Blueprint Medicines Presents Preclinical Data Highlighting Broad Precision Therapy Research Pipeline at AACR Annual Meeting 2021
"Our data presentations at the AACR annual meeting showcase
BLU-701 and BLU-945: Double- and triple-mutant inhibitors in EGFR-driven NSCLC
Lung cancer is the leading cause of cancer death globally, and approximately 17 percent of patients with lung adenocarcinoma, the most common form of non-small cell lung cancer (NSCLC), have EGFR-driven disease. While first- and third-generation EGFR inhibitors have improved treatment outcomes for patients with EGFR-driven NSCLC, resistance inevitably emerges, with the T790M and C797S mutations being the most common on-target resistance mechanisms. Together, BLU-701 and BLU-945 are designed to provide comprehensive coverage of the most common activating and on-target resistance mutations, spare wild-type EGFR to limit toxicities driven by wild-type EGFR inhibition and treat or prevent central nervous system (CNS) metastases. Ultimately, with these characteristics, BLU-701 and BLU-945 have the potential to be used either as monotherapy or in combination, together or with other agents, to potentially overcome or prevent on-target resistance across multiple lines of treatment.
BLU-701 is a potential best-in-class, selective, potent, fourth-generation double-mutant EGFR inhibitor with activity against EGFR activating mutations and the C797S osimertinib-resistant mutation. Preclinical data presented at the conference showed strong and durable inhibition of tumor growth at doses that are EGFR wild-type sparing. BLU-701 also indicated significant CNS penetration in preclinical models, with comparable exposure in the plasma and brain, which illustrates its potential to treat or prevent CNS metastases in patients with EGFR-driven tumors. With activity also shown against the activating EGFR mutants, BLU-701 has potential to be used in both first- and second-line settings.
BLU-945 is a potential first- and best-in-class, selective, potent, fourth-generation triple-mutant EGFR inhibitor with activity against the T790M and C797S resistance mutations. BLU-945 is highly selective over wild-type EGFR and off-target kinases, highlighting its potential to enable tolerable combinations with BLU-701 or other therapies. Data presented at the conference demonstrated potent anti-tumor activity in triple-mutant osimertinib-resistant tumor models, as well as activity in a triple-mutant intracranial patient-derived xenograft model. In addition, the combination of BLU-945 with either gefitinib or osimertinib showed enhanced anti-tumor activity when compared with either gefitinib or osimertinib alone.
The preclinical data presented for BLU-701 and BLU-945 support the continued development of both candidates in patients with EGFR-driven NSCLC. An investigational new drug (IND) application for BLU-945 has been cleared by the
BLU-222: CDK2 inhibitor in cyclin E-aberrant cancers
Cyclin dependent kinases (CDKs) and their cyclin partners regulate the cell cycle. In subsets of patients across multiple cancer types, aberrant cyclin E (CCNE) hyperactivates CDK2, resulting in cell cycle dysregulation and tumor proliferation. Aberrant CCNE has been observed as a primary driver of disease as well as a mechanism of resistance to CDK4/6 inhibitors and other therapies. In addition, data have shown that ovarian and hormone-receptor-positive breast cancer patients with aberrant CCNE have poor outcomes. Prior drug discovery efforts targeting CDK2 have been hindered by challenges in achieving selectivity over other CDK family members associated with toxicity.
At AACR, preclinical data highlighted a set of potent and selective CDK2 inhibitors designed by
Based on this work and further optimization,
BLU-852: MAP4K1 inhibitor
MAP4K1 is a well-characterized immunokinase target involved in the regulation of immune cells; however, prior drug discovery efforts have been hindered by challenges in achieving selectivity over other MAP4K family members associated with toxicity. In
Data presented at AACR highlighted a set of potent and highly selective MAP4K1 inhibitors designed by
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