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

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.