On April 8, 2022 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies, reported preclinical data characterizing next-generation pan-variant EGFR inhibitors that will be detailed in a live poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting, being held April 8-13, 2022 in New Orleans, Louisiana (Press release, Theseus Pharmaceuticals, APR 8, 2022, View Source [SID1234611790]). The poster highlights advanced lead compounds for use in non-small cell lung cancer (NSCLC) that have been observed to potently inhibit the kinase activity, both in vitro and in vivo, of all major single-, double-, and triple-mutant EGFR variants, including T790M and C797S, with selectivity over wild-type EGFR and the ability to penetrate the central nervous system (CNS).

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"Up to half of all non-small cell lung cancer tumors are driven by activating mutations (single-mutants) in EGFR and up to 90 percent of those mutations are found in exons 19 and 21. Furthermore, as patients progress through lines of treatment, a substantial percentage of patients’ tumors may develop one or more additional EGFR mutations (double- and triple-mutants) that cause resistance to treatment," said William Shakespeare, Ph.D., President of Research and Development at Theseus. "At Theseus, we have developed a series of potent and selective, single molecule, fourth-generation EGFR inhibitors that are designed to inhibit all major classes of EGFR activating and resistance mutations that contribute to later-line clonal heterogeneity in patients who have been failed by current approved therapies. We are finalizing preclinical studies to characterize our lead compounds and look forward to designating a development candidate in the third quarter of this year."

The preclinical data presented at AACR (Free AACR Whitepaper) demonstrates that pan-variant EGFR inhibition of all major single-, double-, and triple-mutants, including T790M and C797S, with selectivity over wild-type, is achievable with a single molecule. Detailed findings show that:

Theseus’ lead compounds potently inhibited all major single-, double-, and triple-mutant EGFR variants in vitro, demonstrating cellular IC50 values between 2-12 nM.
Lead compounds displayed favorable selectivity over wild-type EGFR, with ratios between 11- to 88-fold.
An advanced lead compound demonstrated tumor regressions in mice against variants associated with both 1st and 2nd line osimertinib clinical failure – i.e., C797S double- and triple-mutants – at well-tolerated doses.
This lead compound also demonstrated a brain:plasma ratio consistent with predicted activity against CNS metastatic disease.
Studies to further characterize lead compounds are under way, with additional data expected to be presented at a scientific conference in the second half of 2022.

Presentation details:

Poster Title: Discovery of potent and selective next-generation EGFR inhibitors with activity against single, double, and triple mutant EGFR variants including T790M and C797S

Poster Number: 3342

Presenter: Wei-Sheng Huang, Ph.D., Vice President of Chemistry

Session Date and Time: Live presentation on Tuesday, April 12TH, 1:30pm – 5pm CT

About NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 2.2 million cases of lung cancer diagnosed in 2020. Up to half of NSCLC patients have tumors that are driven by activating mutations in the epidermal growth factor receptor (EGFR) and up to 90 percent of those mutations are found in exons 19 and 21. [Most] patients’ tumors, in response to treatment, develop one or more additional EGFR mutations, causing resistance and rendering current therapies ineffective.