Avapritinib Shows Promise in Systematic Mastocytosis Trial


In the phase 2 PIONEER trial, patients taking avapritinib self-reported improvements in quality of life.

Cem Akin, MD, PhD

Cem Akin, MD, PhD

Treatment of indolent and smoldering systematic mastocytosis (SM) is difficult as there is currently no disease-modifying therapies approved.

Cem Akin, MD, PhD, Michigan Medicine Allergy Clinic, is currently leading the phase 2 placebo controlled PIONEER trial testing avapritinib as a treatment for patients with indolent systematic mastocytosis.

Akin was scheduled to release data on the trial during the American Academy of Allergy, Asthma & Immunology (AAAAI) 2020 Annual Meeting in Philadelphia, PA, but the conference was cancelled due to the coronavirus (COVID-19) outbreak.

Mast cells are best known for mediating allergic reactions, but SM is a rare disease that occurs when mast cells grow uncontrollably and become abnormally activated.

Patients suffering from this disease can experience a wide range of debilitating and unpredictable allergy-like symptoms, as well as other symptoms.

The heterogenous disease is considered a life threatening disease in advanced forms and chronic in non-advanced forms. The majority of patients have the chronic form of the disease, which consists of indolent or smoldering systematic mastocytosis.

“This patient population has significant long-term morbidity, despite often using a number of symptomatic therapies,” Akin said in an interview with HCPLive®. “There is no curative treatment for the disease. Based on my clinical experience, these patients are not satisfied with available symptomatic therapies.”

Systematic mastocytosis is mainly driven by a KIT D816V mutation. Avapritinib is a potent and highly selective inhibitor of KIT D816V specifically designed to target the underlying cause of the disease.

The dose-finding portion of the PIONEER study included 10 patients for each dose group of 25, 50, and 100 mg of the drug, as well as a 9 patient placebo group. Patients at baseline received a median of 4 symptomatic therapies, consistent with the high polypharmacy burden experienced by many patients in clinical practice.

Approximately 20% of the participants could not perform any work activities, with about 50% limited in the work they could perform.

After 16 weeks of treatment, avapritinib showed statistically significant reductions in patient-reported symptoms, which correlated with reductions in mast cell burden and improvements in quality of life.

The investigators measured improvements using the ISM-SAF patient-reported outcomes tool and found a symptom score reduction in approximately 30% across all of the avapritinib dose cohorts with just a 3% reduction in the placebo cohort (P = 0.001).

Akin explained that improvements in avapritinib-treated patients seem to have deepened over time.

“At the lowest dose studied, 25 mg QD, avapritinib showed broad clinical activity across a range of endpoints,” he said. “Treatment with avapritinib led to consistent reductions in the ISM-SAF Total Symptom Score, gastrointestinal, skin and neurocognitive symptoms groups, as well as all 11 individual symptoms assessed.”

The drug also showed improvements in patient-reported quality of life, which was measured by the MC-QoL total score and across all 4 domains assessed—symptoms, social life functioning, emotions, and skin.

The treatment was also well-tolerated across all 3 doses with no discontinuations due to adverse events. Overall, 95% of patients remained in the study.

“What’s particularly striking is how avapritinib reduced mast cell burden patients with indolent SM, and that these results have translated into symptom and quality of life improvements,” Akin said. “I believe avapritinib may change the way we think about managing indolent SM, advancing treatment beyond symptomatic therapies and instead targeting the underlying cause of the disease."

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