Anti-Thrombin siRNA Therapeutic Reduces Bleeding in Hemophilia

Monthly prophylaxis doses of fitusiran, an siRNA therapeutic targeting antithrombin, reduced bleeding in people with hemophilia with or without inhibitors, according to data from the phase 3 ATLAS-INH study (NCT03417102).¹

Data from the study were presented at the 63rd Annual American Society of Hematology (ASH) Meeting, December 11-14, 2021, by Guy Young, MD, director, Hemostasis and Thrombosis Program, and professor of Pediatrics, Keck School of Medicine, University of Southern California.

“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,” Young and colleagues wrote.¹

The randomized, open-label, ATLAS-INH study enrolled 57 male participants with hemophilia. Participants were a mean age of 28.4 years (range, 13-63). The study met its primary end point of significantly reduced annual bleeding rate of treated bleeds (ABR; P <.0001) and significantly reduced all, spontaneous, and joint bleeds compared with on-demand bypassing agents (BPA). 

READ MORE: Hemophilia B Gene Therapy Meets Primary End Points in HOPE-B Trial

Treated bleeding events were reduced to 0 in 25 treated patients (65.8%) and efficacy was seen in patients with both hemophilia A and hemophilia B. Physical health domain score was significantly higher in the fitusiran arm compared with the on-demand BPA arm (95% CI, -28.72 [-39.07 to –18.37]; P <.0001) and health-related quality of life scores were also significantly higher (P <.0001).

Treatment-emergent adverse events (TEAEs) were common, with 38 patients (92.7%) in the fitusiran arm and 11 patients (57.9%) in the on-demand BPA arm experiencing at least one TEAE. Of these TEAEs, 13 events in 7 patients (17.1%) in the fitusiran arm and 8 events in 5 patients (26.3%) in the on-demand BPA arm were serious. 

Serious TEAEs in the fitusiran arm included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19, all reported in 1 patient each. One patient in this arm discontinued the study after experiencing spinal vascular disorder and thrombosis as TEAEs.

“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... A revised fitusiran dosing regimen with reduced dose and dose frequency is currently being evaluated in ongoing clinical studies,” Young and colleagues wrote.¹

ATLAS study protocol was amended in February 2021 to use a reduced dosing regimen after the trial was voluntarily placed on hold in October 2020 to address the serious thrombotic TEAEs. Sanofi presented the amended trial protocol at the Congress of the European Association for Haemophilia and Allied Disorders.²

For more coverage of ASH 2021, click here.

REFERENCES

1. Young G, Srivastava A, Kavkli K, et al. 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). Presented at: 63rd Annual ASH Meeting; December 11-14, 2021, Atlanta, GA. Abstract 4.
2. Joint statement from the European Hemophilia Consortium, the World Federation of Hemophilia, and the National Hemophilia Foundation. News release. National Hemophilia Foundation. February 22, 2021. https://www.hemophilia.org/news/sanofi-revises-fitusiran-dosing-regimen-to-mitigate-risk-of-vascular-thrombosis