Potent single-molecule inhibition of all major classes of EGFR activating and resistance mutations, including C797X and T790M, with a high degree of kinome and wild-type EGFR selectivity
Deep and durable tumor regressions in models of osimertinib-resistant EGFR-mutant NSCLC; substantial CNS activity and extended survival in intracranial mouse models
IND submission to US FDA anticipated in H2 2023
CAMBRIDGE, Mass., Oct. 26, 2022 /PRNewswire/ -- 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, today announced preclinical data characterizing its fourth-generation epidermal growth factor receptor (EGFR) inhibitor, THE-349, will be detailed in a live poster presentation at the 34th EORTC-NCI-AACR Symposium on molecular targets and cancer therapeutics (ENA), taking place in Barcelona, Spain on October 26 – 28, 2022. THE-349 is currently in preclinical development as a single-molecule inhibitor of all major classes of EGFR activating and resistance mutations consisting of single-, double- and triple-mutant EGFR variants, including T790M and C797X, for treatment of EGFR-mutant non-small cell lung cancer (NSCLC).
"We are pleased to share preclinical data characterizing THE-349, our newly nominated fourth-generation EGFR inhibitor," said William Shakespeare, Ph.D., President of Research and Development at Theseus. "NSCLC is the most common form of lung cancer, and, depending on geographical region, between 10-50% of patients with NSCLC have tumors driven by mutations in EGFR, the vast majority of which are found in exons 19 and 21, and for which osimertinib, a third-generation inhibitor, is now considered standard of care treatment. However, patients will inevitably progress on osimertinib, with on-target, C797X-mediated resistance observed in approximately 10% of patients receiving first-line osimertinib and 20% of patients receiving osimertinib after prior treatment with an earlier-generation EGFR inhibitor. No targeted therapy effectively inhibits C797X, and since EGFR mutational heterogeneity increases during sequential treatment with EGFR inhibitors, we believe a potent and selective single molecule capable of targeting all combinations of major EGFR activating and resistance mutations is the optimal way to address this urgent medical need. We look forward to progressing THE-349 and plan to file an IND in the second half of 2023 to evaluate THE-349 in patients with EGFR-mutant NSCLC."
These preclinical data demonstrate that THE-349, as a single agent, exhibits highly potent inhibition of all major EGFR mutant variants with a high degree of kinome and wild-type EGFR selectivity. Coupled with excellent oral bioavailability, this drives deep in vivo tumor regressions in osimertinib-resistant models of EGFR-mutant NSCLC, as well as substantial CNS activity in intracranial mouse models. The activity profile achieved by THE-349 positions the asset for development as a single agent and potentially in combination with other, non-EGFR inhibitor modalities.
Key preclinical data highlights include:
- THE-349 potently inhibits both major classes of EGFR activating mutations – exon 19 deletions (D) and L858R (L) – alone, or in combination with one or both major resistance mutations – T790M (T) and C797X; including C797S (C) and two other variants that drive resistance to osimertinib.
- THE-349 exhibits a high degree of kinome and wild-type selectivity.
- At least 10-fold greater potency against all major EGFR variants than wild-type EGFR (range: 10-56X).
- THE-349 induces robust anti-tumor activity, with deep and sustained tumor regressions observed at well-tolerated doses, in mouse models expressing single-, double- and triple-mutant EGFR.
- Strong regressions (>80% tumor regressions) against osimertinib-resistant C797S double (LC) and triple mutants (LTC and DTC), directly addressing EGFR-mediated resistance after first-line and second-line osimertinib, respectively.
- Deep and/or complete tumor regression in an osimertinib-resistant, patient-derived (PDX) NSCLC model harboring heterogeneous EGFR mutant variants (D and DTC).
- Pharmacokinetic (PK) and pharmacodynamic (PD) analysis establish a wide selectivity window following a single dose of THE-349 at active levels while sparing wild-type.
- THE-349 demonstrates brain-penetrability and exhibits substantial CNS activity, which is necessary to address the relatively common recurrence of NSCLC in the brain.
Title: Preclinical characterization of CNS-active, mutant-selective fourth-generation EGFR inhibitors with potent activity against single, double, and triple mutant EGFR variants including T790M and C797S
Poster Number: 236
Session Date and Time: Thursday, October 27, 2022: 10 a.m. – 5 p.m. (CEST)
Presenter: Sen Zhang, Ph.D. (Theseus Pharmaceuticals, Cambridge, MA, United States)
About EGFR-mutant NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million cases of lung cancer diagnosed globally in 2020. Activating mutations in EGFR occur in 10-15% of Caucasian and up to 50% of Asian NSCLC patients, with up to 90% of those mutations found in exons 19 and 21. In response to treatment with approved EGFR TKI, patients' tumors can develop one or more additional EGFR mutations, causing resistance and rendering current therapies ineffective.
About Theseus Pharmaceuticals, Inc.
Theseus is a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies. Theseus is working to outsmart cancer resistance by developing pan-variant tyrosine kinase inhibitors (TKIs) to target all known classes of cancer-causing and resistance mutations that lead to variants in a particular protein in a given type of cancer. Theseus' lead product candidate, THE-630, is a pan-variant KIT inhibitor for the treatment of patients with advanced gastrointestinal stromal tumors (GIST), whose cancer has developed resistance to earlier lines of kinase inhibitor therapy. Theseus is also developing THE-349, a fourth-generation, selective epidermal growth factor receptor (EGFR) inhibitor for C797X-mediated resistance to first- or later-line osimertinib treatment in patients with non-small cell lung cancer (NSCLC). For more information, visit www.theseusrx.com.
Cautionary Statement Regarding Forward Looking Statements
Certain statements included in this press release are not historical facts but are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements generally are accompanied by words such as "believe," "may," "will," "estimate," "expect," "plan," "potential," "outlook," and similar expressions that predict or indicate future events or trends or that are not statements of historical matters, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements include, but are not limited to, statements regarding: Theseus' strategy, future operations, prospects and plans; the structure and timing of its preclinical studies and clinical trials, expected milestones, market opportunity and sizing and objectives of management; the significance of results of preclinical studies of THE-349, including the ability of the development candidate to potentially inhibit EGFR variants and the outlook of the EGFR inhibitor program; and expectations regarding the submission of an IND for THE-349.
Actual results may differ materially from those indicated by such forward-looking statements as a result of various important risks, uncertainties and other factors, including, but not limited to: uncertainties inherent in preclinical studies; risks and uncertainties regarding whether results from preclinical studies will be predictive of the results of future trials; risks related to the expected timing of submissions to regulatory authorities; risks and uncertainties related to the approval of any potential IND application for THE-349; and other risks, uncertainties and other factors such as those described from time to time in the reports Theseus files with the Securities and Exchange Commission (SEC), including Theseus' Form 10-K for the year ended December 31, 2021, and Quarterly Reports on Form 10-Q for the quarters ended March 31, 2022 and June 30, 2022, which are on file with the SEC and available on the SEC's website at https://www.sec.gov/. However, new risk factors and uncertainties may emerge from time to time which may cause actual results to differ materially from those anticipated or implied by the forward looking statements in this press release, and it is not possible to predict all risk factors and uncertainties. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Any forward-looking statements contained in this press release are based on the current expectations of Theseus' management team and speak only as of the date hereof, and Theseus specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.
Amy Jobe, Ph.D.
Stern Investor Relations
SOURCE Theseus Pharmaceuticals