Nezglyal Nears EU Approval for cALD, but Undisclosed Data and a Narrow Label Cloud Commercial Outlook

CHMP Recommends NEZGLYAL for Cerebral Adrenoleukodystrophy

Minoryx Therapeutics and Neuraxpharm Group announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for NEZGLYAL (leriglitazone). This recommendation is for male cerebral Adrenoleukodystrophy (cALD) patients aged 2-12 years with Gadolinium (Gd) negative brain lesions. European Commission approval is anticipated by the end of September 2026. The positive opinion is based on results from the Phase 2/3 NEXUS study and additional real-world evidence. cALD is a severe neurodegenerative disease with no currently approved pharmacological treatments in the EU, highlighting the significance of this development.

• The positive CHMP opinion for NEZGLYAL marks a critical regulatory milestone, bringing the first pharmacological treatment closer to approval for cerebral Adrenoleukodystrophy (cALD) in the EU. This is particularly impactful for male cALD patients aged 2-12 years with Gd-negative brain lesions, who currently face a severe, rapidly progressive neurodegenerative disease with no approved therapeutic options.
• The CHMP's recommendation is underpinned by robust clinical data from the Phase 2/3 NEXUS study, which demonstrated that pediatric cALD patients achieved clinical and radiological stability after over 96 weeks of treatment. Minoryx is also actively pursuing US approval and future European label expansion, with ongoing trials like CALYX (adult male cALD) and TREE (pediatric Rett syndrome) expected to provide further data by early 2028 and end of 2026, respectively.
• Following the expected European Commission approval by September 2026, Neuraxpharm Group will commercialize NEZGLYAL in Europe under an existing license agreement with Minoryx. This collaboration underscores Neuraxpharm's commitment to addressing significant unmet medical needs in CNS patients and highlights the strategic partnership's role in delivering innovative solutions for rare diseases.

Addressing the Critical Unmet Need in cALD Treatment

Cerebral Adrenoleukodystrophy (cALD) remains a profoundly difficult disease to treat, with current standard-of-care approaches—hematopoietic stem cell transplantation (HSCT) and emerging gene therapies—constrained by narrow therapeutic windows, procedural risks, and incomplete understanding of disease biology. While these interventions can arrest neuroinflammatory progression when applied early, significant barriers in timing, eligibility, cost, and long-term outcomes continue to limit their broader clinical impact.

Timing and Eligibility Constraints

• HSCT efficacy is critically dependent on early-stage intervention; the therapeutic window is often missed, and transplantation at advanced disease stages can accelerate progression rather than halt it

• Many patients are ineligible for HSCT due to age, absence of a matched donor, or presence of corticospinal tract (CST) lesions

• Gene therapy is similarly restricted to pre- or pauci/oligo-symptomatic patients given the long-lasting nature of the intervention

• Time to HSCT averaged 97 days across evaluated hospitals, with notable disparities by ethnicity (117 days for Hispanic patients vs. 80 days for White, non-Hispanic patients), highlighting inequities in access and diagnostic delay

Neurocognitive and Long-Term Outcome Limitations

• Neurologic outcomes correlate with cerebral disease severity at the time of HSCT; boys with greater-than-minimal disease on MRI face risk of severe, persistent neurocognitive deficits

• Among 62 boys treated with HSCT, higher pretransplant MRI severity scores were associated with steeper neurocognitive decline over 5-year follow-up

• Of 33 patients with long-term follow-up testing, 67% (22/33) demonstrated severe impairment in at least one neurocognitive domain at most recent evaluation

• The neurocognitive trajectory following HSCT remains incompletely characterized, limiting prognostic counseling

Procedural Morbidity, Mortality, and Cost Burden

• Post-HSCT mortality was 8% (5/65) at 100 days and 18% (12/65) at 1 year, driven primarily by disease progression (44%) and infection (31%)

• Adverse events included infection (29%), acute grade II–IV GVHD (31%), chronic GVHD (7%), and engraftment failure after first HSCT (18%)

• Average per-patient costs reached $786,846—over 6 times higher than non-HSCT patients—with total charges for a 27-patient cohort reaching $53 million

Disease Biology and Diagnostic Gaps

• Progression to cerebral inflammation and demyelination involves infiltrating monocytes, macrophages, and cytotoxic T cells, driven by ABCD1-deficiency-related impairment in macrophage anti-inflammatory plasticity

• This pro-inflammatory macrophage skewing persists even in adrenomyeloneuropathy patients without overt cerebral inflammation, and is not fully reversed by myelin debris ingestion that would normally trigger anti-inflammatory polarization

• Early recognition and genetic diagnosis of X-ALD remain low due to variable clinical presentation, delaying intervention

• Mechanisms underlying loss of protein function from gene mutations remain unknown, complicating rational therapeutic design

• In some patients, non-functional endogenous ABCD1 protein may act in a dominant-negative fashion or displace therapeutically introduced normal protein—a critical consideration for gene therapy design

Limitations of Emerging Alternatives

• Leriglitazone, while promising for adults ineligible for or awaiting HSCT, showed continued deterioration in two patients over 60 years of age with prominent cognitive impairment, and one fatality from COVID-19 during treatment

• Broader application of gene and antisense oligonucleotide therapies across leukodystrophies remains investigational, with trials still ongoing

Understanding the Impact of cALD on Patient Populations

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder resulting from mutations in the ABCD1 gene, which impairs the beta-oxidation of very long-chain fatty acids. While the condition is X-linked and affects both sexes, its clinical manifestations vary significantly, with the severe neuroinflammatory phenotype, cerebral adrenoleukodystrophy (cALD), occurring almost exclusively in males.

• Male Population and cALD Risk: Males are the primary population affected by the devastating cerebral form of the disease. Data indicates that 40% of male patients develop cALD before the age of 18, and by age 60, the cumulative risk reaches 44%. Phenotypic analysis of one cohort further detailed cALD onset as 58.3% in childhood, 14.6% in adolescence, and 20.8% in adulthood.

• Female Carrier Symptomatology: While female carriers rarely develop cerebral leukodystrophy, the long-held view of them as asymptomatic has been challenged. The majority develop a progressive myelopathy, with symptom prevalence strongly correlating with age—increasing from 18% in women under 40 to 88% in those over 60. Key symptoms in one study cohort included myelopathy (63%), peripheral neuropathy (57%), and fecal incontinence (28%).

• Pediatric Manifestations: The pediatric population is significantly impacted, particularly with early-onset cALD in boys. Beyond cerebral demyelination, X-ALD is an important differential diagnosis for other conditions, accounting for 6% of primary adrenal insufficiency cases in a Finnish pediatric cohort (ages 0-20) and 4.1% of all inherited leukodystrophies in another study of children under 18.

• Epidemiology and Genetic Diversity: A 2025 Danish nationwide study established a point prevalence for X-ALD of 1.42 per 100,000 and an average birth incidence of 1.81 per 100,000. This research also underscored the genetic heterogeneity of the condition, identifying 34 distinct pathogenic ABCD1 variants, with p.(Pro560Leu) being the most common.