Mim8 prophylaxis in adults and adolescents with hemophilia A: 52-week efficacy and safety outcomes from the phase 3 FRONTIER2 study

Abstract Introduction Mim8 (denecimig) is a new-generation, bispecific antibody, activated factor VIII mimetic in clinical development for subcutaneous prophylaxis (PPX) for hemophilia A (HA) with or without inhibitors. The 26-week main phase of the phase 3 FRONTIER2 study (NCT05053139) demonstrated superiority of once-every-week (QW) and once-every-month (QM) Mim8 PPX in reducing annualized bleeding rates (ABRs) for treated bleeds versus on-demand therapy or prior clotting factor concentrate (CFC) PPX. Aim To assess 52-week efficacy and safety of Mim8 PPX in adults and adolescents (aged ≥12 years) with HA with or without inhibitors from the FRONTIER2 extension phase. Methods In the 26-week main phase, participants were randomized to Mim8 QW or QM, or continued on-demand standard-of-care treatment. Participants were grouped by prior treatment regimen: on-demand or CFC PPX. In the 26-week extension, all on-demand participants switched to Mim8 PPX (QW or QM); others continued their assigned regimen. Mim8 was administered using a tiered-dosing approach. Primary endpoint: number of treated bleeds; selected secondary endpoints: number of injection-site reactions (ISRs) and anti-Mim8 antibodies. ABR was estimated using a negative binomial regression model. Safety and immunogenicity were assessed. Ethics approval and informed consent were obtained. Results Of 281 randomized participants, 97% completed the main phase and 96% the extension. Mean (min; max) age at baseline was 32 (13;64) years for the pre-study on-demand group (n=61) and 31 (12;69) years for the pre-study CFC PPX group (n=220). In the pre-study CFC PPX group vs the pre-study on-demand group, there was a higher proportion of patients with severe HA (86% vs 77%) and lower proportion with inhibitors (2% vs 44%). This analysis includes 27 newly reported participants from China. In the main phase, all participants who continued on-demand treatment (n=18) experienced treated bleeds. Estimated mean ABR (95% confidence interval [CI]) was 16.09 (11.21;23.09). All participants entered the extension, during which 88% (Mim8 QW, n=7/8) and 70% (Mim8 QM, n=7/10) had zero treated bleeds. Estimated mean ABRs (95% CI) were 0.67 (0.13;3.61) and 0.79 (0.19;3.33), respectively. For participants previously treated on-demand: of those randomized to Mim8 QW, 86% (n=19/22) had zero treated bleeds in the main phase and 91% (n=19/21) in the extension, with estimated mean ABRs (95% CI) of 0.43 (0.17;1.07) and 0.45 (0.19;1.08), respectively; of those randomized to Mim8 QM, 91% (n=19/21) had zero treated bleeds in the main phase and 86% (n=18/21) in the extension, with estimated mean ABRs (95% CI) of 0.25 (0.08;0.76) and 0.25 (0.08;0.77), respectively. For participants previously on CFC PPX: of those randomized to Mim8 QW, 67% (n=74/111) had zero treated bleeds in the main phase and 70% (n=73/104) in the extension, with estimated mean ABRs (95% CI) of 2.32 (1.35;3.99) and 1.28 (0.78;2.08), respectively; of those randomized to Mim8 QM, 63% (n=69/109) had zero treated bleeds in the main phase and 69% (n=74/108) in the extension, with estimated mean ABRs (95% CI) of 1.79 (1.22;2.63) and 1.54 (0.92;2.59), respectively. Across main and extension phases, median ABR was 0 in all Mim8-treated arms. Adverse events (AEs) were reported in 74% (n=104) of Mim8 QW and 71% (n=100) of Mim8 QM participants. Most AEs were mild: 84% (399/475) of events with Mim8 QW and 82% (321/390) with Mim8 QM. Overall, ISRs occurred in 12% (n=17) of QW and 9% (n=12) of QM participants, accounting for 1.81% and 1.34% of injections, respectively. Overall, anti-Mim8 antibodies were detected in 21 (7%) recipients without clinical evidence of neutralizing activity; all were low (95%) or medium (5%) titer. No thromboembolic events, hypersensitivity reactions, or clinically relevant laboratory abnormalities were observed, including coagulation parameters. Conclusion Over 52 weeks, Mim8 QW and QM PPX provided sustained bleed protection in adults and adolescents with HA, with or without inhibitors, supporting its use as a long-term prophylactic option. During the extension, Mim8 was well tolerated, with infrequent ISRs, few serious AEs, no thromboembolic events or hypersensitivity reactions, and no anti-Mim8 antibodies with clinical impact. Participants completing FRONTIER2 are eligible for the open-label extension, FRONTIER4 (NCT05685238). Mim8 may offer an effective and convenient approach to reducing disease and treatment burden in this population.