Caplacizumab induces faster resolution of acute episodes of acquired thrombotic thrombocytopenic purpura than does conventional therapy by blocking further platelet aggregation mediated by von Willebrand factor, according to a report published online Feb. 11 in the New England Journal of Medicine.
Faster normalization of the platelet count “prevents further consumption of platelets into microthrombi, and the consequent progression of tissue ischemia.” This in turn should prevent further ischemic injury to the brain, heart, and kidneys in both the short and the long term, said Dr. Flora Peyvandi of the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore Policlinico, Milan, and her associates.
The investigators assessed caplacizumab, an anti–von Willebrand factor immunoglobulin, as a potential treatment for acquired TTP in a manufacturer-sponsored phase II trial involving 75 patients treated at 56 medical centers worldwide. All the study participants received standard treatment – daily plasma exchange and immunosuppressive therapy. In addition, they were randomly assigned to receive daily caplacizumab (36 patients) or placebo injections (39 patients) after each plasma exchange procedure and for 30 days following the final procedure, for a maximum of 90 days.
“Caplacizumab rapidly neutralized its target as indicated by suppression of von Willebrand factor–ristocetin cofactor activity to a mean of less than 20% by day 1 and throughout the treatment period,” Dr. Peyvandi and her associates said. These values returned to baseline levels within 1 week of treatment cessation.
The primary endpoint of the study, median time to normalization of the platelet count, was significantly reduced by 39% with caplacizumab compared with placebo. Among the 69 patients who had not undergone an initial plasma-exchange session before study enrollment, the median time to response was 3.0 days with caplacizumab and 4.9 days with placebo. And among the six patients who had undergone an initial plasma-exchange session before enrollment, the median time to response was 2.4 days with caplacizumab and 4.3 days with placebo, Dr. Peyvandi and her associates said (N Engl J Med. 2016 Feb 11;374. doi:10.1056/NEJMoa1505533).
At 1-month follow-up, 81% of the caplacizumab group showed complete remission, compared with 46% of the placebo group. Three patients in the caplacizumab group had TTP exacerbations, compared with 11 in the placebo group. Post hoc analyses showed that the mean number of plasma-exchange days (5.9 vs. 7.9) and the mean volume of plasma administered (19.9 liters vs. 28.3 liters) were lower with caplacizumab than with placebo. And post hoc analyses of markers of end-organ damage, such as lactate dehydrogenase, troponin T, troponin 1, and creatinine levels, showed more rapid normalization with caplacizumab.
As expected, the number of patients who had bleeding-related adverse events was higher with the active treatment (19 patients) than with placebo (14 patients), but these events “were generally mild” and didn’t require treatment. Serious bleeding events occurred in 2 patients in each study group and included subarachnoid hemorrhage, retinal hemorrhage, and metrorrhagia in the caplacizumab group and cerebral hemorrhage and hematuria in the placebo group.
The study was supported by Ablynx, maker of caplacizumab, which also designed and conducted the study, analyzed the data, and prepared the manuscript. Dr. Peyvandi reported ties to Ablynx, Alexion, Biotest, Kedrion Biopharma, Novo Nordisk, Baxter, Bayer, CSL Behring, Grifols, LFB, Roche, and Sobi; her associates’ financial disclosures are available at NEJM.org.