Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI)
Authors: Young Guy , Srivastava Alok , Kavakli Kaan , Ross Cecil , Sathar Jameela , Tran Huyen , Wu Runhui , Sun Jing , Poloskey Stacey , Qui Zhiying , Kichou Salim , Andersson Shauna R. , Mei Baisong , Rangarajan Savita 
Published: November 2021

Abstract
Introduction
Hemophilia A and B are rare bleeding disorders characterized by ineffective clot formation due to impaired thrombin generation as a result of deficiency of FVIII or FIX, respectively. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic targeting antithrombin to restore thrombin generation and rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Here, we present the safety and efficacy of fitusiran prophylaxis for PwHI in a phase 3 study (ATLAS-INH; NCT03417102).
Methods
The ATLAS-INH study is a randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of fitusiran in PwHI. Eligible males ≥12 years receiving on-demand treatment with bypassing agents (BPA) were randomized in a 2:1 ratio to receive once monthly 80 mg SC fitusiran prophylaxis or continue with on-demand BPA. The primary endpoint is annualized bleeding rate (ABR) in PwHI on fitusiran prophylaxis compared to those on BPA on-demand in the efficacy period. The secondary endpoints include spontaneous ABR, joint ABR, and quality of life (QoL) measured by Haem-A-QoL.
Results
57 subjects were randomized into the study. Mean (range) age of the study participants at screening was 28.4 (13-63) yrs. Statistical significance was achieved for primary and all secondary endpoints with significant reduction in ABRs of treated bleeds: all, spontaneous and joint bleeds for fitusiran vs on-demand BPA arm (Table 1). A total of 25 patients in fitusiran arm (65.8%) had zero treated bleeding events. Efficacy of fitusiran prophylaxis treatment was seen in both hemophilia A and hemophilia B patients with inhibitors. Statistical significance was also achieved for improvement in physical health domain score, with a difference (95% CI) of -28.72 (-39.07 to -18.37, p-value &lt;0.0001) as well as overall HRQoL and between fitusiran and on-demand BPA arms.
Overall, 38 patients (92.7%) in the fitusiran arm and 11 patients (57.9%) in the on-demand BPA arm experienced at least 1 treatment emergent adverse event (TEAE). A total of 13 treatment emergent serious adverse events (TESAEs) were reported in 7 patients (17.1%) in the fitusiran arm and 8 TESAEs were reported in 5 patients (26.3%) in the on-demand BPA arm. All TESAEs were reported in 1 patient each; in the fitusiran prophylaxis arm these included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19. One patient (2.4%) in the fitusiran arm experienced TEAEs that resulted in study drug discontinuation (spinal vascular disorder and thrombosis). There were no fatal TEAEs reported.
Conclusions
This Phase 3 study demonstrated the efficacy of the 80 mg monthly subcutaneous prophylaxis dose of fitusiran in people with hemophilia A or B with inhibitors. Specifically, fitusiran significantly reduced bleeding with a median ABR of zero and significant proportion of people with zero bleeds, resulting in a meaningful improvement in health-related quality of life. Reported TESAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A or B with inhibitors, or with the previously identified risks of fitusiran. A revised fitusiran dosing regimen with reduced dose and dose frequency is currently being evaluated in ongoing clinical studies.
Figure 1 Figure 1.

Disclosures
Young: Genentech/Roche, Grifols, and Takeda: Research Funding; Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy. Kavakli: Roche: Consultancy, Other: Clinical Trial Support; Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support; Takeda: Consultancy, Other: Clinical Trial Support. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Qui: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kichou: Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company. Rangarajan: Sanofi: Other: Advisory Board; Pfizer: Other: Advisory Board; Reliance Life Sciences: Consultancy; Takeda: Other: Advisory Board, Conference Support, Speakers Bureau.