The Investigational New Drug application for small molecule dual antagonist TPST-1495 was cleared by the FDA to begin a clinical investigation into the treatment of prostaglandin-driven tumors, according to a press release from Tempest Therapeutics.
The Investigational New Drug (IND) application for small molecule dual antagonist TPST-1495 was cleared by the FDA to begin a clinical investigation into the treatment of prostaglandin-driven tumors, according to a press release from Tempest Therapeutics.1
A phase Ia/Ib trial will be initiated to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TPST-149 alone and in combination with a checkpoint inhibitor in patients with advanced solid tumors. The study will include a dose-escalation phase to determine the maximum tolerated dose of TPST-149 and then a dose-expansion phase.
“Prostaglandins drive the development of diverse human cancers by signaling through four homologous receptors, EP1-EP4. TPST-1495 is a first-in-class orally available dual antagonist that selectively blocks EP2 and EP4, two receptors, which are highly expressed in multiple advanced cancers. EP2 and EP4 receptor signaling promote tumor proliferation, spread, and evasion of immune recognition. In contrast, EP1 and EP3 signaling are critical for generating an anti-tumor response. Indeed, both EP2 and EP4 are highly over-expressed in multiple solid tumor malignancies such as microsatellite stable colorectal cancer (MSS CRC). Pre-clinical data show that TPST-1495 is significantly more potent than a single EP4 antagonist, Tom Dubensky, PhD, chief executive officer of Tempest told Targeted Oncology.”
The preclinical data on TPST-1495 were presented at the 2019 Society of Immunotherapy of Cancer (SITC) Annual Meeting. The study assessed TPST-1495 alone or in combination with anti-PD1 agents in syngeneic mouse colon models. PGE2 immune suppression was reversed following in vitro and in vivo treatment with TPST-1495 compared with antagonism of EP4 alone or all 4 EP receptors. The anti-tumor immune responses and tumor regression brought on by TPST-1495 were potent and significant in two different murine tumor treatment models of colon cancer. Additionally, TPST-1495 monotherapy led to an increase in infiltrating effector T cells, and the TPST-1495 combination led to synergistic inhibition of CT26 tumor progression.2
From the preclinical study, the investigators concluded that the drug overcomes prostaglandin-mediated immune suppression and promotes anti-tumor efficacy.
Although the phase Ia/Ib trial will be open to all solid tumors, Dubensky stated, "the company intends to focus the dose-escalation clinical trial in patients with MSS CRC, both as monotherapy and in combination with pembrolizumab.