In patients with hemophilia A, the concomitant use of Mim8 with factor VIII (FVIII) or activated factor VII (FVIIa) is safe for the management of breakthrough bleeding episodes, according to findings from a study published in the Journal of Thrombosis and Haemostasis.
It is well known that although the gold standard of hemophilia A treatment has been replacement therapy with FVIII, unmet therapeutic needs remain. Ongoing issues include venous access, patient adherence, and the use of prophylactic treatment. Patients with hemophilia A are often further burdened by the development of neutralizing antibodies (ie, inhibitors).
The researchers sought to evaluate the response of Mim8—a next-generation, subcutaneously administered, FVIIa mimetic, anti-FIXa/anti-FX bispecific antibody in clinical development as prophylaxis for individuals with hemophilia A with or without inhibitors—in thrombin-generation assays (TGAs). Recognizing that patients receiving treatment with Mim8 may require supplementary bleed therapy in situations as major trauma or surgery, their aim was to better understand the in vitro effects of Mim8 alone or combined with other hemostatic agents.
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They collected a congenital hemophilia A plasma pool (ie, FVIII level of <1%), along with plasma from a single donor with severe hemophilia B (ie, FIX level of <1%) from George King Bio-Medical Inc.
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The most common TGAs were used to assess the similarities and differences in the mode of action between FVIII and Mim8. The 2 molecules were compared via use of human FXIa or tissue factor as an activator. Next, the results of mixing Mim8 with the main bleeding treatment options for patients with hemophilia A with or without inhibitors were evaluated—that is, FVIII, FVIIa, and activated prothrombin complex concentrates (aPCC).
Because “Mim8 and FVIII both stimulate FIXa-mediated activation of FX on a procoagulant lipid surface, they could be expected to compete for binding FIXa and FX,” the authors said. TGAs that were activated with FXIa or tissue factor were used to examine the effect of mixing variable levels of FVIII and Mim8.
Results of the study showed that with both triggers—FXIa and tissue factor—FVIII and Mim8 exhibited a concentration-dependent increase in thrombin peak height. For patients without inhibitors, Mim8 did not interfere with the mode of action of FVIII. For individuals with inhibitors, in contrast, Mim8 combined with aPCC was associated with a strong synergistic effect that induced thrombin generation greatly exceeding normal levels. Combining Mim8 with FVIIa, on the other hand, was associated with a more controlled addictive effect, which can be detected only when tissue factor is used as a trigger and does not exceed the normal levels of thrombin generation.
“Differences in Mim8 and FVIII are visible in TGAs and using different triggers reflects differences in mechanisms of action,” the researchers explained. “[T]he data suggest that treatment with Mim8 may be of benefit for persons with moderate to mild hemophilia A, as it enhances TG up to 0.3 IU/mL FVIII. However, concomitant use with aPCC carries a potential risk for thrombotic microangiopathy and thrombotic event development[,] and should be accompanied with caution,” they concluded.
Reference
Lund J, Jensen K, Burnier L, Ezban M. In vitro effects of combining Mim8 with factor VIII, FVIIa, and activated prothrombin complex concentrates in thrombin generation assays. J Thromb Haemost. Published online April 8, 2023. doi:10.1016/j.tha.2023.03.007
