Fitusiran for use in improving patient-reported outcomes in patients with hemophilia

Abstract

The present disclosure provides the use of double-stranded oligonucleotide compounds as novel treatments for improving patient-reported outcomes and quality of life for hemophilia A or hemophilia B patients.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority from U.S. Patent Application Nos. 63 / 293,070, filed December 22, 2021; 63 / 305,550, filed February 1, 2022; 63 / 335,535, filed April 27, 2022; 63 / 359,717, filed July 8, 2022; 63 / 382,223, filed November 3, 2022; and 63 / 386,489, filed December 7, 2022. The contents of these priority applications are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, which is hereby incorporated by reference in its entirety. Said XML copy (created on December 21, 2022) is named 022548_WO087_SL.xml and is 28,905 bytes in size. [Background technology]

[0003] Maintenance of normal hemostasis depends on a series of simultaneously regulated procoagulant and anticoagulant processes, in which thrombin plays a central role. Hemophilia A and B are inherited bleeding disorders characterized by the body's inability to control blood clotting. They are caused by deficiencies of factors VIII and IX, respectively. Bleeding in hemophilia A and B results from insufficient production of thrombin (Peyvandi et al., Lancet (2016) 388 (10040): 187-97). Without effective treatment, patients with hemophilia experience recurrent bleeding, which can lead to severe disability due to chronic hemarthropathy and significant pain, and can be life-threatening (Pipe et al., Haemophilia (2007) 13 Suppl 4: 1-16).

[0004] Despite advances in treatment, significant unmet needs and management challenges continue to exist for all hemophilia populations. Prophylaxis based on replacement therapy with factor VIII or factor IX is considered the cornerstone of hemophilia management, but it has significant limitations. For example, prophylactic factor replacement injections are burdensome and impractical, often requiring multiple intravenous infusions per week (Peyvandi supra; Ljung and Andersson, Br J Haematol. (2015) 169(6):777-86; Srivastava et al., Haemophilia (2013) 19(1):e1-47; Bauer, Am J Manag Care (2015) 21(6 Suppl):S112-22; Mannucci and Franchini, Blood Transfus. (2013) 11(Suppl 4):s77-81). Factor replacement is also limited by difficulties with venous access and the risk of infection (Balkaransingh and Young, Ther Adv Hematol. (2018) 9(2): 49-61; Valentino et al., Blood Rev. (2011) 25(1): 11-5). Limitations in the supply of factor replacement also mean that a large proportion of the global hemophilia population does not have access to prophylaxis at first instance (Hemophilia, WFO Treatment Safety and Supply. 2020).

[0005] In addition, treatment with factor replacement products can result in the development of inhibitory alloantibodies, rendering factor treatment ineffective (Morfini et al., Haemophilia (2007) 13(5):606-12). These inhibitors, which usually arise during childhood, limit treatment options and dramatically worsen the prognosis of hemophilia. Furthermore, patients with persistent inhibitors usually have a lower quality of life, more joint disease, higher surgical risks, and higher mortality, including a higher risk of death from hemophilia-related bleeding complications, compared to patients without inhibitors (Morfini, supra; Oladapo et al., Orphanet J Rare Dis. (2018) 13(1):198). Current treatment strategies for individuals with persistent inhibitors include immune tolerance induction (ITI) and prophylaxis with bypassing agents (BPAs) such as activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa) (Benson et al., Eur J Haematol. (2012) 88(5):371-79; Collins et al., Br J Haematol. (2013) 160(2):153-70; Kempton et al., Blood (2014) 124(23):3365-72; Astermark et al., Haemophilia (2007) 13(1):38-45; Eichinger et al., Eur J Clin Invest. (2009) 39(8):707-13). Summary of the Invention [Problem to be solved by the invention]

[0006] There remains an urgent unmet need to develop therapies and treatment methods that prevent recurrent bleeding and improve overall quality of life for patients with hemophilia. [Means for solving the problem]

[0007] The present disclosure provides methods and compositions for treating hemophilia patients. In one aspect, the present disclosure provides a method of improving patient-reported outcomes (PROs) in hemophilia patients (e.g., adult or adolescent patients aged 12 years or older), comprising subcutaneously administering a therapeutically effective amount of fitusiran to a hemophilia patient in need thereof, optionally the patient is a hemophilia A or B patient with or without inhibitors, and optionally the PROs are improved in one or more quality of life (QoL) domains. In a further aspect, the present disclosure provides a method of improving quality of life (QoL) in hemophilia patients (e.g., adult or adolescent patients aged 12 years or older), comprising subcutaneously administering fitusiran to a hemophilia patient in need thereof, optionally the patient is a hemophilia A or B patient with or without inhibitors, and optionally the QoL is improved in one or more QoL domains. In some embodiments, fitusiran is administered at about 10 to about 90 mg per dose.

[0008] In some embodiments, the one or more QoL domains are domains of a QoL questionnaire. In further embodiments, the QoL questionnaire is the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL). In certain embodiments, administration results in a clinically meaningful improvement as indicated by a reduction of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in one or more of the Haem-A-QoL total score, the sports and leisure domain score, and the physical health domain score.

[0009] In some embodiments, the QoL questionnaire is the Hemophilia Quality of Life Questionnaire for Children and Adolescents (Haemo-QoL). In certain embodiments, administration results in a clinically meaningful improvement as indicated by a reduction of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in the Haemo-QoL total score.

[0010] In some embodiments, the QoL questionnaire is the Hemophilia Activity List (HAL). In certain embodiments, administration results in an improvement as indicated by an increase in the HAL total score of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units).

[0011] In some embodiments, the QoL questionnaire is the Pediatric Hemophilia Activity List (pedHAL). In certain embodiments, administration results in an improvement as indicated by an increase of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in the pedHAL total score.

[0012] In some embodiments, the QoL questionnaire is the Treatment Satisfaction Questionnaire for Medication Version 9 (TSQM-9). In certain embodiments, administration results in an improvement as indicated by an increase of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in one or more of the efficacy, satisfaction, and convenience domain scores of the TSQM-9.

[0013] In some embodiments, the QoL questionnaire is the EuroQol 5-Dimension (EQ-5D-5L). In certain embodiments, administration results in an improvement as indicated by an increase in EQ-5D-5L total score of 0.02 or more units (optionally, 0.03 or more, 0.04 or more, or 0.05 or more units), or an increase in EQ-5D-5L visual analog scale (VAS) score of 5 or more units (optionally, 6 or more, 7 or more, or 8 or more units).

[0014] In some embodiments, the patient has hemophilia A, and in further embodiments, the hemophilia A patient is receiving treatment with factor VIII or a bypassing agent (BPA). In some embodiments, the patient has hemophilia B, and in further embodiments, the hemophilia B patient is receiving treatment with factor IX or a BPA.

[0015] In some embodiments, the patient has an inhibitor, and optionally the level of the inhibitor is greater than 0.6 BU / mL as determined by the Bethesda Inhibitor Assay. In certain embodiments, the BPA is activated prothrombin complex concentrate (aPCC) and / or recombinant activated factor VII (rFVIIa). In other embodiments, the patient does not have an inhibitor.

[0016] In some embodiments, the method includes administering multiple doses of fitusiran to the patient at about 10 mg, about 20 mg, about 50 mg, or about 80 mg per dose. In some embodiments, fitusiran is administered to the patient about once every 4 weeks or about once a month, or about once every 8 weeks or about once every two months. In some embodiments, fitusiran is provided in phosphate buffered saline (pH 7) at a concentration of about 1 to about 200 mg / mL, optionally at a concentration of about 6.25, 12.5, or 100 mg / mL.

[0017] In another aspect, the disclosure provides for fitusilan for use in the methods of treatment herein. In yet another aspect, the disclosure provides for an article of manufacture for use in the methods of treatment herein. In some embodiments, the article of manufacture is a disposable container containing about 80 mg of fitusilan in about 0.8 mL of phosphate buffered saline (pH 7), about 50 mg of fitusilan in about 0.5 mL of phosphate buffered saline (pH 7), about 20 mg of fitusilan in about 0.2 mL of phosphate buffered saline (pH 7), or about 10 mg of fitusilan in about 0.1 mL of phosphate buffered saline (pH 7). In certain embodiments, the product is a disposable, pre-filled syringe containing about 80 mg of fitusiran in about 0.8 mL of phosphate buffered saline, pH 7, about 50 mg of fitusiran in about 0.5 mL of phosphate buffered saline, pH 7, about 20 mg of fitusiran in about 0.2 mL of phosphate buffered saline, pH 7, or about 10 mg of fitusiran in about 0.1 mL of phosphate buffered saline, pH 7. In yet another aspect, the disclosure provides for the use of fitusiran for the manufacture of a medicament for treating hemophilia A or B in the methods of treatment herein. [Brief description of the drawings]

