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Designing precision therapies specifically to target the underlying cause of genomically defined diseases

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Avapritinib

Avapritinib is a potent and selective inhibitor of activated KIT and PDGFRA mutant kinases. In certain diseases, mutations in KIT and PDGFRA force protein kinases into an increasingly active state. Avapritinib is uniquely designed to bind and inhibit the active conformation of these proteins.

Activating mutations in KIT and PDGFRA are associated with gastrointestinal stromal tumors (GIST) and systemic mastocytosis (SM) and appear in lower frequency in a broad range of advanced malignancies.

Avapritinib in GIST

  • GIST is a sarcoma of the gastrointestinal tract, and is driven by the PDGFRA gene with exon 18 mutations in about 6% of patients.

  • Prior to tyrosine kinase inhibitor use in GIST, mutational testing in all patients is recommended by expert guidelines. People diagnosed with GIST should be tested for mutations to determine which type of therapy might be right for them.

  • Blueprint Medicines is developing avapritinib as a potential treatment for patients with PDGFRA exon 18 mutant GIST globally. View approved uses of avapritinib. View clinical trials of avapritinib.

Avapritinib in systemic mastocytosis

  • Systemic mastocytosis (SM) is a rare disease driven by the KIT D816V mutation in approximately 95 percent of cases. Uncontrolled proliferation and activation of mast cells results in chronic, severe and often unpredictable symptoms across multiple organ systems.

  • SM comprises a disease spectrum ranging from non-advanced SM to advanced SM.

    – The vast majority of those affected have indolent SM (ISM), which frequently results in a broad range of burdensome symptoms that can lead to a profound negative impact on quality of life.

    – A minority of patients have advanced SM, which is associated with organ damage due to mast cell infiltration and poor overall survival.

  • Blueprint Medicines is developing avapritinib as a potential treatment for a broad population of patients with SM globally, including advanced SM and ISM. View approved uses of avapritinib. View clinical trials of avapritinib.

Presentations and publications

Avapritinib in GIST

Long-term efficacy, tolerability and overall survival in patients with unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumor treated with avapritinib: NAVIGATOR phase 1 trial update. Robin L. Jones, M.D., European Society for Medical Oncology (ESMO) Virtual Congress, September 18, 2020.
Clinical Efficacy Comparison of Avapritinib With Other Tyrosine Kinase Inhibitors (TKIs) in Gastrointestinal Stromal Tumors (GIST) With PDGFRA D842V Mutation: A Retrospective Analysis of Clinical Trial and Real-World Data. Margaret von Mehren, M.D., European Society for Medical Oncology (ESMO) Virtual Congress, September 17, 2020.
Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Michael Heinrich, M.D., The Lancet Oncology, June 29, 2020.
Clinical Response to Avapritinib by RECIST and Choi Criteria in ≥ 4th Line and PDGFRA Exon 18 Gastrointestinal Stromal Tumors (GIST). Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) Annual Meeting, November 14, 2019.
Avapritinib for the Treatment of GIST: Analysis of Efficacy, Safety, and Patient Management Strategies at the Recommended Phase 2 Dose. Cissimol P. Joseph, NP-C, Connective Tissue Oncology Society (CTOS) Annual Meeting, November 14, 2019.
Clinical Activity of Avapritinib in ≥4th Line (4L+) and PDGFRA Exon 18 Gastrointestinal Stromal Tumors (GIST). Michael Heinrich, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 1, 2019.
Avapritinib is Highly Active and Well-tolerated in Patients With Advanced GIST Driven by a Diverse Variety of Oncogenic Mutations in KIT and PDGFRA. Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting, November 15, 2018.
Correlation of ctDNA and Response in Patients with PDGFRα D842 GIST Treated with Avapritinib. Suzanne George, M.D., European Society for Medical Oncology (ESMO) Congress, October 22, 2018.
An Open-label, Randomized, Phase 3 Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Metastatic or Unresectable Gastrointestinal Stromal Tumor. Sebastian Bauer, M.D., European Society for Medical Oncology (ESMO) Congress, October 22, 2018.
Clinical activity of BLU-285, a highly potent and selective KIT/PDGFRα inhibitor designed to treat gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., Connective Tissue Oncology Society (CTOS) Annual Meeting, November 10, 2017.
Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., American Society of Clinical Oncology (ASCO) Annual Meeting, June 5, 2017.
BLU-285: A potent and highly selective inhibitor designed to target malignancies driven by KIT and PDGFRα mutations. Erica Evans, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 2, 2017.
Preliminary safety and activity in a first-in-human Phase 1 study of BLU-285, a potent, highly selective inhibitor of KIT and PDGFRα activation loop mutants in advanced gastrointestinal stromal tumor (GIST). Michael Heinrich, M.D., EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium, December 1, 2016.

