The European Commission has granted marketing authorization for caplacizumab (Cablivi™), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.
Sanofi Genzyme said it will work with relevant local authorities to make caplacizumab available in countries across Europe.
“The approval of Cablivi provides an important addition to the standard-of-care treatment for patients with aTTP in Europe because it can significantly reduce time to platelet count normalization and induce a clinically meaningful reduction in recurrences,” said Marie Scully, MD, of University College Hospital in London, UK.
The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
Results from the TITAN trial were published in The New England Journal of Medicine in 2016.
The study included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care—daily plasma exchange and immunosuppressive therapy.
The study’s primary endpoint was time to response, which was defined as platelet count normalization (150,000/mm3 or higher).
Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
Among the 69 patients who had not undergone a plasma exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.
Among the 6 patients who did undergo a plasma exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.
The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and two in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.
Results from the HERCULES trial were presented at the 2017 ASH Annual Meeting.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n=72) or placebo (n=73) in addition to standard care—plasma exchange and immunosuppression.
The study’s primary endpoint was the time to platelet count response (normalization), which was defined as an initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. The incidence of at least one major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The proportion of patients with at least one study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least one study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least one AE was 7.0% and 12.3%, respectively.
During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.