RARE Daily

Blueprint Reports Results from Trial of Treatment for Systemic Mastocytosis

March 16, 2020

Blueprint Medicines reported updated results from its phase 2 PIONEER trial of its drug avapritinib that showed clinical improvement in patients with indolent systemic mastocytosis compared to a placebo.

In Part 1 of the PIONEER trial, patients treated with avapritinib showed a statistically significant mean decline of approximately 30 percent in total symptom score (TSS) at 16 weeks compared to 3 percent in the placebo group, and with reductions in symptom scores deepening over time. In addition, patients treated with avapritinib achieved consistent improvements across objective measures of mast cell burden and patient-reported quality of life, the primary measure of clinical benefit.

Systemic mastocytosis (SM) is a rare disease driven by the KIT D816V mutation and characterized by uncontrolled mast cell proliferation and activation. The disorder can lead to debilitating symptoms and life-threatening complications, including anaphylaxis, maculopapular rash, pruritis, brain fog, fatigue, and bone pain, all of which often persist despite treatment with a number of symptomatic therapies. Patients often live in fear of attacks, have limited ability to work or perform daily activities, or isolate themselves to protect against unpredictable triggers. Currently, there are no approved therapies that selectively inhibit D816V mutant KIT.

Avapritinib is a potent and highly selective kinase inhibitor of D816V mutant KIT, the common driver of disease in approximately 95 percent of all SM patients. It was well-tolerated across three doses, with no patients discontinuing treatment due to adverse events. Based on the full Part 1 data, 25 mg once daily has been selected as the recommended Part 2 dose, and results from part 1 are available on an American Academy of Allergy, Asthma & Immunology virtual forum.

“Indolent SM causes devastating symptoms that wreak havoc on patients’ lives, often involves a high polypharmacy burden, and may result in frequent urgent care visits and hospitalizations,” said Cem Akin, professor of medicine at the University of Michigan and an investigator on the PIONEER trial. “These data show the promise of avapritinib to offer sustained, clinically meaningful improvements across multiple measures of disease, including quality of life and reductions in mast cell burden, and a well-tolerated safety profile. Avapritinib has the potential to advance treatment beyond symptomatic therapies and fundamentally change the way we manage this debilitating disease.”

Part 1 of the PIONEER trial was designed to determine the best dosage to use by evaluating three doses of avapritinib versus placebo. Key eligibility criteria include adults with indolent SM confirmed by central pathology review and moderate-to-severe symptom burden despite best supportive care medicines. Overall, 39 patients were enrolled across four concurrent cohorts, consisting of 10 patients each in the avapritinib dose cohorts and nine patients in the placebo cohort.

Avapritinib showed broad activity across measures of mast cell burden, the patient-reported outcomes clinical benefit measure, and quality of life. The consistency of results observed across multiple measures of disease burden support the further evaluation of avapritinib in indolent SM. As of the data cutoff date, 37 patients have remained on study with a median follow-up of 18 weeks.

“Avapritinib was specifically designed to inhibit D816V mutant KIT, with the goal of delivering transformative benefit to patients,” said Andy Boral, chief medical officer at Blueprint Medicines. “In indolent SM, these placebo-controlled data are the first to show consistent clinical activity across multiple measures of disease, from mast cell burden to clinical outcomes and quality of life.”

Blueprint Medicines plans to initiate patient screening for the registration-enabling Part 2 of the PIONEER trial in June 2020. Part 2 is designed to evaluate the efficacy of avapritinib versus placebo. Blueprint Medicines anticipates completing enrollment in Part 2 of the PIONEER trial by the end of 2020.

Avapritinib is approved by the U.S. Food and Drug Administration under the name “Ayvakit” for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. It has been granted Breakthrough Therapy designation for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia, and for the treatment of unresectable or metastatic GIST harboring the PDGFRA D842V mutation.

Author: Rare Daily Staff

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