Category: Adrenomyeloneuropathy (AMN)

X-linked adrenoleukodystrophy (ALD) is the most common peroxisomal disease. The product of the affected gene is a peroxisomal membrane protein (ADLP), a member of the large family of ABC transporters (ATP-binding cassette, ATP binding cassette): ABCD1. The ABCD1 protein-deficient mouse model of X-ALD exhibits lateonset, progressive axonal degeneration resembling AMN in humans. We observe an early onset of oxidative stress accompanied by lesions, one year before the onset of the disease.

In these mice, treatment with a combination of antioxidants including α-tocopherol, N-acetyl-cysteine ​​and α-lipoic acid reverses oxidative damage, improves energy deficit as well as axonal degeneration and damage. Oxidative stress therefore appears to be underlying axonal degeneration in adrenoleukodystrophy; it is one of the hallmarks of the pathogenesis of X-ALD.

Our group has helped to demonstrate the glutathione imbalance present in the blood of patients with X-ALD, thus highlighting the importance of imbalance of forms of glutathione (its oxidised form versus its reduced form) as a characteristic and potential biomarker of this disease.

More recently, a new drug, called EPI-743 (alphatocotrienol quinone), has been designed to reconstitute glutathione in reduced form (anti-oxidant form). The exact mechanism of action of EPI-743 has not yet been determined, but EPI-743 has been shown to be  potent in vitro protector of cells taken from patients with diseases of the mitochondrial respiratory chain, such as Friedreich’s ataxia, Leigh’s syndrome (SURF1) and Leber’s inherited optic neuropathy.

Six patients with Leber’s hereditary optic neuropathy are currently being treated with EPI-743 in open-label emergency treatment studies. Improvements in visual acuity, visual field and color vision have been observed.

Several pediatric patients with Leigh syndrome, Kearns-Sayre syndrome, POLG1 deficiency, MELAS syndrome and Friedreich’s ataxia are currently being treated with EPI-743 in open-label clinical studies. Clinical improvement associated with biomarkers was observed.

In a recently completed Phase 2A trial, EPI-743 was associated with signs of neurological improvement in 10 included children with Leigh syndrome.

Our goal is to determine the efficacy and safety of EPI-743 in an open study in 10 patients with X-linked adrenomyeloneuropathy (AMN).

The main objective of this study is to evaluate the effect of EPI-743 administered orally to subjects with AMN on the change in the association between clinical ALD score in adults ( AACS, Adult ALD Clinical Score) and the dependency rating scale (mRS-9Q) between baseline and the end of 48 weeks of treatment.

The secondary objectives of this study are evaluated from baseline to up to 48 weeks of treatment. They  are:

• to assess the safety of EPI-743 for 48 consecutive weeks;
• to assess the effect of EPI-743 on motor functions (6 minute walk test distance (6MWT), time required to travel 25 feet (T25FW);
• to assess the effect of EPI-743 on disease progression as assessed by the Clinical Overall Impression Improvement Scale (CGIIMP);
• to assess the effect of EPI-743 on the change in quality of life (SF-36 questionnaire);
• to assess the effect of EPI-743 on the evolution of the auditory evoked potential of the brainstem;
• to assess the effect of EPI-743 on changes in hormone levels;
• to explore the effect of EPI-743 on altering components of the glutathione cycle.

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi , Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group – 2023

A clinical trial carried out in several countries has just been completed. Although it has not shown a favorable effect on adrenomyeloneuropathy, it provides interesting information for the treatment of cerebral adrenoleukodystrophy. Indeed, no patient who received the drug developed brain damage during the trial, unlike the men in the placebo group.

Most adults with the adrenoleukodystrophy gene develop adrenomyeloneuropathy, a chronic myelopathy which usually begins before the age of 30. Adrenomyeloneuropathy is characterized by severe and continuous axonal damage in the central and peripheral nervous system, and in particular causes stiffness when walking and balance disorders.

Cerebral adrenoleukodystrophy (cALD) is an aggressive inflammation of the brain. It affects 30 to 40% of boys aged 4 to 8 born with an ABCD1 gene mutation. Men with adrenomyeloneuropathy also develop cerebral adrenoleukodystrophy for more than half of them.

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

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi, Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group

Background

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.

Methods

ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.

Findings

Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: −27·7 [41·4] m; placebo: −30·3 [60·5] m; least-squares mean difference −1·2 m; 95% CI −22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.

Interpretation

The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.

Funding: Minoryx Therapeutics

Reference : Köhler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M.J., Pascual, S., et al. (2023). 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. 22, 127–136

Adrenomyeloneuropathy is a debilitating lifelong disorder that currently has not treatments available. As an inherited disorder, gene correction is clearly necessary to alter the trajectory of disease burden. We have a developed an approach to deliver a healthy copy of the faulty gene directly into brain and spinal cord.

We have tested this in mice with the disease and have made key insights into a cell type critical to this process: neurons in the brain and alongside the spinal cord. With this knowledge we are now improving gene delivery using new viral vectors.

Importantly we have also developed industry partnerships that can help with manufacturing and setting up future clinical trials. Beyond creating a much-needed treatment, we are also through our studies gaining a better understanding of the disease biology of adrenomyeloneuropathy.

Project financed by ELA up to: 92 300 €