Purposefully designed medicines and clinical candidates
Designing precision therapies specifically to target the underlying cause of genomically defined diseases
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 that results from the abnormal proliferation of mast cells; across all forms of SM, the KIT D816V mutation is the primary driver of disease.
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.
– The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life.
– A minority of patients have advanced SM; in addition to mast cell activation symptoms, it is associated with organ damage due to mast cell infiltration and poor overall survival.
Avapritinib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe indolent SM.
Blueprint Medicines is developing avapritinib as a potential treatment for a broad population of patients with SM globally, including advanced and non-advanced SM. View approved uses of avapritinib. View clinical trials of avapritinib.
Presentations and publications
Avapritinib in GIST
Avapritinib in systemic mastocytosis
Clinical trials
Systemic mastocytosis (SM)
A clinical trial for people with advanced systemic mastocytosis
Trial Phase
Target Population
Aggressive SM, SM with associated hematologic neoplasm and mast cell leukemia
Study Status
arrow
ClinicalTrials.gov
Study Number
NCT03580655
A clinical trial for people with indolent systemic mastocytosis
Trial Phase
Target Population
Indolent SM
Study Status
arrow
ClinicalTrials.gov
Study Number
NCT03731260
Pralsetinib
Pralsetinib is a potent and selective inhibitor of oncogenic RET alterations. 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.
In preclinical studies, pralsetinib has achieved sub-nanomolar potency against common RET fusions and mutations. and inhibited RET at lower concentrations than other pharmacologically relevant kinases, including VEGFR2, FGFR2, and JAK2.
Oncogenic RET alterations occur in many tumor types, including 1-2% of non-small cell lung cancer (NSCLC), 90% of advanced 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.
Blueprint Medicines and Roche are developing pralsetinib globally for the treatment of patients with RET fusion-positive NSCLC. View approved uses of pralsetinib. View clinical trials of pralsetinib.
Pralsetinib in 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.
Blueprint Medicines and Roche are developing pralsetinib globally for the treatment of patients with RET-mutant MTC and RET fusion-positive thyroid cancer. View approved uses of pralsetinib. View clinical trials of pralsetinib.
Presentations and publications
Clinical trials
A clinical trial for people with RET-altered cancers
Trial Phase
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
arrow
ClinicalTrials.gov
Study Number
NCT03037385
A clinical trial for people with RET fusion-positive, metastatic non-small cell lung cancer (NSCLC)
Trial Phase
Target Population
First-line RET fusion-positive, metastatic NSCLC
Study Status
arrowplus
ClinicalTrials.gov
Study Number
NCT04222972
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 non-advanced systemic mastocytosis (SM).
Elenestinib in systemic mastocytosis
Systemic mastocytosis (SM) is a rare disease that results from the abnormal proliferation of mast cells; across all forms of SM, the KIT D816V mutation is the primary driver of disease.
The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life.
The initial focus of the elenestinib development program is non-advanced SM. View clinical trials of elenestinib.
Presentations and publications
BLU-945, BLU-525 & BLU-451
BLU-945, BLU-525 and BLU-451 are investigational EGFR inhibitors designed to address a broad range of activating mutations and on-target resistance mechanisms in EGFR-driven non-small cell lung cancer (NSCLC), with the goal of prolonging patient benefit.
NSCLC is the most common form of lung cancer, the leading cause of cancer death worldwide. Among patients with non-small cell lung cancer, it is estimated that the EGFR mutation is present in approximately 22% of cases in the U.S., about 15% in Europe and about 40-50% in Asia.
BLU-945 and BLU-525 in EGFR-mutated NSCLC
For patients with NSCLC, about 80 percent of activating EGFR mutations are exon 19 deletions and L858R, combined.
BLU-945 and BLU-525 are selective, potent EGFR inhibitors designed to provide comprehensive coverage of common activating and on-target resistance mutations, and spare wild-type EGFR and other kinases to help limit off-target toxicities. In addition, the drug candidates were designed to prevent or treat central nervous system metastases.
Blueprint Medicines is working to improve patient outcomes by advancing development of combinations with its investigational EGFR inhibitors.
Blueprint Medicines is developing BLU-945 and BLU-525 for the treatment of EGFR-mutated NSCLC. View clinical trial of BLU-945.
BLU-451 in NSCLC harboring EGFR exon 20 insertions and other uncommon EGFR activating mutations
Uncommon activating EGFR mutations, including exon 20 insertions, represent about 10-20 percent of EGFR-mutated NSCLC cases, varying by geography.
Patients with NSCLC harboring EGFR exon 20 insertion mutations have been historically associated with worse outcomes than those driven by common EGFR activating mutations.
BLU-451 is designed to potently target EGFR exon 20 insertion variants and other uncommon EGFR activating mutations, with marked selectivity over wild-type EGFR and off-target kinases. In addition, BLU-451 has shown central nervous system penetration in preclinical studies.
Blueprint Medicines is developing BLU-451 for the treatment of patients with NSCLC harboring EGFR exon 20 insertion mutations. View clinical trial of BLU-451.
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
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-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
At the American Association for Cancer Research (AACR) Annual Meeting 2022, we presented new clinical and preclinical data
for multiple programs across genomically defined cancers, including lung, ovarian and breast cancers.