Adding caplacizumab to standard of care for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) shortened the time to the normalization of platelet counts compared with standard care alone, according to a study published in the New England Journal of Medicine. However, two-thirds of patients receiving caplacizumab experienced a bleeding-related adverse event (AE).
The standard treatment for aTTP includes plasma exchange therapy to replenish ADAMTS13 and immunosuppressive treatment to modulate the formation of auto-antibodies, lead author Marie Scully, MD, from the University College London Hospitals, explained to ASH Clinical News. “In aTTP, auto-antibodies inhibit ADAMTS13, a protease that regulates the size of von Willebrand factor (vWF) multimers, leading to vWF-mediated platelet adhesion and platelet consumption in microthrombosis.”
“The faster improvement in platelet count and sustained platelet normalization protects patients from recurrences, until immunosuppression reduces anti-ADAMTS13 antibodies and increases ADAMTS13,” study coauthor Hilde De Winter, MD, senior medical director for Ablynx (which supported the study), told ASH Clinical News. “[This also] translated into a tangible benefit for the patients, who needed less plasma exchange and shorter stays in the hospital and intensive care unit.”
In the double-blind, randomized, phase III HERCULES trial, Drs. Scully, De Winter, and researchers evaluated the safety and efficacy of caplacizumab, an anti-vWF nanobody, in patients who had a clinical presentation of aTTP (defined as both thrombocytopenia and microangiopathic hemolytic anemia with schistocytes seen on blood smear) and had received exactly one plasma exchange treatment. People were excluded from the trial if they had suspected thrombotic microangiopathies that were not associated with TTP, such as hemolytic uremic syndrome.
All 145 eligible patients received standard of care (daily plasma exchange and glucocorticoids) plus either caplacizumab 10 mg/day (n=72) or placebo (n=72). Participants were treated for 30 days, during which the investigators monitored time to platelet count normalization (≥150×109/L) and discontinuation of daily plasma exchange therapy (primary endpoint).
During the treatment period and 28-day follow-up, treatment with caplacizumab was associated with a significantly shorter time to platelet normalization, compared with placebo: 2.69 days (95% CI 1.89-2.83] versus 2.88 days (95% CI 2.68-3.56; p=0.01). The authors also reported that caplacizumab-treated patients were 1.55 times more likely than placebo-treated patients to have a normalization of the platelet count at any time point (p=0.01).
Caplacizumab significantly outperformed standard-of-care alone in other secondary outcomes, including:
- composite of TTP-related death, TTP recurrence, or a thromboembolic event: 12% vs. 49% (p<0.001)
- recurrence of TTP at any time: 12% vs. 38% (p<0.001)
Disease exacerbation, defined as recurrence of TTP within 30 days after daily plasma exchange, occurred in 31 patients (28 in the placebo group and 3 in the caplacizumab group). Of these, 28 had an unresolved autoimmune disease that may have been the underlying culprit, the researchers noted.
Health-care resource use also appeared lower in the caplacizumab group: In the placebo group, patients required an average of 9.4 days of plasma-exchange therapy, compared with 5.8 days in the caplacizumab group. This represented a 38-percent shorter duration of treatment and a 41-percent lower volume of plasma exchanged (p values not reported). Duration of hospitalization and intensive care unit stays were reduced, as well.
The most commonly reported AEs in either treatment group were bleeding-related; mucocutaneous bleeding occurred most frequently, in 65 percent and 48 percent of patients in the caplacizumab and placebo groups, respectively (p value not reported). Most of these events were mild or moderate in severity and resolved without intervention, the authors wrote. Five patients in the caplacizumab group and nine patients in the placebo group experienced an AE that led to discontinuation of the of the trial regimen.
During the trial, death occurred in three patients who received placebo, while one patient who received caplacizumab died due to cerebral ischemia at the end of treatment, which was considered unrelated to treatment.
“Overall, caplacizumab showed value when added to the standard treatment for aTTP,” the authors concluded, although “this added value was associated with a higher incidence of low-grade mucosal bleeding than that with placebo.” As a limitation of the study, Dr. Winter noted variation in the immunosuppressive therapy used among the 92 international sites involved in the trial. He added that the trial protocol required that patients undergo “one plasma exchange prior to randomization while, ideally, caplacizumab would be started on confirmation of TTP.”
The authors report relationships with Ablynx, which supported the trial.
Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380:335-46.