Targeting glioblastoma with CM93, a novel EGFR inhibitor with exceptional brain penetration

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PROJECT SUMMARY The epidermal growth factor receptor (EGFR) gene is mutated and/or amplified in majority of primary glioblastoma (GBM). While EGFR-mutant GBM cancer cells are dependent on EGFR signaling for survival, numerous small molecule EGFR tyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease. There are two main reasons for these failures: i) Many of these EGFR-TKIs fail to cross the blood-brain barrier (BBB); ii) These EGFR-TKIs were developed to specifically target mutant EGFRs with mutations in the kinase domain found in non-small cell lung cancer (NSCLC), but they have poor activity (low binding affinity) against GBM EGFR variants with a wild-type tyrosine kinase domain. CM93 has been developed at Crimson Biopharm as a novel therapeutic agent to specifically tackle these challenges in treating GBM. CM93 has distinct features that set it apart from all other EGFR-TKIs, including osimertinib. CM93 is highly enriched in the brain, with an exceedingly low blood concentration (>2,000% brain penetration). This extraordinary property of CM93, in conjunction with its high potency against EGFR with wild-type tyrosine kinase domain, offers a powerful and unique opportunity for CM93 to effectively inhibit GBM with EGFR variants without significant systemic toxicity. Notably, CM93 has received IND approval for the first-in-human phase 1 clinical trial in GBM patients and is currently part of NIH/NCI’s “Glioblastoma Therapeutics Network (GTN)” to conduct phase 1 and surgical window studies led by Dr. Patrick Wen, Director of Neuro-Oncology at Dana-Farber Cancer Institute (DFCI). The overall objective of this STTR application is to evaluate the combination of CM93 with abemaciclib (an approved CDK4/6 inhibitor with notable CNS activity as proposed in Aim1 and biomarker analyses in Aim 2 in patient-derived GBM models to provide important pre-clinical proof of concept to better support CM93’s first-in-human phase 1 and window-of-opportunity surgical studies.