Results of the randomized, double-blind, placebo-controlled, phase-III-Hercules-study of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura.
In a phase-III-trial, patients with acquired TTP, a rare blood clotting disorder, who received the investigational drug caplacizumab showed significant improvements in the time it took to normalization of their platelet count compared to those receiving a placebo. These findings confirm the promising results of previous trials of the drug, which was fast-tracked for FDA review earlier this year.
Acquired TTP (aTTP) is caused by antibodies that block the activity of ADAMTS-13, an enzyme that that cleaves von Willebrand Factor (vWF). The disorder can emerge suddenly, is associated with a high mortality, may last for weeks, and can recur. During an acute aTTP episode, small clots form that deprive tissues of oxygen. This can lead to organ damage and in severe cases to stroke or heart attack.
If aTTP is left untreated, about 90% of patients will die within 30 days of the acute presentation, when the platelet count is at its lowest and the condition most active. Standard treatment consists of exchanging the patient’s plasma with donated plasma and immunosuppression therapy to remove the antibody-producing cells. While this regimen is effective in clearing the harmful antibodies and replenishing the missing ADAMTS-13 enzyme, it can take over 10 days for a patient to realize the treatment’s full effect, during which time he or she can die from a stroke or other complications while waiting for the antibodies to clear.
Caplacizumab is designed to prevent further clots forming during an acute aTTP episode. The drug aims to reduce the immediate risks and prevent organ damage while the standard treatments are used to resolve the underlying disease.
The trial enrolled 145 patients suffering acute episodes of aTTP. All patients received standard of care, including plasma exchange and steroids until resolution of the episode, and could have received monoclonal antibody therapy (rituximab) or further immunosuppressive therapy per investigator practice. In addition, half of the patients were randomized to receive caplacizumab, and the other half received placebo. The first administration of caplacizumab was given intravenously, before plasma exchange. Subsequent daily doses were given subcutaneously for the duration of the daily plasma exchange, and 30 days thereafter, and treatment could be extended for up to an additional 4 weeks maximum if the underlying disease was still ongoing. All patients were monitored for safety for at least 28 days after their treatment ended.
Patients randomized to receive caplacizumab were, at any time point during the study, 1,55 times more likely than those in the placebo group to achieve platelet count normalization. Furthermore, those receiving caplacizumab showed a 74% lower risk of a composite of TTP-related death, recurrence, or a major thromboembolic event (such as stroke) while undergoing treatment, and a 67% lower risk of experiencing an aTTP recurrence during the entire study period. Those receiving caplacizumab also showed greater responsiveness to treatment, faster normalization of organ damage markers compared to the placebo group, and only minor side effects, such as nosebleeds, bleeding of the gums, and bruising.
Patients receiving caplacizumab also saw a significant reduction in the number of days they required plasma exchange (38%), time spent in the intensive care unit (65%), and overall time spent in the hospital (31%). These reductions suggest the drug could have significant financial implications for treatment of aTTP, researchers said.
„This is a real game-changer in the way we treat patients with aTTP,“ said lead study author Marie Scully, MD, a consultant at University College London Hospitals NHS Trust who specializes in TTP. „Caplacizumab is a treatment that offers protection during the most acute, risky period of this disease and bridges the time one has to wait for the inhibitory autoantibody levels to be cleared. It is very beneficial for patient outcomes and is an important addition to the therapeutic armamentarium for clinicians and the hospital.“
ASH Annual Meeting 2017, abstract #LBA-1