A Multiple Ascending Dose Study of Mim8 in Patients with Severe Hemophilia a with or without Factor VIII Inhibitors

Introduction: Mim8 is a subcutaneously administered, activated factor VIII (FVIIIa) mimetic bispecific antibody that bridges factors IXa and X, and is currently in clinical development for patients with hemophilia A with or without inhibitors. Mim8 has demonstrated hemostatic efficacy in animal bleeding models, with preclinical data suggesting a higher potency than a sequence-identical analog of emicizumab. FRONTIER 1 (EudraCT:2019-000465-20; NCT04204408) is a 2-part phase 1/2 study of Mim8, consisting of single ascending dose and multiple ascending dose (MAD) parts in healthy participants and patients with hemophilia A, respectively. Here, we report results from all 5 cohorts of the MAD part of the study, which investigates the safety and tolerability, as well as the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous Mim8 in patients with severe hemophilia A, with or without FVIII inhibitors.

Methods: Patients with hemophilia A were administered multiple ascending doses of Mim8 for 12 weeks, targeting average plasma concentrations of 1 µg/mL (cohort 1, once weekly [QW] dosing), 3 µg/mL (cohort 2, QW dosing), 9 µg/mL (cohort 3, QW dosing; cohort 4, once every 4 weeks [Q4W] dosing), or 20 µg/mL (cohort 5, QW dosing). Patients in cohorts 3 and 4 were randomized 1:1 to either QW or Q4W dosing, respectively. Adverse events, serious adverse events, and adverse events of special interest were monitored, and the assessment of PK and PD at steady state was undertaken on days 57-64 (QW) or days 57-85 (Q4W). Preliminary efficacy was assessed as an exploratory endpoint as number of treated bleeding episodes over 12 weeks of treatment.

Results: Forty-two patients in total were included in the 5 MAD cohorts (cohort 1, n=7; cohort 2, n=9; cohort 3, n=8; cohort 4, n=8; cohort 5, n=10). Four (9.5%) patients had FVIII inhibitors. All patients were males older than 12 years of age (mean [SD] age of 34 [13] years).

Mim8 was well tolerated, with no evidence for dose impacting the rate, causality, type, or severity of adverse events (Table 1). Injection site reactions occurred in <1% of injections (4 mild injection site reactions in 4 [9.5%] patients) and no anti-Mim8 antibodies were observed. There was 1 serious adverse event (moderate noncardiac chest pain), deemed to be unrelated to Mim8. One patient was withdrawn from the study due to a hypersensitivity reaction, but there was no lack of treatment efficacy, and the symptoms resolved when treatment was discontinued. Steady-state median prothrombin fragment 1+2 levels increased in a dose-dependent manner (cohort 1, 93 pmol/L; cohort 2, 159 pmol/L; cohort 3, 372 pmol/L; cohort 4, 346 pmol/L; cohort 5, 460 pmol/L). Other coagulation parameters showed no dose-dependent changes from baseline to week 12.

Steady-state Mim8 area under the curve and maximum concentration increased with dose, consistent with dose proportionality (Figure 1). PK profiles were similar between patients with and without inhibitors. Mean-concentrations at steady-state PK concentrations were comparable between QW (cohort 3) and Q4W (cohort 4) dosing, which targeted similar Mim8 plasma concentrations. PD was monitored at steady state using a thrombin generation assay, and peak thrombin increased with dose, with comparable peak thrombin heights between cohorts 3 and 4.

Six out of 7 patients reported treated bleeds in cohort 1, while few patients had treated bleeds in the higher dose cohorts. All bleeds reported in cohorts 2-4 were traumatic non-joint bleeds

Conclusion: Data from the MAD part of FRONTIER 1 showed proof of concept and demonstrated a good safety profile, thereby providing support for the continued clinical development of Mim8 for patients with hemophilia, with and without inhibitors. No thrombotic events and no antibody development were observed. PK and PD properties were consistent with dose proportionality, supporting both QW and Q4W dosing. Additionally, the study provided some encouraging data regarding the efficacy of Mim8, with few patients reporting bleeds beyond the lowest dose cohort. The study has continued into an extension phase.

Lentz:Argenx: Consultancy; Novo Nordisk: Consultancy; Takeda: Consultancy. Chowdary:Chugai: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lopez Jaime:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposia, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposia, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored syposium, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Sponsored symposium, Speakers Bureau. Mahlangu:Roche: Consultancy, Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding; Takeda: Consultancy, Speakers Bureau; UniQure: Research Funding; WFH: Speakers Bureau; ISTH: Speakers Bureau; Norvatis: Research Funding; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding; Catalyst Biosciences: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Matytsina:Novo Nordisk: Current Employment, Current equity holder in private company. Nielsen:Novo Nordisk: Current Employment. Windyga:Alnylam: Research Funding; Bayer AG: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Sobi: Honoraria; Swixx BioPharma: Honoraria; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria.