Zovegalisib shows early promise in PIK3CA-driven vascular anomalies

Relay Therapeutics announced initial phase 2 data (NCT06789913) for zovegalisib, an investigational PI3Kα mutant-selective inhibitor, showing early clinical activity in patients with PIK3CA-driven vascular anomalies. The findings were presented at the 2026 International Society for the Study of Vascular Anomalies World Congress in Philadelphia.^1,2

What are PIK3CA-driven vascular anomalies?

Vascular anomalies are rare disorders involving abnormal development of blood vessels, lymphatic vessels, and surrounding tissues. PIK3CA-driven vascular anomalies include conditions such as PIK3CA-related overgrowth spectrum (PROS), lymphatic malformations, and venous malformations. These disorders can lead to chronic pain, swelling, impaired mobility, bleeding, and reduced quality of life. Current systemic treatment options remain limited, particularly for long-term management.

“These data demonstrate, for the first time, the promise of PI3Kα mutant-selective inhibition for patients with vascular anomalies,” said Don Bergstrom, MD, PhD, president of research and development at Relay Therapeutics.

How was the ReInspire trial designed?

The data come from the ongoing phase 2 ReInspire trial evaluating zovegalisib in adults and children with vascular anomalies driven by PIK3CA mutations. The study includes 3 pediatric and adult age groups: patients aged 12 years and older, children aged 6 to 11 years, and children aged 2 to 5 years. The current analysis focused on adults and adolescents aged 12 years and older enrolled in the dose-randomization portion of the study.

As of the April 15, 2026, data cutoff, 32 patients had enrolled across 3 dose cohorts: 100 mg twice daily, 300 mg twice daily, and 400 mg twice daily. Twenty-two patients had PROS, 8 had lymphatic malformations, and 2 had venous malformations. Nearly three-quarters of participants previously received treatment with sirolimus and/or alpelisib.

What efficacy outcomes were reported?

Investigators reported efficacy findings for 20 patients who reached the first imaging assessment at 12 weeks. Volumetric response was defined as at least a 20% reduction in lesion volume by blinded independent central review using magnetic resonance imaging.

Among response-evaluable patients, 60% achieved a volumetric response at the first imaging time point. Responses occurred in patients with PROS and lymphatic malformations and across multiple PIK3CA mutation types. Ninety-five percent of patients experienced some degree of lesion reduction. Four patients who underwent 24-week imaging demonstrated continued deepening of lesion reduction.

The company also reported updated findings after the cutoff date, noting that an additional patient converted to an unconfirmed response. Including that patient, the overall volumetric response rate across doses increased to 65%.

Did patients report symptomatic improvement?

In addition to imaging-based responses, investigators observed improvements in patient- and clinician-reported outcomes. At week 12, investigator global impression of change scores showed clinical improvement in 89% of patients, while patient global impression of change scores improved in 79%. Pain-related symptom improvement was reported in 71% of assessments. According to the company, these measures continued trending toward improvement at later time points.

“The combination of robust volumetric responses, symptomatic improvement, and a safety profile that supports chronic dosing underscores the potential of zovegalisib to meaningfully change the treatment paradigm for this underserved population,” Bergstrom said.

What safety findings were observed?

Safety findings suggested improved tolerability at lower dose levels. Among patients receiving 100 mg or 300 mg twice daily, no dose discontinuations occurred, and median dose intensity exceeded 99%. Only 2 patients experienced grade 3 or higher treatment-related adverse events. Investigators also reported no rash or stomatitis of any grade and no grade 3 hyperglycemia or diarrhea in these cohorts.

The 400-mg twice-daily dose showed a less favorable safety profile and will not be prioritized for continued development in vascular anomalies. Relay Therapeutics selected 400 mg once daily and 300 mg twice daily for expansion cohorts, which are currently enrolling adolescents and adults aged 12 years and older. Pediatric dose-escalation enrollment for children aged 6 to 11 years is also ongoing.

What are the next steps for zovegalisib?

According to the company, approximately 170,000 individuals in the United States are estimated to live with PIK3CA-driven vascular anomalies. Investigators said the ongoing trial will continue evaluating safety, efficacy, and patient-reported outcomes as enrollment expands into younger pediatric populations.

References

1. Relay Therapeutics. Relay Therapeutics Announces Initial Clinical Data Demonstrating That Zovegalisib Has Potential for Differentiated Safety and Efficacy in Patients with PIK3CA-Driven Vascular Anomalies. Relay Therapeutics. May 19, 2026. Accessed May 19, 2026. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-initial-clinical-data-0

2. A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation. clinical trials.gov. Updated May 5, 2026. Accessed May 19, 2026. https://clinicaltrials.gov/study/NCT06789913