Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial

Summary

Background

Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors.

Methods

This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete.

Findings

Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8–7·8) in the fitusiran group and 7·8 months (7·8–7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0–3·4) in the fitusiran group and 21·8 (8·4–41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3–4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1–45·5]; rate ratio 0·101 [95% CI 0·064–0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported.

Interpretation

In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia.

Funding

Sanofi.

Introduction

Haemostasis depends on balanced procoagulant and anticoagulant pathways that generate sufficient thrombin to control bleeding.¹ Haemophilia is a bleeding disorder that arises from deficiency of coagulation factors VIII (haemophilia A) or IX (haemophilia B), resulting in insufficient thrombin generation.1, 2 Prophylaxis sufficient to prevent bleeds at all times is recommended in people with haemophilia A or B who have a severe bleeding phenotype.² However, prophylaxis with clotting factor concentrates requires frequent intravenous infusions to ensure sufficient plasma concentrations to provide bleed protection.³ Such regimens can be burdensome and are limited by the development of inhibitory antibodies, which render treatment ineffective, in approximately 30% of people with haemophilia A and 10% of people with haemophilia B.2, 4, 5 Clinical trial data suggest that 27–50% of people with haemophilia who receive mostly high doses of frequently administered intravenous clotting factor concentrate prophylaxis have no bleeding events;6, 7, 8, 9, 10 however, the occurrence of such events in some people despite clotting factor concentrate prophylaxis can result in subsequent joint damage.¹¹ Efforts into the development of alternative therapies are therefore underway to potentially overcome these limitations of efficacy, safety, and convenience. One alternative is subcutaneous emicizumab prophylaxis, which has been shown to provide effective bleed protection in people with haemophilia A only, regardless of inhibitor status, with a less burdensome regimen than prophylaxis with clotting factor concentrates; however, breakthrough bleeds can still occur with emicizumab.12, 13, 14 Additional therapeutic options are needed to overcome the remaining limitations of prophylaxis with clotting factor concentrates for people with haemophilia A or B, particularly those with inhibitors.2, 15, 16

Research in context

Evidence before this study

We searched PubMed for clinical trials published in English from database inception to July 1, 2022, using the terms “siRNA OR RNAi”, “haemophilia OR hemophilia”, and “clinical trial”; no published trials of siRNA molecules other than fitusiran in haemophilia were found. In phase 1/2 studies of fitusiran prophylaxis, dose-dependent lowering of antithrombin resulted in increased thrombin generation and marked reductions in the number of bleeding events in people with haemophilia A or B, with or without inhibitors.

Added value of this study

The phase 3 ATLAS-A/B trial was designed to investigate fitusiran prophylaxis versus episodic (on-demand) treatment with clotting factor concentrates in people with haemophilia A or B without inhibitors. Our findings show that subcutaneous fitusiran prophylaxis provides sustained protection against bleeding and results in markedly improved bleeding phenotype in participants with haemophilia A or B without inhibitors, with approximately 50% of participants having no bleeding events with fitusiran prophylaxis. These efficacy outcomes were accompanied by a meaningful improvement in quality of life and an overall reduction of both treatment and disease burden. Reported treatment-emergent adverse events were generally consistent with previously reported risks of fitusiran or those anticipated in an adult and adolescent population with severe haemophilia A or B.

Implications of all the available evidence

The evidence from available phase 3 studies of fitusiran (NCT03417102, NCT03549871, and this study NCT03417245) suggests that subcutaneous fitusiran prophylaxis provides effective bleed protection for all people with haemophilia—type A or B, with or without inhibitors—resulting in a reduced treatment burden. Fitusiran has the potential to be the first prophylactic therapy that is effective in all people with haemophilia, irrespective of subtype, thereby potentially advancing health equity and progress in closing the quality-of-life gap between people with and without haemophilia.

Fitusiran is an investigational, subcutaneous, prophylactic siRNA therapeutic that is designed to lower antithrombin levels with the goal of generating sufficient thrombin to rebalance haemostasis in people with haemophilia A or B, with or without inhibitors.17, 18 Unlike other drugs for the treatment of haemophilia, fitusiran uses natural cellular RNA interference mechanisms to cleave and degrade antithrombin mRNA and reduce antithrombin synthesis. Previous studies19, 20 have shown that fitusiran lowers antithrombin levels, resulting in increased thrombin generation and translating to enhanced clinical haemostasis.19, 20 This phase 3 trial evaluated the efficacy and safety of fitusiran prophylaxis compared with on-demand (episodic) treatment with clotting factor concentrates in people with severe haemophilia A or B without inhibitors.