GenFleet Therapeutics Announces Potent Anti-tumor Efficacy of GFH375, an Oral KRAS G12D (ON/OFF) Inhibitor, and its Potential in Combination Therapy with RAF/MEK Clamp at 2024 AACR Annual Meeting
- GFH375 (VS-7375) is a highly potent and selective KRAS G12D inhibitor targeting both 'ON' and 'OFF' states of the protein.
- Preliminary safety data, favorable oral bioavailability, and potent efficacy across preclinical models highlight the potential of GFH375 in treating KRAS G12D mutant cancers with brain metastases.
- GenFleet's GFH925 (KRAS G12C inhibitor) has its New Drug Application accepted with Priority Review Designation in China, showcasing the company's expertise in developing RAS pathway inhibitors.
- The combination of avutometinib and GFH375 demonstrates enhanced anti-tumor efficacy, indicating future clinical potential.
- GenFleet's collaboration with Verastem Oncology to advance three oncology programs, with GFH375 being the first selected program, signifies strategic partnerships for innovative therapies.
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Insights
The discovery of GFH375's dual inhibition of both 'ON' and 'OFF' states of KRAS G12D represents a significant advance in targeted cancer therapy. The KRAS protein plays a pivotal role in cell signaling pathways that control cell growth and death and mutations in KRAS are implicated in a variety of cancers. The G12D mutation, being the most common, has been notoriously difficult to target due to its high affinity for GTP and the dynamic nature of its active and inactive states.
GFH375's ability to penetrate the blood-brain barrier and target brain metastases could fill a substantial unmet need in oncology, as central nervous system involvement often portends a poor prognosis. The oral bioavailability of the drug simplifies administration and could improve patient compliance compared to intravenous therapies. The combination therapy with avutometinib, which has shown enhanced efficacy, suggests a synergistic approach that could be more effective than monotherapies currently available.
GenFleet's strategic partnership with Verastem Oncology and the Priority Review Designation for their KRAS G12C inhibitor in China positions the company favorably within the precision oncology market. The KRAS inhibitor market is rapidly evolving and GenFleet's GFH375 could potentially capture a significant market share if clinical trials confirm its preclinical promise. The breakthrough therapy designation for avutometinib, when used in combination with defactinib, highlights the potential of combination therapies involving GFH375.
Investors should monitor GenFleet's progress closely, as the transition from preclinical to clinical stages will be critical in determining the company's future valuation. Success in clinical trials could lead to substantial returns, but the inherent risks of drug development must be considered, including the possibility of unfavorable clinical outcomes or regulatory hurdles.
The intellectual property surrounding KRAS inhibitors is highly competitive and the novelty of GFH375's mechanism of action could be a key differentiator. Protecting the innovation through patents will be essential for GenFleet to secure a competitive advantage. The company must navigate the complex patent landscape, ensuring that they do not infringe on existing patents while also establishing a robust patent portfolio around their own discoveries.
Furthermore, the collaboration with Verastem Oncology may involve intricate licensing agreements, especially concerning combination therapies. These agreements will need to be structured to ensure mutual benefit and clear terms regarding the commercialization of any successful treatments arising from their partnership.
GFH375 (VS-7375) is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. With preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models, GFH375 also holds the potential for treating KRAS G12D mutant cancers with brain metastases.
"G12D mutation is the most prevalent KRAS mutation detected in human carcinomas, and no G12D-targeted therapies have been approved yet. Preliminary research has shown potent efficacy and safety of orally administered GFH375 in animal models. Additionally, GenFleet's GFH925 (KRAS G12C inhibitor) has had its New Drug Application accepted with Priority Review Designation in
Preclinical research also demonstrated the combination of avutometinib (RAF/MEK clamp) and GFH375 confers enhanced anti-tumor efficacy relative to either agent alone, indicating potential for future clinical combination. Avutometinib in combination with defactinib (FAK inhibitor) is being developed by Verastem Oncology with clinical development across multiple indications and was granted breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status and after one more prior lines of therapy, including platinum-based chemotherapy. 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.
Abstract Title: GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy
Abstract No. : 3318
- Original mechanism targets both active and inactive KRAS G12D
GFH375 inhibits GTP-bound KRAS G12D and its binding with downstream proteins such as RAF; the drug candidate also targets the GDP-GTP exchange to inhibit the activation of KRAS G12D.
- Potent single agent anti-tumor efficacy of GFH375 and its potential for treating KRAS G12D mutant cancers with brain metastases
GFH375 potently and selectively inhibits phospho-ERK signaling and proliferation in KRAS G12D mutant tumor cells. GFH375 also accumulates in tumor tissue and elicits sustained inhibition of the protein following a single oral administration.
GFH375 induces tumor regression in multiple KRAS G12D CDX tumor models via oral administration. It also demonstrates potent anti-tumor activity in an intracranial CDX tumor model, which suggests the potential of GFH375 as a treatment for KRAS G12D mutant cancers with brain metastases.
- Combination of GFH375 and avutometinib enhances anti-tumor efficacy while retaining favorable toxicity profile in vivo
The combination of GFH375 and avutometinib enhances anti-tumor efficacy and leads to more significant tumor regression over either drug candidate alone. Meanwhile, the results exhibit favorable toxicity profile of this combination.
About RAS and KRAS mutations
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.
About KRAS G12D and GFH375
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 inhibitor holds promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alteration is 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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