[0018] [Figure 1-1] The expanded structural formula, chemical formula, and molecular mass of phytusirane (sodium form) are shown. [Figure 1-2] Continued from Figure 1-1. [Diagram 2] FIG. 1 shows the design for the study of inhibitor-carrying patients. Abbreviations are as follows: BPA, bypassing agent; HA, hemophilia A; HB, hemophilia B; R, randomized. In the on-demand group, patients are treated with on-demand factor concentrates routinely prescribed by physicians per local standard clinic. [Diagram 3] FIG. 2 shows the design for the study of inhibitor-free patients. Abbreviations are as described in FIG. 2. [Figure 4] FIG. 1 shows the patient demographics enrolled in a Phase 3 clinical trial of fitusiran in patients with hemophilia A and B with inhibitors. [Diagram 5] 1 is a bar graph showing key aspects of hemophilia treatment determined according to patient exit interviews. [Figure 6] 1 is a bar graph showing improvement with Fitusiran prophylaxis according to patient exit interview. [Figure 7] 1 is a line graph showing mean antithrombin levels in inhibitor-bearing patients treated with fitusiran. [Figure 8] 1 is a line graph showing thrombin generation in inhibitor-bearing patients treated with fitusiran. [Figure 9] 1 is a line graph showing mean antithrombin levels in non-inhibitor patients treated with fitusiran. [Figure 10] 1 is a line graph showing thrombin generation in non-inhibitor patients treated with fitusiran. [Figure 11]1 shows the mean change in peak thrombin generation in inhibitor-bearing (ATLAS-INH) and non-inhibitor-bearing (ATLAS-A / B) patients treated with fitusiran. [Figure 12] The median ABR observed for patients treated with fitusiran is shown. [Figure 13] 1 is a bar graph showing the percentage of patients who experienced zero or three or fewer bleeding episodes during the effective period of Fitusiran. [Figure 14-1] The mean consumption of factors and BPA by patients during the Fitusiran treatment period is shown. [Figure 14-2] Continued from Figure 14-1. [Figure 15] The percentage of patients who did not use factors or BPA during the effective period of Fitusiran is shown. [Figure 16-1] The total number of bleeds and BPA / factor injections treated within the Fitusiran effective period are shown. [Figure 16-2] Continued from Figure 16-1. [Figure 17] The mean annual injection rates of BPA and factors in patients are shown. [Figure 18] The weight-adjusted doses of BPA and replacement factors administered per bleed during the Fitusiran treatment period are shown. [Figure 19-1] Figure 1 shows a bar graph depicting bleeding events during the efficacy period. Panel A shows the annualized bleeding rate of treated bleeding estimated by the negative binomial model, and Panel B shows the median annualized bleeding rate of treated bleeding. Abbreviations are as follows: ABR, annualized bleeding rate; BPA, bypassing agent; CI, confidence interval; IQR, interquartile range. [Figure 19-2] Continued from Figure 19-1. [Figure 20]Forest plot of estimated annualized bleeding rates for treated bleeds during the efficacy period based on the on-treatment strategy using a negative binomial model (ITT Set) with baseline factors. In the hemophilia B subgroup, convergence of the negative binomial model is questionable due to limited sample size. The efficacy period is from day 29 to day 246 or the last bleeding follow-up date, whichever comes first. The analysis was based on the on-treatment strategy and excluded any bleeding events during the intercurrent events period. Abbreviations are as follows: BPA, bypassing agent; ITT, intent-to-treat; NA, not applicable; RR, rate ratio. [Figure 21] Bar graphs showing improvement from baseline to end of study in Haem-A-QoL total score and physical health domain converted score (secondary endpoints). Clinically meaningful improvement was defined as a 7-point reduction for total score and a 10-point reduction for physical health domain score. Analysis of covariance models included treatment group and randomization strata for number of bleeds in the 6 months prior to the study (<10, >10) as fixed effects, and baseline score as a covariate. Haem-A-QoL score range 0–100; lower score = improved HRQoL. Abbreviations are as follows: BPA, bypassing agent; CI, confidence interval; Haem-A-QoL, Quality of Life Questionnaire in Hemophilia for Adults; HRQoL, health-related quality of life; LS, least squares mean). [Figure 22-1] The mean (±SE) change in antithrombin levels compared to baseline (Panel A) and peak thrombin generation compared to baseline (Panel B) are shown. [Figure 22-2] Continued from Figure 22-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present disclosure features methods of using fitusiran for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia, such as hemophilia A (congenital factor VIII deficiency) or hemophilia B (congenital factor IX deficiency), with or without inhibitors. In some embodiments, the patients are adults or adolescents aged 12 years or older. These methods enhance the quality of life of hemophilia patients. In certain embodiments, the methods improve the patient's quality of life scores, such as scores related to health-related quality of life (HRQOL), physical activity, and treatment satisfaction and health utility.

[0020] Hemophilia A or B patients with inhibitors refer to patients who have developed alloantibodies to a factor to which they have previously received (e.g., factor VIII for hemophilia A patients, or factor IX for hemophilia B patients). Hemophilia A or B patients with inhibitors may be refractory to clotting factor replacement therapy. Patients without inhibitors refer to patients who do not have such alloantibodies. The present method of treatment is beneficial for hemophilia A patients with or without inhibitors, and for hemophilia B patients with or without inhibitors.

[0021] I. Fitusilan Pharmaceutical Compositions Hemophilia results in a severe deficiency in thrombin generation, and the severity of hemophilia correlates with the inability to generate thrombin. Without being bound by theory, it is believed that the fitusiran-mediated reduction in antithrombin (AT) levels may increase thrombin generation and thus improve hemostasis in hemophilia patients. Antithrombin is encoded by the SERPINC1 gene.

[0022] Fitusiran (the structure of which is described herein) is a synthetic, chemically modified, double-stranded, small interfering RNA (siRNA) oligonucleotide that is covalently linked to a triantennary N-acetyl-galactosamine (GalNAc) ligand that targets AT3 mRNA in the liver, thereby inhibiting the synthesis of antithrombin. The nucleosides in each strand of Fitusiran are linked by either 3'-5' phosphodiester or phosphorothioate linkages, thus forming the sugar-phosphate backbone of the oligonucleotide.

[0023] The sense and antisense strands of phytosilan contain 21 and 23 nucleotides, respectively. The 3' end of the sense strand is linked to a GalNAc-containing moiety (also called L96) via a phosphodiester bond. The sense strand contains two consecutive phosphorothioate bonds at its 5' end. The antisense strand contains four phosphorothioate bonds, two at the 3' end and two at the 5' end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs and a 2-base overhang at the 3' end of the antisense strand. See also U.S. Pat. No. 9,127,274, U.S. Pat. No. 11,091,759, and WO 2019 / 014187.

[0024] The two nucleotide strands of phytosillan are shown below: Sense strand: 5'Gf-ps-Gm-ps-Uf-Um-Af-Am-Cf-Am-Cf-Cf-Af-Um-Uf-Um-Af-Cm-Uf-Um-Cf-Am-Af-L96 3' (SEQ ID NO: 1), and Antisense strand: 5'Um-ps-Uf-ps-Gm-Af-Am-Gf-Um-Af-Am-Af-Um-Gm-Gm-Uf-Gm-Uf-Um-Af-Am-Cf-Cm-ps-Am-ps-Gm 3' (SEQ ID NO: 2) (In the formula, Af = 2'-fluoroadenosine (i.e., 2'-deoxy-2'-fluoroadenosine) Cf = 2'-fluorocytidine (i.e., 2'-deoxy-2'-fluorocytidine) Gf = 2'-fluoroguanosine (i.e., 2'-deoxy-2'-fluoroguanosine) Uf = 2'-fluorouridine (i.e., 2'-deoxy-2'-fluorouridine) Am = 2'-O-methyladenosine Cm = 2'-O-methylcytidine Gm = 2'-O-methylguanosine Um = 2'-O-methyluridine "-" (hyphen) = 3'-5' phosphodiester bond sodium salt "-ps-" = 3'-5' phosphorothioate bond sodium salt and L96 is represented by the following formula: [ka] (Having).

[0025] The expanded structural formula, molecular formula, and molecular weight of phytusiran (sodium form) are shown in FIG.

[0026] The structure of phytosilane is shown in the following diagram: [ka] (wherein X is O) It can also be written using:

[0027] For use in the present methods of treatment, fitusiran may be provided in a pharmaceutical composition comprising fitusiran and a pharma- ceutically acceptable excipient, hi certain embodiments, fitusiran is in the form of a sodium salt.

[0028] In some embodiments, the fitusiran is provided in an aqueous solution at a concentration of about 1 to about 200 mg / mL (e.g., about 50 to about 150 mg / mL, about 80 to about 110 mg / mL, about 90 to about 110 mg / mL, about 5 to about 25 mg / mL, about 7.5 to about 20 mg / mL, or about 10 to about 15 mg / mL). As used herein, values ​​intermediate to the recited ranges and values ​​are also intended to be part of the disclosure. Additionally, ranges of values ​​using any combination of the 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 about 6.25, about 12.5, about 50, about 75, about 100, about 125, about 150, or about 200 mg / mL.

[0029] Unless otherwise stated, the weight of fitusiran stated in this disclosure is the weight of fitusiran free acid (active moiety), even though fitusiran is injected subcutaneously to a patient in its sodium form (in an aqueous solution). For example, 100 mg / mL of fitusiran means 100 mg of fitusiran free acid per mL (equivalent to 106 mg of fitusiran sodium drug substance).

[0030] In some embodiments, the pharmaceutical composition comprises fitusiran in phosphate buffered saline. The phosphate concentration in the solution can be about 1 to about 10 mM (e.g., about 2, about 3, about 4, about 5, about 6, about 7, about 8, or about 9 mM) at a pH of 6.0 to 8.0. The pharmaceutical compositions herein can include a preservative, such as EDTA. Alternatively, the pharmaceutical composition does not include a preservative. In certain embodiments, the fitusiran pharmaceutical composition does not include a preservative and comprises, consists of, or consists essentially of about 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 dilute phosphoric acid can be used to adjust the pH of the composition to 7.0.

[0031] The pharmaceutical composition may be provided in a container (e.g., a vial or a syringe). The container may contain a single or multiple doses. In some embodiments, the container is a disposable container (e.g., a disposable ampoule or a disposable syringe, e.g., a disposable pre-filled syringe), each container containing about 10 to about 100 mg of fishiran (e.g., about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, or about 80 mg). The fishiran may be provided in solid form in the container and reconstituted in an aqueous solution (e.g., PBS) prior to use, the reconstituted solution containing about 1 to about 150 mg / mL (e.g., about 6.25 mg / mL, about 12.5 mg / mL, or about 100 mg / mL) of fishiran. In some embodiments, the fishiran is provided in sodium salt form in a disposable glass vial or a disposable pre-filled syringe (e.g., one with a safety system). In a further embodiment, each vial or syringe contains about 80 mg of fitusiran in about 0.8 mL of 5 mM phosphate buffered saline solution (pH 7.0) (or about 50 mg of fitusiran in about 0.5 mL, about 20 mg of fitusiran in about 0.2 mL, or about 10 mg of fitusiran in about 0.1 mL), and the solution is administered to a patient by subcutaneous injection. The solution can be stored at 2-30° C. (e.g., 2-8° C.).

[0032] In a particular embodiment, the fitusiran composition for subcutaneous injection contains 0.64 mM NaH 2 PO 4 , 4.36 mM Na 2 HPO 4 and 84 mM NaCl in 5 mM phosphate buffered saline at pH 7.0. In a particular embodiment, the composition of the fitusiran solution for subcutaneous injection is shown in Table 1A below.

[0033] [Table 1]

[0034] In a particular embodiment, the composition of the Fitusiran solution for subcutaneous injection is shown in Table 1B below.

