Blueprint Medicines Announces Updated Data from Ongoing Phase 1 EXPLORER Clinical Trial of Avapritinib in Patients with Advanced Systemic Mastocytosis Showing Profound and Durable Clinical Activity
The updated data from the EXPLORER clinical trial showed an overall response rate (ORR) of 83 percent, as of the data cutoff date of
Based on the compelling clinical data from the EXPLORER trial and feedback from regulatory authorities,
"As a clinician treating patients with this devastating and sometimes fatal rare disease, I'm excited to see that most patients with advanced systemic mastocytosis respond to treatment with avapritinib, and these responses deepen over time and are durable," said
"These highly encouraging data, coupled with favorable
Data from the Ongoing Phase 1 Clinical Trial
As of the data cutoff date of
As of the data cutoff date, avapritinib was generally well-tolerated. Most adverse events (AEs) reported by investigators were Grade 1 or 2. Across all grades, the most common treatment-emergent AEs reported by investigators (≥20 percent) included periorbital edema, anemia, fatigue, nausea, diarrhea, peripheral edema, thrombocytopenia, cognitive effects, vomiting, hair color changes and dizziness. Investigators reported treatment-related Grade ≥3 AEs in 28 patients (54 percent).
Among all 52 enrolled patients, 42 remained on treatment as of the data cutoff date. Four patients discontinued treatment with avapritinib due to AEs (three treatment-related and one unrelated). Three patients discontinued treatment with avapritinib due to clinical progression as determined by the investigator. No patients had documented disease progression by IWG-MRT-ECNM criteria. An additional three patients discontinued treatment, including two patients due to an investigator's decision and one patient who withdrew consent.
Clinical Activity Data:
IWG-MRT-ECNM Response Assessment
As of the data cutoff date, 23 patients were evaluable for response by the IWG-MRT-ECNM criteria, a rigorous method of assessing clinical response in patients with advanced SM with regulatory precedent in the U.S. and
Across all 23 evaluable patients, the data showed an ORR of 83 percent. Four patients (17 percent) had a confirmed complete response with a full or partial recovery of peripheral blood counts. Twelve patients (52 percent) had a partial response (7 confirmed, 5 pending confirmation) and three patients (13 percent) had clinical improvement (2 confirmed, 1 pending confirmation). The duration of response was up to 22 months, with 79 percent of responders on treatment as of the data cutoff date. All responses observed in the dose escalation portion of the trial have been confirmed, and all responses in the dose expansion portion of the trial are pending confirmation.
Additional Clinical Assessments
All patients evaluable on objective measures of mast cell burden showed clinically significant improvements, regardless of advanced SM subtype, previous treatment or dose level:
- 92 percent of patients had a ≥50 percent decrease in bone marrow mast cells. Among these patients, 58 percent had a complete response (no neoplastic mast cells in bone marrow).
- 98 percent of patients had a ≥50 percent decrease in serum tryptase. Among these patients, 66 percent had a complete response (serum tryptase level <20 μg/L).
- 95 percent of patients had a ≥35 percent decrease in spleen volume or a ≥50 percent decrease by palpation. Among these patients, 47 percent had a complete response (normal spleen length).
- 88 percent of patients had ≥50 percent decrease in KIT D816V mutant allele burden.
In addition, 87 percent of patients had improvement in skin symptoms, based on investigator assessments.
Clinical Activity in Patients with Smoldering SM
Two patients with smoldering SM, an intermediate form of SM, were treated with avapritinib in the EXPLORER clinical trial. Consistent with the broader trial population, the patients with smoldering SM showed clinically significant improvements on multiple measures of mast cell burden. Among these two patients with smoldering SM, one patient had a bone marrow mast cell complete response, and both patients had a serum tryptase complete response.
About the Phase 1 EXPLORER Clinical Trial for Avapritinib in Advanced SM
The Phase 1 EXPLORER clinical trial of avapritinib is designed to evaluate the safety and tolerability of avapritinib in adults with advanced SM. The trial is currently enrolling patients in three defined cohorts for specific subtypes of advanced SM, including ASM, SM‑AHN and MCL. Trial objectives include assessing safety and tolerability, response per IWG-MRT-ECNM criteria and additional clinical outcome measures of mast cell burden, organ function and disease symptoms. The EXPLORER trial is designed to enroll approximately 60 patients, including approximately 35 patients in expansion cohorts, at multiple sites in the United States and the European Union. To learn more about the EXPLORER trial, visit www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT02561988).
Patients and physicians interested in the Phase 1 EXPLORER or Phase 2 PATHFINDER trials for avapritinib in advanced SM or the Phase 2 PIONEER trial for avapritinib in indolent and smoldering SM can contact the
In approximately 90 to 95 percent of all SM cases, constitutively active KIT D816V protein is present and is central to disease pathogenesis. KIT activation leads to increased degranulation, proliferation, and survival of mast cells, which in turn leads to constitutional symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, and diarrhea. In advanced cases of SM, mast cell infiltration leads to organ damage and reduced survival. There are several forms of SM, including indolent SM, smoldering SM and more advanced forms of SM, which include ASM, SM-AHN and MCL. Patients with advanced SM have a poor prognosis, with a median overall survival of approximately 3.5 years in patients with ASM, 2 years in those with SM-AHN, and less than 6 months in those with MCL. Currently, there are no approved therapies for advanced SM that selectively target the KIT D816V mutation. Patients with indolent SM suffer from a broad range of moderate to severe acute and chronic symptoms that are poorly controlled by symptom-directed therapies and have significant impact on quality of life. Currently, there are no approved treatments for patients with indolent SM.
Avapritinib is an orally available, potent and highly selective inhibitor of KIT and PDGFRA. In certain diseases, a spectrum of clinically relevant mutations forces the KIT or PDGFRA protein kinases into an increasingly active state. Avapritinib is uniquely designed to bind and inhibit the active conformation of these proteins, including KIT D816V and PDGFRα D842V at sub-nanomolar potency.
Blueprint Medicines is developing a new generation of targeted and potent kinase medicines to improve the lives of patients with genomically defined diseases. Its approach is rooted in a deep understanding of the genetic blueprint of cancer and other disease driven by the abnormal activation of kinases.
Cautionary Notes Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans and timelines for the clinical development of avapritinib, including plans and timelines for initiating the Phase 2 PATHFINDER clinical trial of avapritinib in patients with advanced SM and plans and timelines for initiating the Phase 2 PIONEER clinical trial of avapritinib in patients with indolent and smoldering SM; expectations regarding the potential for the Phase 2 PATHFINDER clinical trial and for the Phase 2 PIONEER clinical trial to be registration-enabling for avapritinib in their respective patient populations;
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Investor and Media Relations Contacts: Kristin Hodous, 617-714-6674, KHodous@blueprintmedicines.com; Jim Baker, 617-844-8236, JBaker@blueprintmedicines.com