By Eric Mallack, MD
Assistant Professor of Pediatrics and Neurology, Division of Child Neurology, Weill Cornell Medical College; Director, Leukodystrophy Center at Weill Cornell Medicine
SYNOPSIS: A 96-week trial of leriglitazone to slow the progression of symptoms in adrenomyeloneuropathy did not meet the primary endpoint. However, post-hoc analyses revealed a beneficial effect in patients treated earlier in their disease course.
SOURCE: Köhler W, Engelen M, Eichler F, et al. Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): A randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. Lancet Neurol 2023;22:127-136.
X-linked adrenoleukodystrophy is a neurometabolic disorder caused by loss of function pathogenic variants in the ABCD1 gene. The clinical spectrum of disease in males is characterized by adrenal insufficiency, the development of progressive cerebral demyelination and neurodegeneration in about half of patients, and the development of progressive myeloneuropathy (AMN) in nearly all adult patients. Leriglitazone is an orally administered, central nervous system-penetrant selective peroxisome proliferator-activated receptor gamma agonist demonstrated in preclinical models to be neuroprotective against the inflammation and neurodegeneration responsible for clinical symptoms. The investigators tested the safety and efficacy of leriglitazone in patients with AMN without evidence of progressive, inflammatory cerebral adrenoleukodystrophy.
Over the 96-week study, randomized in a double-blind 2:1 drug to placebo fashion, there was no statistical difference detected in the six-minute walk test (the primary endpoint), nor in the majority of secondary endpoints. In a post-hoc analysis, when stratified by symptom duration (myelopathy for less than 10 years vs. more), Expanded Disability Status Scale (EDSS) score at 96 weeks increased more in the placebo group vs. the study drug group, indicating earlier treatment may confer more benefit.
The notable exception in this study was the development and progression of cerebral adrenoleukodystrophy. Namely, cerebral lesions progressed in eight (21%) placebo magnetic resonance imaging time points over six total patients vs. three (4%) timepoints on the study drug. Zero patients in the study arm developed de novo cerebral adrenoleukodystrophy vs. three patients who developed new cerebral disease in the placebo group. Experimental serum biomarker analysis revealed higher concentrations of neurofilament light chain, MMP-9 (indicative of blood-brain barrier breakdown), and proinflammatory cytokines in the placebo group. The drug was well tolerated, and the adverse event rate was in line with the expected profile for this class of medications.
COMMENTARY
The work by Köhler and colleagues is well executed. From a trial design standpoint, they demonstrate that randomized, placebo-controlled trials are possible in rare disorders. Additionally, the placebo arm of this work produces a systematically studied natural history of AMN. The failure of meeting the primary endpoint may be attributed to limitations in, first, the sensitivity of the primary endpoint itself over, second, the duration of the study. AMN is a slowly progressive myeloneuropathy that occurs over years, with variable rates of disease between patients, which imposes significant difficulty on finding tools to capture meaningful clinical outcomes in a practical trial period. Importantly, when analyzing those treated “early” in disease (symptoms for less than 10 years) vs. “later,” there is an indication of beneficial effect treating patients earlier in disease by slowing the rate of disability (measured by EDSS).
Patients in the study group had, by post-hoc analysis, a lower incidence (zero) and progression of cerebral adrenoleukodystrophy vs. those in the placebo group. This key observation is in line with preclinical models supporting the use of leriglitazone in patients with cerebral adrenoleukodystrophy. Hematopoietic stem
cell transplant and gene therapy, when delivered early in the disease, has been demonstrated to halt disease progression.
The drawbacks to these therapies include exposure to chemotherapy, treatment-related morbidity and mortality, and a time delay of several months from diagnosis to transplant, followed by weeks to months for the disease to halt post-treatment. Because of this unmet need, the scientific, and now clinical, observations noted earlier, leriglitazone is in a clinical trial (NCT04528706) for the treatment of boys with early-stage cerebral adrenoleukodystrophy.
Overall, this work represents an important step in the study and treatment of rare neurodegenerative disease. Although the primary endpoint was not met, much was learned by the trial’s execution, post-hoc analysis observations, and the exploratory data presented in the study appendix.
