On May 22, the U.S. Food and Drug Administration (FDA) approved the tyrosine kinase inhibitor avapritinib (Ayvakit) for the treatment of adults with indolent systemic mastocytosis. Avapritinib is the first and only approved therapy for indolent systemic mastocytosis. Systemic mastocytosis is a rare hematologic disorder that can lead to a range of debilitating symptoms across multiple organ systems and can have a significant impact on patients' quality of life; indolent systemic mastocytosis represents the vast majority of systemic mastocytosis cases. Avapritinib is designed to potently and selectively inhibit KIT D816V, the primary underlying driver of the disease, and has been FDA-approved for the treatment of advanced systemic mastocytosis since June 2021.
PIONEER Trial
The approval of avapritinib in indolent systemic mastocytosis is based on data from the double-blind, placebo-controlled PIONEER trial (ClinicalTrials.gov identifier NCT03731260), in which patients received avapritinib at 25 mg once daily plus best supportive care or placebo plus best supportive care. Avapritinib demonstrated significant improvements vs placebo in the primary and all key secondary endpoints, including overall symptoms and measures of mast cell burden.
Avapritinib was well tolerated with a favorable safety profile compared to placebo, and most adverse reactions were mild to moderate in severity. The most common adverse reactions for patients receiving avapritinib (≥ 10%) were eye edema, dizziness, peripheral edema, and flushing. Serious adverse reactions and treatment discontinuations due to adverse reactions occurred in less than 1% of patients.
Detailed results from the PIONEER trial, including open-label extension study data showing the clinical benefits of avapritinib through 48 weeks of treatment, were presented in February 2023 at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting. According to a press release issued by Blueprint Medicines on May 23, results from PIONEER were also published by Gotlib et al in NEJM Evidence.
"After decades of caring for people with indolent systemic mastocytosis, I have seen firsthand its profound impact on patients' underlying mast cell burden, symptoms, physical and mental health, and ability to work and participate in daily activities," said Cem Akin, MD, PhD, Professor of Medicine at the University of Michigan and an investigator on the PIONEER trial. "Despite the use of multiple supportive care treatments, a considerable number of patients with indolent systemic mastocytosis continue to experience a substantial disease burden. [Avapritinib] advances the treatment of indolent systemic mastocytosis by targeting KIT D816V, the primary underlying cause of the disease, and establishes a new standard of care for a broad population of patients with this disorder. [Avapritinib] delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those affected by the disease."
Judith Kain Emmel, Board Chair of The Mast Cell Disease Society, also weighed in on results from the PIONEER trial and the FDA’s approval of avapritinib. "People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers. Ultimately, the disease can disrupt an individual's quality of life, career, and ability to interact with family and friends, and those affected often face frequent health-care visits and significant polypharmacy burden,” she explained. “Since we began nearly 30 years ago, our goals as an organization have been to educate, advocate, and collaborate for the advancement of knowledge and research in mast cell disorders like systemic mastocytosis. [The] approval is a historic moment for the systemic mastocytosis community and offers new hope for patients and their families. We are honored to have contributed to this milestone by facilitating systemic mastocytosis community insights on the design of the PIONEER trial and supporting the development of the validated symptom assessment tool used in the study."
