GENFLEET-B (02595) announced that the first patient has been enrolled in the Phase I/II clinical trial of GFH276 for treating RAS-mutant advanced solid tumors. The National Medical Products Administration approved GFH276's clinical trial application in early September for an open-label, multi-center study. This product is a proprietary molecular glue Pan RAS(ON) inhibitor developed by GENFLEET with global rights.
According to Frost & Sullivan data, global cancer incidence is projected to reach nearly 22 million cases in 2025, with approximately 30% (over 6.5 million) of cancer patients having different subtypes of RAS gene mutations (KRAS, NRAS, HRAS) in their tumor cells. Currently, no pan-RAS targeted therapy has been approved globally, and GFH276's development progress ranks among the top three in the global Pan RAS(ON) inhibitor pipeline.
GFH276 represents the third RAS-targeted therapy in GENFLEET's pipeline to enter clinical research. The KRAS G12C inhibitor GFH925 has already been successfully launched, while GFH375 is positioned in the first tier of oral KRAS G12D inhibitor development.
The Phase Ia clinical trial of GFH276 will be conducted at approximately 10 research centers, including Sun Yat-sen University Cancer Center and Fudan University Shanghai Cancer Center. The primary objectives of the overall Phase I trial include evaluating the safety and tolerability of GFH276 in patients, determining the Phase II recommended dose, and assessing the pharmacokinetic characteristics and preliminary efficacy of GFH276.
GFH276 can target and inhibit most activated wild-type and mutant RAS proteins. According to poster data from the 2025 AACR Annual Meeting, GFH276 demonstrated lower effective doses and superior pharmacokinetic characteristics compared to similar overseas products across multiple RAS-mutant tumor models. The drug also showed favorable safety and target specificity in kinase selectivity and safety-related target testing. Additionally, GFH276 maintained potent activity across multiple mechanistically-induced KRAS inhibitor-resistant cell lines, demonstrating multi-resistance potential.
Dr. Wang Yu, Chief Medical Officer of GENFLEET, commented: "Through the successful development of GFH925 and GFH375, we have accumulated extensive experience in RAS-targeted therapy development. GFH276 is the first molecular glue product in GENFLEET's pipeline to enter clinical research, and our proprietary EGFR-Pan RAS ADC has also entered the clinical application stage. The multi-target, diversified molecular modalities of innovative products demonstrate the depth of our RAS therapy matrix. We also look forward to GFH276 demonstrating favorable efficacy in clinical research to benefit patients globally."
RAS proteins function as binary molecular switches, alternating between an inactive state bound to GDP (guanosine diphosphate) and an active state bound to GTP (guanosine triphosphate), thereby regulating pathways such as RAF-MEK-ERK and PI3K-AKT mTOR. Oncogenic RAS mutations impair GTPase activity, causing RAS proteins to predominantly exist in the activated GTP-bound form, leading to malignant cell proliferation and behavioral changes.
The RAS protein family primarily consists of three categories: KRAS, HRAS, and NRAS, with KRAS mutations being among the most common genetic mutations in tumors. GFH276 is a mechanistically unique oral molecular glue Pan RAS(ON) inhibitor that employs a ternary complex mechanism (CypA-GFH276-RAS) to more efficiently inhibit most activated wild-type and mutant RAS protein subtypes, including common KRAS mutant proteins (G12C, G12D, G12V, etc.).
Preclinical studies show that GFH276 exhibits dose-dependent anti-tumor activity and promotes tumor regression in multiple KRAS-mutant tumor models. Compared to first-generation SIIP (switch II pocket) binding KRAS inhibitors, GFH276 is expected to overcome the adaptive and acquired resistance limitations of existing drugs.