining a measurement of the AT level at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.

18. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of10 mg every month or every four weeks; and(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.151MF-364681141Attorney Reference: 15979-20207.4019. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

20. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

21. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the method comprising:152MF-364681141Attorney Reference: 15979-20207.40(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks;(b) performing one of the following steps:(i) repeating step (a) if an antithrombin (AT) level is 15-35% in one or more measurements,(ii) subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks if an AT level is >35% in one or more measurements, or(iii) then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks if an AT level is <15% in one or more measurements; wherein one or more measurements of an AT level in the patient are or have been obtained before step (a), after step (a), and after any fitusiran dose modification.

22. The method of any one of claims 18-21, wherein step (b)(ii) is: if the AT level is >35% in more than one measurement, optionally two measurements, optionally starting with the third fitusiran injection at the 10 mg dose, subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks, and / or step (b)(iii) is: if the AT level is <15% in more than one measurement, optionally in two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

23. The method of claim 22, wherein the more than one measurements in step (b)(iii) are within 12 months.

24. The method of claim 22, comprising, after step (b)(ii), if the AT level at steady state in the patient is >35% in more than one measurement, optionally in two measurements, optionally starting with the third fitusiran injection at the 20 mg dose, subcutaneously administering to the patient fitusiran at 50 mg every month or every four weeks.

25. The method of any one of claims 18-24, comprising, after step (b)(iii), performing one of the following steps:153MF-364681141Attorney Reference: 15979-20207.40(I) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks,(II) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks, or(III) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 7.5 mg every month or every four weeks.

26. The method of claim 25, comprising, after step (b)(iii)(I), performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, discontinuing or pausing fitusiran treatment,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 1.25 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 2.5 mg every month or every four weeks.

27. The method of claim 25, comprising, after step (b)(iii)(III), performing one of the following steps:(A) if the AT level is <15% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks,(B) if the AT level is 15-35% in one or more measurements, optionally two measurements, subcutaneously administering to the patient fitusiran at a dose of 7.5 mg every month or every four weeks, or(C) if the AT level is >35% in one or more measurements, optionally two measurements, optionally at steady state, subcutaneously administering to the patient fitusiran at 10 mg every month or every four weeks.154MF-364681141Attorney Reference: 15979-20207.4028. The method of any one of claims 22-27, wherein if the AT level is <15% in one or more measurements, the optionally two measurements comprise a first AT level <15% and a second AT level <15% measured within 1 week of site receipt of the first AT level measurement.

29. The method of any one of claims 18-28, further comprising subcutaneously administering fitusiran to the patient at their latest dose amount and dosing frequency so long as the patient maintains an AT level at 15-35%.

30. The method of any one of claims 18-29, wherein each AT level measurement is or has been obtained after the patient has received at least two doses of fitusiran at a given dose amount.

31. The method of any one of claims 18-30, further comprising after step (b):(c) if the patient: has an AT level of 15-35%, has had at least two doses of fitusiran at the step (b) dose amount, and has two or more treated bleeds within a 12- week period starting with the third fitusiran injection at the step (b) dose amount, subcutaneously administering to the patient a higher dose amount of fitusiran than the step (b) dose amount.

32. The method of any one of claims 18-31, wherein step (b)(iii) comprises pausing fitusiran administration if an AT level is <15% in one or more measurements, optionally until an AT level in the patient is >15%, optionally >22%, then subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

33. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.155MF-364681141Attorney Reference: 15979-20207.4034. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

35. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors having an antithrombin (AT) level of <15%, the patient having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

36. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

37. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

38. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.156MF-364681141Attorney Reference: 15979-20207.4039. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

40. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.

41. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

42. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of 15-35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 10 mg every month or every four weeks.

43. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of >35%, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 20 mg every month or every four weeks.157MF-364681141Attorney Reference: 15979-20207.4044. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, the patient having an antithrombin (AT) level of <15% and having previously received fitusiran at a dose of 10 mg every month or every four weeks, the method comprising: subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

45. The method of any one of claims 35, 38, 41, and 44, wherein fitusiran administration is first paused, optionally until an AT level in the patient is >15%, optionally >22%, before subcutaneously administering to the patient fitusiran at a dose of 5 mg every month or every four weeks.

