Translational data for its investigational anti-tumor medicine BLU-285

Blueprint Medicines today announced the publication of translational data for its investigational medicine BLU-285 in Science Translational Medicine. Reported preclinical data and clinical case studies showed that BLU-285 is a potent and highly selective inhibitor of KIT and PDGFRα kinases, which are implicated in multiple diseases including gastrointestinal stromal tumors (GIST) and systemic mastocytosis (SM). Blueprint Medicines is currently evaluating BLU-285 in two ongoing Phase 1 clinical trials in patients with advanced GIST and patients with advanced SM, and plans to present updated results from both clinical trials in the fourth quarter of 2017.

The publication of our work in Science Translational Medicine highlights the power of our proprietary drug discovery platform to successfully target specific drivers of disease with potent and highly selective kinase medicines," said Erica Evans, Ph.D., Senior Director of Biology at Blueprint Medicines and the lead author of the paper. "Importantly, the preclinical activity of BLU-285 has been substantiated in our ongoing Phase 1 clinical trials. BLU-285 has induced meaningful responses and prolonged progression free survival in patients with KIT-driven and PDGFRα-driven GIST, as well as objective and clinically significant decreases in mast cell burden and improvements in symptoms in patients with advanced SM. We look forward to presenting additional data from our ongoing trials at upcoming medical meetings and continuing to rapidly advance the development of BLU-285 for patients with these severe diseases."

The paper highlighted the in-depth mechanistic evaluation conducted by Blueprint Medicines' scientists to characterize the activity of BLU-285 across a continuum of clinically relevant oncogenic KIT and PDGFRα mutations.

Key insights included:

• Currently available therapies for advanced GIST and advanced SM have limited activity against KIT and PDGFRα activation loop mutations, including KIT D816V, PDGFRα D842V, and additional resistance mutations located on exons 17 and 18. These mutations induce the KIT and PDGFRα proteins to adopt an active conformation, resulting in structural changes in the kinases that decrease the binding affinity of current therapeutic agents. BLU-285 was specifically designed to inhibit KIT and PDGFRα activation loop mutations.
• In vitro studies demonstrated potent activity of BLU-285 against activation loop mutations, as well as a broad spectrum of additional clinically relevant mutations, with a selectivity profile minimizing inhibition of other kinases. In vivo studies in multiple disease models showed BLU-285 induced potent anti-tumor effects.
• BLU-285 has demonstrated clinical proof-of concept in ongoing Phase 1 clinical trials in patients with advanced GIST and advanced SM.

About BLU-285

BLU-285, an investigational medicine, is an orally available, potent and highly selective inhibitor of KIT and PDGFRα. Blueprint Medicines is initially developing BLU-285 for the treatment of patients with advanced GIST and advanced SM.

In June 2017, BLU-285 received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. Previously, the FDA granted orphan drug designation to BLU-285 for the treatment of GIST and SM. The FDA also granted fast track designation to BLU-285 for the treatment of patients with unresectable or metastatic GIST that progressed following treatment with imatinib and a second tyrosine kinase inhibitor and for the treatment of patients with unresectable or metastatic GIST who have the PDGFRα D842V mutation regardless of prior therapy.

BLU-285 was discovered by Blueprint Medicines' research team, which leveraged its proprietary compound library. The Company retains worldwide development and commercialization rights for BLU-285.

About GIST

GIST is the most common sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50-80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction. Approximately 80 percent of GIST patients have KIT-driven GIST, and Blueprint Medicines estimates that KIT exon 17 mutations occur in approximately 90 percent of GIST patients with KIT-driven GIST following treatment with at least two tyrosine kinase inhibitors. Approximately five percent of all advanced GIST cases are driven by D842V mutant PDGFRα. Patients diagnosed with GIST at an early stage may undergo surgery. For patients with KIT-driven GIST, treatment with the currently approved frontline therapy typically leads to treatment resistance and disease progression. Treatment options for KIT-driven GIST patients whose disease progresses or develops resistance are currently limited, with approved therapies providing a progression free survival of up to six months and a response rate between five percent and seven percent. There are no effective treatment options for patients with PDGFRα D842V-driven GIST, and progression often occurs in as little as three months with available treatment options.

About SM

There are several forms of SM, including indolent SM and more advanced forms of SM, which include aggressive SM, SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL). SM is characterized by the buildup of mast cells, which are immune cells that produce histamine and other mediators of the body's inflammatory and allergic responses. In patients with SM, mast cell mediator release leads to mild to life-threatening symptoms, including pain, nausea, rash, fever, fatigue and anaphylaxis. In patients with advanced SM, including aggressive SM, SM-AHN and MCL, mast cell infiltration in bone marrow, liver and other vital organs can eventually lead to organ dysfunction and lower life expectancy, with a median overall survival of approximately four years or less. Patients with indolent SM have a normal life expectancy, but symptoms can have a significant impact on their quality of life. The KIT D816V mutation is the primary driver of disease in approximately 90 to 95 percent of SM patients, and there is a clear need for more effective therapies for patients with advanced SM and for patients with indolent SM who have a heavy symptom burden.

More information:
Erica K. Evans et al. A precision therapy against cancers driven by KIT/PDGFRA mutations, Science Translational Medicine (2017). DOI: 10.1126/scitranslmed.aao1690

Provided by Blueprint Medicines Corporation