FRONTIER1 multiple ascending dose extension: a safety, tolerability, pharmacokinetics, and pharmacodynamics study of Mim8 in people with hemophilia A

Background: Mim8 (denecimig) is a next-generation, factor VIIIa mimetic, human bispecific antibody for hemophilia A. Mim8 was well tolerated in the phase 1/2 FRONTIER1 (NCT04204408) dose-escalation part. Objectives: Report Mim8 long-term safety in the FRONTIER1 multiple ascending dose (MAD) extension phase. Methods: People (≥12 years) with severe hemophilia A with/without inhibitors who completed the 12-week FRONTIER1 MAD main phase enrolled in the extension and continued Mim8 once weekly or once every 4 weeks for up to 148 weeks; patients could switch doses or transition to maintenance doses designed to achieve target exposure in phase 3 trials. Primary endpoint: treatment-emergent adverse events (TEAEs). Secondary endpoints: injection-site reactions, anti-Mim8 antibodies. Results: = 1 patient switched between doses. Total exposure: 69.5 patient-years. Thirty-five patients experienced 174 TEAEs. Seven serious TEAEs occurred (none Mim8-related). TEAE rate, type, and severity were not dose-dependent. Of 3128 injections, 6 (0.2%) injection-site reactions were recorded in 6 (14.6%) patients. There was no evidence of anti-Mim8 antibodies. Mim8 exposure and peak thrombin levels remained consistent across cohorts and maintenance doses. No dose-dependent changes in D-dimer, prothrombin fragment 1 + 2, or fibrinogen levels were observed. Most patients experienced no bleeds during maintenance dosing. Conclusion: Mim8 was well tolerated, with no safety concerns nor anti-Mim8 antibodies during the FRONTIER1 MAD extension, supporting phase 3 development of Mim8 once weekly and once every 4 weeks.