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    Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. (PubMed, Nat Cancer)
    Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode...We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.
    Journal • Metastases
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    RET (Ret Proto-Oncogene)
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    RET mutation
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    vepafestinib (TAS0953/HM06)
    1year
    Efficacy of vepafestinib in preclinical models of RET fusion-driven sarcoma models (AACR 2023)
    Background: Vepafestinib (TAS0953/HM06, Vepa) is a 2nd generation RET-selective inhibitor that effectively penetrates the brain, and inhibits the wildtype RET kinase domain (KD) and RET KD mutants (G810, V804, Y806, L730) (presented at AACR-NCI-EROTC 2021 meeting)...Vepa was more effective than vandetanib and similar to the FDA-approved RET inhibitors, selpercatinib (Selp) and pralsetinib (Pral), in all in vitro assays... Our preclinical results suggest that vepafestinib has the potential to more effectively manage CNS metastasis compared to selpercatinib, representing a promising new therapeutic option for patients with RET-driven sarcomas. Vepafestinib is currently in a phase 1/2 trial for adult patients with advanced solid tumors harboring RET alterations (margaRET, NCT04683250).
    Preclinical • PARP Biomarker
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    RET (Ret Proto-Oncogene) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCND1 (Cyclin D1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CASP3 (Caspase 3) • SPECC1L (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1 Like) • CASP7 (Caspase 7) • SELP (Selectin P)
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    RET fusion • RET mutation • RET rearrangement • MYC expression • CCND1 expression • STAT3 expression • RET V804* • RET expression • CASP3 elevation
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    Retevmo (selpercatinib) • Gavreto (pralsetinib) • Caprelsa (vandetanib) • vepafestinib (TAS0953/HM06)
    1year
    (MARGARET): Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities (clinicaltrials.gov)
    P1/2, N=202, Recruiting, Helsinn Healthcare SA | Trial completion date: Aug 2024 --> Sep 2025 | Trial primary completion date: Dec 2023 --> Mar 2025
    Trial completion date • Trial primary completion date • Metastases
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    RET (Ret Proto-Oncogene)
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    RET fusion
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    vepafestinib (TAS0953/HM06)
    over1year
    Vepafestinib is effective in preclinical models of sarcomas with RETfusion including a brain metastasis model (AACR-NCI-EORTC 2022)
    Vepafestinib (TAS0953/HM06) is a brainpenetrant 2nd generation RET-selective inhibitor that is also effective againstRET solvent front (G810) and gatekeeper (V804) mutations...In all in vitro assays vepafestinibwas more effective than vandetanib and as effective as the FDA-approvedRET inhibitors selpercatinib and pralsetinib... Our preclinical results suggest that vepafestinib is moreeffective than selpercatinib in the brain and represents a therapeutic strategyfor RET-driven sarcomas. Vepafestinib is currently in phase 1/2 clinical trialsfor adult patients with advanced solid tumors with RET alterations(margaRET, NCT 04683250).
    Preclinical • PARP Biomarker
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    RET (Ret Proto-Oncogene) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCND1 (Cyclin D1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CASP3 (Caspase 3) • SPECC1L (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1 Like) • CASP7 (Caspase 7)
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    RET fusion • MYC expression • RET V804*
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    Retevmo (selpercatinib) • Gavreto (pralsetinib) • Caprelsa (vandetanib) • vepafestinib (TAS0953/HM06)
    2years
    Comparison of TAS0953/HM06 and selpercatinib in RET fusion-driven preclinical disease models of intracranial metastases. (ASCO 2022)
    Tumor-bearing mice were treated with TAS0953/HM06 (50 mg/kg BID), selpercatinib (10 mg/kg BID) or vandetanib (multi-kinase RET inhibitor, 50 mg/kg QD), and assessed weekly for tumor growth via bioluminescence imaging. Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and extending survival. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions with acquired resistance mutations, including those with brain metastasis and those resistant to first-generation selective RET inhibitors. TAS0953/HM06 is currently undergoing a biomarker-driven phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250).
    Preclinical
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    RET (Ret Proto-Oncogene) • TRIM33 (Tripartite Motif Containing 33) • SPECC1 (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1)
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    RET fusion • RET V804* • RET positive
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    Retevmo (selpercatinib) • Caprelsa (vandetanib) • vepafestinib (TAS0953/HM06)
    over3years
    (MARGARET): Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities (clinicaltrials.gov)
    P1/2, N=202, Recruiting, Helsinn Healthcare SA
    Clinical • New P1/2 trial
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    RET (Ret Proto-Oncogene)
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    RET fusion
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    vepafestinib (TAS0953/HM06)