Fitusiran, a Subcutaneous (SC) investigational siRNA therapeutic, lowers Antithrombin (AT) to increase thrombin generation and rebalance haemostasis in people with Haemophilia (PwH) A or B, regardless of inhibitor status. We report interim safety and efficacy of the fitusiran Antithrombin-based Dose Regimen (AT-DR) in a Phase 3 Open-Label Extension (OLE) study (ATLAS-OLE; NCT03754790).

Males aged ≥12-years with severe haemophilia A or B, with or without inhibitors, who completed a fitusiran Phase 3 study were enrolled. The original 80 mg SC monthly (QM) dose regimen [ODR] was adjusted to the AT-DR, targeting AT activity levels 15%–35% to mitigate adverse events. Participants received fitusiran prophylaxis 50 mg or 20 mg every other month (Q2M) or QM. Doses were individually adjusted to achieve target AT activity. Safety was compared with the ODR across all fitusiran studies, and efficacy was compared with control groups in the parental studies.

Overall, 227 participants were enrolled. Mean (SD) AT level was 23.5 (4.6) on AT-DR. 78% of participants were on Q2M regimes; 38% required zero and 56% required one dose adjustment to achieve AT 15%–35%. Safety analyzes included all participants exposed to fitusiran (n = 270 ODR, n = 286 AT-DR). For ODR, total patient (pt)-years of exposure was 306.8 (≥ 12-months exposure n = 101). For AT-DR, total patient (pt)-years of exposure was 486.0 (≥ 12-months exposure n = 238). The exposure-adjusted incidence rate of adverse events was substantially reduced on AT-DR: Thrombotic Events (TE) (ODR 2.28 vs. AT-DR 0.82/100 pt-years), ALT/AST > 3×ULN (ODR 16.62 vs. AT-DR 2.26/100 pt-years), and cholecystitis/cholelithiasis (ODR 14.67 vs. 2.26/100 pt-years). All TE had significant contributing risk factors. Median ABR (IQR) was 3.7 (0.0; 7.5); 1.9 (0.0; 5.6) in PwH with inhibitors and 3.8 (0.0; 11.2) in PwH without inhibitors. Superior bleed control was demonstrated vs on-demand Clotting Factor Concentrations (CFC)/By Passing Agents (BPA) in PwH with or without inhibitors (73% and 71% reductions, p < 0.0006, 0.0001, respectively). Bleed rate was reduced by 70% vs. BPA prophylaxis (p = 0.0002) and was comparable with CFC prophylaxis (p = 0.6).

In this study, the fitusiran AT-DR targeting AT levels of 15%–35% improved the safety profile substantially versus the ODR and maintained bleed protection in PwH A or B, with or without inhibitors, with most on a Q2M regimen.