García-Cazorla Ángeles, Sevin Caroline, Constante Juliana Ribeiro, Yazbeck Elise, Rosewich Hendrik, Jimenez Sandra, Chia-Yi Chiang Gloria, Rapalino Otto, Caruso Paul, Balentine Daniel, Helmer Karl G, Bennett Seth, Emanuele Marco, Rodriguez-Pascau Laura, Pizcueta Pilar, Pina Guillem, Vilà Anna, Rovira Maria, Mantilla Adriana, Meya Uwe, Mistry Arun, Pascual María, Pascual Sílvia, Martinell Marc, Musolino Patricia L, Mallack Eric
Neurometabolic Unit, Neurology Department, Institut de Recerca, CIBERER and MetabERN, Hospital Sant Joan de Déu, Barcelona, Spain.
Pediatric Neurology Department, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Bicêtre Hospital, Le Kremlin Bicêtre, Paris, France.
EClinicalMedicine. 2025 May 24;84:103265. doi: 10.1016/j.eclinm.2025.103265. eCollection 2025 Jun.
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.
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.
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.
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.
Minoryx Therapeutics.
在约90%未经治疗的脑型肾上腺脑白质营养不良患者中，病情进展迅速。目前的治疗方法——造血干细胞移植（HSCT），具有高发病率且未广泛应用。需要能够在病灶识别后立即给予的低风险治疗方法。罗格列酮，一种过氧化物酶体增殖物激活受体γ激动剂，可能会减缓疾病进展。
NEXUS（NCT04528706）是一项为期96周的2/3期开放标签多中心研究，于2020年2月13日至2025年4月进行，纳入了2至12岁患有X连锁肾上腺脑白质营养不良且有白质病变的男孩。参与者每天口服一次罗格列酮。主要终点是第96周疾病停止进展的患者比例。这项预先定义的中期分析评估了第24周的继续标准，定义为病变生长减速或疾病停止进展的患者比例（成功：单侧95%CI>10%）。次要终点包括神经功能评分（NFS）、洛伊斯评分和钆增强强度评分（GIS）相对于基线的变化、继续服用罗格列酮患者的总生存率以及符合研究HSCT标准的患者数量。
在第24周有11名患者可评估，所有患者均符合继续标准。所有患者临床均保持稳定，且病变生长减速。5名（45%，95%CI 16·7 - 76·6）患者疾病停止进展。在大多数患者中，NFS、洛伊斯评分和GIS在第24周时趋于稳定。继续服用罗格列酮患者的生存率为100%（95%CI 69·2 - 100·0）。5名患者因钆持续增强符合研究HSCT标准，但病变无显著生长。罗格列酮耐受性良好；发生了87起不良事件，且没有与治疗相关的严重不良事件。
所有可评估患者均符合继续标准。临床和放射学数据表明，与现有的自然病史数据相比，疾病进展减缓，这表明罗格列酮可能对患有脑型肾上腺脑白质营养不良的男孩有益。进一步的随访将全面评估罗格列酮在脑型肾上腺脑白质营养不良中的安全性和有效性。
Minoryx Therapeutics公司。
