Leriglitazone Demonstrates Lesion Growth Deceleration in Pediatric Cerebral Adrenoleukodystrophy

Eric J. Mallack, MD

New interim results from the phase 2 open-label NEXUS (NCT04528706), 96-week study on leriglitazone (Minoryx Therapeutics), a peroxisome proliferator-activated receptor γ agonist, for pediatric cerebral adrenoleukodystrophy (cALD) showed that all evaluable patients were clinically stable and radiologically displayed disease arrest or lesion growth stabilization after 24 weeks of treatment.¹ This analysis supports the use of leriglitazone to treat pediatric patients with progressive cALD, a rapidly fatal neurodegenerative phenotype of X-linked Adrenoleukodystrophy characterized by inflammatory brain demyelination.²

Among the 11 evaluable patients that demonstrated lesion growth deceleration or disease arrest (95% confidence interval [CI]: 71.5, 100), 5 showed arrested disease (45.5%, 95% CI, 13.9–68.4%) and all had met the pre-defined continuation criteria for the trial. Notably, the median change from baseline was 0.0 (0.0–1.0) for the neurological function score (NFS) and 0.0 (0.0–3.0) for the Loes score (LS).

These findings were presented as an abstract presentation in the second emerging sciences session at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by lead author Eric J. Mallack, MD, assistant professor of pediatrics and neurology at Weill Cornell Medicine. The 24-week interim analysis was pre-designed to be conducted when at least 13 patients enrolled and reached week 24.

In the trial, 17 boys enrolled between the ages of 2–12 years old with cALD with or without gadolinium-enhancing lesions received a once-daily oral leriglitazone. The primary endpoint was the proportion of patients with clinically and radiologically arrested disease at week 96 with the success criteria as one-sided 95% CI greater than 10%. The analysis included the assessment of study continuation criteria (at least 4 out of 13 patients with arrested disease or lesion growth deceleration without clinical progression). As for the secondary endpoints, change from baseline in NFS and LS were assessed. Also as an exploratory endpoint, change from baseline in plasma biomarker concentrations was analyzed.

In radiological changes assessed by LS, results showed as similar to those attained with Hematopoietic Stem-Cell Transplantation (HSCT)-based therapies. Hence, there either was no change or minimal growth with plateauing observed at week 24. Additionally, plasma levels of neurofilament light stabilized and trended as paralleling the results of lesion volume. Neurofilament light chain concentrations stabilized in most patients following a parallel profile to lesion volume change.

In all patients, leriglitazone was well tolerated and there were no treatment related serious adverse events or discontinuations of the treatment from adverse events reported. After 96 weeks of treament, a confirmatory assessment well be conducted of disease arrest in patients. Enrollment for the study is currently ongoing.

The only available current treatments for pediatric patients with cALD are the allogeneic HSCT and the FDA-approved eli-cel. Despite the avialable treatment, some patients are not eligible for them or suitable donors may not be available. As for leriglitazone, the treatment was granted orphan drug status by the FDA and the EMA for X-linked adrenoleukodystrophy (X-ALD). Additionally, the treatment was granted fast track, rare pediatric disease designation by the agency for the treatment of X-ALD.

"Allogeneic stem-cell transplantation (HSCT) may halt disease progression, but is limited by a lack of suitable donors, regionally-restricted access, a several month time delay from cALD diagnosis to infusion, engraftment failure and severe side effects. There is an unmet need for less invasive treatments that can be administered at the moment lesions are identified, notably now that newborn screening opens the window for earlier disease rescue treatments," Patricia Musolino, MD, PhD, global principal investigator of NEXUS, said in a statement.² "Our interim analysis shows early changes to the natural history of cALD in boys treated with leriglitazone; lesions underwent slower growth than untreated lesions and more akin to that of lesions typically treated with HSCT in cALD. We found signals of this effect in both neuroimaging and serum biomarkers. These promising results will be need to be confirmed by clinical benefit of leriglitazone at week 96."

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REFERENCES
1. Mallack EJ, Garcia-Cazorla A, Constante JR, et al. Interim Results from the NEXUS Open-Label Registration Study on the Safety and Efficacy of Leriglitazone in the Treatment of Childhood Cerebral AdrenoleukodystrophyPresented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 002. Emerging Science Session 2.
2. Minoryx presents positive interim results from NEXUS registration study for leriglitazone targeting pediatric ALD patients with cerebral adrenoleukodystrophy (cALD). News Release. Minoryx Therapeutics. Published April 25, 2023. Accessed April 27, 2023. https://www.minoryx.com/media/minoryx-presents-positive-interim-results-from-nexus/