[0035] [Table 2]

[0036] The fitusiran dosage weights described herein refer to the weight of fitusiran free acid (active moiety), while administration of fitusiran to a patient herein refers to administration of fitusiran sodium (the drug substance) provided in a pharma- ceutical suitable aqueous solution (e.g., phosphate buffered saline at physiological pH).

[0037] II. Therapeutic Uses of Fitusiran Fitusiran can inhibit hepatic 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 can be used to treat individuals with impaired hemostasis.

[0038] For example, fitusiran can be used to treat hemophilia A or B, with or without inhibitors, in patients for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In certain embodiments, fitusiran is used to treat hemophilia A or B (congenital factor VIII or factor IX deficiency, respectively), with or without inhibitors, in adult and adolescent patients (ages 12 and older).

[0039] The method includes administering a therapeutically effective amount of fitusiran to a hemophilia patient (e.g., a hemophilia A or B patient) in need thereof. A "therapeutically effective amount" refers to an amount of fitusiran that helps the patient achieve a desired clinical endpoint. The desired clinical endpoint can be, for example, a reduction in annualized bleeding rate (ABR) (e.g., greater than 10, greater than 20, greater than 30, greater than 40, greater than 50, greater than 60, greater than 70, greater than 80, greater than 90, or 100%). The desired clinical endpoint can be a reduction in the patient's antithrombin levels to normal levels (e.g., about 64-210 nM), a reduction in annualized bleeding rate (ABR), a reduction in spontaneous bleeding rate, and an improvement in the patient's quality of life (QoL).

[0040] The desired clinical endpoint may also be an improvement in a patient-reported outcome (PRO), as described further below. In some embodiments, the efficacy of treatment may be measured by a reduction in signs and symptoms or severity of the disease, as assessed by the patient based on a valid and reliable PRO instrument. For example, any positive effect resulting in a reduction in signs and symptoms or severity of the disease, as measured using an appropriate scale, is indicative of suitable treatment using the pharmaceutical compositions described herein.

[0041] Hemophilia directly impacts the health-related quality of life (HRQoL) of patients through its associated symptoms, functional limitations and treatment burden. Improving HRQoL is an important aspect of disease management of hemophilia. The present method improves the HRQoL of patients, determined by well-designed, detailed and validated questionnaires. For example, HRQoL in adult patients (age 17 years or older, e.g., age 18 years or older) can be measured by the questionnaires Haem-A-QoL, EuroQol 5-Dimensions (EQ-5D-5L) (EuroQol Group, Health Policy (1990) 16(3):199-208), Hemophilia Activity List (HAL), and Treatment Satisfaction Questionnaire for Medication (TSQM-9). HRQoL in adolescent patients (ages 12 to 17) can be measured, for example, by the Hemophilia Quality of Life Questionnaire for Teenagers (Haemo-QoL) (see, e.g., Bullinger et al., Value Health. (2009) 12(5):808-20; and Remor, Int J Behav Med. (2013) 20(4):609-17) and the Pediatric Hemophilia Activity List (pedHAL).

[0042] In some embodiments, the treatment improves the patient's quality of life in one or more of the QoL domains (e.g., hemophilia-specific QoL domains). These QoL domains include, for example, domains related to physical health, emotions, View of Self, sports and leisure, work and school, coping with hemophilia, treatment, the future, family planning, and / or partnership and sexuality. Improvements in these domains may be assessed by Patient Reported Outcomes (PROs) and assisted by questionnaires. For example, improvements in these domains may be reported by the patient to their physician and / or scored by a QoL questionnaire.

[0043] The PRO instrument can be, for example, the Hemophilia Quality of Life Questionnaire for Adults ("Haem-A-QoL"; von Mackensen et al., Haematologica (2005) 90(s2):115-6, Abstract 0290; Wyrwich et al., Haemophilia (2015) 21(5):578-84). In certain embodiments, the HRQoL of an adult patient is measured by a score on the Haem-A-QoL. See, e.g., von Mackensen et al., Value in Health. (2005) 8(6):A127; von Mackensen et al., J Thrombosis and Haemostasis. (2005) 3(Sup1):P0813; von Mackensen and Gringeri, "Quality of Life in Hemophilia" In: Handbook of Disease Burdens and Quality of Life Measures. Heidelberg: Springer; 2009, pp. 1910-1; and Bullinger et al., Value in Health. (2009) 12(5):808-20; Wyrwich, supra. The Haem-A-QoL questionnaire contains 46 items contributing to 10 domains, including physical health (5 items), emotions (4 items), self-image (5 items), sports and leisure (5 items), work and school (4 items), coping with hemophilia (3 items), treatment (8 items), the future (5 items), family planning (4 items), and partnership and sexuality (3 items).

[0044] All Haem-A-QoL items are measured based on a 5-point frequency scale (1=never, 2=rarely, 3=sometimes, 4=often, and 5=always). A response option of "not applicable" is also possible for the domains "Sports & Leisure", "Work & School" and "Family Planning" if the question does not apply to the participant. A "total score" is also used to represent the average of all 10 domains of the Haem-A-QoL questionnaire. Haem-A-QoL domain scores and total scores are transformed (using a method-specific scoring system) into a scale of 0 to 100, with higher scores representing greater functional impairment. A reduction in scores relative to the corresponding baseline score (score before the procedure being assessed) indicates an improvement in the patient's quality of life.

[0045] The fitusiran treatment improves from baseline a score from at least one of the Haem-A-QoL domains (e.g., physical health, emotions, self-image, sports and leisure, work and school, coping with hemophilia, treatment, future, family planning, and / or partnership and sexuality) and / or improves from baseline a Haem-A-QoL total score. In particular, the method may improve the quality of life of a patient with hemophilia, including improvement (e.g., reduction and elimination) of patient-reported hemophilia-related symptoms (e.g., painful swelling and joint pain) and physical function (e.g., pain with exercise and difficulty walking far) as determined by the Haem-A-QoL physical health score and / or total score. Clinically meaningful quality of life improvements include, for example, a reduction of about 7 points or more in the total score, a reduction of about 10 points or more in the sports and leisure domain score, and / or a reduction of about 10 points or more in the physical health domain score. See Wyrwich, supra. In some embodiments, one or more of the ten domain scores of the Haem-A-QoL (e.g., physical health domain score or total score) is reduced by 1 or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units).

[0046] For patients under 17 years of age, PROs can be measured using the Haemo-QoL, a shortened version of the Haem-A-QoL, specifically used for children and adolescents in age group II / III (8-16 years). The Haemo-QoL survey has nine domains, including physical health, emotions, self-image, coping with hemophilia, treatment, family, friends, others, and sports. A "total score" is also used to represent the average of all nine domains of the Haemo-QoL questionnaire. Scoring of the Haemo-QoL instrument follows the same method as described above for the Haem-A-QoL instrument. In some embodiments, one or more of the nine domain scores of the Haemo-QoL (e.g., physical health domain score or total score) is reduced by one or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units).

[0047] The EQ-5D-5L is a standardized disease-generic instrument for use as a measure of QoL outcomes. It consists of questionnaires on five dimensions (mobility, self-care, daily activities, pain / discomfort, and anxiety / depression, and a visual analog scale). Scoring of the questionnaire is based on a five-level disability (none, mild, moderate, severe, or extreme). The EQ-5D-5L instrument further includes a separate visual analog scale (VAS), with VAS scoring ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate better health state. See also, e.g., Herdman et al., Qual Life Res (2011) 20(10):1727-36.

[0048] The fitusiran therapy improves scores from at least one of the EQ-5D-5L dimensions (e.g., mobility, self-care, daily activities, pain / discomfort, and anxiety / depression) from baseline. In some embodiments, one or more of the five dimension scores or total score in EQ-5D-5L is increased by 0.01 or more units (e.g., 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, 0.9 or more, 0.10 or more, 0.11 or more, 0.12 or more, 0.13 or more, 0.14 or more, 0.15 or more, 0.16 or more, 0.17 or more, 0.18 or more, 0.19 or more, or 0.20 or more units). In some embodiments, the VAS score is increased by 1 or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units).

[0049] The method improves patient satisfaction with treatment as determined by well-designed and detailed questionnaires, including the Treatment Satisfaction Questionnaire for Medication Therapy (TSQM-9). The TSQM-9 is a validated psychometric tool that provides a general measure of patient satisfaction with medication. See also, e.g., Atkinson et al., Health Qual Life Outcomes (2004) 2:12 and Bharmal et al., Health Qual Life Outcomes (2009) 7:36. The TSQM-9 questionnaire includes nine items that contribute to three domains, including efficacy, convenience, and overall satisfaction. TSQM-9 domain scores range from 0 to 100, with higher scores indicating improved HRQoL. An increase in score relative to the corresponding baseline score (score before the treatment being assessed) indicates improved patient satisfaction with the treatment. The EQ-5D-5L and TSQM-9 surveys are administered to patients aged 18 years and older.

[0050] The fitusiran treatment improves scores from at least one of the TSQM-9 domains (i.e., efficacy, convenience, and overall satisfaction) from baseline. In particular, the method may improve treatment satisfaction in hemophilia patients. In some embodiments, one or more of the three domain scores in TSQM-9 (i.e., efficacy, convenience, and satisfaction) are increased by one or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units).

[0051] The method improves subjective functional ability to perform activities of daily living as determined by well-designed and detailed questionnaires including the Hemophilia Activity List (HAL) and the Pediatric Hemophilia Activity List (pedHAL).

[0052] HAL is used to assess patients aged 18 years or older, and pedHAL is used to assess patients under 18 years of age. See also, e.g., van Genderen et al., Haemophilia (2006) 12(1):36-46. The HAL questionnaire includes 42 items that contribute to 10 domains, including lying / sitting / kneeling / standing, leg function, arm function, transportation use, self-care, household chores, leisure activities and sports, basic lower limb activities, upper limb activities, and complex lower limb activities. Also, a "total score" is used to represent the average of all 10 domains of the HAL questionnaire. HAL domain scores range from 0 to 100, with higher scores representing greater self-perceived functional ability. An increase in score relative to the corresponding baseline score (score before treatment being assessed) indicates an improvement in the patient's self-perceived functional ability.

[0053] The pedHAL questionnaire contains 53 items contributing to seven domains, including lying / sitting / kneeling / standing, leg function, arm function, use of transportation, self-care, household chores, and leisure activities and sports. Scoring of the pedHAL instrument follows the same methodology as described above for the HAL instrument.

