EVALUATION of the OVERALL HAEMOSTATIC CAPACITY of MIM8 with GLOBAL HAEMOSTASIS ASSAYS and FIBRIN CLOT ULTRASTRUCTURE

Plain-language summary

Hemophilia A is an X linked disorder characterized by a deficiency in Factor VIII. The clinical hallmark of this disease is increased tendency to spontaneous bleeding with hemarthrosis accounting for 90% of the hemorrhages. In addition to development of hemophilic arthropathy, the emergence of alloantibodies that inhibit the coagulant activity of FVIII remains the most feared complication related to the treatment of hemophilia A. 30% of patients with hemophilia A develop these inhibitors, making treatment with standard replacement therapy ineffective. Up until the approval of emicizumab, bypassing agents like activated prothrombin complex concentrate (aPCC) and activated recombinant activated factor VII (rFVIIa) were the only approved therapies for the treatment hemophilia A with inhibitors. The response to bypassing therapy is often unpredictable, variable and difficult to monitor. Emicizumab is a first generation bispecific antibody mimicking the activity of FVIIIa in tenase complex. Early in the HAVEN 1 clinical trial with emicizumab (1), cases of thrombotic microangiopathy (TMA) and thrombotic events were reported when on average a cumulative amount of \>100 U/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving emicizumab, resulting in a protocol adjustment for the HAVEN 1 trial and subsequent trials to recommend using the lowest doses of bypassing agents expected to achieve hemostasis, and avoiding the combination of emicizumab and aPCC if possible. So far the only proposed strategies for treating events of breakthrough bleeds in patients on emicizumab prophylaxis include rFVIIa, FVIII in patients with a low titer of inhibitors, and lower doses of aPCC, knowing that emicizumab provides an existing level of thrombin generation. (2) While the exact mechanism leading to the development of thrombotic complications (TMA and VTE) remains poorly understood, many speculated on the accumulation of FIX and FX, the substrates of emicizumab, with multiple doses of aPCC (3) Mim8 is a novel, next-generation FVIIIa mimetic designed for the subcutaneous prophylactic treatment of patients with HA with and without inhibitors. Mim8 is a fully human, bispecific antibody that mimics FVIIIa function by bridging FIXa and FX on the phospholipid surface of activated platelets, enhancing the proteolytic activity of FIXa, and thus facilitating effective FX activation. 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 (4). Mim8 nonclinical safety program in cynomolgus monkeys showed that subcutaneous administration of up to 3 mg/kg/week (several fold greater than expected clinical exposure) for 26 weeks resulted in relevant pharmacodynamic effects, observed in thrombin generation and APTT, with no signs of thrombi or excessive coagulation activation. So far, Mim8 procoagulant activity was evaluated in platelet poor plasma samples only (5,6) This in vitro study aims to evaluate TGA to monitor Mim8. We hypothesized that TG profiles (ETP and peak thrombin) may be different with different triggers used. We recently modified TGA to better detect haemostatic activity of emicizumab, by using a combined trigger (low TF+low FIXa). Differently from emicizumab, Mim8 stimulates the proteolytic activity of FIXa in the range of 15,000-fold. TGA test conditions may be therefore different for Mim8 and emicizumab.

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