Image by Erhabor Osaro
Micrograph showing TTP
Caplacizumab can improve upon standard care for patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to results reported by Ablynx, the company developing caplacizumab.
In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care to placebo plus standard care in patients with aTTP.
Patients who received caplacizumab had a significant reduction in time to platelet count response.
In addition, they were significantly less likely than patients who received placebo to achieve the combined endpoint of aTTP-related death, aTTP recurrence, and experiencing at least 1 major thromboembolic event during the treatment period.
The safety profile of caplacizumab in this trial was said to be consistent with results from the phase 2 TITAN trial.
“The results of this landmark trial constitute a complete game-changer for patients with aTTP,” said HERCULES investigator Marie Scully, MBBS, of the University College Hospital in London, UK.
“They will revolutionize how we manage the acute phase of the disease, which is when patients are at highest risk for organ damage, recurrence, and death.”
Treatment
The HERCULES trial included 145 patients with an acute episode of aTTP. They were randomized 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression (standard of care).
Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange.
If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.
In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment.
Baseline characteristics
At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. A majority of patients in both arms were female—68.1% and 69.9%, respectively.
The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.
Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.
The mean platelet count at baseline was 32.0 x 109/L in the caplacizumab arm and 39.1 x 109/L in the placebo arm.
Efficacy
The study’s primary endpoint was the time to confirmed normalization of platelet count response. 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 key 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.
Another key secondary endpoint was the incidence of aTTP recurrence during the overall study period, which was 12.7% (n=9) in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).
The incidence of aTTP recurrence during the follow-up period alone was 9.1% (n=6) in the caplacizumab arm and 0% (n=0) in the placebo arm.
A third key secondary endpoint was the percentage of patients with refractory aTTP, which was 0% (n=0) in the caplacizumab arm and 4.2% (n=3) in the placebo arm (P=0.0572).
Safety
The number and nature of treatment-emergent adverse events (AEs) were similar between the treatment arms, according to Ablynx. The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.
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 rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
The incidence of bleeding-related AEs was higher in the caplacizumab arm than the placebo arm—66.2% and 49.3%, respectively. However, most bleeding-related events were mild or moderate in severity.
The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) 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.
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.
