Pharma Focus Asia

GenFleet Receives IND Approval from China’s NMPA for GFH375, an Oral KRAS G12D (ON/OFF) Inhibitor, to Initiate Phase I/II Clinical Trials in Patients with Advanced Solid Tumors

Thursday, June 20, 2024

GenFleet Therapeutics, a biotech company in the clinical stage focusing on advanced therapies for cancer and immunological conditions, announced that the Chinese National Medical Products Administration (NMPA) has approved the clinical trial application for their drug candidate GFH375 (VS-7375). This open-label, multi-center phase I/II study will target advanced solid tumor patients with the KRAS G12D mutation, the most prevalent KRAS mutation found in human cancers, which currently lacks approved targeted therapies.

GFH375 is a potent and selective inhibitor of the KRAS G12D mutation, effective against both its active (GTP-bound) and inactive (GDP-bound) forms. Preclinical results presented at the 2024 AACR annual meeting showed that GFH375 has favorable safety data, good oral bioavailability, and strong efficacy in preclinical models. Additionally, GFH375 has shown potential for treating G12D-mutant cancers that have metastasized to the brain.

In 2023, GenFleet partnered with Verastem Oncology (Nasdaq: VSTM) to develop three oncology programs, with GFH375 being the first to move forward. This collaboration marks a significant achievement for GenFleet as GFH375 is their first product to secure overseas out-licensing at the preclinical stage and to gain IND approval in China, demonstrating their expertise in developing RAS-targeted therapies.

The GFH375X1101 study will be conducted at around 40 hospitals, including the prominent Shanghai Chest Hospital. In phase I, the study will assess the safety, tolerability, and preliminary efficacy of GFH375 in patients with advanced G12D-mutant solid tumors and will determine the recommended phase II dose (RP2D). Phase II will further evaluate the efficacy of GFH375 in treating advanced solid tumors such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC), which have high rates of G12D mutations. The study will also investigate the mechanisms behind patient responses and resistance to the treatment.

Dr. Shun Lu, a professor in the Department of Medical Oncology at Shanghai Chest Hospital, expressed excitement over the trial's approval, emphasizing the significant unmet medical needs for patients with G12D-mutant cancers and the potential of GFH375 as a new, life-saving treatment.

GenFleet, highlighted the company’s enthusiasm for advancing the G12D-targeted program and exploring future combination therapies. He noted that GenFleet’s success with fulzerasib (GFH925), a KRAS G12C inhibitor, and the NDA acceptance for its monotherapy in NSCLC in China, positions the company well to progress GFH375 and other RAS-targeted therapies in their pipeline.

RAS proteins, which can be in an active GTP-bound form or an inactive GDP-bound form, are crucial molecular switches in cellular signaling pathways such as RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. KRAS is the most frequently mutated oncogene in humans, with G12D, G12V, and G12C being the top three mutations. KRAS G12D is common in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. Many patients with KRAS G12D mutations, particularly those without a smoking history, show poor responses to PD-1 inhibitors. Mutant-selective G12D inhibitors like GFH375 could benefit a significant portion of KRAS-driven PDAC patients, where G12D mutations are highly prevalent and the 5-year survival rate is below 10%.

GFH375 is an orally active, selective small-molecule inhibitor designed to target KRAS G12D in both its GTP-bound and GDP-bound states, disrupting downstream pathways and inhibiting tumor cell proliferation. Preclinical studies demonstrated that GFH375’s inhibition of tumor growth improves with increased dosage and duration, and it has shown low off-target risks in kinase selectivity and safety assays.

GenFleet’s collaboration with Verastem Oncology aims to develop three novel oncology programs targeting RAS pathway-driven cancers. This partnership allows Verastem Oncology a milestone-based option to license up to three compounds, providing them with development and commercialization rights outside China, while GenFleet retains these rights within mainland China, Hong Kong, Macau, and Taiwan.



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