On May 25, 2023 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-classi therapeutics that combine both targeted and immune-mediated mechanisms, reported that Phase 1 clinical trial data for TPST-1495, the company’s novel dual receptor inhibitor of prostaglandin (PGE2) signaling, will be presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held in Chicago from June 2-6, 2023 (Press release, Tempest Therapeutics, MAY 25, 2023, View Source [SID1234632079]).

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The first-in-human Phase 1a/1b, multicenter, open-label, dose-escalation trial included patients with metastatic or unresectable solid tumors and treatment-refractory disease with no remaining standard therapy to confer clinical benefit.

The data showed that in a diverse and treatment-refractory patient population, treatment with TPST-1495 as a monotherapy and in combination with pembrolizumab resulted in tumor shrinkage and prolonged stable disease in certain patients, as well as a durable confirmed partial response (PR) in a combination therapy patient with microsatellite stable colorectal cancer (MSS CRC), an indication not normally responsive to immunotherapy.

The safety profile for TPST-1495 monotherapy on the recommended once-daily schedule was tolerable, with predominantly Grade 1-2 treatment related adverse events (TRAEs), including abdominal pain (17.9% All Grade and 0% Grade 3+), nausea (20.5% All Grade and 0% Grade 3+), and diarrhea (15.4% All Grade and 2.6% Grade 3+). For the combination with pembrolizumab, the most common TRAEs were nausea (29.2% All Grade and 0% Grade 3+), fatigue (20.8% All Grade and 4.2% Grade 3+) and diarrhea (20.8% All Grade, 0% Grade 3+). No TRAEs of Grade ≥4 were reported.

On the recommended once-daily schedule, the disease control rate (DCR) by RECIST v1.1 was 44% for patients on monotherapy TPST-1495 and 40.9% for patients on TPST-1495 with pembrolizumab (including a confirmed PR in a patient with MSS CRC and a stable disease rate of 36.4%).

TPST-1495 also demonstrated near-linear relationship of exposure-to-dose that was unaffected by combination therapy, and pharmacodynamic activity was observed in assays of both immune activation and PGE2 modulation.

"These results from our first-in-human clinical trial in patients with late-line refractory disease are encouraging and support a tolerable safety profile and clinical activity of TPST-1495 as a novel agent targeting the prostaglandin pathway," said Sam Whiting, M.D., Ph.D., chief medical officer of Tempest. "Based on the well-understood biology of PGE2 signaling, we are enrolling patients in a combination therapy cohort focused on endometrial cancer, and we are exploring TPST-1495 monotherapy to treat the high unmet-need inherited cancer syndrome known as familial adenomatous polyposis, or FAP."

About TPST-1495

TPST-1495 is an orally-available and potent small molecule designed to block the receptors EP2 and EP4 in the prostaglandin pathway, which promote both tumor growth and the proliferation of suppressive immune cell populations. Several malignancies are thought to be prostaglandin driven through expression of high levels of COX-2, the cellular enzyme that produces PGE2, including endometrial, bladder, breast, colorectal, and cervical cancers. PGE2 promotes tumor cell growth through EP2 and EP4 signaling and is strongly immune suppressive. Tempest has conducted multiple IND-enabling studies with peripheral blood mononuclear cells (PBMCs) from healthy adult donors and in several mouse tumor models that demonstrate a significant increase in immune activation and anti-tumor potency by inhibiting both EP2 and EP4, when compared to EP4-only targeted molecules and non-steroidal anti-inflammatory drugs (NSAIDS) such as celecoxib.