Motor Neuron Disease Drug Safe and Effective at Low Doses

New research from the MIROCALS (Modifying Immune Responses and Outcomes in ALS) clinical trial has found that low-dose interleukin-2 (IL2_LD) is both safe and effective for use on people with Motor Neurone Disease (MND), also known as amyotrophic lateral sclerosis (ALS) compared to placebo.

The research, published in The Lancet, did not show an overall improvement in survival rates, it did find a statistically significant survival benefit in about 80% of the study participants with a key biomarker.

Interleukin-2 is a molecule known to regulate the immune system in humans. The drug used in the trial, aldesleukin, is a manufactured Human Interleukin-2 which has been used in high doses in some cancers. Low doses of interleukin-2 (IL2_LD) have been found to specifically reduce inflammation by increasing the number of white blood cells known as regulatory T cells (Tregs) in the blood. Previous studies have suggested that inflammation in the central nervous system is linked to an increased rate of progression of ALS/MND, and that increased numbers of Tregs are associated with better survival.

Between 2017 and 2019 the MIROCALS trial recruited 220 people newly diagnosed with ALS/MND, who were initially treated with riluzole (the standard treatment for ALS/MND) before being randomized to receive either IL2_LD or a placebo for 18 months. The trial was double-blind, to prevent participants and investigators knowing which treatment participants were given. During the trial safety was monitored and day-to-day function measured. As ALS/MND greatly shortens life, the key (primary) measure of the effect of IL2_LD at the end of the trial was survival.

Researchers found that IL2_LD was safe with no excess of untoward effects compared to placebo. Although the primary analysis of survival did not show a significant benefit for survival, a pre-planned more detailed analysis taking into account the complexity of ALS revealed a statistically significant survival benefit in about 80% of the study participants who had lower levels of cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain protein (pNFH), a biomarker indicating the rate of motor neuron damage. In these people, the risk of death at the end of the study was reduced by over 40%.

Dr Gilbert Bensimon, MIROCALS study coordinator and principal investigator, stated: "ALS/MND is a complex disorder. The encouraging findings of the MIROCALS trial represent a significant step toward designing better trials and expediting the development of urgently needed treatments for ALS/MND. Importantly IL2_LD, was safe and well-tolerated over a long period. Our findings underline the importance of the immune system as a target for treatments aimed at slowing the progression of this devastating condition.”

Professor Nigel Leigh, Chief Investigator and co-coordinator of the MIROCALS study, and Professor of Neurology at BSMS, added: "This trial provides very promising evidence that IL2_LD benefits people with ALS/MND. The data, blood and CSF samples from the people who generously took part in the trial are now being used to advance our understanding of ALS and help the development of new therapies that can further slow disease progression and improve the lives of people living with ALS/MND. We are extremely grateful to The Motor Neurone Disease Association, The MyName’5 Doddie Foundation, MND Scotland, AFM-Téléthon France, and Association pour la Recherche sur la SLA who have contributed to this ongoing work.”

Professor Timothy Tree, Professor of Immune Regulation and Immunotherapy at King's College London and one of the study's joint first authors said, "These groundbreaking results offer the strongest evidence yet that targeting the immune system can make a real difference in the fight against this devastating disease. Thanks to the generosity of our trial participants, who donated vital samples, we are now conducting further research to better understand how the immune system drives disease progression anddevelop even more effective treatments.”

Reference: Bensimon G, Leigh PN, Tree T, et al. Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial. The Lancet. doi: 10.1016/S0140-6736(25)00262-4

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