FoRx Therapeutics has achieved a significant milestone in precision oncology by dosing the first patient with FORX-428, a novel PARG inhibitor designed to target DNA damage response pathways in advanced solid tumors. The Basel-based clinical-stage biotechnology company announced on August 11, 2025, that the first-in-human Phase 1 trial is now underway following FDA clearance.
Novel Mechanism Targets DNA Repair Deficiencies
FORX-428 represents a next-generation approach to DNA damage response (DDR) targeting by inhibiting poly (ADP-ribose) glycohydrolase (PARG), a key DNA repair enzyme necessary for the survival of certain genetically defined cancers. This strategy builds upon the transformative success of PARP inhibitors, which gained approval more than 10 years ago after researchers discovered that distinct genetic subsets of cancer are exceptionally vulnerable to drugs that interfere with DDR.
"PARG inhibition holds tremendous promise as a treatment option for patients whose cancers do not or no longer respond to PARP inhibitors," said Tarig Bashir, CEO of FoRx Therapeutics. "FORX-428 has demonstrated exquisite anti-tumor efficacy in multiple preclinical in vivo tumor models, suggesting best-in-class potential."
Preclinical Data Shows Promise Across Multiple Tumor Types
The proprietary, orally available small molecule demonstrated robust anti-tumor activity across multiple solid tumor types in preclinical studies, highlighting its potential in both monotherapy and combination settings. Importantly, FORX-428 was well tolerated in preclinical testing, demonstrating drug-like pharmacology and a favorable safety profile.
Dr. Manish R. Sharma, Co-Director of Clinical Research at START Midwest and Principal Investigator on the trial, emphasized the clinical need: "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."
Rapid Clinical Development Timeline
The trial progression demonstrates efficient clinical development execution. FORX-428 received Investigational New Drug (IND) clearance from the FDA on June 13, 2025, with the first patient visit occurring on July 22 and the first patient dosed on August 6.
"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," said Dr. Jens Wuerthner, Chief Medical Officer of FoRx Therapeutics.
Phase 1 Study Design and Timeline
The open-label study, initially taking place in the United States, is evaluating safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with advanced solid tumors who have exhausted standard-of-care options. An initial data readout from the trial is expected by mid-2026.
The study targets patients with cancers harboring specific DDR deficiencies or high replication stress, representing a precision medicine approach to cancer treatment. FORX-428's mechanism of action involves causing tumor cell death by inhibiting PARG, which is essential for the survival of certain genetically defined cancers.
FoRx Therapeutics is a privately held clinical-stage biotechnology company pioneering precision therapeutics targeting the DNA Damage Response in treatment-resistant cancers. The company's pipeline includes several small molecule programs addressing distinct DNA repair mechanisms, with FORX-428 serving as the lead product candidate in Phase 1 testing for advanced solid tumors.
