GenFleet Therapeutics (2595.HK), a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced the first patient has been dosed in a phase I/II trial of GFH276 treating advanced solid tumors with RAS mutations. China’s National Medical Products Administration (NMPA) approved the clinical trial application for GFH276, a molecular glue Pan RAS (ON) inhibitor developed by GenFleet with global rights, in an open-label and multi-center phase I/II study in early September.
According to Frost & Sullivan's 2025 projection, annual global cancer incidence is expected to reach nearly 22 million cases, with RAS mutations (KRAS, NRAS, HRAS) occurring in the tumor cells of approximately 30% of cancer patients (over 6.5 million) worldwide. Currently no Pan RAS inhibitors have been approved worldwide, and GFH276 has emerged as one of the top three clinical-stage molecules driving innovation in the global Pan-RAS (ON) landscape. GFH276 is the third candidate in GenFleet’s RAS-targeted matrix to enter clinical research, following successful development of a marketed KRAS G12C inhibitor (fulzerasib) and a phase-II KRAS G12D inhibitor (GFH375).
The phase Ia trial of GFH276 will be conducted at approximately 10 investigational sites including the Sun Yat-sen University Cancer Center in southeastern China and Fudan University Shanghai Cancer Center. The primary objectives of the overall phase I study are to evaluate the safety/tolerability of GFH276 among patients, and to determine the recommended phase II dose (RP2D). Additionally, the study will assess its pharmacokinetic profile and its preliminary efficacy.
GFH276 is designed to target and inhibit most wild-type and mutant RAS proteins in their activated states. According to the poster presentation at 2025 AACR annual meeting: GFH276 displayed superior pharmacokinetic properties across multiple RAS-mutant tumor models and achieved equivalent or enhanced tumor regression at substantially lower effective dosages compared to overseas RAS-inhibiting therapies. Notably, GFH276 exhibited high selectivity with no off-target activity observed in kinase selectivity or safety evaluation, and cellular assays further suggested its potential to overcome multiple drug resistances induced by diverse mechanisms.
“Through the development of fulzerasib and GFH375, we have gained extensive experience in early discovery and clinical research of RAS-targeted therapies. GFH276 is the first molecular glue candidate in our pipeline to advance into clinical development, and an EGFR-Pan RAS ADC has also reached the IND-enabling stage. The diversity of targets and molecular modalities within our RAS-focused pipeline highlights its depth and innovation. We hope that GFH276 will demonstrate promising efficacy in the study and ultimately benefit global patients.” stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.
About RAS and GFH276
RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAF-MEK-ERK and PI3K-AKT-mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.
GFH276 is an oral novel small-molecule Pan RAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH276 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH276 also holds the potential to outperform the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance.
About GenFleet Therapeutics
With a focus on cutting-edge therapies, GenFleet Therapeutics is dedicated to serving significant unmet medical needs globally in oncology and immunology. Leveraging its deep understanding of disease biology and translational medicine, GenFleet has established a proprietary and fully integrated R&D system that yields a robust pipeline of multiple cutting-edge products with novel mechanisms and global IP.
Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates spanning small molecules and biologics. Its pipeline comprises numerous programs that have advanced to later-stage or pivotal clinical trials across China, the United States and Europe.
The company has has set up a highly differentiated RAS-targeted matrix including selective and pan-RAS inhibitors of diverse molecular types, with most assets leading their categories in clinical progress in China or globally. In addition, the company has pioneered a series of first-in-class combination therapies based on dual-target synergistic mechanisms. By integrating clinical needs and insights, GenFleet is dedicated to expanding its portfolio into major therapeutic areas including pancreatic cancer, NSCLC, and cachexia. Furthermore, it's strengthening its commercial collaborative network through strategic out-licensing agreements or clinical cooperations with prestigious listed companies across the world.
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