On December 18, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported a potential best-in-class KRAS G12D oral inhibitor as the lead program of its discovery and development collaboration with GenFleet Therapeutics ("GenFleet") (Press release, Verastem, DEC 18, 2023, View Source [SID1234638667]).
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"We are pleased to announce this oral KRAS G12D inhibitor with a potential best-in-class profile as the lead program from our collaboration with GenFleet supporting our mission to bring needed therapies to patients with RAS pathway-driven cancers," said Dan Paterson, President and Chief Executive Officer of Verastem Oncology. "Although there has been significant progress in therapeutics targeting KRAS mutations, there are currently no available therapies approved by the U.S. Food and Drug Administration targeting KRAS G12D, the most prevalent KRAS mutation across human cancers. The GLP toxicology studies are complete and we look forward to GenFleet’s anticipated filing of the IND for this KRAS G12D inhibitor in the first half of 2024."
GFH375/VS-7375 is an orally bioavailable, potent and selective small molecule KRAS G12D (ON/OFF) inhibitor. Preclinical models demonstrate strong tumor regression as a single agent and support approaches in combination with Verastem Oncology’s RAF/MEK clamp avutometinib as well as other rational combinations across KRAS G12D-driven cancers. KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancer. KRAS G12D mutation occurs most commonly in pancreatic (37%), colorectal (12.5%), endometrial (8%) and non-small cell lung (5%) cancers.
As previously announced, the discovery and development collaboration between Verastem Oncology and GenFleet aims to advance three oncology discovery programs related to RAS pathway-driven cancers. The collaboration builds on the strengths of both companies in oncology small molecule drug development, enabling Verastem Oncology to partner its clinical development and regulatory expertise with GenFleet’s accomplished discovery capabilities. This synergistic collaboration includes Verastem Oncology’s experience and established network of collaborators, including scientific and clinical experts in RAS biology and RAS pathway-driven cancers and GenFleet’s accomplishments with its KRAS G12C inhibitor program. The IND filing and initial Phase 1 studies will be led and funded by GenFleet in China. The collaboration provides Verastem Oncology with an exclusive option to obtain a license to each of the three compounds in the collaboration after successful completion of pre-determined milestones in a Phase 1 trial. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain development and commercialization rights inside of China.
About Avutometinib
Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. Avutometinib is currently in late-stage development.
In contrast to currently available MEK inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The U.S. Food and Drug Administration granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.
Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its RAMP (Raf And Mek Program) trials. RAMP 201 is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation. Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205, a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.