New drug candidate slows progression of adrenoleukodystrophy

The work of Professor Fanny Mochel (AP-HP, Sorbonne University) at the Institut du Cerveau, in collaboration with clinical research teams spread over eight countries and the Spanish biotech Minoryx Therapeutics, has highlighted the protective effects of leriglitazone in the development of adrenoleukodystrophy, a rare genetic disease in which there is damage to the white matter of the central nervous system. The researchers’ results are described in The Lancet Neurology.

Most rare neurodegenerative diseases suffer from the lack of effective treatments. This is the case of X-linked adrenoleukodystrophy (or X-ALD), a hereditary condition that affects 6 to 8 births out of 100,000. It is characterized by the excessive accumulation of very long chain fatty acids in body tissues, including the brain, spinal cord and adrenal glands.

When they reach adulthood, these patients present with spinal cord degeneration. As a result, they often manifest adrenomyeloneuropathy (AMN) causing chronic disabling symptoms, in particular walking stiffness and balance disorders that increase the risk of falls. Urinary disorders are frequently associated.

Change the trajectory of the prognosis

The disease is progressive, and because it is linked to a mutation on the X sex chromosome, its most serious forms mainly affect male subjects. It is estimated that a third of boys and more than half of men affected by AMN also develop an aggressive inflammation of the brain, called cerebral adrenoleukodystrophy (cALD), in which the myelin sheaths that surround neuron extensions are attacked. Disturbances in the circulation of nerve impulses cause rapid cognitive and motor decline, the outcome of which can be fatal within a few years.

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Controlling inflammation appears to be an avenue to explore in order to slow the progression of the disease and alleviate the symptoms, since no pharmacological treatment currently exists. This is the path taken by the teacher Fanny Mochel at the Paris Brain Institute, in collaboration with European and American teams.

In ADVANCE, a randomized, double-blind, placebo-controlled study, researchers studied 116 adult male patients with clinical signs of adrenomyeloneuropathy for two years to test the effectiveness of a new drug developed by the Spanish biotech Minoryx Therapeutics: leriglitazone. Able to enter the brain, this molecule, a PPAR gamma agonist, regulates the expression of genes that contribute to the neuroinflammation and neurodegeneration observed in disease progression.

Promising results

At the end of ADVANCE phase II/III, researchers found that taking leriglitazone daily reduced the progression of some key symptoms – such as unsteadiness of standing – and more importantly reduced the risk to see the appearance of cALD, the acute cerebral form of the disease, very dreaded because it is associated with premature death. Only patients in the placebo group were affected by cALD, suggesting a protective effect of the drug.

Daily intake of leriglitazone has only caused side effects of moderate severity – mainly weight gain and superficial edema. This safety profile is therefore likely to promote adherence to treatment.

The study is now undergoing an extension phase in order to confirm the ability of the molecule to delay the progression of the disease. In addition, Professor Mochel’s team now treats around ten adult patients with cALD in a compassionate setting, and has observed stabilization or even regression of brain damage in them.

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Given these very encouraging results, a marketing authorization application for leriglitazone has been filed with the European Medicines Agency for the treatment of adult male patients with X-linked adrenoleukodystrophy. .

Better monitoring for better care

The need for an effective and non-binding treatment is indeed pressing: currently, only hematopoietic stem cell transplantation is likely to cure cALD. It is a heavy procedure associated with chemotherapy; it requires finding a donor, which can be difficult: close relatives may carry the genetic abnormality present in X-linked adrenoleukodystrophy.

Finally, the challenge today is to identify patients with adrenoleukodystrophy as early as possible and to monitor them throughout life, in particular via MRI imaging. Fanny Mochel now coordinates, for this purpose, a national surveillance network within the Reference Center for leukodystrophies and leukoencephalopathies based at the Pitié-Salpêtrière Hospital.

Following the results of the Advance study, leriglitazone will be evaluated for other indications in which it is likely to act on neuroinflammation, in particular other forms of leukodystrophies.


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’, The Lancet Neurology, 2023; 22: 127–36.

doi: 10.1016/PIIS1474-4422(22)00495-1

Team “Mov’It: Movement, Investigations, Therapy. Normal and abnormal movement: physiopathology and experimental therapy”


MD, PhD, PU-PH, Sorbonne University, AP-HP
MD, PU-PH, Sorbonne University, AP-HP

Basal ganglia, neurosurgery, abnormal movements
Main field: Neurophysiology
Secondary domain: Clinical and translational neurosciences

The Mov’it team, led by Marie VIDAILHET & Stéphane LEHERICY aims to study the dysfunctions of neural networks in pathologies of movement and behavior. The team’s approach is based on neuroimaging, neurophysiology, genetics and metabolomics in animals and humans.

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