On November 18, 2021 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing potentially first-in-class therapeutics that combine both tumor-targeted and immune-mediated mechanisms, reported the first patient has been dosed with TPST-1495 in combination with pembrolizumab in the Phase 1a/1b open-label, dose and schedule optimization study of TPST-1495 in patients with solid tumors (Press release, Tempest Therapeutics, NOV 18, 2021, View Source [SID1234595775]).
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"We’re very pleased to announce the start of patient dosing with TPST-1495 in combination with pembrolizumab," said Sam Whiting, MD, Ph.D., chief medical officer of Tempest. "TPST-1495 is designed to inhibit key components of the Prostaglandin E2, or PGE2, pathway, which is both a driver of tumor cell proliferation and an important suppressor of anti-tumor immune function. In addition, recent data show that PGE2 is involved in enabling tumors to escape from immune checkpoint inhibitors such as pembrolizumab, a process known as adaptive immune resistance. Based on this mechanistic rationale and our preclinical data, we are excited about the potential of this combination to be superior to either approach alone and bring benefit to patients."
The first-in-human Phase 1a/1b, multicenter, open-label, dose and schedule optimization study is being conducted at academic and Phase 1 sites in the U.S. and evaluates TPST-1495 as a single agent and in combination with pembrolizumab to determine its maximum tolerated dose and/or recommended Phase 2 dose, safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity in subjects with advanced solid tumors. The preliminary dose-finding stage of the study allows patients with any solid tumor histology, while the study expansion stages are designed both to focus upon patients with prostaglandin-driven cancers, including colorectal cancer, endometrial cancer, squamous cell carcinoma of the head and neck, as well as biomarker-selected patients with tumor-driver mutations in the PIK3CA gene, which are known to enhance the level of prostaglandin production in tumor cells.
About TPST-1495
TPST-1495 is an orally available small molecule designed to block the tumor-promoting EP2 and EP4 receptors in the prostaglandin (PGE2) pathway, while sparing the homologous but immune-supporting EP1 and EP3 receptors. PGE2 signaling through EP2 and EP4 has been observed both to enhance tumor progression and promote immune suppression. Tempest has conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP2 and EP4 and observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro, as well as significantly increased anti-tumor activity in mouse models of human colorectal cancer. Tempest is currently evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and possible anti-tumor activity of TPST-1495 as a single agent and in combination with pembrolizumab in a multicenter Phase 1a/1b dose and schedule optimization study in subjects with advanced solid tumors.