Mim8 Clinical Development Program: An Overview of the Frontier Studies

Background Mim8 is a bispecific antibody, mimicking activated factor VIII (FVIIIa), currently in clinical development as a treatment for patients with hemophilia A (PwHA), independent of inhibitor status. Preclinical data demonstrate that Mim8 is highly potent with an efficacious hemostatic effect. The FRONTIER program aims to expedite Mim8 development, recruiting participants from >30 countries including women, previously untreated patients (PUPs), and patients with mild/moderate disease severity. FRONTIER 1 (NCT04204408; EudraCT:2019-000465-20), a phase 1/2 study of Mim8 in healthy participants and PwHA, provided proof of concept that Mim8 enables clinically relevant levels of thrombin generation with no safety concerns, and no occurrences of anti-Mim8 antibodies. The study also used biomarker bridging (in vitro and ex vivo) to benchmark against emicizumab. The outcomes from FRONTIER 1 support the further development of Mim8 in the ongoing phase 3 studies (FRONTIER 2 and 3).

Methods & Study Design To allow for rapid clinical development, the observational run-in phases of both phase 3 studies were initiated prior to FRONTIER 1 completion (Figure 1A) and are running in parallel.

FRONTIER 2 (NCT05053139; EudraCT:2020-001048-24) is an ongoing, open-label, randomized control study investigating the efficacy and safety of Mim8 dosed once-weekly (QW) and once-monthly (QM) in adult and adolescent PwHA (≥12 years of age). The study aims to recruit ~250 PwHA. The primary endpoint is the annualized bleeding rate. Prior to their first Mim8 dose, patients currently on FVIII or bypassing agent prophylaxis will remain on this treatment for ≥26-week observational run-in period (Figure 1B). Patients currently treated on demand with ≥5 bleeds in the 26 weeks prior to screening can join the main phase of the trial without a run-in period. Participants receiving emicizumab must discontinue use and switch to factor prophylaxis when entering the run-in period. Exclusion criteria include planned major surgery, ongoing/planned immune tolerance induction (ITI), and previous or current thromboembolic diseases/events.

FRONTIER 3 (NCT05306418; EudraCT:2020-003467-26) is an ongoing, open-label, uncontrolled study investigating the safety of Mim8 in pediatric PwHA (aged 1-11 years). It is targeting recruitment of 70 children with HA with or without inhibitors, who will receive subcutaneous doses of Mim8 QW for 26 weeks. Thereafter, participants can choose between QW and QM prophylaxis regimen for the next 26 weeks (Figure 1B). The primary endpoint is the number of treatment-emergent adverse events during the 52-week treatment period. Key inclusion criteria for FRONTIER 3 include: previously treated patients prescribed FVIII, or by-passing agents, and PUPs with severe HA. Key exclusion criteria are the same as FRONTIER 2. ITI would need to be discontinued prior to joining the trial.

To collect further data on the safety and efficacy of Mim8, FRONTIER 1-3 study participants will be invited to join the long-term, open-label extension FRONTIER 4 study. Additionally, plasma samples will be collected from participants with the aim of future exploratory analysis of further biomarkers.

Conclusions The FRONTIER studies are a comprehensive clinical development program designed to evaluate Mim8 in PwHA, with or without inhibitors. The FRONTIER 2 and FRONTIER 3 studies initiated recruitment prior to the completion of FRONTIER 1 to accelerate the development of a novel alternative to current HA treatments. Moreover, Mim8 is being investigated in a broad patient population across many different countries and the inclusion criteria were designed to allow for the incorporation of female patients, PUPs, all disease severities, and all ages. This aims to ensure that the study population is as comparable to and representative as possible of the real-world population of PwHA.

Seremetis:Novo Nordisk: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Clausen:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company. Matytsina:Novo Nordisk: Current Employment, Current equity holder in private company. Nissen:Novo Nordisk: Current Employment, Current equity holder in private company. Wåhlander:Novo Nordisk: Current Employment, Current holder of stock options in a privately-held company.