Relay Therapeutics (Nasdaq: RLAY) has reported initial zovegalisib (RLY-2608) clinical data from the Phase II ReInspire trial in PIK3CA-driven vascular anomalies, showing a 60% volumetric response rate at 12 weeks alongside a tolerability profile that the company says supports chronic dosing — a combination that has historically been difficult to achieve with existing PI3Kα inhibitors in this population.
The ReInspire trial is a Phase II, multi-part study evaluating zovegalisib across three age groups in patients with PIK3CA-driven vascular anomalies, including PIK3CA-related overgrowth spectrum (PROS), lymphatic malformations, and venous malformations. The data reported here cover Part 1 — randomized dose selection — in adults and adolescents aged 12 and older. As of the April 15, 2026 data cut-off, 32 patients had been enrolled and randomized across three dose cohorts: 100 mg twice daily (BID), 300 mg BID, and 400 mg BID.
The patient population reflected the refractory nature of the disease: 72% had prior treatment with sirolimus and/or Novartis's Piqray (alpelisib), the two agents most commonly used in PIK3CA vascular anomalies treatment today.
Zovegalisib efficacy at 12 weeks
Of the 32 enrolled patients, 20 had reached the 12-week MRI assessment and were evaluable for response. A volumetric response was defined as a 20% or greater reduction in target lesion volume from baseline, assessed by blinded independent central review.
Twelve of those 20 patients — 60% — achieved a volumetric response, with all responses occurring at the first MRI timepoint. Among the 13 patients treated at the two lower doses (100 mg and 300 mg BID), 62% responded. The same response rate of 62% was observed in the 13 patients with prior alpelisib or sirolimus exposure, suggesting that prior treatment with existing PIK3CA-driven disease therapy did not preclude benefit. Across all 20 evaluable patients, 95% experienced some degree of lesion reduction.
Four patients had reached the 24-week scan by the data cut-off, and all four showed confirmation of response with deepening lesion volume reduction, indicating that responses were durable rather than transient at this early stage.
After the cut-off date, one additional patient in the 100 mg BID cohort converted to an unconfirmed response, updating the across-dose response rate to 65% (13/20) and the 100 mg BID rate to 43% (3/7). All 32 patients remained on treatment as of the data cut-off.
Investigator- and patient-reported outcomes reinforced the imaging findings. At week 12, 89% of patients achieved clinical improvement per investigator global impression of change (IGIC), and 79% per patient global impression of change (PGIC). Pain scores measured by investigator assessment showed improvement in 71% of symptoms. All three measures trended toward further improvement at later timepoints.
The tolerability data are central to the Relay Therapeutics zovegalisib positioning in vascular anomalies due to the chronic nature of the conditions requiring long-term management.
Among the 22 patients treated at 100 mg or 300 mg BID, dose reductions occurred in 23% and median dose intensity exceeded 99%. Only two patients (9%) experienced a Grade 3 or higher treatment-related adverse event, and no patients discontinued due to adverse events. Notably, no rash or stomatitis of any grade was observed, and no Grade 3 hyperglycemia or diarrhea was recorded — adverse events that have historically limited the clinical utility of orthosteric PI3Kα inhibitors such as alpelisib in both oncology and vascular anomalies settings. No prophylactic treatment was administered for any adverse event.
The 400 mg BID dose, which is the dose being evaluated in Relay's Phase III ReDiscover-2 breast cancer trial, showed a less favorable tolerability profile in this population and has been deprioritized for further development in vascular anomalies. Expansion cohorts have been opened at 400 mg once daily and 300 mg BID.
Zovegalisib clinical data in context
Zovegalisib is designed as an allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor — a mechanistic profile distinct from approved orthosteric agents. Conventional PI3Kα inhibitors, including alpelisib, target the active catalytic site and carry activity against wild-type PI3Kα and other PI3K isoforms. That off-target activity is widely considered responsible for the class-associated toxicities — hyperglycemia, rash, diarrhea — that force dose reductions and limit treatment duration.
Relay used cryo-EM structural data and long time-scale molecular dynamics simulations to identify conformational differences between wild-type and mutant PI3Kα, enabling the design of a compound that binds an allosteric site and preferentially inhibits mutant forms. The company says the approach underpins the tolerability profile seen in ReInspire.
Cross-trial comparisons are limited by differences in patient populations, prior treatment histories, and response definitions, but the absence of rash, stomatitis, and Grade 3 metabolic toxicity in the 100 mg and 300 mg BID cohorts contrasts with the established tolerability profile of alpelisib in PIK3CA vascular anomalies treatment, where those events have contributed to treatment discontinuation in published case series and clinical experience.
Approximately 170,000 patients in the US are estimated to be living with PIK3CA-driven vascular anomalies, and current systemic options remain limited. Sirolimus, an mTOR inhibitor, is used off-label and does not directly target the PIK3CA mutation. Alpelisib has shown activity in PROS but carries the tolerability burden described above and lacks formal approval in this setting. The vascular anomalies drug efficacy data from ReInspire represent the first prospective, randomized dose-selection data for a mutant-selective PI3Kα inhibitor in this population.
Relay plans to continue enrollment in the Part 2 expansion cohorts for adults and adolescents at 400 mg QD and 300 mg BID, advance Part 1 dose escalation in the 6–11 pediatric age group, and implement a fit-for-purpose patient-reported outcome tool developed specifically for the ReInspire population. In breast cancer, the Phase III ReDiscover-2 trial of zovegalisib plus AstraZeneca's Faslodex (fulvestrant) in PI3Kα-mutated, CDK4/6 pre-treated HR+/HER2- advanced breast cancer continues to enroll, with frontline Phase III combination readiness activities targeting initiation in early 2027, subject to regulatory feedback.
This article was generated with AI assistance and reviewed and edited by the AllSci editorial team
Explore more at AllSci News: https://allsci.com/news/
Spot something wrong? Report an issue with this article