[0054] The fitusiran treatment improves scores from at least one of the HAL or pedHAL domains (i.e., lying / sitting / kneeling / standing, leg function, arm function, transportation use, self-care, housework, leisure activities and sports, basic lower limb activities (HAL only), upper limb activities (HAL only), and complex lower limb activities (HAL only)) from baseline. In particular, the method may improve the subjective functional ability of a patient with hemophilia to perform activities of daily living. In some embodiments, one or more of the HAL or pedHAL domain scores are increased by 1 or more units (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more units).

[0055] For all of the above questionnaires, the questionnaires can be obtained before and after one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more) doses of treatment with fitusiran (e.g., about 10, about 20, about 50, or about 80 mg administered subcutaneously about once every 4 weeks or about once a month, or about once every 8 weeks or about once every two months). For example, the questionnaires can be obtained 8, 12, 16, 20, 24, 28, 32, 35, 36, 37, or 38 weeks after the initiation of fitusiran treatment. The questionnaires can be obtained about 253 days (e.g., 250, 251, 252, 253, 254, or 255 days) after the initiation of fitusiran treatment.

[0056] In some embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 50 mg per dose about every two months (or about every eight weeks). In other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 50 mg per dose about every month (or about every four weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 80 mg per dose about every two months (or about every eight weeks). In yet other embodiments, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 80 mg per dose about every month (or about every four weeks). In yet another embodiment, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 20 mg about every two months (or about every eight weeks). In yet another embodiment, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 20 mg about every month (or about every four weeks). In yet another embodiment, patients with hemophilia A or B, with or without inhibitors, are treated with fitusiran at a subcutaneous dose of about 10 mg about every month (or about every four weeks).

[0057] III. Administration of Fitusiran Pharmaceutical Compositions The fitusiran pharmaceutical composition may be administered by any means known in the art, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, transdermal, or hepatic portal vein administration. In certain embodiments, the pharmaceutical composition is administered by subcutaneous injection at a dosage strength of, for example, about 10 to about 100 mg per dose (e.g., about 10 to about 90 mg, about 10 to about 80 mg, about 20 to about 80 mg, about 40 to about 90 mg, about 50 to about 100 mg, about 50 to about 90 mg, about 50 to about 85 mg, or about 50 to about 80 mg). In certain embodiments, fitusiran is administered subcutaneously in the above PBS solution at about 10, about 20, about 50, or about 80 mg (weight of active moiety) per dose.

[0058] Multiple fitusiran doses may be administered to a subject at intervals of about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, or about 3 months. In certain embodiments, a fixed dose of fitusiran (e.g., a subcutaneous injection of about 10 mg, about 20 mg, about 50 mg, or about 80 mg) is administered to a hemophilia patient (e.g., a hemophilia A or hemophilia B patient, optionally aged 12 years or older, with or without inhibitor development) about once every 4 weeks or about once a month, or about once every 8 weeks or about once every other month.

[0059] In some embodiments, the pharmaceutical compositions can be administered in conjunction with other medications and / or other therapeutic methods, such as those currently used to treat bleeding disorders. For example, in certain embodiments, fitusiran is administered in combination with a second agent useful for treating hemophilia A and / or B. Examples of such second agents are fresh frozen plasma (FFP); rFVIIa; aPCC; recombinant or plasma-derived FVIII or FIX; virally inactivated vWF-containing FVIII concentrates; desensitization therapy, which may include high doses of FVIII or FIX along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide; plasma exchange combined with immunosuppression and infusion of FVIII or FIX, with or without antifibrinolytic therapy; immune tolerance induction (ITI), with or without immunosuppressive therapy (e.g., cyclophosphamide, prednisone, and / or anti-CD20); desmopressin acetate (DDAVP); antifibrinolytic agents such as aminocaproic acid and tranexamic acid; antihemophilic agents; corticosteroids; immunosuppressants; and estrogens. The fitusiran composition and the additional therapeutic agent and / or treatment may be administered simultaneously and / or in the same combination, e.g., parenterally, or the additional therapeutic agent may be administered as part of a separate composition or at a different time, and / or by other methods known in the art or described herein.

[0060] IV. Products and Kits The present invention also provides a kit comprising a pharmaceutical composition for use in the treatment method. Such a kit comprises one or more vials or one or more pre-filled syringes comprising the pharmaceutical composition of the present invention and instructions for use, e.g., instructions for administering a therapeutically effective amount of fitusiran. The kit may optionally further comprise a means for administering fitusiran (e.g., an injection device) or a means for measuring inhibition of SERPINC1 (e.g., a means for measuring inhibition of SERPINC1 mRNA, expression of a protein encoded by SERPINC1, and / or SERPINC1 activity). Such a means for measuring inhibition of SERPINC1 may comprise a means for obtaining a sample from a subject, e.g., a plasma sample. The kit of the present invention may optionally further comprise a means for determining a therapeutically or prophylactically effective amount.

[0061] Additional definitions of terms and exemplary embodiments are set forth in the Examples and are incorporated herein by reference.

[0062] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, however methods and materials similar or equivalent to those described herein may also be used in the practice or testing of this disclosure. In the event of a conflict, the present specification, including definitions, will control. In general, the nomenclature used in connection with and techniques of hematology, medicine, pharmaceutical and pharmaceutical chemistry, and cell biology described herein are those known and commonly used in the art. Furthermore, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. All publications and other references mentioned herein are incorporated by reference in their entirety. Although many documents are cited herein, this citation does not constitute an admission that any of these documents form part of the common general knowledge in the art. As used herein, the words "approximately" or "about" when applied to one or more values ​​of interest, refer to a value similar to the stated reference value. In certain embodiments, the term refers to a range of values ​​that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated reference value, unless otherwise stated or clear from the context.

[0063] According to this disclosure, a back reference in a dependent claim is intended as a shorthand for a direct and explicit disclosure of any and all combinations of the claims set forth by the back reference. Moreover, the headings herein are made for ease of organization and are not intended to limit the scope of the invention as claimed in any way.

[0064] In order that the present invention may be better understood, the following examples are set forth below, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. EXAMPLES

[0065] Example 1: Clinical Study Design and Population This example describes the Phase 3 clinical trial protocol used in the study of fitusiran administered subcutaneously to male patients with severe hemophilia A or B, with or without inhibitors.

[0066] Research evaluation Patient-reported outcomes were used to assess health-related quality of life (HRQOL), physical activity, and treatment satisfaction and health utility. The Haem-A-QoL was administered to patients aged 17 years and older. The Haemo-QoL (short version for children and adolescents in age group II / III [8-16 years]) was administered to patients under 17 years of age. The Treatment Satisfaction Questionnaire for Medication (TSQM) was used to assess patient satisfaction with the procedure in patients aged 18 years and older. The HAL is assessed in patients aged 18 years and older, and the pedHAL is assessed in patients under 18 years of age. The EQ-5D-5L was used as a measure of QOL outcomes in patients aged 18 years and older.

[0067] research design The clinical trial described herein is an open-label, Phase 3 study designed to evaluate the efficacy and safety of fitusiran in prophylactically naive male patients aged 12 years and older with hemophilia A or B (with or without inhibitory antibodies to FVIII or FIX). The study design is depicted in Figure 2 (patients with inhibitors) and Figure 3 (patients without inhibitors). Figure 4 describes the patient demographics enrolled in the Phase 3 clinical trial of fitusiran in hemophilia A and B patients with inhibitors.

[0068] Eligible patients were randomized in a 2:1 ratio to the following groups: i. Fitusiran treatment group: monthly subcutaneous administration of 80 mg of Fitusiran as prophylaxis, together with on-demand use of BPA or factor concentrate for the treatment of breakthrough bleeding episodes, and ii. On-Demand Group: On-Demand (OD) use of BPA or factor concentrate for the treatment of breakthrough bleeding episodes.

[0069] On-demand use of BPA or factor concentrates is defined as the use of these agents for incident bleeding episodes as needed, and not as a regular regimen intended to prevent spontaneous bleeding. Throughout the study, patients in the fitusiran-treated group received on-demand treatment with BPA or factor concentrates for breakthrough bleeding episodes, as appropriate. In clinical trials, factor concentrates are also called clotting factor concentrates (CFCs).

[0070] All patients were treated for a total of 9 months, and patients randomized to the fitusiran treatment group received a total of 9 subcutaneous injections of fitusiran. Because the full PD effect of fitusiran is not achieved until approximately 28 days after receiving the first dose, efficacy was evaluated during the final 8 months of the study (days 29–month 9). Thus, the total fitusiran treatment period was defined as the initiation period (days 1–28 after receiving the first dose, during which the AT-lowering ability of fitusiran is increasing but has not yet reached therapeutic levels) plus the efficacy period (days 29 and beyond, during which the AT-lowering ability of fitusiran has reached the therapeutic target range).

[0071] Study population The inclusion criteria were: i. Males aged 12 years or older; ii. Severe hemophilia A or B, with or without inhibitors, evidenced by central laboratory measurement or documented medical record evidence of pre-treatment FVIII levels <1% or FIX levels ≤2%, and iii. At least six bleeding episodes requiring treatment with BPA or factor concentrate within the six months immediately preceding the procedure.

[0072] Patients with severe hemophilia A or B with inhibitors must meet at least one of the following Nijmegen modified Bethesda assay result criteria, as evidenced by on-demand use of BPA to manage bleeding episodes for at least 6 months immediately prior to treatment: i. Pre-treatment inhibitor titer ≥ 0.6 BU / mL, or ii. Medical record evidence of a pretreatment inhibitor titer of <0.6 BU / mL and two consecutive titers of ≥0.6 BU / mL; or iii. Pre-treatment inhibitor titer <0.6 BU / mL with medical record evidence of a prior reaction.

[0073] Patients with severe hemophilia A or B without inhibitors, as evidenced by on-demand use of factor concentrates to manage bleeding episodes for at least 6 months immediately prior to treatment, must meet each of the following criteria: i. The inhibitor titer in the modified Nijmegen Bethesda assay is less than 0.6 BU / mL; ii. Have not used BPA to treat bleeding episodes for at least the past six months; and iii. No history of immune tolerance induction therapy within the past 6 months.

