This article is more than 5 years old. Information may no longer be current.
Caplacizumab induces response in acquired thrombotic thrombocytopenic purpura
Click Here to Manage Email Alerts
ATLANTA — Caplacizumab reduced time to platelet count response and resulted in faster resolution of acquired thrombotic thrombocytopenic purpura than placebo, according to a randomized phase 3 study presented during the late-breaking abstract session at the ASH Annual Meeting and Exposition.
“In this trial, treatment with caplacizumab [Ablynx] in addition to standard of care resulted in a significantly shorter time to platelet count response (P < 0.01); a significant reduction in acquired thrombotic thrombocytopenic purpura (TTP)-related death, recurrence of TTP, or at least one major thromboembolic event during study drug treatment (P < 0.0001); and a significantly lower number of TTP recurrences in the overall study period (P < 0.001),” Marie Scully, MD, professor of hematology at University College London Hospitals, told HemOnc Today. “Analysis of the third and fourth key secondary endpoints showed the potential of caplacizumab to prevent refractory disease and positively impact normalization of organ damage markers — lactate dehydrogenase, cardiac troponin I and serum creatinine.”
TTP is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor-cleaving enzyme ADAMTS13, leading to intravascular von Willebrand factor-platelet aggregation and microvascular thrombosis.
The mainstays of treatment for TTP are plasma exchange and immunosuppression. Caplacizumab is a bivalent nanobody that blocks binding of platelets to von Willebrand factor.
“No drug products are approved for the treatment of TTP,” Scully told HemOnc Today. “Prior to the introduction of plasma exchange, TTP was associated with extremely high mortality of about 90%. The introduction of plasma exchange treatment has substantially improved survival. However, in the last 20-plus years, in spite of greater understanding of disease pathogenesis and the use of newer immunosuppressants, outcomes for patients with TTP have not changed, with significant morbidity in the form of strokes and heart attacks, and reported mortality rates as high as 20%.”
In their double-blind, placebo-controlled study, researchers randomly assigned 145 patients with an acute episode of TTP who had received one plasma exchange treatment to placebo (n = 73; median age, 47.3 years; 70% women) or 10 mg caplacizumab (n = 72; median age, 44.9 years; 68% women), in addition to daily plasma exchange and corticosteroids.
Patients received a single IV dose of study drug before the first on-study plasma exchange, and they received a subcutaneous dose daily during the plasma exchange period and 30 days thereafter. If there was evidence of ongoing disease, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks, along with optimizing immunosuppression.
All patients entered a 28-day treatment-free follow-up period after the last dose of caplacizumab. Time to platelet count response — defined as platelet count of at least 150×109/L with stop of daily plasma exchange within 5 days — served as the primary endpoint.
Researchers considered four key secondary endpoints:
A composite of TTP-related death, TTP recurrence or major thromboembolic event during the study drug treatment period;
Recurrences during the entire study period, including the follow-up period;
Refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and lactate dehydrogenase still above normal; and
Time to normalization of three organ damage markers: lactate dehydrogenase, cardiac troponin I and serum creatinine.
Compared with patients treated with placebo, those on caplacizumab were more than 50% more likely to achieve a platelet response at any time (platelet count normalization rate = 1.55, 95% CI, 1.1-2.2; P < .01).
Treatment with caplacizumab resulted in a 74% reduction in the proportion of patients with TTP-related death, recurrence of TTP or a major thromboembolic event (12.7% vs. 49.3%; P < .0001).
Twenty-eight patients (38.4%) in the placebo group experienced a recurrence, compared with nine patients (12.7%) in the caplacizumab group, a 67% reduction (P < .001).
In all six caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still less than 10% at stop of study drug, reflecting ongoing disease.
No caplacizumab-treated patients were refractory to therapy, compared with three patients on placebo (P = .057). Treatment with caplacizumab was associated with a trend toward faster normalization of the three organ damage markers. In the caplacizumab group, the most common study drug-related treatmentemergent adverse events included epistaxis, gingival bleeding and bruising.
During the study drug treatment period, three patients on placebo died. One death occurred during the follow-up period and was deemed unrelated to caplacizumab.
“Treatment with caplacizumab also resulted in a substantial reduction in the use of plasma exchange and length of stay in the ICU and the hospital,” Scully said. “The number of days of plasma exchange during the overall treatment period was 38% lower in the caplacizumab group compared with the placebo arm (5.8 days vs. 9.4 days), resulting in a 41% reduction in the volume of plasma used (35.9 L vs. 21.3 L).”
The number of days in the ICU decreased 65% for patients treated with caplacizumab compared with placebo (3.4 days vs. 9.7 days) and the overall hospitalization stay in the caplacizumab group dropped 31% compared to the placebo group (9.9 days vs. 14.4 days).
Caplacizumab should be considered for all patients with TTP who are not on anticoagulation “because even those who don’t look particularly sick at presentation can deteriorate very rapidly,” Scully said.
“The current treatment of plasma exchange and immunosuppression needs to continue and we need to be very mindful of their side effects,” Scully said. “But, caplacizumab needs to be used early on to avoid deaths, but also to detect patients so we can ensure utilization and and achieve remission.”
Scully and colleagues are conducting a 3-year follow-up study of patients who completed the HERCULES study to evaluate the long-term safety and efficacy of caplacizumab, the safety and efficacy of repeated use of caplacizumab as treatment for new episodes of TTP, and to characterize the long-term impact of TTP.
“We look forward to working together with regulatory authorities to make caplacizumab available for patients suffering from TTP,” Scully said. – by Chuck Gormley
Reference:
Scully M, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Scully reports honoraria and researching funding from Ablynx and Shire, and honoraria from Alexion and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.