Synergistic effects of a procoagulant bispecific antibody and rescue therapy on thrombin generation - a potential safety risk?

R. Hartmann1, S. Knappe1, B. Goldstein2, B. Ewenstein2, L. Valentino3, F. Scheiflinger1 (1Vienna, Austria, 2Cambridge, United States, 3Bannockbum, United States)

Bleeding disorders - Basic science
Date: 17.02.2017,
Time: 08:00 - 09:15

Objective: Investigational non-factor products, such as ACE 910 (emicizumab), offer potentially new treatment for hemophilia patients with inhibitors. However, their uncertain and unregulated mechanisms of action raise multiple concerns regarding safety and efficacy in specific clinical contexts. As an antibody to FIX(a) and FX(a), ACE 910 lacks the inherent regulatory characteristics for hemostasis present in replacement factor and bypassing agents. FEIBA is a plasma-derived, activated prothrombin complex concentrate. It has been used over 40 years to treat and prevent bleeding episodes in hemophilia A and B patients with inhibitors. Extensive prospective clinical study and post-approval pharmacovigilance data demonstrated that the product is safe and highly effective. A phase III study of emicizumab (NCT02622321) is currently being conducted in hemophilia A patients with inhibitors. To evaluate the treatment options for those experiencing breakthrough bleeding, we studied the in vitro thrombin generation profile of various combinations of FEIBA and a biosimilar version of ACE 910.

Methods: A biosimilar antibody to emicizumab (BS-Em) expressed in mammalian cells, purified, and biochemically characterized was analyzed in standard thrombin generation (TG) experiments using plasma from individual inhibitor patients. Therapeutic doses of BS-Em (20-600nM) in combination with various concentrations of FEIBA (0.05-1IU/ml) were tested. A normal range of TG was established using plasma from healthy individuals.

Results: The combination of FEIBA and BS-Em induced peak thrombin values of >500nM (600nM BS-Em/1IU/ml FEIBA), while the reference range for peak levels was ~50-120nM. FEIBA concentrations higher than 0.25IU/ml combined with 600 nM BS-Em induced peak thrombin values up to 5-fold of normal.

Conclusion: These in vitro experiments demonstrate the potential for excessive thrombin generation after co-administration of FEIBA and BS-Em at antibody concentrations expected to occur in patients participating in this study. Therefore, caution and clinical judgement will be required when treating potential breakthrough bleeds in patients receiving emicizumab, as AEs may occur.