[0074] The exclusion criteria were as follows: i. Known coexisting bleeding disorder other than hemophilia A or B, i.e. von Willebrand's disease, additional factor deficiencies, or platelet disorders; ii. Current use of BPA (for inhibitor patients) or factor concentrates (for non-inhibitor patients) as regularly administered prophylaxis designed to prevent spontaneous bleeding episodes; iii. AT activity before treatment is less than 60%; iv. The presence of clinically significant liver disease, as indicated by any of the following conditions: 1. INR>1.2, 2. ALT and / or AST > 1.5 × upper limit of normal (ULN), 3. Total bilirubin > ULN (in patients with Gilbert syndrome, > 1.5 × ULN), 4. History of portal hypertension, esophageal varices, or hepatic encephalopathy, and / or 5. Presence of ascites on physical examination, v. Hepatitis C virus antibody positive, except for patients with a history of HCV infection who are both: 1. Have completed definitive treatment at least 12 weeks prior to enrollment and have achieved a sustained virologic response as demonstrated by negative HCV RNA at screening, or have naturally cleared infection as demonstrated by negative HCV RNA at screening, and 2. No evidence of cirrhosis according to one of the following assessments: a. FibroScan < 12.5kPa (if available), or b. FibroTest score <0.75 and APRI <2 (if FibroScan is not available), vi. Presence of acute hepatitis, i.e. hepatitis A or E; vii. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or HBsAg positive), viii. Platelet count ≦100,000 / μL, ix. the presence of acute infection prior to treatment; x. Known HIV positive with a CD4 count <200 cells / μL, xi. Estimated glomerular filtration rate ≤ 45 mL / min / 1.73 m 2 (Using the Modification of Diet in Renal Disease [MDRD] formula), xii. A coexisting thrombophilic disorder as determined by the presence of any of the following: 1. FV Leiden mutation (homozygous or heterozygous), 2. Protein S deficiency, 3. Protein C deficiency, or 4. Prothrombin mutation (G20210A; homozygous or heterozygous), xiii. History of antiphospholipid syndrome, xiv. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina pectoris, transient ischemic attack, or stroke (except for patients who have experienced thrombosis associated with indwelling venous access); xv. Malignancy within 2 years prior to treatment (excluding successfully treated basal cell or squamous cell carcinoma of the skin), xvi. Significantly active and poorly controlled (unstable) cardiovascular, neurological, gastrointestinal, endocrine, renal or psychiatric disorder unrelated to hemophilia, as identified by significant laboratory abnormalities or medical history; xvii. The anticipated need for surgery during the study, or any planned surgery to be performed during the study; xviii. Completion of surgical procedures within 14 days prior to the procedure or currently receiving additional BPA injections for post-operative hemostasis; xix. A history of multiple drug allergies or an allergic reaction to oligonucleotides or GalNAc; xx. Inadequate venous access to allow blood sampling as required by the study protocol; xxi. History of intolerance to subcutaneous injections; xxii. Current or future participation in another clinical study that will be conducted during this study, including any investigational drug or investigational device other than Fitusiran; to participate in this study, patients must discontinue any investigational drug or investigational device at least 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1); xxiii. Current or previous participation in a gene therapy clinical trial; and xxiv. History of alcohol abuse within 12 months prior to treatment. Alcohol abuse is defined as consuming more than 14 units (units: 1 glass of wine = 1 measure of spirits = 1 / 2 pint of beer) on a regular weekly basis. 1 glass of wine = 1 measure of distilled spirits = 1 / 2 pint of beer).

[0075] Baseline demographics of patients treated in each study are shown in Table 2. Baseline demographics are for the intention to treat (ITT) analysis set (i.e., all randomized patients). Overall, baseline patient characteristics were similar between groups.

[0076] [Table 3]

[0077] Dosage regimen and formulation Fitusiran (SAR439774) solution for injection (subcutaneous use) was supplied as a sterile solution. Patients randomized to the fitusiran treatment group received open-label 80 mg fitusiran as a subcutaneous injection once a month for a total of 9 months.

[0078] Example 2: Improvement of patient-reported outcomes with Fitusiran treatment The objective of the Fitusiran Phase 3 clinical trial study was to evaluate patient-reported outcomes (PROs) to assess health-related quality of life (HRQOL), physical activity, and perceptions of treatment. Patient age at randomization determined which age-specific questionnaires were utilized, which were validated throughout the study period.

[0079] In this study, PROs were collected using: · Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL); · Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL); · Hemophilia Activity List (HAL); · Pediatric Hemophilia Activity List (pedHAL); Treatment Satisfaction Questionnaire for Medication, version 9 (TSQM-9); and · EuroQol 5-Dimensions, 5-Levels (EQ-5D-5L) questionnaire.

[0080] The following sections describe the characteristics and results of each procedure. All patients were evaluated. For each questionnaire discussed in this example, the change reported is from baseline to day 253, also referred to as the end of study (EOS).

[0081] Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) The Haem-A-QoL was administered to participants aged 17 years and older. Scoring of each item was based on a 5-point Likert scale (never, rarely, sometimes, often, and always), with higher scores representing greater impairment. Negative values ​​indicate improvement in health-related quality of life (HRQoL). Changes in Haem-A-Qol by domain from baseline to day 253 are reported in Table 3 below.

[0082] [Table 4]

[0083] Physical health domain scores showed clinically meaningful improvements versus baseline in the fitusiran prophylaxis arms of both the inhibitor and non-inhibitor studies. Fitusiran-treated participants achieved relatively improved physical health (painful swelling, joint pain, pain with movement, difficulty walking, time to get ready), with mean estimates suggesting that inhibitor patients derive slightly more benefit than non-inhibitor patients.

[0084] Haem-A-QoL total scores also showed an overall improvement in perceived QoL in the fitusiran prophylaxis group, who reported a clinically meaningful mean decrease from baseline. Both inhibitor and non-inhibitor patients benefited from treatment with fitusiran, with inhibitor patients showing slightly more improvement from baseline.

[0085] Additional analyses of Haem-A-Qol (secondary outcomes) were conducted on the total score and physical health domains using analysis of covariance models (ANCOVA) controlling for potential study confounders. The results of these additional analyses are presented in Table 4.

[0086] [Table 5]

[0087] Physical health domain scores showed significantly meaningful improvements over baseline in the fitusiran-prevention group in both studies, regardless of analysis method (based on simple and ANCOVA analyses). Fitusiran-treated participants achieved relatively improved physical health (painful swelling, joint pain, pain with movement, difficulty walking, time to get ready), with mean estimates suggesting that inhibitor patients benefited slightly more than non-inhibitor patients.

[0088] Haem-A-QoL total scores also showed an overall improvement in perceived QoL in the fitusiran prophylaxis group, with a significant mean reduction from baseline reported on fitusiran prophylaxis regardless of analysis method (i.e., based on simple and ANCOVA analyses). Both inhibitor and non-inhibitor patients showed benefit from treatment with fitusiran, with inhibitor patients showing slightly more improvement from baseline.

[0089] Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) The Haemo-QoL questionnaire is a psychometrically tested QoL assessment instrument for participants with hemophilia aged 17 years and under. The Haemo-QoL questionnaire and proxy version were adapted from the original adult Haem-A-QoL for adolescents and children. Negative values ​​indicate improvement in hemophilia-related quality of life (HRQoL). Haemo-QoL results by domain and study are presented in Table 5.

[0090] [Table 6]

[0091] Fitusiran patients generally reported improvements in all domains, with the exception of the friends domain in the inhibitor studies and the friends and sports domains in the non-inhibitor studies. In both cases, the Haemo-QoL total score showed improvement in patients receiving fitusiran.

[0092] Hemophilia Activity List (HAL) The HAL score assesses the subjective functional ability to perform activities of daily living (e.g., activities involving upper and lower limbs, basic activities involving lower limbs, and complex activities involving lower limbs). Scores range from 0 to 100, with higher scores indicating fewer functional limitations. HAL results by domain and study are presented in Table 6.

[0093] [Table 7]

[0094] HAL total mean scores (change from baseline to EOS) demonstrate that in both studies, fitusiran-prophylactic patients showed improvement in total scores, consistent across all 10 domains. The higher improvement observed in the inhibitor-carrying patient study suggests that inhibitor-carrying patients would benefit most from fitusiran treatment.

[0095] Pediatric Hemophilia Activity List (pedHAL) Child and adolescent-specific pedHAL scores were calculated for participants under the age of 18 (Table 7).

[0096] [Table 8]

[0097] Fitusiran prophylaxis demonstrated beneficial results in patients with and without inhibitors, as measured by change from baseline to EOS for the total score and across each of the individual procedure domains.

[0098] Satisfaction with Drug Therapy Questionnaire Version 9 Studies of hemophilia A or B patients with and without inhibitors also assessed patient-reported outcomes according to the Treatment Satisfaction Questionnaire version 9 (TSQM-9) for medication. The TSQM-9 is a validated psychometric tool that provides a general measure of patient-reported perceptions of medication and includes the domains of effectiveness, convenience, and overall satisfaction. Domain scores range from 0 to 100, with higher scores indicating improved HRQoL. TSQM-9 results by domain and study are presented in Table 8.

[0099] [Table 9]

[0100] Overall results for mean TSQM-9 scores (change from baseline to EOS) consistently showed improvement with fitusiran in all three domains. Here again, the improvement in inhibitor patients suggests that inhibitor-bearing patients will benefit most from fitusiran treatment.

[0101] EuroQol 5-dimensions, 5 levels (EQ-5D-5L) and EuroQoL visual analogue scale (EQ-VAS) The EQ-5D-5L is a standardized disease-generic instrument for use as a measure of QoL outcomes. It consists of a questionnaire on five dimensions (mobility, self-care, daily activities, pain / discomfort, and anxiety / depression). Scoring of the questionnaire is based on a five-point impairment (none, mild, moderate, severe, or extreme) on a scale of 0 (worst imaginable health state) to 1 (better health state). Higher scores indicate better health state. The EQ VAS is a continuous score ranging from 0 to 100. Scoring of the visual analog scale is based on a visual scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The results of the EQ-5D-5L total score and VAS score are presented in Table 9.

[0102] [Table 10]

[0103] Results from EQ-5D-5L and EQ VAS showed improvement from baseline in both studies, with more pronounced changes in patients with inhibitors.

[0104] Closing Interview The aim of the exit interview analysis was to better understand patient and caregiver experiences with hemophilia A or B (with or without inhibitors) and their treatment, including fitusiran, and how this experience changed over the course of the clinical trial, as well as their perceptions of and satisfaction with the treatment they received during the trial.

