A factor VIIIa–mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice

Abstract

Hemophilia A (HA) is a bleeding disorder resulting from deficient Factor VIII (FVIII), which normally functions as a cofactor to activated Factor IX (FIXa) that facilitates activation of Factor X (FX). To mimic this property in a bispecific antibody (biAb) format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting biAb (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant (KD) of 16 nM. Binding affinity with FIXa and FX in solution was much lower, with KD-values for FIXa and FX of 2.3 and 1.5 µM, respectively. In addition, the activity of Mim8 was dependent on stimulatory activity contributed by the anti-FIXa arm, which enhanced the proteolytic activity of FIXa by four orders of magnitude. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation with potencies 13 and 18 times higher than a sequence-identical analog of emicizumab, respectively. A similar potency difference was observed in a tail-vein transection model in hemophilia A mice, while reduction of bleeding in a severe tail-clip model was observed only for Mim8. Furthermore, the pharmacokinetics of Mim8 were investigated and a half-life of 14 days demonstrated in cynomolgus monkey. In conclusion, Mim8 is a FVIIIa-mimetic with a potent and efficacious hemostatic effect based on preclinical data.

Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options

“…HA mice showed reduction of bleeding with severe tail-vein transection and demonstrated a half-life of 14 days in the cynomolgus monkey. 49 These in vitro and in vivo characterizations are encouraging for the clinical development of Mim8 as a potential next-generation FVIII-mimetic prophylactic treatment for individuals with hemophilia A. Currently, Phase 1 and Phase 2 clinical trials are underway (NCT04204408).…”

“…HA mice showed reduction of bleeding with severe tail-vein transection and demonstrated a half-life of 14 days in the cynomolgus monkey. 49 …”

Impact of novel hemophilia therapies around the world

“…Since emicizumab was approved, new activated FVIII mimetic bispecific antibodies have been developed, such as BS‐027125 (Bioverativ, Waltham, MA, USA) 39 and Mim8 (Novo Nordisk, Bagsvaerd, Denmark). Preclinical analysis of Mim8, including in vitro assays with FVIII deficient human plasma and in vivo assay using a hemophilia A mouse model, suggest that this new bispecific antibody could be more potent than emicizumab 40 …”

“…(Bioverativ, Waltham, MA, USA) 39 assays with FVIII deficient human plasma and in vivo assay using a hemophilia A mouse model, suggest that this new bispecific antibody could be more potent than emicizumab. 40…”

A novel next‐generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys

“…Data from studies using in vitro HA-like human blood, as well as in vivo HA mouse models, indicate that Mim8 is ~15-fold more potent than a sequence identical analogue (SIA) of the FVIII mimetic emicizumab. 12 The nonclinical characterization of Mim8 has demonstrated that it potently increases thrombin generation triggered by both tissue factor and FXIa. 12 This increased potency is primarily due to the monovalent anti-FIXa arm's strong stimulation of FIXa's proteolytic activity.…”