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Vials of drug
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of caplacizumab (Cablivi) for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).
Caplacizumab is a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
The CHMP’s recommendation regarding caplacizumab will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
TITAN trial
Results from TITAN were published in NEJM in 2016. TITAN 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 (platelet count normalization). 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. And the rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.
HERCULES trial
Results from HERCULES were presented at the 2017 ASH Annual Meeting.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
The study’s primary endpoint was the time to normalization of platelet count response, 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 1 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. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The proportion of patients with at least 1 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 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.