Haemophilia A and B are rare bleeding disorders with characteristic impaired blood clotting due to insufficient levels of thrombin. In collaboration with Sanofi, Alnylam pharmaceuticals have developed an investigational RNA interference treatment fitusiran, for people with haemophilia A or B, with or without inhibitors (neutralizing antibodies that may render conventional replacement therapies ineffective). The treatment is designed to inhibit antithrombin, a protein which normally inactivates thrombin and hence blood clotting.
A phase 3 (ATLAS-INH; NCT03417102) study was recently conducted to evaluate the safety and efficacy of fitusiran in haemophilia A and B patients.
A randomized open-label phase 3 study enrolled 57 eligible males (≥12 years) who were randomized in a 2:1 ratio to receive 80 mg SC fitusiran prophylaxis or continue with on-demand bypassing agents (BPA). The primary endpoint of the study was to compare annualized bleeding rate (ABR) in fitusiran and BPA-treated patients. The secondary endpoint of the study included evaluating spontaneous ABR, joint ABR, and health-related quality of life (HRQoL), as assessed by the Haem-A-QoL questionnaire.
Among all the participants, fitusiran significantly reduced ABRs for all bleeds (1.67 vs. 18.07), spontaneous bleeds (0.87 vs. 15.68), and joint bleeds (1.35 vs. 13.76) as compared with BPA in haemophilia A and B patients with inhibitors. Bleeding events were not observed in 25 patients (65.8%) treated with fitusiran. Significant improvements in overall HRQoL were seen in participants who received preventive treatment with fitusiran as compared with on-demand treatment with BPA.
38 patients (92.7%) who received fitusiran experienced attests one treatment-emergent adverse event, compared to 11 (57.9%) in the BPA group. Further, 13 and 8 treatment-emergent serious adverse events were observed in 7 (17.1%) (fitusiran group) and 5 (BPA group) patients, respectively. Serious side effects observed in the fitusiran group included infection, blood in the urine, spinal vascular disorder, thrombosis (blood clot formation), gallbladder inflammation, and asymptomatic COVID-19. One patient in the fitusiran treatment group left the study due to complications (spinal vascular disorder and thrombosis). Importantly, no deaths were reported during the study.
This phase 3 study demonstrates the efficacy of fitusiran in people with haemophilia A or B with inhibitors. Ongoing clinical studies are evaluating reduced dose and dose frequency of fitusiran.