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Publications

Journal Article Review Ahead of print

PubMed: 42875408 DOI: 10.1080/13543784.2026.2750463

Zovegalisib for PIK3CA-driven vascular and lymphatic malformations: a drug evaluation.

Expert Opin Investig Drugs

Authors: Emmanuel Seront, An Van Damme, Julien Coulie, Miikka Vikkula, Laurence M Boon

Affiliations

  • Institut Roi Albert II, Department of Medical Oncology, Cliniques Universitaires St Luc, University of Louvain, Brussels, Belgium.
  • Institut Roi Albert II, Department of Pediatric Hematology-Oncology, Cliniques universitaires St Luc, University of Louvain, Brussels, Belgium.
  • Division of Plastic Surgery, Cliniques universitaires St Luc, University of Louvain, Brussels, Belgium.
  • UCLouvain, Human Molecular Genetics, Brussels, Belgium.
  • Genes & Health, de Duve Institute, Brussels, Belgium.
  • WELBIO department, WEL Research Institute, Wavre, Belgium.

Abstract

INTRODUCTION

PIK3CA-driven overgrowth and vascular malformations are mosaic developmental disorders in which chronic pathway inhibition may be required from childhood into adulthood. Alpelisib established PI3Kα as a clinically actionable target, but inhibition of wild-type PI3Kα can produce on-target toxicities, principally hyperglycemia, diarrhea and stomatitis, that are relevant to long-term therapy. Zovegalisib (RLY-2608) is an oral allosteric, pan-mutant-selective PI3Kα inhibitor designed to preferentially inhibit mutant over wild-type PI3Kα.

AREAS COVERED

This Drug Evaluation reviews PIK3CA biology, the current systemic-treatment landscape, zovegalisib pharmacology, and the preliminary Phase 2 ReInspire data. PubMed/MEDLINE, ClinicalTrials.gov, regulatory sources, and publicly available conference materials and company disclosures were reviewed through 20 August 2026.

EXPERT OPINION

At the formal 15 April 2026 cutoff, early ReInspire results showed a 60% week-12 volumetric response rate in 20 evaluable adults/adolescents; one unconfirmed response reported after the cutoff in a sponsor press release increased the descriptive rate to 65%. Activity after prior sirolimus and/or alpelisib and encouraging short-term tolerability support further development. Mutant selectivity could be especially valuable in chronic nonmalignant disease, but superiority over alpelisib is unproven.

MeSH

Pharmaceutical Preparations, Precision Medicine, Therapeutics, Drug Evaluation