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. 2025 May 24:84:103265.
doi: 10.1016/j.eclinm.2025.103265. eCollection 2025 Jun.

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

Ángeles García-Cazorla  1 , Caroline Sevin  2 , Juliana Ribeiro Constante  1 , Elise Yazbeck  2 , Hendrik Rosewich  3   4   5 , Sandra Jimenez  6 , Gloria Chia-Yi Chiang  7 , Otto Rapalino  8 , Paul Caruso  9 , Daniel Balentine  10 , Karl G Helmer  10   11 , Seth Bennett  12 , Marco Emanuele  13 , Laura Rodriguez-Pascau  13 , Pilar Pizcueta  13 , Guillem Pina  13 , Anna Vilà  13 , Maria Rovira  13 , Adriana Mantilla  13 , Uwe Meya  13 , Arun Mistry  13 , María Pascual  13 , Sílvia Pascual  13 , Marc Martinell  13 , Patricia L Musolino  14 , Eric Mallack  15
Affiliations

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

Ángeles García-Cazorla et al. EClinicalMedicine. .

Abstract

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.

Keywords: Cerebral adrenoleukodystrophy; PPARγ agonist; Paediatric adrenoleukodystrophy.

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Conflict of interest statement

AGC has received honoraria for research support and lectures from Immedica and PTC Therapeutics, honoraria for lectures from BioMarin and Recordati Rare Diseases Foundation, and is a co-founder of Neuroprotect Life Sciences. CS has received research grants, conference support and consulting fees from BioMarin, Bluebird Bio, Forge Biologics, Minoryx Therapeutics, Shire and Takeda, and served as principal or co-principal investigator in clinical trials for Bluebird Bio, Ionis, Minoryx, and Takeda. JR, EY, SJ, OR, PC and DB have no disclosures. HR has received institutional research support from the German Research Council and the Eva Luise and Horst Köhler Foundation and has received research support/grants and travel support from Minoryx Therapeutics SL. GCC has been compensated as consultant for Life Molecular Imaging and as an invited speaker for CME with Efficient CME and Horizons CME, and has received institutional research support from the National Institutes of Health and National Institute on Aging (R01AG068398, R01AG080011). KGH has received institutional research support from Minoryx Therapeutics SL and the National Institutes of Health. SB is an employee of CTI Clinical Trial and Consulting Services, Inc. ME and PP are employees of Minoryx Therapeutics SL. MR, LRP, GP, AV, A Mistry, and SP are employees of, and have stock in, Minoryx Therapeutics SL. MP and A Mantilla are former employees of Minoryx Therapeutics SL. UM is a former employee and stockholder of, and serves as a consultant for, Minoryx Therapeutics SL. MM is an employee of, serves on the board of directors of, and has stock in, Minoryx Therapeutics SL, and has received intellectual property interests from a discovery or technology relating to healthcare. PLM has received consulting fees from INC Pharma, Inozyme, IONIS Pharmaceuticals, Biogen, Bluebird Bio, Minoryx Therapeutics SL, and Vertex Pharmaceuticals Inc, and served a leadership or fiduciary role for ALD connect, Young Genetic Stroke Alliance, and the United Leukodystrophy Foundation. EM has received support from the National Institutes of Health, National Institute of Neurological Disorders and Stroke (K12NS066274, K23NS118044), for the development of the quantitative MRI models subsequently adopted by this work and has been compensated for serving on a Scientific Advisory or Data Safety Monitoring Board for Grace Science and Lysogene.

Figures

Fig. 1
Fig. 1
Disposition of patients. HSCT, haematopoietic stem-cell transplantation; MRI, magnetic resonance imaging. ∗Patients who received at least one dose of leriglitazone. †Patients who received at least one dose of leriglitazone and had at least one post-baseline MRI. ‡Both patients underwent allogeneic HSCT or autologous-modified HSCT at the physician's discretion, study HSCT criteria were not met. §Patients who completed the week 24 study visit at the cut-off date.
Fig. 2
Fig. 2
Radiological and clinical outcomes, lesion volumetric data, and biomarker data in patients receiving leriglitazone. (A) Loes score. (B) NFS. (C) Total lesion volume fold change. (D) Neurofilament light chain plasma concentration in patients receiving leriglitazone. Data are presented from patients in the modified intent-to-treat analysis set (n = 15). Dashed lines represent the mean and 95% CIs from natural history data. Data in (B) are plotted on a 0–25 scale to represent the range of the NFS assessment. ∗Patients included in interim analysis set. NFS, neurologic function score.
Fig. 3
Fig. 3
T2 FLAIR and T1-post contrast MRI scans from an untreated patient from a natural history cohort, and patients in populations 1 and 2 of the NEXUS study. Rows 1 and 2: early-stage lesion progression in an untreated 4-year-old patient at baseline, visit 1 (3·5 months) and visit 2 (4·4 months), demonstrating the development of lesional enhancement and lesion growth acceleration. Rows 3 and 4: lesion progression in an 8-year-old participant from Population 1 at baseline, visit 1 (3·0 months) and visit 2 (6·0 months), demonstrating a lack of lesional enhancement and slow lesion growth compared to natural history. Rows 5 and 6: lesion progression in a 6-year-old participant from Population 2 at baseline, visit 1 (3·0 months) and visit 2 (6·0 months), demonstrating resolving lesional enhancement and significant lesion growth deceleration inconsistent with the natural history of early-stage childhood cerebral adrenoleukodystrophy. Accel, acceleration; eALD, early-stage adrenoleukodystrophy; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; T1POST, T1-post contrast; Vol, volume.
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