FoRx Therapeutics has initiated a first-in-human clinical trial of FORX-428, a novel PARG inhibitor designed to target the DNA damage response (DDR) pathway in patients with advanced solid tumors.

The open-label Phase 1 study is underway in the United States following Investigational New Drug (IND) clearance from the FDA in June 2025. Initial data from the trial are expected by mid-2026.

The DDR pathway has been a key focus in cancer therapy since the approval of PARP inhibitors over a decade ago. FoRx is advancing this strategy by targeting PARG, a DNA repair enzyme essential for survival in specific genetically defined cancers exhibiting DNA damage repair deficiencies or high replication stress. FORX-428 aims to address cancers that are resistant or non-responsive to current PARP inhibitors.

Tarig Bashir, CEO of FoRx Therapeutics, said: “FoRx is built on the disruptive potential of PARG inhibition as a therapeutic strategy. FORX-428 has demonstrated exquisite anti-tumor efficacy in multiple preclinical in vivo tumor models, suggesting best-in-class potential. The entry of FORX-428 into clinical development is a major milestone in our mission to redefine cancer therapy by offering better treatment options for patients.”

The trial, led by Manish Sharma, co-director of clinical research at START Midwest and Principal Investigator, is evaluating safety, tolerability, pharmacokinetics, and preliminary efficacy in patients who have exhausted standard-of-care therapies.

Sharma said: “There is an unmet need to develop new therapies for advanced cancer patients with distinct DNA damage repair deficiencies or high replication stress. The PARG inhibitor, FORX-428, has a novel mechanism of action, and preclinical studies have shown it had impressive activity in cancers resistant to chemotherapy and PARP inhibitors.”

Jens Wuerthner, Chief Medical Officer at FoRx, praised the rapid progress from IND clearance to patient dosing, attributing it to effective collaboration among clinical, regulatory, and operational teams.

He said: “The efficient pace from IND clearance to dosing the first patient is a testament to the dedication and coordination of our clinical, regulatory, operational, and research teams, including the team at START Midwest. We are thrilled to have begun investigating FORX-428 in patients with advanced cancer and believe this compound could be a significant advancement in solid tumor therapy.”

FORX-428 is an orally administered small molecule that inhibits poly (ADP-ribose) glycohydrolase, disrupting DNA repair processes vital to tumor cell survival. Preclinical studies have shown robust anti-tumor activity across multiple tumor types, with a favorable safety and pharmacology profile supporting its further clinical investigation.