Adding caplacizumab (Cablivi) to plasma exchange cut the time for platelet count normalization and was associated with a reduction in mortality and disease recurrence in patients with acquired thrombotic thrombocytopenic purpura (TTP), the randomized phase III HERCULES study found.
Caplacizumab-treated patients were 1.55 times more likely to see their platelet counts normalize, and use of the drug reduced the primary endpoint of median time to platelet count normalization compared with placebo (2.69 vs 2.88 days, P=0.01), according to the researchers led by Marie Scully, MD, of University College London Hospitals in England.
Treatment with caplacizumab was also associated with a 74% reduction in the composite outcome of TTP-related death, TTP recurrences, or major thromboembolic event, they wrote in the New England Journal of Medicine.
“These results demonstrate that Cablivi has the potential to address a major unmet medical need and to help those facing the potentially devastating consequences of this disorder,” Scully said in a statement from manufacturer Sanofi.
TTP is a rare autoimmune-based clotting disorder that is characterized by excessive clot formation, leading to thrombocytopenia and hemolytic anemia. The current standard of care is daily plasma exchange and immunosuppressive therapy. Without treatment, the disease has a mortality rate of more than 90%. Even with treatment, mortality rates have been reported to be as high as 20%.
According to Scully and her colleagues, some patients die or incur irreversible neurologic damage before treatment takes effect, and just one episode of TTP can have long-term consequences that include cognitive deficits, depression, arterial hypertension, and premature death.
Caplacizumab is a bivalent anti-von Willebrand factor nanobody. It interferes with the adhesion of von Willebrand factor multimers to platelets, helping to prevent the formation and accumulation of clots that cause thrombocytopenia.
In this randomized, double-blind, placebo-controlled trial, Scully’s group randomly assigned 145 patients with TTP to either a 10-mg intravenous loading bolus of caplacizumab (followed by 10 mg of the drug daily, subcutaneously) or placebo during plasma exchange and for the following 30 days.
During the trial treatment period, the composite of TTP death, recurrence of TTP, or a major thromboembolic event occurred in 9 patients (12%) treated with caplacizumab versus 36 patients (49%) in the placebo group — representing a 74% lower incidence in the caplacizumab group.
When specifically examining the rate of recurrences of TTP, Scully and her colleagues found that during the trial period — which included a 28-day follow-up period in which patients were receiving neither caplacizumab nor placebo — patients on caplacizumab had a 67% lower rate of recurrence than patients on placebo.
In addition, refractory TTP did not develop in any of the caplacizumab patients, compared to three patients in the placebo group. Caplacizumab patients also needed a lower average number of plasma exchange treatments (5.8 vs 9.4 days).
As for safety, 68 patients (96%) in the caplacizumab group and 66 (90%) in the placebo group experienced at least one adverse event during the trial period. However, the researchers reported that, overall, the drug demonstrated a safety profile consistent with previous studies, including an increased risk of bleeding.
The most common adverse event was mucocutaneous bleeding, which occurred in 65% of patients in the caplacizumab group and 48% of patients in the placebo group. The most commonly reported serious bleeding event was epistaxis, which occurred in four patients in the caplacizumab group.
Four patients died during the trial — one in the caplacizumab group during the follow-up period, and three in the placebo group during the treatment period of the trial. All were considered to be TTP-related.
The study was funded by Ablynx, a Sanofi company.
Scully and co-authors reported relationships with Ablynx and other relevant industry.