Mim8: Advancing Hemophilia A Treatment with a Potent FVIII Mimetic Bi-Specific Antibody

Hemophilia A (HA) is typically treated by replacing factor VIII (FVIII), with bypassing agents used for those with inhibitors. Emicizumab, a FVIII mimetic bispecific antibody, has been approved for both HA and HA with inhibitors, providing a prophylactic, subcutaneous treatment that could significantly reduce the treatment burden.

Mim8, a novel bispecific antibody, is being developed as the next generation of FVIII mimetics. It is designed to bridge factor IXa (FIXa) and factor X (FX), offering a potent subcutaneous treatment option for HA and HA with inhibitors.

The development of Mim8 involved the use of the Duobody platform to screen for compatible antibodies, followed by optimization through systematic mutational processes. Over 30,000 bispecific antibodies were evaluated, with the aim of achieving efficient activation of FX by FIXa on procoagulant membranes, minimal binding in solution, low risk of immunogenicity, and favorable biophysical properties, including low viscosity.

In vitro studies have shown that Mim8 effectively targets FIXa and FX to the phospholipid surface, enhancing FXa activation. The monovalent arm targeting FIXa significantly boosts proteolytic activity, contributing to the overall efficacy of the bispecific antibody. Mim8's dissociation constants for FIXa and FX are in the micromolar range, which minimizes binding in the blood. It has been shown to normalize thrombin generation and blood clot formation in assays, demonstrating approximately 15 times greater potency than emicizumab. In a mouse model, Mim8, when co-administered with human FIX and FX, was able to normalize coagulation. The terminal half-life of Mim8 in cynomolgus monkeys was estimated at 14 days, with a subcutaneous bioavailability of 97%.

Mim8 is a promising next-generation FVIII mimetic bispecific antibody with high potency, enabling small volume administration, favorable pharmacokinetic parameters, minimal blood binding, and good biophysical properties. These characteristics suggest that Mim8 could be a more effective prophylactic treatment for hemophilia A, irrespective of inhibitor status.

Disclosures indicate that several individuals are employed by Novo Nordisk A/S and have varying degrees of equity ownership, patent ownership, and royalty agreements with the company.