We assessed efficacy and safety of leriglitazone in boys with cerebral adrenoleukodystrophy (cALD). 

cALD is a rapidly fatal, X-linked neurodegenerative disorder characterized by inflammatory brain demyelination. Hematopoietic stem cell transplantation (HSCT) may halt disease progression, but an unmet need for less invasive therapies that can be administered immediately upon lesion identification remains. Leriglitazone is a peroxisome proliferator-activated receptor γ agonist with potential to treat cALD.

NEXUS (NCT04528706) was a phase 2/3, 96-week, open-label, multicenter study of once-daily oral leriglitazone in boys aged 2–12 years with cALD with or without gadolinium-enhancing lesions. Primary endpoint was proportion of patients with clinically and radiologically arrested disease at week 96 or last visit before HSCT (success criterion: greater proportion of patients with arrested disease versus natural history [one-sided 95% confidence interval >10%]). Arrested disease was defined as change in neurological function score (NFS) ≤5 from baseline, no major functional disabilities (MFD) and no lesion progression on MRI. Secondary endpoints included change from baseline in NFS and Loes score. Exploratory endpoints included volumetric assessment, MFD-free survival and change in plasma biomarker concentrations. 

Of 23 patients recruited, 20 were evaluable at week 96 or visit before HSCT. Seven patients (35%) had arrested disease, meeting the primary endpoint; a significantly higher proportion than would be expected from natural history data (10%, p<0.05). All patients remained clinically stable (MFD free and stable NFS) during treatment. There were no treatment-related serious adverse events or discontinuations due to adverse events. Further data on secondary and exploratory endpoints will be presented. 

Leriglitazone treatment resulted in cerebral disease arrest with clinical and radiological stabilization in a significant number of patients and was well tolerated. These data demonstrate the efficacy and safety profile of leriglitazone in treating childhood cALD, with potential to address significant unmet treatment need.