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4 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)

Program: General Sessions
Session: Plenary Scientific Session
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Bleeding Disorders, Clinical Trials, Adults, Hemophilia, Non-Biological, Clinical Research, Diseases, Therapies, Young Adults, Study Population
Sunday, December 12, 2021, 2:00 PM-4:00 PM

Guy Young, MD1, Alok Srivastava, MD, FRACP, FRCPA, FRCP2, Kaan Kavakli, MD, PhD3*, Cecil Ross, MBBS, MD4*, Jameela Sathar, MD5*, Huyen Tran, MD, PhD6*, Runhui Wu, MD, PhD7*, Jing Sun, MD8, Stacey Poloskey, MD9*, Zhiying Qui, PhD10*, Salim Kichou, MD11*, Shauna Andersson, MD, PhD12*, Baisong Mei, MD, PhD12 and Savita Rangarajan, MBBS, MD, FRCP, FRCPath13

1Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA
2Department of Hematology, Christian Medical College, Vellore, India
3Department of Hematology, Ege University Faculty of Medicine, Children's Hospital, Izmir, Turkey
4Department of Hematology, St. John's Medical College Hospital, Bangalore, India
5Department of Hematolgy, Ampang Hospital, Petlaing Jaya, MYS
6Ronald Sawers Hemophilia Treatment Centre, Monash University, Melbourne, Australia
7Department of Hematology, National Center for Children's Health, Beijing Children's Hospital, Beijing, China
8Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
9Sanofi, Waltham, MA
10Sanofi, Bridgewater, NJ
11Sanofi, Paris, MA, France
12Sanofi, Cambridge, MA
13KJ Somaiya Super Specialty Hospital, Mumbai, India

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 <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.

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. Srivastava: Takeda: Other: Advisory Board, Research Funding; Bayer Healthcare: Other: Grant Review & Awards Committee; Pfizer: Other: Advisory Board, Research Funding; Sanofi: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board, Research Funding; Roche: Other: Advisory Board, Research Funding. Kavakli: Roche, Bayer, Pfizer, Novo Nordisk, Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer, Bayer, Roche, Novo Nordisk, Takeda: Speakers Bureau; Pfizer, Bayer, Takeda, Roche, Novo Nordisk: Honoraria. 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: WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees; Sanofi: Current Employment, Current equity holder in publicly-traded company. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company. Rangarajan: Takeda: Other: Advisory Board, Conference Support, Speakers Bureau; Reliance Life Sciences: Consultancy; Pfizer: Other: Advisory Board; Sanofi: Other: Advisory Board.

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