Purposefully designed therapeutic candidates

Investigational precision therapies specifically designed 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, a spectrum of clinically relevant mutations force KIT or PDGFRA 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. Preclinical and clinical data show avapritinib is active across a broad spectrum of clinically relevant KIT and PDGFRA mutations, including activation-loop mutants.

Avapritinib in GIST

  • GIST is the most common sarcoma of the GI tract, and is driven by primary mutations in the KIT gene (about 75-80%), PDGFRA gene (about 10%) or other genes in rare cases.
  • Currently, there is no highly effective therapy following first-line Gleevec® (imatinib), and FDA-approved therapies for second-line and third-line GIST offer limited sustained disease control. In addition, there is no effective therapy for PDGFRα D842V-driven GIST.
  • Avapritinib has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of patients with advanced PDGFRα D842V-driven GIST.
  • Blueprint Medicines has submitted a New Drug Application to the U.S. Food and Drug Administration for avapritinib for the treatment of PDGFRA Exon 18 mutant GIST, regardless of prior therapy, and fourth-line GIST.
  • European Medicines Agency has validated Marketing Authorization Application for avapritinib for the treatment of PDGFRα D842V mutant GIST, regardless of prior therapy, and fourth-line GIST.
  • Blueprint Medicines is developing avapritinib as a potential treatment for a broad population of patients with GIST, including PDGFRα D842V-driven, fourth-line, third-line and second-line GIST.

Avapritinib in systemic mastocytosis

  • Systemic mastocytosis (SM) is a rare disease that results from the abnormal proliferation of mast cells; across all forms of SM, approximately 90-95% of patients have the KIT D816V mutation.
  • SM comprises a disease spectrum ranging from indolent SM, which is predominantly characterized by severe constitutional symptoms caused by mast cell degranulation and mediator release, to advanced SM, which is characterized by organ dysfunction and reduced survival due to mast cell infiltration.
  • Currently, there are no approved therapies that selectively target the KIT D816V mutant, the underlying cause of most SM cases.
  • Avapritinib has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of patients with advanced SM.
  • Blueprint Medicines is developing avapritinib as a potential treatment for a broad population of patients with SM, including advanced, smoldering and indolent SM.

Presentations and publications

Avapritinib in GIST

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 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.
GIST: imatinib and beyond - 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.
Discovery and development of BLU-285: A potent, highly selective inhibitor of KIT and PDGFRα activation loop mutants. Brian L. Hodous, Ph.D. 253rd American Chemical Society National Meeting & Exposition, April 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

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

Gastrointestinal stromal tumors (GIST)

Trial Phase

Trial Phase 1

Target Population

Target Population

Advanced GIST

Study Status

Study Status

Active, fully enrolled

ClinicalTrials.gov
Study Number

Study Number

NCT02508532

Trial Phase

Trial Phase 3

Target Population

Target Population

Third-line or fourth-line GIST

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT03465722

Systemic mastocytosis (SM)

Trial Phase

Trial Phase 1

Target Population

Target Population

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

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT02561988

Trial Phase

Trial Phase 2

Target Population

Target Population

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

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT03580655

Trial Phase

Trial Phase 2

Target Population

Target Population

Indolent SM and smoldering SM

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT03731260

BLU-667 diagram.

Pralsetinib

Pralsetinib (BLU-667) is an oral precision therapy designed for highly potent and selective targeting of oncogenic RET alterations and resistance mutants. Across a wide range of cancers, oncogenic alterations in RET result in kinase activation, driving tumor formation and growth. The two primary mechanisms of oncogenic RET activation are fusions and mutations.

Pralsetinib has consistently achieved sub-nanomolar potency against the most common RET fusions, activating mutations and resistance mutations in preclinical studies. By suppressing primary and secondary RET mutants that confer resistance to multi-kinase inhibitors, pralsetinib has the potential to overcome and prevent the emergence of clinical resistance.

Pralsetinib achieves greater selectivity for RET compared to approved multi-kinase inhibitors and was specifically designed to spare VEGFR2 and other kinases with the potential to drive off-target toxicity.

Oncogenic RET alterations occur in many tumor types, including 1-2% of non-small cell lung cancer (NSCLC), 60% of medullary thyroid cancer (MTC), and 10-20% of papillary thyroid cancer (PTC) cases. Oncogenic RET alterations are also observed at low frequencies in colorectal, breast, pancreatic and other cancers.

Pralsetinib in non-small cell lung cancer

  • Lung cancer is the most common cancer worldwide and is the leading cause of cancer death. NSCLC is the most common form of lung cancer, making up 80-85% of cases.
  • The 5-year survival rate for NSCLC is estimated to be 18 percent.
  • RET fusions are implicated as the underlying cause of disease in about 1-2% of NSCLC cases.
  • There are no approved therapies for patients with RET-driven NSCLC.
  • Pralsetinib has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of RET-fusion-positive NSCLC that has progressed following platinum-based chemotherapy.

