We are currently investigating the use of our pan-variant tyrosine kinase inhibitors to help people with lung cancer.
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.
The most common EGFR resistance mutations that NSCLC tumors develop in response to treatment with osimertinib, the current standard of care and a third-generation inhibitor, are T790M and C797X.
To address this problem of treatment resistance, Theseus is developing THE-349: 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 NSCLC.
Theseus has demonstrated preclinically that inhibition of all major single-, double-, and triple-mutant EGFR variants, including those with the T790M and C797X mutations, with kinome and wild-type selectivity and CNS activity, can be achieved with a single molecule. In vitro, 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.
In vivo, 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, and deep and/or complete tumor regression in an osimertinib-resistant, patient-derived (PDX) NSCLC model harboring heterogeneous EGFR mutant variants (D and DTC) were observed. 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.
We expect to submit an IND application for this program to the US FDA in the fourth quarter of 2023.
We are developing a pipeline of TKIs designed to inhibit all major cancer-causing and drug resistance mutations in tyrosine kinase targets.
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