TPST-1495

P2, N=10, Recruiting, University of Oklahoma | Trial primary completion date: Sep 2025 --> Dec 2025

P1, N=89, Completed, Tempest Therapeutics | Active, not recruiting --> Completed | N=175 --> 89

P2, N=10, Recruiting, University of Oklahoma | Trial completion date: Apr 2026 --> Sep 2026 | Trial primary completion date: Apr 2025 --> Sep 2025

Here, we assessed PGE2 signaling in PTEN-deficient HNSCC and evaluated the effect of aspirin or TPST-1495, a dual EP2/EP4 antagonist, on the growth of PTEN knockout (KO) and PIK3CA-altered HNSCC tumors in immunocompetent mice. To date, there are no FDA-approved therapies for PI3K pathway-altered HNSCC. Our findings suggest that NSAIDs demonstrate anti-tumor activity in PTEN-deficient or PI3K-altered tumors whereas EP2/EP4 targeting may augment FDA-approved anti-PD1 therapy in HNSCC.

P1, N=175, Active, not recruiting, Tempest Therapeutics | Recruiting --> Active, not recruiting | Phase classification: P1a/1b --> P1 | Trial primary completion date: Apr 2024 --> Sep 2024

P2, N=10, Recruiting, University of Oklahoma | Not yet recruiting --> Recruiting

P2, N=10, Not yet recruiting, University of Oklahoma

Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC) spontaneous colorectal tumor model, compared with celecoxib...Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist. Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.

In preclinical models, dual EP2/EP4 inhibition with TPST-1495 increased anti-tumor efficacy, reduced immune suppression, and activated immune effector response significantly better than single EP2 or EP4 antagonists and the COX-2 inhibitor celecoxib. PGE2 is an important target for cancer and immunotherapy but remains ineffectively drugged. TPST-1495 is a novel oral therapy that inhibits signaling only at the tumor promoting EP2/EP4 receptors. In patients with heavily treated solid tumors, primarily MSS CRC, TPST-1495 had pharmacodynamic activity, a manageable safety profile, and a potential signal of activity consistent with the preclinical data and IO combination mechanism.

Indication-specific Expansion Stage cohorts will evaluate TPST-1495 at the selected RP2D and schedule for both monotherapy and combination in endometrial cancer, squamous cell carcinoma of the head and neck, and microsatellite stable colorectal cancer (combination only), as well as in a biomarker-specific cohort enrolling patients with pathogenic tumor PIK3CA gene mutation. Dose and Schedule Optimization enrollment (monotherapy and combination) is ongoing at abstract submission while Expansion Stages are planned after identification of the RP2Ds.

P1a/1b, N=175, Recruiting, Tempest Therapeutics | N=117 --> 175 | Trial completion date: Jul 2022 --> Oct 2024 | Trial primary completion date: Aug 2021 --> Apr 2024

TPST-1495 monotherapy demonstrated a decrease of both the intestinal tumor size and number in Adenomatous Polyposis (APCmin/+) mice, as compared to a single EP4 antagonist. Conclusions TPST-1495 is a potent inhibitor of PGE2 mediated immune suppression and is currently being evaluated in an ongoing Phase 1 first-in-human study (NCT04344795) to characterize PK, PD, safety, and to identify a recommended phase 2 dose for expansion cohorts in key indications and biomarker selected patients.