RARE Daily

Blueprint Reports Positive Results from Ayvakyt Study in Non-Advanced Systemic Mastocytosis

August 17, 2022

Blueprint Medicines reported Ayvakyt met its primary and secondary endpoints in its registrational Part 2 of the PIONEER clinical trial of Ayvakyt in patients with non-advanced systemic mastocytosis.

Based on these top-line data, Blueprint Medicines plans to submit a supplemental new drug application to the U.S. Food and Drug Administration for Ayvakyt in non-advanced systemic mastocytosis (SM) in the fourth quarter of 2022, with a subsequent submission of a type II variation marketing authorization application to the European Medicines Agency anticipated in 2023.

“As a physician and clinical researcher who has been treating non-advanced systemic mastocytosis patients for over 25 years, I have been awaiting a therapy that decreases the abnormal mast cell burden and activation, improves a wide range of symptoms, and ultimately provides an improved quality of life to patients,” said Mariana Castells, director of the Mastocytosis Center at Brigham and Women’s Hospital, and an investigator on the PIONEER trial. “For patients with non-advanced SM, PIONEER is the first study to show significant clinical improvements over best available care across patient-reported symptoms and objective measures of disease, with a safety and tolerability profile supporting chronic treatment.”

SM is a rare disease primarily driven by the KIT D816V mutation. Uncontrolled proliferation and activation of mast cells result in chronic, severe, and often unpredictable symptoms for patients across the spectrum of SM. The vast majority of those affected have non-advanced SM, with debilitating symptoms that lead to a profound, negative impact on quality of life. A minority of patients have advanced SM, which encompasses a group of high-risk SM subtypes including ASM, SM-AHN and MCL. In addition to mast cell activation symptoms, advanced SM is associated with organ damage due to mast cell infiltration and poor survival. Across advanced SM subtypes, the median overall survival is approximately 3.5 years in ASM, approximately two years in SM-AHN and less than six months in MCL.

Debilitating symptoms, including anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue, and bone pain, often persist across all forms of SM despite treatment with a number of symptom-directed therapies. Patients often live in fear of severe, unexpected symptoms, have limited ability to work or perform daily activities, and isolate themselves to protect against unpredictable triggers. Historically, there had been no approved therapies for the treatment of SM that selectively inhibit D816V mutant KIT.

Ayvakyt was designed to potently and selectively inhibit D816V mutant KIT, the driver of SM in about 95 percent of cases. Ayvakyt is approved by the FDA for the treatment of adults with Advanced SM, including aggressive SM (ASM), SM with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL), and adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.

It is approved in Europe for the treatment of adults with ASM, SM-AHN or MCL, after at least one systemic therapy, and adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation. The FDA granted breakthrough therapy designation to Ayvakyt for the treatment of moderate to severe indolent SM.

PIONEER is a randomized, double-blind, placebo-controlled, registrational trial evaluating Ayvakyt in patients with non-advanced SM. The trial includes three parts: dose-finding Part 1, registrational Part 2 and long-term treatment Part 3. Key trial endpoints include the change in patient-reported disease symptoms as measured by the ISM-SAF TSS, patient-reported quality of life, quantitative measures of mast cell burden and safety. Patients who completed Part 1 or 2 were eligible to participate in Part 3. All patients receive Ayvakyt treatment during Part 3, including those rolling over from the control arm.

The trial, which was designed to assess Ayvakyt plus best available care versus placebo plus best available care (control arm), achieved its primary endpoint with a highly significant difference in the mean change in total symptom score (TSS) at 24 weeks. TSS was assessed by the Indolent SM Symptom Assessment Form (ISM-SAF). The Ayvakyt arm had a reduction of 15.6 points in mean TSS at 24 weeks, which continued to deepen to 20.2 points at 48 weeks in patients who rolled over to the Part 3 open-label extension study.

At 24 weeks, the control arm had a reduction of 9.2 points in mean TSS. In addition, the PIONEER trial met all key secondary endpoints, including significant improvements across all measures of mast cell burden. More than half of Ayvakyt-treated patients had a ≥50 percent reduction of serum tryptase, compared to no patients in the control arm (53.9% vs. 0%). Ayvakyt was well-tolerated and had a favorable safety profile, and 96.5 percent of Ayvakyt-treated patients completed 24 weeks of therapy, compared to 93 percent for the control arm. Overall, 0.7 percent of patients in the Ayvakyt arm and no patients in the control arm discontinued due to treatment-related adverse events.

Ayvakyt had a favorable safety profile compared to the control arm. The rate of adverse events (AEs) was 90.8 percent in the Ayvakyt arm and 93.0 percent in the control arm. Serious AEs occurred in 5.0 percent of Ayvakyt-treated patients, compared to 11.3 percent of patients in the control arm. Discontinuations due to treatment-related AEs occurred in 0.7 percent of Ayvakyt-treated patients and 0 percent of patients in the placebo arm. The Ayvakyt arm had a lower rate of cognitive AEs than the control arm (2.8% Ayvakyt vs. 4.2% control), and there were no intracranial bleeding events. Treatment-related AEs reported in at least three patients in either arm and at least 5 percent of Ayvakyt-treated patients included headache (7.8% Ayvakyt vs. 9.9% control), nausea (6.4% Ayvakyt vs 8.5% control), peripheral edema (6.4% Ayvakyt vs. 1.4% control) and periorbital edema (6.4% Ayvakyt vs. 2.8% control). In the Ayvakyt arm, 93.0 percent of edema AEs were Grade 1, and the remainder were Grade 2.

In addition, Blueprint Medicines plans to present detailed data from the PIONEER trial at an upcoming medical meeting.

“Non-advanced systemic mastocytosis is a lifelong disease with severe physical, emotional and social impacts that profoundly reduce patients’ quality of life,” said Lauren Denton, executive director of The Mast Cell Disease Society. “Patients with SM continue to be challenged by efforts to avoid various triggers of everyday life while also managing complex therapies. The PIONEER clinical trial results offer hope to these patients and help pave the way for new innovation in treatment.”

Author: Rare Daily Staff

Stay Connected

Sign up for updates straight to your inbox.