NMPA Approves GenFleet's GFH375 for Phase I/II Trial in KRAS G12D Solid Tumors

Shanghai, June 19, 2024 – GenFleet Therapeutics, a biotechnology firm specializing in oncology and immunology therapies, has received approval from China's National Medical Products Administration (NMPA) for a clinical trial application for GFH375 (VS-7375). This open-label, multi-center phase I/II study will focus on advanced solid tumor patients with the KRAS G12D mutation, the most common KRAS mutation in human cancers. Currently, there are no approved therapies targeting the G12D mutation.

GFH375 is a highly effective and selective inhibitor of the KRAS G12D mutation, targeting both the active (GTP-bound) and inactive (GDP-bound) states of the protein. Preclinical data presented at the 2024 AACR annual meeting showed that GFH375 has promising safety data, high oral bioavailability, and strong efficacy in preclinical models. Furthermore, GFH375 may treat G12D-mutant cancers with brain metastases.

In 2023, GenFleet partnered with Verastem Oncology to advance three oncology programs, with GFH375 being the flagship project. This collaboration marks a significant milestone for GenFleet as GFH375 is the company's first product to achieve overseas out-licensing at the preclinical stage and receive IND approval in China. This underscores GenFleet's expertise in developing RAS-targeted therapies.

The clinical study, designated GFH375X1101, will be conducted at approximately 40 hospitals, including Shanghai Chest Hospital. Phase I of the study will focus on evaluating the safety, tolerability, and initial efficacy of GFH375 in patients with advanced G12D-mutant solid tumors. This phase will also establish the recommended phase II dose (RP2D). In Phase II, the study will further assess GFH375's efficacy in treating advanced solid tumors, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – three cancers with the highest prevalence of the G12D mutation. The study will also explore the mechanisms behind patient responses and resistance to the treatment.

Dr. Shun Lu, a professor at Shanghai Chest Hospital, expressed enthusiasm about the trial's approval, noting the significant unmet medical needs for G12D-mutant cancer patients. He highlighted the importance of developing G12D-targeted therapies given the mutation's prevalence, and he hopes GFH375 will become a novel treatment option for these patients.

Yu Wang, Chief Medical Officer of GenFleet, echoed Dr. Lu's excitement, emphasizing GenFleet's expertise in developing RAS-targeted therapies. He cited the successful development of fulzerasib (GFH925), a KRAS G12C inhibitor, and its NDA acceptance in China as evidence of GenFleet's capabilities. Wang believes GFH375 will further solidify GenFleet's position in developing innovative RAS-inhibiting therapies.

RAS proteins, which exist in either an active GTP-bound form or an inactive GDP-bound form, play a crucial role in cellular signaling pathways. The KRAS gene is frequently mutated in human cancers, with the G12D mutation being particularly common in PDAC, CRC, and lung adenocarcinoma. Patients with the KRAS G12D mutation often do not have a smoking history and show poor responses to PD-1 inhibitors. Mutant-selective G12D inhibitors, like GFH375, offer hope for these patients, particularly in PDAC, where KRAS G12D mutations are prevalent.

Preclinical studies indicate that GFH375 effectively inhibits tumor growth, with enhanced results at higher doses and longer treatment durations. The drug also showed low off-target risks in selectivity and safety assays.

GenFleet's collaboration with Verastem Oncology aims to advance RAS pathway-driven cancer therapies. This partnership allows Verastem Oncology to license and commercialize up to three compounds outside of China, while GenFleet retains rights within China and nearby regions.

Founded in 2017, GenFleet Therapeutics is dedicated to addressing significant unmet medical needs in oncology and immunology through its cutting-edge R&D platform. The company has built a robust pipeline of over 10 programs, many of which are in multi-regional clinical trials. GenFleet aims to transition from a clinical-stage biotech company to a commercial-stage biopharmaceutical company in the next few years.