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

Abstract

Background: Mim8 is a novel, next-generation factor VIIIa mimetic in development for subcutaneous prophylactic treatment of patients with hemophilia A with and without inhibitors. In vitro and in vivo models indicate that Mim8 has a distinct hemostatic potential.Objectives: To test the nonclinical safety and pharmacodynamics of Mim8. Methods:The Mim8 nonclinical safety program in cynomolgus monkeys consisted of three studies of 4-26 weeks in duration with Mim8 doses ranging from 0.3-60 mg/ kg/week intravenously or subcutaneously. After sacrifice, macroscopic and microscopic pathological examinations were performed.Results: Mim8 was well tolerated with no noteworthy clinical observations. No signs of excessive coagulation or pathological macroscopic or microscopic findings were observed at doses 0.3-3 mg/kg/week subcutaneous. Thrombosis-related findings were detected during histopathological examination in a small proportion of animals (16%) receiving doses ranging 6-20 mg/kg/week. Dose-dependent increases in factor X (FX) and factor IX (FIX) concentrations were observed. Shortening of activated partial thromboplastin time (APTT) and increased thrombin generation under ex vivo hemophilia A-like conditions were observed at all Mim8 dose levels.Conclusions: Thrombosis-related findings observed at doses above 6 mg/kg/week Mim8 may have been exaggerated pharmacological reactions to a procoagulant compound in normocoagulant animals. Increases in FX and FIX concentrations could be because of a half-life prolongation due to binding to Mim8, but were limited at clinically relevant exposure levels. Subcutaneous administration of up to 3 mg/kg/week (several fold greater than expected clinical exposure) for 26 weeks resulted in relevant

Next generation FVIII mimetic bispecific antibody for hemophilia A

“…8,17 Finally, an increase in FX levels was observed in animals receiving a dose of 3 mg/kg/week. 8 Increased levels of FX suggest that at least part of the Mim8 circulates in complex with FX thereby preventing its clearance from the circulation. No effect on circulating levels of FIX was observed, which was unexpected in view of the similar affinity of Mim8 for FX and FIX.…”

“…6 Two recent preclinical studies on the hemostatic and pharmacokinetic properties of a next-generation FVIII mimetic bispecific antibody designated Mim8 have been described. 7,8 Interestingly, based on their data the authors conclude that Mim8 is 15-fold more potent in correcting hemostasis compared to "a sequence identical analogue (SIA)" of emicizumab. 7,8 In this Commentary we summarize the design and biochemical properties of emicizumab and Mim8.…”

“…7,8 Interestingly, based on their data the authors conclude that Mim8 is 15-fold more potent in correcting hemostasis compared to "a sequence identical analogue (SIA)" of emicizumab. 7,8 In this Commentary we summarize the design and biochemical properties of emicizumab and Mim8. Clinical trials of Mim8 in hemophilia A patients are ongoing (NCT04204408; NCT05053139) but as yet no results have been published.…”

“…In this issue Lauritzen et al report on additional studies on the safety profile and pharmacodynamics of Mim8 in non-human primates. 8 The pharmacodynamic profile of the Mim8 compound is favorable showing a very good bioavailability upon subcutaneous infusion.…”

“…In 5 out of 26 animals microscopic thrombi were observed in cynomolgous monkeys treated with 6/12/20 mg/kg/week of Mim8. 8 The significance of these findings is not entirely clear, but the authors argue that this may result from adding a potent hemostatic agent to animals with normal levels of hemostatic proteins. Anti-drug antibodies were observed in more than half of the animals treated.…”