New Hope for Treatment of Rare Metabolic Brain Disease

Scientists reveal the results of a controlled clinical trial for a new drug to treat X-linked adrenoleukodystrophy.

X-ALD is the most prevalent of the approximately 50 rare diseases that affect the white matter of the brain, referred to as leukodystrophies. The genetic damage in X-ALD is due to a defect in the X chromosome. Men who are affected by X-ALD experience a progressive deterioration of their mobility, balance, and sensory abilities, leading to issues such as incontinence and sexual dysfunction.

Although X-ALD is inherited through the X chromosome, female carriers can also experience symptoms of the disease. Approximately 30% of male children and 60% of adult men develop encephalitis, which is a fatal form of the disease that leads to death within two to three years. X-ALD affects roughly one in every 20,000 births globally.

Now, for the first time, scientists from all relevant leukodystrophy centers in Europe and the US have jointly succeeded in obtaining controlled trial data for X-linked adrenoleukodystrophy. Of the 116 patients, 77 received the drug leriglitazone and 39 a placebo. The drug had already shown in preclinical studies that it can prevent neurodegeneration and offer protection against the life-threatening inflammation of the brain.

“Our clinical trial has in fact also shown that none of the patients who took the drug were affected by brain inflammation. In contrast, among the participants who were given a placebo, 15 percent developed this life-threatening form of the disease within two years,” explains study leader and first author Dr. Wolfgang Köhler, head of the leukodystrophy outpatient clinic at the Department of Neurology at Leipzig University Hospital.

The actual aim of the study had been to show that the drug would prevent gait disorders in X-ALD patients from worsening over the course of two years. “This worked particularly well in those who were treated early. The more advanced the gait disorder, the less apparent the effect. Overall, there was no significant difference, so the actual aim of the study was not achieved,” explains Dr. Köhler. Nevertheless, many points indicated a clinical effect of the new drug: besides the indication that brain inflammation could be prevented, other effects included improvements in neurological conditions such as balance disorders, which had a positive impact on quality of life.

More Information on the Study

All participants in the study currently have the option to continue treatment with leriglitazone for a total of five years as part of an open-label extension study. In addition, follow-up studies are planned in patients with pre-existing involvement of the brain. “This gives us hope that we will also be able to effectively treat patients with advanced, inflammatory brain involvement with a drug in the future, especially those whom we can no longer help with a stem cell transplant. This is only possible at a very early stage of brain inflammation,” explains Dr. Köhler.

A center for myelin disorders, which include leukodystrophy and multiple sclerosis, is to be established at Leipzig University Hospital before the end of this year, and will be the first of its kind in Germany. “With such rare diseases, it is of utmost importance to bring together the excellence of different areas of treatment and research in order to jointly gain new insights and make further progress,” says initiator Dr. Köhler.

Reference: “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” by 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 and Syed Hashmi, 19 January 2023, The Lancet Neurology.
DOI: 10.1016/S1474-4422(22)00495-1

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is currently reviewing the marketing authorization application of the Spanish pharmaceutical company Minoryx for the drug leriglitazone for the treatment of adult male patients with X-ALD. This study was sponsored by Minoryx.

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