Safety and Efficacy of Mim8 Prophylaxis Administered Once Every Two Weeks for Patients with Hemophilia A with or without Inhibitors: Interim Analysis of the FRONTIER4 Open-Label Extension Study

Introduction

Mim8 (denecimig) is a next-generation, activated factor VIII mimetic, fully human bispecific IgG4 antibody in clinical development as a subcutaneous prophylactic treatment for patients with hemophilia A with or without factor VIII inhibitors. In the phase 2, open label, multiple ascending dose part of the FRONTIER1 study (NCT04204408), Mim8 was well tolerated with no safety concerns and few treated bleeding episodes beyond the lowest dose cohort. Efficacy for reducing annualized bleeding rate (ABR) and safety of weekly (QW) or monthly (QM) prophylaxis were established in the phase 3 FRONTIER2 study (NCT05053139; Mancuso, et al. ISTH 2024; LB01.5). FRONTIER4 (NCT05685238) is an open-label extension study enrolling participants from FRONTIER1 (Arm 1) or several phase 2/3 studies of Mim8 (Arm 2).

Aim

This interim analysis investigates the safety and efficacy of Mim8 prophylaxis once every two weeks (Q2W) in Arm 1 of FRONTIER4 (26 weeks).

Methodology

Adults and adolescents (12–17 years old) with hemophilia A with or without inhibitors who completed the 12-week phase 2 part of FRONTIER1, along with at least 12 weeks of its extension, enrolled in Arm 1 of FRONTIER4. Patients received Mim8 prophylaxis Q2W for 26 weeks (part 1), after which they could remain on Q2W dosing or switch to QW or QM (part 2). The primary endpoint was number of treatment-emergent adverse events and secondary endpoints included number of treated bleeding episodes, subtypes of bleeds, number of injection site reactions, and occurrence of anti-drug antibodies. In this interim analysis we report safety and efficacy from part 1 of FRONTIER4 (26-week Q2W dosing).

Results

Of 39 patients who completed the FRONTIER1 phase 2 extension study, 37 transferred to FRONTIER4; all completed part 1 of the study. Mean (standard deviation [SD]) age was 35 (12) years (two adolescents and 35 adults; all male). All participants had severe hemophilia A, four of whom were positive for inhibitors. Mean (SD) ABR from the phase 2 FRONTIER1 study (previous 12 months) was 1.76 (5.34) and mean (SD) exposure time on Mim8 prophylaxis during the extension was 1.73 (0.33) years.

Of the 60 adverse events (AEs) reported by 20 patients, none were AEs of special interest (thromboembolic and thrombotic microangiopathy events) or hypersensitivity reactions. All AEs were non-serious, except three (two patients), which were considered unlikely to be related to Mim8 and resolved. Two participants reported 14 mild, transient injection site reactions (mainly erythema). One participant, who had zero bleeding episodes, had one low-titer positive anti-drug antibody result at one visit, which did not impact Mim8 concentration (measured by Meso Scale Discovery immunoassay) or activity (measured by modified FVIII chromogenic assay). Values for laboratory parameters, including coagulation parameters (D-dimer, fibrinogen, Factor IX, and X antigens), were generally within the normal range and remained stable over time. No trend was observed with prothrombin fragments 1 and 2; outlying values were observed from a single site, which may be attributed to technical issues.

Six participants had seven treated bleeding episodes (four spontaneous and three traumatic), five of which were joint bleeds. This resulted in an estimated mean ABR of 0.4 (95% confidence interval [CI] 0.17, 0.82) for treated bleeding episodes with Mim8 Q2W dosing. Median ABR was 0 and 31/37 (84%) participants had zero treated bleeding episodes. Estimated mean ABR (95% CI) for treated spontaneous, traumatic, and joint bleeds were 0.2 (0.07, 0.60), 0.2 (0.03, 0.81), and 0.3 (0.11, 0.65), respectively. Mim8 plasma concentration was stable at steady state with Q2W dosing (C_max 5.0 μg/mL and C_trough 4.8 μg/mL).

Conclusions

This interim analysis of FRONTIER4 showed that Mim8 Q2W prophylaxis was well tolerated with no participants discontinuing treatment, and no safety concerns were observed. Few participants experienced treated bleeding episodes with Mim8 Q2W dosing and a large proportion had zero treated bleeding episodes.

These data are consistent with the findings from FRONTIER2, which reported no safety concerns and a low number of treated bleeding episodes with either QW or QM prophylaxis. Further data from this ongoing arm of FRONTIER4, as well as data for participants enrolled from other studies in the FRONTIER program, will provide valuable long-term data for different Mim8 dosing regimens.