ATLANTA – Adding caplacizumab to standard therapy for acquired thrombotic thrombocytopenic purpura (aTTP) significantly improved platelet response and prevented recurrent episodes in an international, randomized, double-blind, phase 3 placebo-controlled trial.
“Patients were 55% more likely to achieve normalization of platelet count in the caplacizumab group, and this was highly significant,” Marie Scully, MD, said during a late-breaking presentation at the annual meeting of the American Society of Hematology.
“So far, phase 2 and phase 3 studies confirm no deaths in patients treated with caplacizumab,” said Dr. Scully of University College London Hospitals NHS Trust.
Acquired TTP is an acute, life-threatening thrombotic microangiopathy that occurs when inhibitory autoantibodies cause a deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWF). Inadequate levels of ADAMTS13 activity lead to the formation of ultra-large vWF multimers, platelet strings, and microthrombi. Caplacizumab is a humanized immunoglobulin that helps stop this process by binding the A1 domain of vWF.
“Caplacizumab addresses the pathophysiological platelet aggregation that leads to the formation of microthrombi,” Dr. Scully said.
In this phase 3 trial (), 145 patients who had received plasma exchange (PE) at least once for an acute episode of aTTP were randomly assigned to receive caplacizumab or placebo injections plus daily PE and corticosteroids. Caplacizumab (10-mg) therapy consisted of one IV bolus followed by subcutaneous treatment for 30 days. Patients whose ADAMTS13 activity remained below 10% were able to continue treatment for another 28 days, after which all patients were followed for another 28 days without treatment.
At any given time, platelet normalization was 55% more likely with caplacizumab (10 mg) than placebo (platelet normalization rate ratio, 1.55; 95% confidence interval, 1.10-2.20; P less than .01).
Rates of a key combined secondary endpoint – aTTP-related death/recurrence/major thrombotic events – were 12.7% with caplacizumab and 49.3% with placebo (P less than .0001).
Rates of major thrombotic events were 8% in each arm, and deaths were rare overall, meaning that the difference in rates of recurrence drove most of the effect on the combined secondary endpoint. However, patients who received caplacizumab also received 41% less plasma and had 38% fewer days of PE, 65% fewer days in the intensive care unit, and 31% fewer days in the hospital than patients in the placebo arm.
Refractory aTTP affected 4.2% of placebo patients and no caplacizumab patients, which trended toward statistical significance (P = .057). Caplacizumab therapy also led to a faster normalization of several markers of organ damage, including lactate dehydrogenase, cardiac troponin 1, and serum creatinine.
Safety findings reflected earlier-phase studies and caplacizumab’s mechanism of action, Dr. Scully said. Nearly all trial participants experienced at least one treatment-emergent adverse event. Such events led 7% of patients to stop caplacizumab and 12% to stop placebo. Caplacizumab was associated with a range of bleeding-related events, most commonly epistaxis (23.9 vs. 1.4% with placebo), gingival bleeding (11.3% vs. 0%), bruising (7.0% vs. 4.1%), and hematuria (5.6% vs. 1.4%).
Patients in both arms tended to be in their 40s and two-thirds were female. At baseline, about 85% had less than 10% ADAMTS13 activity, and about 40% had severe aTTP (French severity scores of at least 3 or severe neurologic or cardiac involvement).
“Most [66%] patients in the caplacizumab group presented with de novo aTTP, and this is relevant because patients who are in their first episode are much harder to treat,” Dr. Scully said. About half of placebo patients had de novo disease.
In July 2017, caplacizumab received a fast-track designation from the Food and Drug Administration for aTTP after a phase 2 trial showed that platelet counts normalized 39% faster with caplacizumab versus placebo plus standard of care (P = .005). Of eight patients in that study who relapsed within a month of stopping caplacizumab, seven still had less than 10% ADAMTS13 activity, “suggesting unresolved autoimmune activity,” the investigators wrote at the time in the New England Journal of Medicine ().
Dr. Scully reported similar findings in the phase 3 HERCULES trial, noting that all patients had ADAMTS13 levels less than 5% on stopping caplacizumab.
Ablynx provided funding for the study. Dr. Scully reported financial relationships with Ablynx, Shire, Novartis, and Alexion.
SOURCE: Scully M et al., ASH 2017 .