46. The method of any one of claims 18-45, wherein a measurement of the AT level in the patient has been obtained every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every 12 months.

47. The method of any one of claims 18-45, wherein a measurement of the AT level has been obtained at four weeks or one month, twelve weeks or three months, 20 weeks or five months, and 24 weeks or six months following administration of the starting dose of fitusiran or following administration of a modified dose as compared to the prior dose.

48. The method of any one of claims 1-47, wherein the body weight of the patient is 8 kg or greater.

49. The method of any one of claims 1-48, wherein the body weight of the patient is less than 45 kg.

50. The method of any one of claims 1-48, wherein the body weight of the patient is less than 22 kg.

51. The method of any one of claims 1-49, wherein the body weight of the patient is between about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg.158MF-364681141Attorney Reference: 15979-20207.4052. The method of any one of claims 1-51, wherein the AT levels are at steady state.

53. The method of any one of claims 1-52, wherein the patient is 1 year of age or older.

54. The method of any one of claims 1-53, wherein the patient is less than 12 years of age.

55. The method of any one of claims 1-54, wherein the patient is between 1 year of age and 12 years of age.

56. The method of any one of claims 1-55, wherein the patient continues a previous non- fitusiran prophylactic treatment for one week after the first dose of fitusiran, optionally wherein the previous non-fitusiran prophylactic treatment is a clotting factor concentrate treatment, a replacement factor treatment, or a bypassing agent treatment.

57. The method of any one of claims 1-56, wherein the patient has hemophilia A or B with inhibitors.

58. The method of claim 57, further comprising treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a bypassing agent (BPA), wherein the effective amount of the BPA is reduced as compared to the recommended effective amount of the BPA.

59. The method of claim 58, wherein the patient has an AT level of <60%, optionally wherein the patient has an AT level of <60% before administration of fitusiran.

60. The method of claim 58 or claim 59, wherein the bypassing agent is activated prothrombin complex concentrate (aPCC) and a single dose of aPCC is no more than 50 U / kg and is optionally 30 U / kg, optionally wherein the aPCC administration is repeated, if needed, in no less than 24 hours.159MF-364681141Attorney Reference: 15979-20207.4061. The method of claim 58 or claim 59, wherein the bypassing agent is recombinant factor Vila (rFVIIa) and a single dose of rFVIIa is no more than 45 pg / kg, optionally wherein the rFVIIa administration is repeated, if needed, in no less than two hours.

62. The method of claim 58 or claim 59, wherein the bypassing agent is efanesoctocog alfa and a single dose of efanesoctocog alfa is no more than 45 pg / kg, optionally wherein the efanesoctocog alfa administration is repeated, if needed, in no less than 72 hours.

63. The method of any one of claims 1-56, wherein the patient has hemophilia A or B without inhibitors.

64. The method of claim 63, further comprising treating a bleeding episode occurring eight or more days after the first dose of fitusiran by administering to the patient an effective amount of a replacement factor, wherein the effective amount of the replacement factor is reduced as compared to the recommended effective amount of the replacement factor.

65. The method of claim 63 or claim 64, wherein the replacement factor is Factor VIII and a single dose of the replacement factor is no more than 20 lU / kg and optionally is 10 lU / kg, optionally wherein the Factor VIII administration is repeated, if needed, in no less than 24 hours.

66. The method of claim 63 or claim 64, wherein the replacement factor is Sevenfact, and wherein the reduction compared to the recommended effective amount of Sevenfact is half the standard dose with standard treatment frequency.

67. The method of claim 63 or claim 64, wherein the replacement factor is Factor IX and a single dose of the replacement factor is 30 lU / kg and optionally is 20 lU / kg, optionally wherein the Factor IX administration is repeated, if need, in no less than 24 hours for standard half-life Factor IX or in no less than 5-7 days for extended half-life Factor IX.

68. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or160MF-364681141Attorney Reference: 15979-20207.40 the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 1.25 mg of fitusiran every month or every four weeks.

