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Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory

Isao Miyazaki1, Igor Odintsov2,3,4, Keiji Ishida5

  • 1Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan. isao-miyazaki@taiho.co.jp.

Nature Cancer
|September 24, 2023
PubMed

Insights

Vepafestinib, a next-generation RET inhibitor, effectively targets RET-driven cancers, including those with resistance mutations and brain metastases. It demonstrates superior brain penetration and tumor control compared to existing therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RET receptor tyrosine kinase alterations drive various cancers.
  • Current RET inhibitors face limitations due to resistance mutations and poor brain penetration.
  • Brain metastasis is a significant challenge in RET-driven malignancies.

Purpose of the Study:

  • To characterize vepafestinib (TAS0953/HM06), a novel next-generation RET inhibitor.
  • To evaluate vepafestinib's efficacy against RET alterations and resistance mutations.
  • To assess vepafestinib's pharmacokinetic properties, particularly brain penetration.

Main Methods:

  • Preclinical characterization of vepafestinib.
  • In vitro assessment of selectivity and activity against resistance mutations (RET variants L730, V804, G810).
  • Pharmacokinetic studies, including brain penetration analysis.
  • Evaluation in an intracranial model of RET-driven cancer.

Main Results:

  • Vepafestinib exhibits best-in-class selectivity for RET.
  • It demonstrates activity against common on-target RET resistance mutations.
  • Vepafestinib shows superior brain pharmacokinetic properties compared to approved RET inhibitors.
  • Improved tumor control was observed in an intracranial model.

Conclusions:

  • Vepafestinib represents a promising next-generation RET inhibitor.
  • Its unique binding mode and properties address limitations of current therapies.
  • Vepafestinib shows significant clinical potential for treating RET-driven cancers, including those with brain metastases.

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