Abstract Details

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

To assess 24-week safety, efficacy and study continuation criteria in boys with cerebral adrenoleukodystrophy (cALD) treated with leriglitazone.

This 96-week, open-label, multicenter study for European registration (NEXUS; NCT04528706) of once-daily oral leriglitazone has enrolled 17 boys (target: 13) 2–12 years old with cALD with or without gadolinium-enhancing lesions. The primary endpoint is the proportion of patients with clinically and radiologically arrested disease at week 96 (success criteria: one-sided 95% confidence interval [CI] > 10%). We present a prespecified 24-week interim analysis, including assessment of study continuation criteria (≥ 4/13 patients with arrested disease or lesion growth deceleration without clinical progression). Secondary endpoints include change from baseline in neurological function score (NFS) and Loes score (LS). Change from baseline in plasma biomarker concentrations is an exploratory endpoint.

Eleven patients were evaluable at week 24. Continuation criteria were met: all patients demonstrated lesion growth deceleration. All remained clinically stable (free of major functional disability and stable NFS). Five patients had arrested disease (45.5%, 95% CI: 13.9–68.4%). Median (range) change from baseline was 0.0 (0.0–1.0) for NFS and 0.0 (0.0–3.0) for LS. Neurofilament light chain concentrations stabilized in most patients. Matrix metalloproteinase-9 concentrations decreased in all patients. There were no severe adverse events, treatment-related serious adverse events or deaths.

Leriglitazone was well tolerated, continuation criteria were met, and disease arrest or stabilization was demonstrated radiologically, clinically and via plasma biomarkers. LS changes were similar to those attained with HSCT-based therapies. Enrolment is ongoing.