On January 5, 2023 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 key anticipated milestones for 2023 and introduced its third development program, a pan-variant tyrosine kinase inhibitor (TKI) targeting BCR-ABL for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (Press release, Theseus Pharmaceuticals, JAN 5, 2023, View Source [SID1234625875]).

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"Theseus is gaining momentum in our quest to outsmart cancer resistance as we focus on execution and expansion of our pipeline in 2023, with preliminary dose-escalation data from our ongoing Phase 1/2 trial of THE-630 in patients with previously treated GIST expected in the second and fourth quarters of 2023," said Tim Clackson, Ph.D., President and Chief Executive Officer of Theseus. "We plan to file an IND for THE-349, our fourth-generation EGFR inhibitor, in the fourth quarter of 2023, and are delighted to introduce our third development program targeting BCR-ABL, an area in which our approach could meaningfully improve patient outcomes. With the continued productivity of our drug discovery platform, we are excited by the opportunity to deliver new standards of care to underserved populations plagued by resistance to available cancer treatments."

Pipeline update:

THE-630 is a pan-variant inhibitor of the receptor tyrosine kinase KIT, designed for patients with gastrointestinal stromal tumors (GIST) which have developed resistance to earlier lines of therapy.

● Enrollment is ongoing for the Phase 1 portion of the Phase 1/2 dose-escalation and expansion clinical trial evaluating THE-630 in patients with advanced GIST, with all seven U.S. sites open and accruing. Theseus is treating patients in cohort 5 of dose escalation as of the end of 2022.
● Theseus plans to present preliminary safety, pharmacokinetic, and initial clinical activity data, as well as an analysis of circulating tumor DNA (ctDNA), at a scientific conference in the second quarter of 2023, with follow-up data on additional cohorts expected in the fourth quarter of 2023.
o Patients enrolled in the trial have had a median of four prior therapies.
o ctDNA samples are being collected before, during, and after treatment and are being analyzed by next-generation sequencing (NGS) to characterize mutational heterogeneity and the effects of THE-630 on mutant allele fraction over time.
● Theseus aims to develop THE-630 as a best-in-class molecule for patients with KIT-driven GIST. Preclinical data demonstrate the potential of THE-630 as a pan-variant inhibitor of all major classes
of activating and resistance mutations in KIT, which could overcome a critical limitation of approved therapies.
● Based on clinical data from the ongoing Phase 1/2 study, Theseus plans to pursue parallel registration trials in second- and fifth-line patients with advanced GIST.

THE-349 is a fourth-generation (4G) epidermal growth factor receptor (EGFR) TKI candidate with activity against single-, double-, and triple-mutant EGFR variants, including T790M and C797X, found in the tumors of patients with EGFR-mutant non-small cell lung cancer (NSCLC) who have developed resistance to first- or later-line osimertinib.

● Preclinical data demonstrate THE-349 can potently inhibit all major classes of EGFR activating and resistance mutations observed in a post-first- or later-line osimertinib setting, with kinome and wild-type selectivity, and central nervous system (CNS) activity.
● Theseus expects to submit an investigational new drug (IND) application for THE-349 to the U.S. Food and Drug Administration in the fourth quarter of 2023 and to initiate the Phase 1/2 trial as soon as possible thereafter.
● Theseus plans to pursue an initial registration as monotherapy in patients with on-target resistance, as well as rapidly expand into evaluation of combination treatment with other relevant modalities and, if clinical data support, target a broader second line patient population.

BCR-ABL Program: Theseus is aiming to develop a potent, selective, pan-variant, next-generation BCR-ABL TKI candidate that optimally balances safety and efficacy, for patients with relapsed/refractory CML and patients with newly diagnosed Ph+ ALL.

● CML is a disease which remains BCR-ABL driven through multiple lines of therapy, and patients commonly will relapse with a BCR-ABL resistance mutation.
o Multiple therapies for CML have been approved; however, approximately 30-40% of patients started on any TKI will switch to an alternative TKI due to side effects or inadequate response.
o For patients refractory to first-generation (1G) and second-generation (2G) TKIs, the treatment options include ponatinib or asciminib, but neither has an optimal balance of safety and efficacy.
● Newly diagnosed Ph+ ALL adults have historically received chemotherapy followed by allogenic hematopoietic stem-cell transplant (HSCT), and more recently the addition of BCR-ABL TKIs have improved outcomes in 1L treatment, despite their lack of FDA approval (five are NCCN recommended).
o However, in newly diagnosed patients treated in combination therapy with 1G or 2G TKIs, relapse is associated with BCR-ABL resistance mutations in up to 75% of patients, with the T315I mutation observed most frequently.
o Ponatinib, a pan-variant inhibitor, has been shown to improve clinical outcomes compared to 1G and 2G TKIs; however, toxicity limits optimal dosing.
● Preclinically, Theseus lead molecules have shown a high degree of potency against BCR-ABL and clinically relevant resistance mutations, and significant kinome selectivity, including against key off-target kinases.
● Theseus expects to nominate a development candidate for this program by early 2024, with the goal of pursuing clinical development in patients with CML who have been previously treated with a 2G TKI or have the T315I mutation, and in combination therapy treatment for newly diagnosed patients with Ph+ ALL.

"Today, we are happy to introduce BCR-ABL as the target for our next development program," said Bill Shakespeare, Ph.D., Co-Founder and President of R&D at Theseus. "BCR-ABL is one of targeted oncology’s greatest success stories, yet there still remains a significant unmet medical need for patients with CML and Ph+ ALL and a pan-variant TKI that combines potency, selectivity, and efficacy."