[0105] Patients were asked to participate in a semi-structured exit interview to share their experiences. If the patient was unable to participate (e.g., the patient was under 18 years old or cognitively unable), the patient's caregiver was asked to participate in the interview. A total of 24 people were asked to participate in a 60-minute telephone interview. Following a semi-structured interview guide to ensure consistency across interviews, participants were asked to describe their experiences with hemophilia and its treatment before participating in any of the fitusiran clinical trials. Participants were then asked about their perception of the impact of hemophilia and its treatment on their daily life, their expectations of treatment, and their experience with fitusiran during the clinical trial. Participants were asked to rate various aspects of hemophilia treatment (improved joint health, reduced bleeding, protection from bleeding for a full month, improved joint mobility, prevention of fear / anxiety about bleeding, minimization of anxiety / stress in managing hemophilia, and convenience) as "moderately important," "very important," or "extremely important."

[0106] The data presented in Figures 5 and 6 reflect an interim analysis conducted on the first 10 interviews. Eight patients with hemophilia A or B and two caregivers were interviewed. All participants rated improvement in joint health as extremely important, with most participants rating reduction in bleeding (90%), protection from bleeding for a full month (90%), improvement in joint mobility (90%), prevention of fear / anxiety about bleeding (80%) and minimization of anxiety / stress in managing hemophilia (80%) as "extremely important" aspects of hemophilia treatment (Figure 5). All participants reported improvement in these treatment aspects under Fitusiran prophylaxis. Notably, in each of these aspects, 100%, 100%, 90%, 100%, 90% and 80% of patients, respectively, rated there as "much improved" (Figure 6). Nearly all participants (n=9) preferred fitusiran prophylaxis over their previous hemophilia treatment, and all participants reported being "very satisfied" with fitusiran treatment, especially with regard to its ability to prevent bleeding, durability of effect, and convenience. In quotations recorded during the interviews, patients with hemophilia A or B reported, for example, "After taking fitusiran, I felt like a normal person," and "I feel very confident because I can say that if I take fitusiran, I won't have bleeding."

[0107] These exit interviews provide an encouraging and positive interim insight into the experiences of patients with hemophilia A or B, with or without inhibitors, and their caregivers. Prophylactic treatment with Fitusiran demonstrated added value in patients with hemophilia A or B, regardless of inhibitor status, specifically resulting in improved joint health, reduced bleeding, and improved joint mobility, with an overall reduction in treatment burden.

[0108] Example 3: Improvement of additional clinical endpoints with fitusiran treatment Antithrombin levels and thrombin production Monthly administration of fitusiran in inhibitor-bearing patients resulted in sustained reductions in antithrombin levels (Figure 7). At day 29, antithrombin activity levels were reduced by a mean of 84.1% from baseline, and reductions of 87.6–89.9% were maintained from day 43 onward. Furthermore, thrombin generation increased with the reduction in antithrombin, with an average increase in peak thrombin generation of 30.8 nM at day 29 and a sustained increase of 36.8–47.5 nM from day 43 onward. Peak thrombin generation reached an average of 46.67 nM by day 43 (Figure 8), approaching the lower level of peak thrombin generation of 64 nM previously observed in healthy volunteers, as indicated by the blue dotted line in Figure 8. Participants receiving fitusiran prophylaxis reached the target pharmacodynamic effects of reduced antithrombin and increased thrombin generation by day 29, which were sustained over the course of fitusiran treatment, demonstrating that hemostasis was maintained and sustained throughout the study period. Fitusiran prophylaxis increased peak thrombin generation levels to near the lower levels previously observed in healthy volunteers.

[0109] Similar results were observed in non-inhibitor patients. At day 29, antithrombin activity levels decreased by a mean of 79.8% from baseline (Figure 9). Fitusiran prophylaxis resulted in a sustained decrease in antithrombin levels (Figure 9) and a sustained increase in thrombin generation (Figure 10). At day 29, peak TG increased by a mean of 24.4 nM from baseline in non-inhibitor patients (Figure 11).

[0110] The mean change from baseline in peak thrombin generation in patients with (ATLAS-INH) or without inhibitors (ATLAS-A / B) is shown in Figure 11. TGs remained elevated throughout the entire study period. This finding suggests that fitusiran has the potential to rebalance hemostasis and provide sustained steady-state bleeding protection in people with hemophilia A or B, with or without inhibitors.

[0111] Safety and Tolerability No treatment-emergent thrombotic adverse events were reported in the phase 3 study in non-inhibitor patients (Table 10). Reported adverse events were generally consistent with previously identified risks of fitusiran.

[0112] [Table 11]

[0113] Reduced bleeding rate Fitusiran prophylaxis provided sustained protection from bleeding in people with hemophilia A or B, with or without inhibitors (Figures 12 and 13). The median ABR in each fitusiran treatment group was 0.0.

[0114] BPA and CFC consumption The mean total consumption of aPCC and rFVIIa was 97.5% and 98.2% less in the Fitusiran group compared with the on-demand BPA group, and the mean total consumption of FVIII and FIX was less in the Fitusiran group than in the on-demand replacement factor group (95.9% and 94.7%, respectively) (Figure 14; Table 11).

[0115] [Table 12]

[0116] In the inhibitor trial, participants who received fitusiran required fewer mean injections per bleed (1.2 vs. 3.7) and a lower mean BPA dose compared with participants who received on-demand BPA (Table 12). In the non-inhibitor trial, participants in both groups required an average of 1.2 injections per bleed. Participants who received fitusiran required a lower mean dose of replacement factor compared with participants who received on-demand replacement factor.

[0117] The proportion of participants with zero BPA / factor use was greater in the Fitusiran prophylaxis group compared to the on-demand BPA / factor treatment group (Figure 15), and the total number of procedural bleeds and BPA / factor injections was lower in the Fitusiran prophylaxis group compared to the on-demand BPA / factor group (Figure 16; Table 12). The total number of procedural bleeds was 82.0% and 79.2% lower in the Fitusiran group compared to the on-demand BPA and factor groups, respectively.

[0118] [Table 13]

[0119] [Table 14]

[0120] The mean annual injection rates of BPA and CFC were lower with Fitusiran prophylactic treatment compared to on-demand BPA / CFC treatment (Figure 17). Furthermore, the dose of BPA / CFC required to treat a bleed was lower in patients treated prophylactically with Fitusiran compared to on-demand BPA / CFC (Figure 18; Table 12). Notably, · aPCC dose was 43.5% lower with Fitusiran. · rFVIIa dose was 87.2% lower with fitusiran. · FVIII dose was 57.8% lower with Fitusiran. · FIX dose was 58.5% lower with Fitusiran.

[0121] In summary, reduced BPA / CFC consumption and a reduced number of injections and lower BPA and CFC doses required to treat bleeds were observed in patients receiving fitusiran prophylaxis compared to patients with on-demand / episodic BPA / CFC treatment.

[0122] Example 4: Adolescent subgroup analysis Overall, 33 adolescents (12-17 years) were enrolled (10 with inhibitors and 14 without inhibitors). Median ABR was 1.7 (inhibitors) and 3.4 (without inhibitors) in the fitusiran group compared with 18.4 and 16.8 in the on-demand CFC and BPA groups, respectively. Fitusiran prophylaxis improved HRQoL, with mean changes from baseline to month 9 in the converted total score of -18.2 (inhibitors) and -10.8 (without inhibitors) compared with -2.1 and 4.3 in the on-demand BPA and CFC treatment groups, respectively. The safety profile of fitusiran in adolescents was consistent with that observed in adult participants.

[0123] In summary, fitusiran prophylaxis demonstrated improvement in bleeding phenotype in adolescents with hemophilia A or B, with or without inhibitors. Reductions in Haemo-QoL scores support a broader improvement in HRQoL with fitusiran prophylaxis compared with CFC and BPA treatment. Benefit / risk assessment was favorable.

[0124] Example 5: Efficacy and safety of fitusiran prophylaxis in individuals with hemophilia A or B with inhibitors (ATLAS-INH) This multicenter, randomized, open-label, phase 3 study was conducted at 26 centers in 12 countries. Males aged 12 years or older with severe hemophilia A or B and inhibitors who had previously been treated on demand with a bypassing agent (BPA) were randomized 2:1 to receive monthly subcutaneous fitusiran prophylaxis at 80 mg or BPA on demand for 9 months. The primary endpoint was annualized bleeding rate (ABR) during the treatment period. Safety and tolerability were assessed.

[0125] participants Eligible participants were men aged 12 years or older with severe hemophilia A (defined by central laboratory measurement or documented medical record evidence for FVIII <1% at screening) or hemophilia B (FIX ≤2%), inhibitory antibodies to FVIII or FIX (defined as ≥0.6 Bethesda units / mL by Nijmegen modified Bethesda assay at screening), and who had experienced six or more bleeding episodes requiring on-demand BPA treatment within the 6 months prior to screening.

[0126] Participants were excluded if they had antithrombin activity at screening that was less than 60% as determined by central laboratory measurement or if they had a history of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina pectoris, transient ischemic attack, or stroke. Participants with a history of thrombosis associated with indwelling venous access were permitted to enroll. Written informed consent was obtained before any study-related procedures were performed.

[0127] Randomization and Masking Eligible participants were randomized 2:1 to receive fitusiran prophylaxis 80 mg subcutaneously once a month (0.8 mL) with on-demand BPA use for the treatment of breakthrough bleeding or to continue on-demand BPA for the treatment of bleeding episodes. Participants were assigned to study arms by stratified permuted block randomization (block size 3). On-demand use of BPA was defined as the use of these agents as needed for incident bleeding events (Table 13). Randomization was stratified by the number of bleeding episodes in the 6 months prior to screening (≦10 vs. >10). The investigator or his / her representative contacted the interactive response system after confirming that participants met all inclusion criteria. The trial was open-label, and both participants and investigators were aware of the treatment assignment.

[0128] [Table 15]

[0129] procedure The trial consisted of several periods: an initiation period from days 1 to 28, during which fitusiran gradually reached its target pharmacodynamic effect of antithrombin reduction (Pasi et al., N Engl J Med (2017) 377(9):819-28); an efficacy period from days 29 to 246, and a treatment period consisting of both the initiation and efficacy periods. The follow-up period lasted for 1 to 6 months until antithrombin levels returned to approximately 60% after the last dose or until enrollment in an open-label extension study.

