Minoryx Therapeutics and Neuraxpharm Group have submitted a new Marketing Authorization Application (MAA) to the European Medicines Agency for leriglitazone (NEZGLYAL®) as a treatment for cerebral adrenoleukodystrophy (cALD), marking a renewed regulatory push following a previous setback. The EMA has validated the MAA file, which is now under review by the Committee for Medicinal Products for Human Use (CHMP).
Pivotal NEXUS Study Results Drive New Application
The new submission is anchored by data from the successfully concluded NEXUS study, a 96-week, pivotal, open-label study evaluating once-daily oral leriglitazone in pediatric patients with cALD. The study met its primary endpoint, with all 20 evaluable patients remaining clinically stable during treatment. Notably, 7 out of 20 evaluable patients (35%) met the arrested disease criteria, significantly exceeding the 10% self-arrest rate expected from natural history (p<0.05).
"We believe the new and positive data from Nexus provide compelling evidence for the efficacy of leriglitazone giving hope to patients and their families that a new treatment will be available in the near future," said Marc Martinell, CEO of Minoryx. "Leriglitazone, if approved, would be the only pharmacological treatment for patients suffering from this devastating orphan disease with a major unmet medical need."
The drug was well tolerated in the NEXUS study, with no discontinuations due to adverse events. The submission is further supported by data from the previously concluded ADVANCE study, a 116-patient, double-blind, placebo-controlled study conducted in Europe and the United States, where leriglitazone reduced the incidence and progression of cerebral lesions in adults.
Previous Regulatory Challenges
This new application follows a significant regulatory setback in May 2024, when the CHMP recommended against granting marketing authorization for leriglitazone following completion of a re-examination procedure. Despite the negative opinion, both companies remained committed to continued development of the therapy.
"NEZGLYAL® has shown a clinically relevant effect in both adults and children with cALD, and we are very disappointed that the Committee considered the benefit insufficiently established, which is different from the views expressed by the CHMP's Neurology Scientific Advisory Group (SAG-N)," Martinell had stated following the previous decision.
Addressing Critical Unmet Medical Need
X-linked adrenoleukodystrophy (X-ALD) affects approximately 6-8 per 100,000 live births globally. Boys and adult men with X-ALD can develop cALD at any point in their lifetime, characterized by demyelinating brain lesions that may become rapidly progressive, leading to acute neurological decline and death within three to four years.
Progressive cALD occurs in 31-35% of ALD patients in childhood, typically between ages 2-12, and up to 60% of adult patients with X-ALD will develop progressive cALD over time. Currently, no pharmacological treatment is available for cALD. While hematopoietic stem cell transplantation (HSCT) can arrest the disease in childhood, it is an aggressive procedure available only to a portion of patients. In adults, HSCT experience is very limited and often not recommended.
Drug Profile and Mechanism
Leriglitazone is a novel orally bioavailable, selective PPAR gamma agonist with demonstrated brain penetration and a favorable safety profile. In preclinical studies, it showed robust proof-of-concept in animal models by modulating pathways leading to neuroinflammation, demyelination, mitochondrial dysfunction, oxidative stress, and axonal degeneration.
Results from the NEXUS study demonstrate that pediatric cALD patients remained clinically and radiologically stable after over 96 weeks of treatment. Data from the ADVANCE study showed that leriglitazone stabilizes lesion growth and reduces the incidence of progressive cALD, potentially delaying or preventing life-threatening disease progression in adult patients.
Ongoing Development Program
The companies continue advancing leriglitazone development through the ongoing CALYX trial in adult patients with cALD and the TREE study in pediatric Rett patients, both of which remain open to recruitment. The drug has received orphan drug status for X-ALD from both the FDA and EMA, along with Fast Track and Rare Pediatric Disease designation from the FDA.
Dr. Jörg-Thomas Dierks, CEO of Neuraxpharm, expressed optimism about the regulatory process: "The EMA's validation of the leriglitazone MAA submission is a key step forward as we look to bring this much needed treatment to patients. Given the terrible impact of this devastating disease and the lack of effective options, we remain hopeful of a positive outcome from the CHMP."