Pralsetinib in medullary thyroid cancer

  • Thyroid cancer is the most common form of endocrine malignancy.
  • MTC comprises about 3-5% of thyroid cancer cases. RET mutations are found in nearly all cases of inherited MTC and 50% of sporadic MTC.
  • PTC comprises about 70% of thyroid cancer cases. RET fusions are found in about 10-20% of PTC cases.
  • Currently approved multi-kinase inhibitors for MTC have low tolerability, with high rates of dose reduction and discontinuation due to off-target toxicities.
  • Pralsetinib has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of RET-mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

Presentations and publications

Clinical activity of pralsetinib, a highly selective RET inhibitor, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study. Mimi I. Hu, M.D., American Thyroid Association (ATA) Annual Meeting, October 6, 2018.
Activity of osimertinib and the selective RET inhibitor pralsetinib in an EGFR-mutant patient with acquired RET rearrangement. Zofia Piotrowska, M.D., IASLC World Conference on Lung Cancer, September 26, 2018.
Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and PRALSETINIB (BLU-667) for acquired RET fusion. Zofia Piotrowska, M.D., et al., Cancer Discovery, September 26, 2018.
Highly potent and selective RET inhibitor, pralsetinib, achieves proof of concept in ARROW, a phase 1 study of advanced, RET-altered solid tumors. Vivek Subbiah, M.D., American Association for Cancer Research (AACR) Annual Meeting, April 15, 2018.
Precision targeted therapy with pralsetinib for RET-driven cancers. Vivek Subbiah, M.D., et al., Cancer Discovery, April 15, 2018.
Pralsetinib is a Potent and Highly Selective RET Inhibitor Being Developed for RET-Driven Cancers. Rami Rahal, Ph.D.
, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, October 29, 2017.
Pralsetinib is a potent and highly selective RET inhibitor in development for RET-driven thyroid cancers. Rami Rahal, Ph.D., 
World Congress on Thyroid Cancer, July 30, 2017.
The development of potent and selective RET inhibitors. Rami Rahal, Ph.D., American Association for Cancer Research (AACR) Annual Meeting, April 18, 2016.

Clinical trials

Trial Phase

Trial Phase 1/2

Target Population

Target Population

RET-altered non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) or other solid tumors with a RET fusion or mutation

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT03037385

BLU-554 diagram.

Fisogatinib

Fisogatinib (BLU-554) is an orally administered, potent, irreversible inhibitor of fibroblast growth factor receptor 4 (FGFR4). Fisogatinib was specifically designed to selectively inhibit FGFR4 and spare other kinases including FGFR1, FGFR2 and FGFR3. Blueprint Medicines estimates about 30% of patients with hepatocellular carcinoma (HCC) have tumors with aberrantly activated FGFR4 signaling and is working to develop fisogatinib for the treatment of patients with FGFR4-driven HCC.

Fisogatinib in hepatocellular carcinoma

  • Liver cancer is the second leading cause of cancer-related deaths worldwide, with HCC accounting for most liver cancers.
  • In the United States, HCC is the fastest rising cause of cancer-related death. Over the past two decades, the incidence of HCC has tripled while the five-year survival rate has remained below 12%.
  • The highest incidence of HCC occurs in regions with endemic hepatitis B virus, including Asia and sub-Saharan Africa. More than half of all new cases of HCC occur in China annually.
  • Despite available treatments, the overall prognosis for patients with HCC is typically poor.

Presentations and publications

Clinical activity Of Fisogatinib, a potent, highly-selective FGFR4 inhibitor in advanced HCC with FGFR4 pathway activation. Yoon-Koo Kang, M.D., Ph.D., International Liver Cancer Association (ILCA) Annual Meeting, September 17, 2017.
A clinical trial for people with hepatocellular carcinoma Richard Kim, M.D., European Society for Medical Oncology (ESMO) Congress, September 10, 2017.
Discovery and development of Fisogatinib: a potent, highly selective covalent inhibitor of fibroblast growth factor receptor 4 (FGFR4) in development for the targeted treatment of advanced hepatocellular carcinoma (HCC) patients with amplified and overexpressed FGF19. Chandra V. Miduturu, Ph.D.
, 253rd American Chemical Society National Meeting & Exposition, April 5, 2017.
First-in-human study of Fisogatinib, a potent, highly selective FGFR4 inhibitor designed for hepatocellular carcinoma (HCC) with FGFR4 pathway activation. Richard Kim, M.D.
, EORTC-NCI-AACR Symposium, November 29, 2016.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Margit Hagel, et al., Cancer Discovery, April 2015.

Clinical trials

Fisogatinib in patients with hepatocellular carcinoma (HCC)

Trial Phase

Trial Phase 1

Target Population

Target Population

FGFR4-activated HCC, defined as overexpression of FGF19 assessed by an immunohistochemistry test

Study Status

Study Status

Active, recruiting

ClinicalTrials.gov
Study Number

Study Number

NCT02508467

BLU-782 diagram.

BLU-782

BLU-782 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 BLU-782.

BLU-782 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-up 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.