[0130] A treated bleeding episode was defined as any occurrence of a bleeding episode requiring administration of BPA. Definitions of bleeding episode types followed the recommendations of the International Society on Thrombosis and Hemostasis (Table 14).

[0131] [Table 16]

[0132] Health-related quality of life (HRQoL) was assessed in adults aged 17 years and older on day 1 and at the end of the treatment period using the validated Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) instrument (see, e.g., von Mackensen et al., Haemophilia (2017) 23(3):383-91).

[0133] Safety assessments consisted of treatment-emergent adverse events (TEAEs), including treatment-emergent serious adverse events (TESAEs) and treatment-emergent adverse events of special interest (TEAESIs); physical examinations, including vital signs and electrocardiograms; and laboratory tests, including coagulation markers.

[0134] For pharmacodynamic evaluation, antithrombin activity levels were measured from blood samples drawn within 4 hours before dosing and monitored at monthly intervals starting on day 1 until estimated activity levels returned to 60% after the final fitusiran dose (unless the participant elected to continue fitusiran in the open-label extension study). Thrombin generation was also assessed at monthly intervals. Anti-drug antibodies (ADA) to fitusiran were measured from serum samples drawn within 4 hours of treatment administration using a validated enzyme-linked immunosorbent assay method at day 1, month 1, and month 3, and at the end of treatment.

[0135] Outcomes The primary efficacy outcome was ABR during the efficacy period. ABR was defined as the number of eligible bleeding episodes divided by the total number of days in the efficacy period multiplied by 365.25. Prespecified subgroup analyses of the primary outcome were performed according to hemophilia type (A vs. B), number of bleeding episodes in the 6 months prior to the study (≤10 vs. >10), and age group (<18, 18-64, ≥65 years) during the efficacy period. Secondary outcomes included ABR during the treatment period, annualized spontaneous bleeding rate (AsBR) during the efficacy period, and annualized joint bleeding rate (AjBR) during the efficacy period. Changes from baseline in the Haem-A-QoL physical health domain and total scores during the treatment period were also assessed as secondary outcomes.

[0136] Safety and tolerability endpoints included incidence, severity, seriousness, and relevance of adverse events. TEAESIs were predefined as elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN), suspected or confirmed thrombosis, severe or serious injection site reactions, and systemic infusion-related reactions.

[0137] Prespecified exploratory endpoints included the number of target joint bleeding episodes during the efficacy period, the pharmacokinetic and pharmacodynamic effects of fitusiran (including antithrombin activity and thrombin generation), and the incidence and titer of ADA in the fitusiran-prophylactic group. Multiplicity was not considered for exploratory outcomes.

[0138] Determining sample size Using a negative binomial regression model with a two-sided type I error rate of 0.05, an estimated sample size of 14 participants in the BPA-on-demand group (assuming a mean [SD] ABR of 18

[14] ) and 28 participants in the Fitusiran prophylaxis group (assuming a mean [SD] ABR of 4 [6]) was predicted to provide greater than 90% power to detect a treatment difference in the primary endpoint. The planned sample size was 54 randomized participants, assuming a 20% dropout rate.

[0139] statistical analysis All statistical analyses were performed using SAS statistical software version 9.4. The primary analysis was performed in the intention-to-treat analysis set (all randomized participants). Before any Chinese participants could be randomized to receive 80 mg subcutaneous fitusiran prophylaxis, the first three participants were enrolled in a China-specific non-randomized fitusiran group and received subcutaneous fitusiran prophylaxis every 4 weeks, starting at an initial starting dose of 50 mg, increasing to 80 mg after the observation period, as planned in the protocol to comply with the regulatory requirements of the Chinese FDA Commission. These participants were not included in the intention-to-treat population but were included in the safety set.

[0140] The number of bleeding episodes during the efficacy period was analyzed using a negative binomial model with fixed effects of treatment group and number of bleeding episodes in the 6 months prior to study entry (≤10 vs. >10). The logarithm of the number of days each participant spent during the efficacy period corresponding to the bleeding episode data analyzed was included as an offset variable to account for unequal follow-up times due to early withdrawal, surgery, etc. From this model, the estimated mean ABR in both treatment groups was presented with its 95% confidence interval (CI). Summary statistics for ABR including median and IQR were also calculated for each group. Sensitivity analyses were performed for efficacy outcomes.

[0141] AsBR and AjBR were analyzed using the same methods as the primary analysis. Least squares (LS) mean changes from baseline in Haem-A-QoL physical health score and total score were analyzed using an analysis of covariance model with fixed effects of treatment group, baseline Haem-A-QoL physical health score and total score, and number of bleeding episodes 6 months prior to enrollment (≦10 vs. >10). A hierarchical testing approach was used to control for family-wise error rate in testing the primary and secondary endpoints.

[0142] Safety, pharmacokinetic, pharmacodynamic, and immunogenicity results were summarized narratively. In the safety population, all participants received at least one dose of fitusiran or were randomized to the on-demand group; all treatment-specific analyses based on the safety analysis set followed the treatment actually received.

[0143] This trial was registered at www.clinicaltrials.gov with identifier NCT03417102.

[0144] result A total of 85 participants were screened, of which 25 failed screening, 3 were not randomized, and 57 participants were randomized to the BPA on-demand group (n=19) and the Fitusiran prophylaxis group (n=38). All randomized participants completed the study. Baseline demographics and clinical characteristics were similar between both groups in the safety set (Table 15); most participants had hemophilia A (n=48, 80%) and had multiple target joints at baseline (67% of participants had ≥1 target joint). Median duration of Fitusiran exposure was 252.0 days (min 203 days; max 271 days).

[0145] [Table 17]

[0146] The mean ABR estimated by the negative binomial model during the efficacy period was statistically significantly lower in the Fitusiran prophylaxis group (1.7 [95% CI: 1.0, 2.7]) compared with the BPA on-demand group (18.1 [95% CI: 10.6, 30.8]; Table 16, Figure 19), corresponding to a statistically and clinically significant reduction in bleeding rate of 90.8% (95% CI: 80.8, 95.6%) in favor of the Fitusiran prophylaxis group (p<0.0001). The median ABR was consistent with these findings: 0.0 (IQR: 0.0, 1.7) in the Fitusiran prophylaxis group and 16.8 (IQR: 6.7, 23.5) in the BPA on-demand group (Table 16, Figure 19). During the efficacy period, 25 participants in the Fitusiran prophylaxis group (66%) had zero procedural bleeding compared with 1 participant in the BPA on-demand group (5%). In the fitusiran group, 13 participants experienced a procedural bleed, of which 2 received aPCC and 11 received rFVIIa. In the BPA-on-demand group, 18 participants experienced a procedural bleed, of which 9 received aPCC and 13 received rFVIIa (n=4 received both). Annualized bleeding rates during the treatment period demonstrated similar results to the primary endpoint. When analyzed by hemophilia subtype, median ABR during the efficacy period was lower in the fitusiran prophylaxis group compared with the BPA-on-demand group in both patients with hemophilia A (0.0 [IQR: 0.0, 0.0] vs. 15.9 [IQR: 6.7, 23.5], respectively) and patients with hemophilia B (1.7 [IQR: 0.0, 5.0] vs. 18.4 [IQR: 5.1, 23.5], respectively) (Table 17).

[0147] [Table 18]

[0148] [Table 19]

[0149] Subgroup analyses confirmed the primary endpoint. In all subgroups, estimated ABR results favored fitusiran prophylaxis (Figure 20, Table 17). Sensitivity analysis results supported the primary efficacy outcome and are reported in Table 18.

[0150] [Table 20]

[0151] During the efficacy period, the median AsBR was 0.0 (IQR: 0.0, 0.0) and 13.4 (IQR: 3.4, 21.8) in the Fitsiran prophylaxis and BPA on-demand groups, respectively. A greater proportion of participants in the Fitsiran prophylaxis group had zero spontaneous bleeding (76%) compared with the BPA on-demand group (11%). The median AjBR was 0.0 (IQR: 0.0, 1.7) and 11.7 (IQR: 3.4, 16.8) in the Fitsiran prophylaxis and BPA on-demand groups, respectively. In the Fitsiran prophylaxis group, 11 (29%) participants had one or more joint bleeds compared with 18 (95%) participants in the BPA on-demand group; 2 (5%) and 13 (68%) participants, respectively, had more than three joint bleeds. Among participants with one or more target joints identified at baseline, 4 / 26 (15%) and 12 / 12 (100%) participants in the Fitusiran prophylaxis and BPA on-demand groups, respectively, had a spontaneous target joint bleeding event treated during the treatment period. Most participants in the Fitusiran prophylaxis group (85%) had zero target joint bleeding events compared with no participants (0%) in the BPA on-demand group with zero target joint bleeding events (Table 19).

[0152] [Table 21]

[0153] The proportion of participants with significant protocol deviations identified during the study was similar between treatment groups: 68.4% (n=13) in the BPA on-demand group and 76.3% (n=29) in the Fitusiran prophylaxis group.

[0154] The LS mean (95% CI) of the transformed scores for the Haem-A-QoL physical health domain was statistically significantly decreased (improved) from baseline in the Fitsiran prophylaxis group (-30.7 [-36.9, -24.4]) compared with the BPA on-demand group (-1.9 [-10.3, 6.4]), with a LS mean difference of -28.7 (-39.1, -18.4) in favor of Fitsiran prophylaxis (p<0.0001) (Figure 21). A statistically significant decrease was also observed in the Haem-A-QoL transformed total score in the Fitusiran prophylaxis group (-15.3 [-19.3, -11.2]) compared with the BPA on-demand group (-0.4 [-5.7, 4.8]), with an LS mean difference of -14.9 (-21.4, -8.3) in favor of Fitusiran prophylaxis (p<0.0001) (Figure 21).

[0155] Overall, 38 (93%) participants in the fitusiran prophylaxis group and 11 (58%) participants in the BPA on-demand group experienced at least one TEAE; the most common TEAEs (reported in >5% of participants in the fitusiran prophylaxis group) are summarized in Table 20. TESAEs were reported in seven participants (17%) in the fitusiran prophylaxis group and five participants (26%) in the BPA on-demand group. In the fitusiran prophylaxis group, one participant (2%) experienced two TESAEs (spinal vascular accident and thrombosis "[suspected spinal vascular thrombosis]) that were assessed by the investigator as possibly related to fitusiran and that led to discontinuation of study drug. There were no TEAEs leading to study withdrawal or death.

