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Published on: September 9, 2012
In vitro effects of combining Mim8 with factor VIII, FVIIa, and activated prothrombin complex concentrates in
Jacob Lund1, Kasper Jensen1, Laurent Burnier1
1Novo Nordisk A/S, Måløv, Denmark.
Background:
Mim8 is a novel antifactor IXa/antifactor X bispecific antibody in clinical development for prophylactic treatment of hemophilia A with and without inhibitors. Patients treated with Mim8 may need supplementary bleed treatment under certain conditions such as surgery or major trauma.
Objectives:
This study aimed to better understand the response of Mim8 in thrombin generation assays (TGAs) alone or in combination with other hemostatic proteins.
Methods:
We used TGAs with different activators (tissue factor (TF) and activated factor XI) to better understand the similarities and differences between the mode of action of Mim8 and factor VIII (FVIII). Following this, we investigated the effects of mixing Mim8 with the main bleed treatment options for persons with hemophilia A with or without inhibitors: FVIII, activated factor VII (FVIIa), and activated prothrombin complex concentrates (aPCC).
Results:
The results indicated that for patients without inhibitors, Mim8 does not interfere with FVIII's mode of action. For patients with inhibitors, Mim8 mixed with aPCC results in a strong synergistic effect causing thrombin generation far exceeding the normal levels. Contrary to this, mixing Mim8 with FVIIa results in a more controlled additive effect, visible only when using TF as a trigger, which does not exceed the normal level of thrombin generation.
Conclusion:
These findings support the use of approved clinical doses of FVIIa for bleed treatment of patients with FVIII inhibitors treated with Mim8. Additionally, the findings suggest that concomitant use of FVIII and Mim8 is safe for managing breakthrough bleeds.
Insights
Mim8 shows safe interactions with Factor VIII (FVIII) and Factor VIIa (FVIIa) for hemophilia A treatment. For patients with inhibitors, Mim8 combined with activated prothrombin complex concentrates (aPCC) creates significant thrombin generation.
Area of Science:
- Hematology
- Pharmacology
- Biochemistry
Background:
- Mim8 is an investigational bispecific antibody for hemophilia A prophylaxis.
- Patients on Mim8 may require additional treatment for severe bleeds.
Purpose of the Study:
- To evaluate Mim8's interaction with hemostatic agents in thrombin generation assays (TGAs).
- To understand Mim8's mechanism of action compared to Factor VIII (FVIII).
Main Methods:
- Utilized TGAs with tissue factor (TF) and activated factor XI activators.
- Investigated Mim8's effects when combined with FVIII, FVIIa, and aPCC.
Main Results:
- Mim8 does not interfere with FVIII in non-inhibitor patients.
- Mim8 with aPCC showed strong synergy in inhibitor patients, exceeding normal thrombin levels.
- Mim8 with FVIIa demonstrated a controlled additive effect, not exceeding normal thrombin generation.
Conclusions:
- FVIIa is suitable for treating bleeds in Mim8-treated patients with inhibitors.
- Concurrent use of FVIII and Mim8 appears safe for breakthrough bleeds.
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