Safety and efficacy of leriglitazone in childhood cerebral adrenoleukodystrophy (NEXUS): an interim analysis of an open-label, phase 2/3 trial.

Background: Cerebral adrenoleukodystrophy rapidly progresses in approximately 90% of untreated patients. Current treatment, haematopoietic stem-cell transplantation (HSCT), is associated with high morbidity and is not widely available. Lower risk treatments that can be administered immediately upon lesion identification are needed. Leriglitazone, a peroxisome proliferator-activated receptor gamma agonist, may slow disease progression. Methods: NEXUS (NCT04528706), a 96-week, phase 2/3, open-label, multicentre study conducted between February 13, 2020 and April 2025, enrolled boys aged 2-12 years with X-linked adrenoleukodystrophy with white matter lesions. Participants received oral leriglitazone once-daily. The primary endpoint is the proportion of patients with arrested disease at week 96. This predefined interim analysis assessed the continuation criteria at week 24, defined as the proportion of patients with lesion growth deceleration or disease arrest (success: one-sided 95% CI >10%). Secondary endpoints were the change from baseline in neurologic function score (NFS), Loes score and gadolinium intensity score (GIS), the overall survival of patients remaining on leriglitazone, and the number of patients meeting study HSCT criteria. Findings: Eleven patients were evaluable at week 24 and all met the continuation criteria. All remained clinically stable and showed lesion growth deceleration. Five (45%, 95% CI 16·7-76·6) had arrested disease. NFS, Loes score, and GIS stabilised by week 24 in most patients. Survival of patients who remained on leriglitazone was 100% (95% CI 69·2-100·0). Five patients met the study HSCT criteria owing to persistent gadolinium enhancement but had no significant lesion growth. Leriglitazone was well tolerated; 87 adverse events occurred and there were no treatment-related serious adverse events. Interpretation: All evaluable patients met the continuation criteria. Clinical and radiological data suggest deceleration of disease progression compared with available natural history data, indicating that leriglitazone may be beneficial in boys with cerebral adrenoleukodystrophy. Additional follow-up will fully assess the safety and efficacy of leriglitazone in cerebral adrenoleukodystrophy. Funding: Minoryx Therapeutics.