Avapritinib in systemic mastocytosis

Results from PIONEER: a randomized, double-blind, placebo-controlled, Phase 2 study of avapritinib in patients with indolent systemic mastocytosis (ISM). Cem Akin, M.D., Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress, June 12, 2020.
Avapritinib induces responses in patients with advanced systemic mastocytosis (AdvSM), regardless of prior midostaurin therapy. Jason Gotlib, M.D., Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress, June 12, 2020.
Avapritinib reduces cutaneous symptoms and mast cell burden in patients with indolent systemic mastocytosis in the PIONEER study. Karin Hartmann, M.D., European Academy of Allergy and Clinical Immunology (EAACI) 2020 Digital Congress, June 6, 2020.
PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy. Cem Akin, M.D., American Academy of Allergy, Asthma & Immunology (AAAAI) Virtual Oral Abstracts, Case Reports and Poster Sessions, March 16, 2020.
PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent or Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy. Cem Akin, M.D., American Society of Hematology (ASH) Annual Meeting, December 8, 2019.
Psychometric Evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) in patients with Advanced Systemic Mastocytosis. International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Europe Conference, November 6, 2019.
Psychometric Performance of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF). International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Europe Conference, November 6, 2019.
Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Induces Complete and Durable Responses in Patients with Advanced Systemic Mastocytosis. Deepti Radia, M.B.B.S., European Hematology Association (EHA) Annual Meeting, June 15, 2019.
Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM). Jason Gotlib, M.D., American Society of Hematology (ASH) Annual Meeting, December 2, 2018.
Avapritinib (BLU-285), a Selective KIT Inhibitor, is Associated with High Response Rate and Tolerable Safety Profile in Advanced Systemic Mastocytosis: Results of a Phase 1 Study. Michael W. Deininger, M.D., Ph.D., European Hematology Association (EHA) Annual Meeting, June 15, 2018.
Clinical activity in a Phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis. Daniel J. DeAngelo, M.D., Ph.D., American Society of Hematology (ASH) Annual Meeting, December 10, 2017.
A precision therapy against cancers driven by KIT/PDGFRA mutations. Erica K. Evans, Ph.D., et al., Science Translational Medicine, November 1, 2017.
BLU-285: A potent and highly selective inhibitor designed to target malignancies driven by KIT and PDGFRα mutations. Erica Evans, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 2, 2017.
Preliminary Safety and Activity in a Phase 1 study of BLU-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (SM). Mark Drummond, MBChB, Ph.D., American Society of Hematology (ASH) Annual Meeting, December 4, 2016.

Clinical trials

Systemic mastocytosis (SM)

Trial Phase

Trial Phase 2

Target Population

Target Population

Aggressive SM, SM with associated hematologic neoplasm and mast cell leukemia

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT03580655

Trial Phase

Trial Phase 2

Target Population

Target Population

Indolent SM

Study Status

Study Status

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ClinicalTrials.gov
Study Number

Study Number

NCT03731260

Elenestinib (BLU-263)

Elenestinib is a next-generation KIT D816V inhibitor developed based on insights from the avapritinib program. Elenestinib was designed to potently inhibit D816V mutant KIT with minimal central nervous system penetration. These attributes may have the potential to optimize its benefit-risk profile for the treatment of broad patient populations with indolent systemic mastocytosis (SM).

Elenestinib in systemic mastocytosis

  • Systemic mastocytosis (SM) is a rare disease driven by the KIT D816V mutation in approximately 95 percent of cases. Uncontrolled proliferation and activation of mast cells results in chronic, severe and often unpredictable symptoms across multiple organ systems.

  • The vast majority of those affected have indolent SM (ISM), which frequently results in a broad range of burdensome symptoms that can lead to a profound negative impact on quality of life.

