GenFleet Receives IND Approval from China's NMPA for GFH375, an Oral KRAS G12D (ON/OFF) Inhibitor, in a Phase I/II Clinical Trial Treating Advanced Solid Tumor Patients with KRAS G12D Mutation
GenFleet Therapeutics has received approval from China's National Medical Products Administration (NMPA) for an open-label, multi-center phase I/II clinical trial of GFH375 (VS-7375), an oral KRAS G12D (ON/OFF) inhibitor, in patients with advanced solid tumors. This trial targets the prevalent KRAS G12D mutation, with no existing G12D-targeted therapies approved. GFH375 has shown promising preclinical safety, bioavailability, and efficacy, including potential for treating brain metastases.
The study will be conducted across ~40 hospitals, including Shanghai Chest Hospital. Phase I will assess safety, tolerability, and preliminary efficacy, determining the recommended phase II dose. Phase II will evaluate efficacy in cancers such as PDAC, CRC, and NSCLC, and investigate response/resistance mechanisms.
GenFleet's collaboration with Verastem Oncology, initiated in 2023, highlights the company's advances in RAS-targeted therapies, exemplified by previous success with KRAS G12C inhibitor fulzerasib.
- Approval for GFH375 clinical trial by China's NMPA.
- Potential new treatment for KRAS G12D-mutant cancers, addressing unmet medical need.
- Positive preclinical data: safety, bioavailability, efficacy.
- Multi-center study across ~40 hospitals.
- Phase II trial to assess efficacy in high-prevalence cancers (PDAC, CRC, NSCLC).
- GenFleet's expertise demonstrated with previous RAS-targeted therapies.
- GFH375 still in early clinical stages with no existing approval.
- Potential risks and unknowns in Phase I/II trial outcomes.
Insights
The approval of the IND application for GFH375 is noteworthy due to its focus on KRAS G12D mutations, which are prevalent in various aggressive cancers such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). These cancers have limited treatment options, making the development of targeted therapies crucial. GFH375's ability to inhibit both 'ON' and 'OFF' states of the KRAS G12D protein is particularly promising as it could potentially overcome the resistance mechanisms that limit the efficacy of current treatments.
However, it is important to approach these initial stages cautiously. While preclinical studies have shown favorable results, clinical trials will need to confirm these findings in human subjects. The fact that the trial will also explore brain metastases is an added advantage, given the poor prognosis associated with such conditions.
For retail investors, this news signifies a potential breakthrough in oncology therapeutics, but it is still in early stages. The progression from Phase I to Phase II will be critical in validating GFH375's efficacy and safety profile.
GenFleet's partnership with Verastem Oncology and subsequent IND approval for GFH375 are significant milestones that can enhance the company's valuation and attract investor interest. The collaboration underscores the confidence in GFH375's potential and opens up opportunities for future out-licensing deals, which can provide substantial revenue streams.
Investors should note that while the approval is a positive signal, the financial impact will largely depend on the trial outcomes and subsequent commercialization. The biotech sector is known for its volatility, especially around clinical trial announcements, so one must be prepared for both positive and negative fluctuations in stock prices.
Additionally, the therapeutic targeting of KRAS G12D mutations positions GenFleet in a niche market with high unmet medical needs, potentially leading to high demand if the drug proves effective. However, investors should remain cautious and monitor the progression of clinical trials closely.
The entry of GFH375 into clinical trials positions GenFleet as a formidable player in the oncology landscape, particularly in the niche segment of KRAS-targeted therapies. The collaboration with Verastem Oncology can amplify the drug's market reach, given Verastem's established presence in the oncology sector.
From a market perspective, the unmet needs in treating KRAS G12D-mutant cancers represent a lucrative opportunity. Should GFH375 progress successfully through clinical trials, it could secure a significant market share, especially since no G12D-targeted therapies have been approved yet. This could lead to substantial market disruption and create competitive pressure on other oncology drug developers.
Moreover, the potential application of GFH375 in treating brain metastases further broadens its market potential, addressing a critical gap in cancer treatment. Investors should keep an eye on the competitive landscape and regulatory developments that could impact GenFleet's market positioning.
GFH375 is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. According to the latest preclinical findings posted at 2024 AACR annual meeting, GFH375 demonstrated preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models; moreover, GFH375 holds the potential for treating G12D-mutant cancers with brain metastases.
GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs. The first program selected is GFH375, which represents a significant milestone as the GenFleet's first product to achieve overseas out-licensing at preclinical stage and the IND approval in
The study (GFH375X1101) will be conducted at ~40 hospitals, including the prominent Shanghai Chest Hospital. In phase I, the study aims to evaluate the safety/tolerability and preliminary efficacy of GFH375 in advanced G12D-mutant solid tumor patients. Additionally, the phase I trial will determine the recommended phase II dose (RP2D). Progressing into Phase II, the study will further assess the efficacy of GFH375 for patients of advanced solid tumors including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – three cancer types with highest prevalence of G12D mutation; the study will also investigate the underlying mechanisms of patients' response and resistance to the treatment.
"I am excited that the clinical trial application for GFH375 has been approved. The therapeutic landscape for G12D-mutant cancers remains challenging with limited treatment options, highlighting the significant unmet medical needs in this population. The G12D mutation is one of the most prevalent KRAS mutations and the development of G12D-targeted therapies has garnered significant attention recently. We eagerly await favorable safety and efficacy outcome for GFH375 in the upcoming trial, with the hope of introducing a novel life-saving treatment for patients." stated Dr. Shun Lu, professor of Dept. of Medical Oncology, Shanghai Chest Hospital.
"We are delighted to enter in a clinical trial to assess the clinical benefits of our G12D targeted program in monotherapy setting and explore the possibilities of synergistic effects that may arise from potential combination regimen in future. GenFleet's expertise in developing RAS-targeted therapies has been exemplified by the successful development of fulzerasib (GFH925, a KRAS G12C inhibitor) and the NDA acceptance of its monotherapy for NSCLC in
References:
1. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma, NPJ Precision Oncology, Feb. 2024
2. Next batter up! Targeting cancers with KRAS G12D mutations, Trends in Cancer (Cell Press), Nov. 2023
3. Pan-KRAS inhibitor disables oncogenic signaling and tumor growth, Nature, May 2023
About KRAS G12D mutation and GFH375
RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-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. Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alterations are the most frequently occurring somatic change in PDAC patients (about
GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.
GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of
About GenFleet Therapeutics
GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights 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 - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across
GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years.
View original content:SOURCE GenFleet Therapeutics
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