[0156] [Table 22]

[0157] In the fitusiran prophylaxis group, a TEAESI of "any ALT or AST elevation >3xULN" was reported in 10 (24%) participants (Table 20). In most participants, the onset of the event occurred within 60 days of starting fitusiran. All events were classified by the investigator as non-serious and mild-to-moderate severity. As a result of these events, fitusiran prophylaxis was interrupted in three (7%) participants (necessitated due to an ALT or AST elevation >5xULN) and in none of the participants fitusiran prophylaxis was discontinued. In all three participants in whom fitusiran prophylaxis was interrupted, the events were reported as resolved or resolved by the investigator; the median time to resolution of the event was 42 days (minimum 5 days; maximum 50 days). In one of these participants, recurrent elevations >3xULN were reported. Of the seven participants who continued on fitusiran prophylaxis, the event was reported by the investigator to have resolved or been cured in four participants; median time to resolution of the event was 76.5 days (min 24 days; max 148 days). Recurrent elevations >3xULN were reported in one of these participants. No laboratory abnormalities consistent with Hy's law were identified. No "any ALT or AST elevations >3xULN" were reported in the BPA on-demand group.

[0158] In the fitusiran prophylaxis group, four TEAESIs of "suspected or confirmed thromboembolic events" were reported in two (5%) participants (Table 20). These events were deep vein thrombosis (non-serious) in a single participant, subclavian vein thrombosis (serious), and superficial thrombophlebitis involving the upper extremities (non-serious) in the setting of central venous access and related complications. All three of these events led to discontinuation of fitusiran and were assessed by the investigator as unlikely to be related to study drug. This participant's antithrombin value prior to the occurrence of these events was 11.9%. In the second participant, the event of thrombosis (suspected spinal vascular thrombosis) was assessed by the investigator as serious and possibly related to study drug, and fitusiran prophylaxis was discontinued. This participant's steady-state antithrombin value prior to the occurrence of the events ranged from 7.8% to 11.6%. No TEAESIs (suspected or confirmed thromboembolic events) were reported in the BPA on-demand group.

[0159] No severe or serious injection site reactions or systemic injection-related reactions (TEAESIs) were reported.

[0160] In the fitusiran group, six participants experienced TEAEs of cholecystitis and / or cholelithiasis. Of these six participants, three participants reported cholecystitis and cholelithiasis simultaneously, one participant reported acalculous cholecystitis, and two participants reported cholelithiasis only. The cholecystitis and / or cholelithiasis event was managed by cholecystectomy in one participant. No cholecystitis or cholelithiasis events were reported in the BPA on-demand group.

[0161] Monthly dosing with Fitusiran prophylaxis resulted in a sustained reduction in antithrombin activity levels, from a mean of 104% (SD: 10.5) from baseline, to a mean reduction of 77% (SD: 8.6) from baseline by day 15 and a mean reduction of 84% (SD: 7.2) by day 29 (Figure 22 Panel A). Antithrombin levels remained reduced by 84-90% from day 29 to the end of the study. At study endpoint, the mean AT level was 11% (SD: 2.9). As expected, treatment with BPA did not affect antithrombin levels. In the fitusiran group, peak thrombin generation increased from baseline by a mean (SD) of 21.9 nM (16.4) on day 15, peak mean thrombin generation increased to 40.3 nM (17.9) on day 29, and to 46.7 nM (23.0) by day 43 (corresponding to a 540% change from baseline), remaining elevated throughout the study in the fitusiran prophylaxis group (Figure 22 panel B).

[0162] Overall, one (3%) participant in the Fitusiran prophylaxis group was confirmed to be ADA positive on day 29 with a low ADA titer of 50 (equivalent to the minimum required dilution of the assay); this was transient and the participant tested negative at subsequent evaluations at 3 and 8 months.

[0163] conclusion In people with hemophilia A or B and inhibitors, monthly subcutaneous prophylactic fitusiran 80 mg resulted in a median ABR of zero, a high proportion of participants (65.8%) with zero bleeds, and improved quality of life, thereby meeting the primary endpoint of the study. These results demonstrate the efficacy of fitusiran prophylaxis in providing consistent protection against bleeds in inhibitor holders.

Claims

1. 1. A method of improving patient-reported outcomes (PRO) in a hemophilia patient, comprising subcutaneously administering a therapeutically effective amount of fitusiran to a hemophilia patient in need thereof, optionally wherein the patient is a hemophilia A or B patient with or without inhibitors, and optionally wherein the PRO is improved in one or more quality of life (QoL) domains.

2. A method of improving quality of life (QoL) in a hemophilia patient, comprising subcutaneously administering fitusiran to a hemophilia patient in need thereof, wherein said QoL is improved in one or more QoL domains, optionally wherein said patient is a hemophilia A or B patient with or without inhibitors.

3. 3. The method of claim 1 or 2, wherein the fitusiran is administered at about 10 to about 90 mg per dose.

4. 4. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally wherein the QoL questionnaire is the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL).

5. 5. The method of claim 4, wherein said administration results in a clinically meaningful improvement as indicated by a reduction of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in one or more of the questionnaire total score, the sports and leisure domain score, and the physical health domain score.

6. 4. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally wherein the QoL questionnaire is the Haemophilia Quality of Life Questionnaire for Children and Adolescents (Haemo-QoL).

7. The administration results in a clinically meaningful improvement as indicated by a reduction of 7 or more units (optionally, 8 or more, 9 or more, or 10 or more units) in the total score on the questionnaire. The method according to claim 6.

8. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally wherein the QoL questionnaire is the Hemophilia Activity List (HAL).

9. 9. The method of claim 8, wherein said administration results in an improvement as indicated by an increase of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in the total score on said questionnaire.

10. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally wherein the QoL questionnaire is the Paediatric Hemophilia Activity List (pedHAL).

11. 11. The method of claim 10, wherein said administration results in an improvement as indicated by an increase of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in the total score on said questionnaire.

12. 4. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally the QoL questionnaire is the Treatment Satisfaction Questionnaire for Medication Version 9 (TSQM-9).

13. 13. The method of claim 12, wherein the administration results in an improvement as indicated by an increase of 7 or more units (optionally 8 or more, 9 or more, or 10 or more units) in one or more of the efficacy, satisfaction, and convenience domain scores of the questionnaire.

14. 4. The method of any one of claims 1 to 3, wherein the one or more QoL domains are domains of a QoL questionnaire, optionally wherein the QoL questionnaire is EuroQol 5-Dimension (EQ-5D-5L).

15. 15. The method of claim 14, wherein the administration results in an improvement as indicated by an increase in the total score of the questionnaire of 0.02 or more units (optionally, 0.03 or more, 0.04 or more, or 0.05 or more units) or an increase in the visual analog scale (VAS) score of the questionnaire of 5 or more units (optionally, 6 or more, 7 or more, or 8 or more units).

16. The method according to any one of claims 1 to 15, wherein the patient is an adult or adolescent patient aged 12 years or older with hemophilia A or B, with or without inhibitors.

17. The method of any one of claims 1 to 16, wherein the patient has hemophilia A.

18. 18. The method of claim 17, wherein the patient is undergoing treatment with a factor VIII or bypassing agent (BPA).

19. 20. The method of claim 18, wherein the patient has an inhibitor, and optionally the level of the inhibitor is greater than 0.6 BU / mL as determined by the Bethesda Inhibitor Assay.

20. 19. The method of claim 17 or 18, wherein the patient does not have an inhibitor.

21. The method of any one of claims 1 to 16, wherein the patient has hemophilia B.

22. 22. The method of claim 21, wherein the patient is undergoing treatment with Factor IX or BPA.

23. 23. The method of claim 22, wherein the patient has an inhibitor, and optionally the level of the inhibitor is greater than 0.6 BU / mL as determined by the Bethesda Inhibitor Assay.

24. 23. The method of claim 21 or 22, wherein the patient does not have an inhibitor.

25. The method of any one of claims 18 to 20 or 22 to 24, wherein the BPA is activated prothrombin complex concentrate (aPCC) and / or recombinant activated factor VII (rFVIIa).

26. 26. The method of any one of claims 1 to 25, comprising administering to the patient multiple doses of fitusiran at about 10 mg, about 20 mg, about 50 mg, or about 80 mg per dose.

27. 27. The method of any one of claims 1 to 26, wherein the fitusiran is administered to the patient about once every 4 weeks or about once a month, or about once every 8 weeks or about once every two months.

28. 28. The method of any one of claims 1 to 27, wherein the fitusillan is provided in a concentration of about 1 to about 200 mg / mL in phosphate buffered saline (pH 7), optionally at a concentration of about 6.25, about 12.5 mg / mL, or about 100 mg / mL.

29. The patient is (i) the presence of clinically significant liver disease; (ii) ALT>1.5×upper limit of normal (ULN); (iii) AST>1.5×upper limit of normal (ULN); (iv) hepatitis C; (v) hepatitis A; (vi) hepatitis E, and / or (vii) Hepatitis B The method according to any one of claims 1 to 28, wherein the method is free of

30. 30. A phytusiran for use in the method according to any one of claims 1 to 29.

31. 30. A product for use in the method of any one of claims 1 to 29.

32. The product is i. about 80 mg of phytusiran in about 0.8 mL of phosphate buffered saline (pH 7); ii. about 50 mg of phytosilan in about 0.5 mL of phosphate buffered saline (pH 7); iii. about 20 mg of phytosilan in about 0.2 mL of phosphate buffered saline (pH 7), or iv. About 10 mg of Physiolobus in about 0.1 mL of phosphate buffered saline (pH 7) 32. The product for use according to claim 31, which is a disposable container containing

33. The product is i. about 80 mg of phytusiran in about 0.8 mL of phosphate buffered saline (pH 7); ii. about 50 mg of phytosilan in about 0.5 mL of phosphate buffered saline (pH 7); iii. about 20 mg of phytosilan in about 0.2 mL of phosphate buffered saline (pH 7), or iv. About 10 mg of Physiolobus in about 0.1 mL of phosphate buffered saline (pH 7) 32. The article of manufacture for use according to claim 31 which is a disposable, pre-filled syringe containing

34. Use of fitusiran for the manufacture of a medicament for the treatment of hemophilia A or B in the method according to any one of claims 1 to 29.

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