Blueprint Medicines Corporation, a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, announced data from its ongoing phase 1 trial evaluating BLU-285, an investigational medicine for the treatment of patients with advanced systemic mastocytosis (SM). Blueprint Medicines is developing BLU-285 as a potent, highly selective inhibitor of D816V mutant KIT. Approximately 90 to 95 percent of patients with SM are estimated to have the KIT D816V mutation, the key driver of SM that triggers the abnormal proliferation and survival of mast cells.  The data were presented at the 2016 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

"Advanced systemic mastocytosis is a rare and severe disease that shortens life expectancy with a wide range of debilitating symptoms and organ damage," said Daniel DeAngelo, M.D., Dana-Farber Cancer Institute, an investigator on the clinical trial. "We need new treatment options that address the underlying cause of the disease and can improve the significant symptoms that impact patients' daily lives. The objective decreases in mast cell burden and improvements in symptoms seen in the early data for this Phase 1 study are encouraging. We believe that BLU-285 has the potential to change the treatment paradigm for patients affected by advanced systemic mastocytosis."

"We are excited by these early data demonstrating a favorable safety profile as well as signs of clinical activity starting at the first dose level," said Andy Boral, M.D., chief medical officer at Blueprint Medicines. "The decreases in bone marrow mast cell burden and serum tryptase, which are indications of clinical activity, along with the fact that ten of 12 patients remain on the study, are encouraging and support the hypothesis that D816V mutant KIT is a driver of this disease. We look forward to the continued evaluation of our investigational medicine BLU-285, which we believe has the potential to be transformative for patients with advanced SM."

BLU-285 is currently being evaluated in the dose escalation portion of a Phase 1 clinical trial in patients with advanced SM. As of the data cutoff date of November 11, 2016, 12 patients had been treated at three dose levels (30 mg, 60 mg and 100 mg once daily (QD)). The median age was 61.5 years (ranging from 39 to 82), and the KIT D816V mutation has been confirmed in bone marrow or blood from 11 of the 12 patients. Ten of the 12 patients remained on the clinical trial as of the data cutoff date.

Consistent with preliminary data reported by Blueprint Medicines from its phase 1 clinical trial for patients with advanced gastrointestinal stromal tumors (GIST), BLU-285 demonstrated a favorable pharmacokinetic profile with a half-life that supports QD dosing.

As of the data cutoff date of November 11, 2016, BLU-285 was observed to be well-tolerated at all doses. No patients discontinued treatment as a result of an adverse event (AE), and no Grade 4 or worse treatment-related AEs were reported. The majority of AEs reported by investigators were Grade 1 or 2, and AEs that occurred in two or more patients were fatigue (4 patients), anemia (3 patients) and alkaline phosphatase elevation (3 patients). All three cases of alkaline phosphatase elevation were Grade 3 but were asymptomatic and transient and occurred in the absence of transaminase or bilirubin elevations. The Grade 3 alkaline phosphatase elevations occurred in the three patients with the highest bone marrow mast cell burden at baseline, suggesting this may be consistent with a pharmacodynamic effect of BLU-285 on mast cells in the bone. One of the three cases of alkaline phosphatase elevation was considered possibly treatment-related and defined as a dose-limiting toxicity at the 60 mg dose level. All three patients continued treatment with BLU-285 without a dose reduction. A maximum tolerated dose (MTD) has not been established, and enrollment in the dose escalation portion of the phase 1 clinical trial is ongoing.

As of the data cutoff date of November 11, 2016, all 12 patients treated in the first three dose levels of the dose escalation portion of the clinical trial were evaluated for signs of clinical activity.

Investigators observed decreases in bone marrow mast cell infiltrate (measured by bone marrow biopsy) in six of the eight patients who had a bone marrow biopsy after starting treatment with BLU-285. Three of the six patients had a decrease of bone marrow mast cell infiltrate of more than 50% from baseline, including one patient with no residual mast cells in the bone marrow.

Based on measurements at a central laboratory, serum tryptase decreased in ten of 12 patients. The serum tryptase decrease was greater than 50% in eight patients.

The allele burden of D816V mutant KIT decreased within the first two treatment cycles in five of six patients in circulating tumor DNA and bone marrow.

Rash improved in five patients with urticaria pigmentosa from baseline based on investigator assessments. Urticaria pigmentosa is an allergy-mediated rash common in SM patients.

Weight increased in ten patients and albumin increased in 11 patients, suggesting improvements in malabsorption.

Ten of 12 patients remained on treatment with treatment duration ranging from 1 month to 8.1 months.

Based on the favorable safety profile and encouraging clinical activity observed to date in the phase 1 clinical trial for BLU-285 for the treatment of advanced SM, Blueprint Medicines plans to continue to enroll patients in the dose escalation portion of this clinical trial until an MTD is reached or a recommended dose is established. Once a recommended dose for further clinical evaluation has been determined or an MTD is reached, Blueprint Medicines plans to open enrollment in expansion cohorts for this phase 1 clinical trial for specific subtypes of advanced SM. In addition, Blueprint Medicines plans to evaluate options to expand the clinical development of BLU-285 in other KIT-driven diseases, including possible opportunities for the treatment of indolent SM and KIT-mutant acute myeloid leukemia, groups of patients in need of more effective treatments. Blueprint Medicines is also collaborating with a health research outcomes group to develop a disease-specific patient reported outcome tool to measure changes in total symptom burden in advanced SM and indolent SM.