  • The initial focus of the elenestinib development program is ISM. View clinical trials of elenestinib.

Presentations and publications

BLU-222


BLU-222 is a potent and selective CDK2 inhibitor for the treatment of patients with CDK2-vulnerable cancers, including hormone receptor (HR)-positive, HER2-negative breast cancer and CCNE1 aberrant tumors. CDK2 and CCNE1 are central to regulating the cell cycle, which is involved in the process of cell growth and division. However, prior drug discovery efforts targeting CDK2 have been hindered by challenges in achieving selectivity over other CDK family members associated with toxicity.

CDK2 is believed to play an important role in tumor proliferation for patients with HR-positive, HER2-negative metastatic breast cancer. In subsets of patients with ovarian cancer and other tumor types, aberrant CCNE1 hyperactivates CDK2, resulting in cell cycle dysregulation and tumor growth. Preclinically, BLU-222 showed significant antitumor activity in a CCNE1-amplified ovarian cancer model, and BLU-222 in combination with standard of care agents led to sustained tumor regression even after treatment cessation.

BLU-222 in hormone receptor-positive metastatic breast cancer

  • Approximately 60 percent of treatment-naïve patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer receive a CDK4/6 inhibitor; however, patients ultimately become resistant to therapy over time.

  • There are limited treatment options for patients following disease progression on a CDK4/6 inhibitor.

  • Blueprint Medicines is developing BLU-222 as a monotherapy and in combination with other agents, including CDK4/6 inhibitors and ER antagonists, in HR-positive, HER2-negative breast cancer. View clinical trial of BLU-222.

BLU-222 in cyclin E aberrant cancers

  • Studies show that CCNE1 amplification across multiple tumor types is correlated with poor patient outcomes.

  • For example, approximately 10 to 20 percent of patients with high grade serous ovarian cancer, a common form of ovarian cancer, harbor CCNE1 amplifications.

  • Blueprint Medicines is developing BLU-222 as a monotherapy and in combination with other agents for the treatment of CCNE1 aberrant cancers. View clinical trial of BLU-222.

Presentations and publications

Fidrisertib (BLU-782, IPN60130)

Fidrisertib is an orally administered, potent and highly selective ALK2 inhibitor. It was designed specifically to target the underlying genetic driver of fibrodysplasia ossificans progressiva (FOP), a rare, severely disabling and ultimately life-shortening genetic disease. FOP is characterized by episodic soft tissue edema (flare-ups), and the progressive replacement of skeletal muscle, ligaments and connective tissue by heterotopic bone. FOP is caused by a gain-of-function mutation in ACVR1, which encodes activin-like kinase 2 (ALK2).

In October 2019, we entered into an exclusive, worldwide license agreement with Clementia Pharmaceuticals, a subsidiary of Ipsen, to develop and commercialize fidrisertib.

Fidrisertib in fibrodysplasia ossificans progressiva

  • FOP is a rare genetic disease, with an estimated prevalence of 1.36 per million.

  • In patients with FOP, mutations in the ACVR1 gene over-activate ALK2, causing disease flare-ups and heterotopic ossification (HO) or abnormal bone formation.

  • Disease flare-ups involve painful tumor-like swelling typically caused by physical trauma.

  • HO causes progressive disability and incapacitation including the locking of joints, ultimately contributing to reduced survival typically due to pulmonary insufficiency.

  • BLU-782 is designed to selectively target mutant ALK2, while sparing closely related anti-targets including ALK1, ALK3, and ALK6.

Presentations and publications

A clinical update on BLU-782, an investigational selective ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP) Alison Davis, Ph.D., American Society for Bone Mineral Research (ASBMR) Annual Meeting, September 22, 2019
BLU-782: A highly selective ALK2 inhibitor, designed specifically to target the cause of fibrodysplasia ossificans progressiva. Andy Garner, Ph.D., American Society for Bone Mineral Research (ASBMR) Annual Meeting, September 30, 2018.
Kinome illustrations reproduced courtesy of Cell Signaling Technology, Inc.

Systemic mastocytosis (SM) is a rare disease that can mask as other more common illnesses, making it difficult to diagnose.
Blueprint Medicines has partnered with the University of Pennsylvania to develop and publish an algorithm applying
machine learning techniques to pinpoint potential SM cases.