Blueprint Medicines Announces Updated Results from Ongoing EXPLORER Clinical Trial of Avapritinib Demonstrating Broad Clinical Activity and Significant Symptom Reductions in Patients with Systemic Mastocytosis
As of the data cutoff date of
In addition, statistically significant improvements in patient-reported disease symptoms were observed. A 41 percent mean reduction (p=0.043) in patient-reported disease symptoms was demonstrated on the Advanced SM Symptom Assessment Form (AdvSM-SAF), the first patient-reported outcomes tool designed specifically to assess advanced SM.
"Systemic mastocytosis is a complex rare disorder that causes debilitating symptoms across all forms of the disease and reduced survival in advanced patients," said
"The data further validate
Data Highlights from the Ongoing Phase 1 EXPLORER Clinical Trial
As of the data cutoff date of
As of the data cutoff date, avapritinib was generally well-tolerated. Most AEs were reported by investigators as Grade 1 or 2. Across all enrolled patients, 52 patients (78 percent) remained on treatment as of the data cutoff date. Three patients (4 percent) discontinued treatment with avapritinib due to treatment-related AEs.
Across all grades, the most common non-hematological treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (>15 percent) were periorbital edema, fatigue, nausea, diarrhea, peripheral edema, vomiting, cognitive effects, hair color changes, arthralgia, dizziness and abdominal pain. The most common hematological treatment-emergent AEs reported by investigators (>10 percent) were anemia, thrombocytopenia and neutropenia. Grade 3 and 4 treatment-related AEs occurred in 44 patients (66 percent), and these events were most commonly hematological AEs, typically in patients with low blood counts (cytopenias) at study entry.
Clinical Activity Data
IWG-MRT-ECNM Assessments and Objective Measures of Mast Cell Burden
As of the data cutoff date, 29 patients were evaluable for response by the modified IWG-MRT-ECNM criteria, a rigorous method for assessing clinical response in advanced SM patients with regulatory precedent in the U.S. and
Avapritinib demonstrated durable clinical responses across all doses studied and in each subtype of advanced SM – ASM, SM-AHN and MCL. The duration of treatment was up to 31 months as of the data cutoff date, with a median follow-up time of 14 months in evaluable patients.
Across all evaluable patients at all doses, the ORR was 83 percent. Seven patients had a CR/CRh (24 percent, two pending confirmation), 14 patients had a partial response (48 percent, three pending confirmation) and three patients had clinical improvement (10 percent, one pending confirmation). Three of the pending responses were previously confirmed responses (two partial responses, one clinical improvement) that are transitioning to a deeper response. No patients had documented disease progression per modified IWG-MRT-ECNM criteria.
In addition, strong clinical activity was demonstrated in evaluable patients treated with a starting dose of less than or equal to 200 mg once daily (QD), the dose under evaluation in the ongoing registration-enabling Phase 2 PATHFINDER clinical trial in patients with advanced SM. These 10 patients had an ORR of 90 percent and a CR/CRh rate of 50 percent (one complete response pending confirmation).
All patients evaluable on objective measures of mast cell burden showed reductions from baseline. These results were shown regardless of disease subtype, prior therapy (including midostaurin or the investigational agent DCC-2618), or co-mutation status. These measures consisted of declines in bone marrow mast cells, serum tryptase, spleen volume and KIT D816V mutant allele burden.
At baseline, 22 SM patients received steroids for mastocytosis symptoms. As of the data cutoff date, 18 patients (80 percent) decreased their steroid dose, including nine patients (41 percent) who were able to entirely discontinue their steroids.
As of the data cutoff date, 32 patients in the dose expansion portion of the Phase 1 EXPLORER trial were evaluated using the AdvSM-SAF, the first patient-reported outcomes tool developed specifically for advanced SM patients. It was designed to evaluate symptoms across the gastrointestinal domain (abdominal pain, diarrhea, nausea and vomiting) and skin domain (spots, itching and flushing), as well as fatigue. Patients reported their symptoms daily using an electronic diary.
In advanced SM patients, benefits were shown across each individual symptom studied. There was a 41 percent improvement from baseline in the AdvSM-SAF Total Symptom Score (p=0.043). The most symptomatic patients (n=16, top 50th percentile) had the largest mean improvement in the AdvSM-SAF Total Symptom Score (46 percent, p=0.038).
In addition, an improvement in patient-reported quality of life was observed. As of the data cutoff date, 30 patients were evaluated using the
Proof-of-Concept in Indolent and Smoldering SM
All evaluable patients with indolent and smoldering SM showed profound reductions in bone marrow mast cells, serum tryptase, spleen volume and KIT D816V mutant allele burden. The data also showed avapritinib led to improvements in patient-reported symptoms. These encouraging data support
The Phase 1 EXPLORER clinical trial of avapritinib was designed to identify the recommended Phase 2 dose for further study and demonstrate proof-of-concept in advanced SM. The dose escalation portion is complete, and the expansion portion of the trial is enrolling patients with ASM, SM-AHN and MCL at multiple sites in
The Phase 2 PATHFINDER clinical trial is an open-label, single-arm, registration-enabling clinical trial in patients with advanced SM. Patient dosing is now ongoing in the clinical trial, which is designed to enroll up to 60 advanced SM patients at sites in
SM patients and clinicians interested in ongoing or planned clinical trials can contact the
SM results from the abnormal proliferation and survival of mast cells, which mediate allergic responses. There are several forms of the disease, including indolent SM, smoldering SM and three advanced subtypes – ASM, SM-AHN and MCL. The KIT D816V mutation drives approximately 90 to 95 percent of all SM cases, causing debilitating and difficult-to-manage symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, anaphylaxis, abdominal pain and fatigue. While these effects occur across SM patients, symptom burden and poor quality of life are the predominant disease manifestations of indolent and smoldering SM. Advanced SM patients experience organ damage and a median overall survival of about 3.5 years in ASM, two years in SM-AHN and less than six months in MCL.
Currently, there are no approved therapies that selectively inhibit KIT D816V in advanced SM, and no approved therapies for indolent and smoldering SM. New treatments are needed that are more effective and better tolerated than existing advanced SM therapy, as well as for indolent and smoldering SM patients whose symptoms are often not well controlled with symptom-directed therapies.
Avapritinib is a potent and selective oral inhibitor of KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with gastrointestinal stromal tumors (GIST), and the most potent activity against activation loop mutations, which currently approved therapies for GIST do not inhibit. In contrast with existing multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to selectively bind and inhibit D816V mutant KIT, the primary driver of disease in approximately 90 to 95 percent of all SM patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.
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 the ongoing Phase 1 EXPLORER clinical trial, ongoing Phase 2 PATHFINDER clinical trial and planned Phase 2 PIONEER clinical trial; expectations regarding the potential for the Phase 1 EXPLORER clinical trial, Phase 2 PATHFINDER clinical trial or Phase 2 PIONEER clinical trial to be registration-enabling for avapritinib in SM;
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Investor Relations Contact Kristin Hodous, 617-714-6674, KHodous@blueprintmedicines.com; Media Relations Contact Andrew Law, 617-844-8205, ALaw@blueprintmedicines.com