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

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

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

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

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

74. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 30 mg of fitusiran every month or every four weeks.161MF-364681141Attorney Reference: 15979-20207.4075. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 50 mg of fitusiran every month or every four weeks.

76. A method of prophylactic treatment of hemophilia A or B in a patient with or without inhibitors, or reducing the frequency of bleeding episodes, optionally the ABR, the AsBR, or the AjBR, in the patient, comprising subcutaneously administering to the patient in need thereof 10 mg of fitusiran every month or every four weeks, wherein the body weight of the patient is < 22 kg.

77. The method of any one of claims 68-76, further comprising monitoring the AT level of the patient every four weeks, every eight weeks, every month, every two months, every four months, every six months, or every twelve months.

78. The method of any one of claims 68-77, wherein the patient is aged 1 year to <12 years old.

79. The method of any one of claims 68-78, wherein the patient has a body weight of less than 45 kg.

80. The method of claim 78, wherein the patient has a body weight of about 8 kg and about 45 kg, optionally between about 8 kg and about 22 kg.

81. The method of any one of claims 1-80, further comprising, after subcutaneous administration of fitusiran, monitoring the AT levels of the patient periodically, optionally every one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks, or every one month, two months, three months, four months, five months, or six months.

82. The method of any one of claims 1-81, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a kinetic or chromogenic assay.162MF-364681141Attorney Reference: 15979-20207.4083. The method of claim 82, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of an excess of factor Xa by AT.

84. The method of claim 82, wherein obtaining a measurement of an antithrombin (AT) level in the patient comprises use of an INNOV ANCE™ Antithrombin assay.

85. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.

86. A method of prophylactic treatment of hemophilia A or B in a pediatric patient with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

87. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.

88. A method of reducing thrombotic risk in a pediatric patient receiving fitusiran for prophylactic treatment of hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

89. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:163MF-364681141Attorney Reference: 15979-20207.40(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.

90. A method of reducing the frequency of bleeding episodes in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

91. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising:(a) subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks; and(b) obtaining one or more measurements of an antithrombin (AT) level in the patient.

92. A method of reducing the annual bleeding rate (ABR), the annual spontaneous bleeding rate (AsBR), and / or the annual joint bleeding rate (AjBR) in a pediatric patient with hemophilia A or B with or without inhibitors, comprising: subcutaneously administering to the patient in need thereof fitusiran at a dose of 10 mg every month or every four weeks, wherein one or more measurements of an antithrombin (AT) level in the patient are or have been obtained.

93. The method of any one of claims 85-92, further comprising adjusting the dose amount or dose frequency of fitusiran being subcutaneously administered to the patient in order to maintain an AT level of 15-35%.

94. The method of any one of claims 1-93, wherein liver function test results are obtained within 7 days prior to each dose of fitusiran, optionally wherein the liver function test results are reviewed prior to each dose of fitusiran.164MF-364681141Attorney Reference: 15979-20207.4095. The method of any one of claims 1-94, wherein fitusiran is provided in a phosphate- buffered saline (PBS) at 1-200 mg / mL, optionally 6.25 mg / mL, 12.5 mg / mL or 100 mg / mL.

96. The method of claim 95, wherein fitusiran is provided in formulation 1 or formulation 2 shown below.

97. Fitusiran for use in a method of any one of claims 1-96.

98. Use of fitusiran for the manufacture of a medicament to treat hemophilia A or B with or without inhibitors in the method of any one of claims 1-96.

99. A pharmaceutical composition comprising fitusiran for use in a method of any one of claims 1-96.

100. An article of manufacture for use in a method of any one of claims 1-96, optionally wherein the article of manufacture is a kit.

101. The article of manufacture of claim 100, wherein the article of manufacture is a container, optionally a vial, containing one or more doses of fitusiran, each dose being 30 mg, 20 mg, 10 mg, 5 mg, 2.5 mg, or 1.25 mg.

102. The article of manufacture of claim 101, wherein the container is a vial containing 2.5 mg of fitusiran.165MF-364681141

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