Results of the MIROCALS (Modifying Immune Responses and Outcomes in ALS) clinical trial are published in The Lancet. This is the first study to investigate the effectiveness and safety of low-dose interleukin-2 (IL2LD) for amyotrophic lateral sclerosis (ALS), also known as Motor Neurone Disease (MND).
Key findings and implications for ALS/MND treatment
The trial demonstrated that IL2LD is safe, compared to placebo. Although the primary analysis did not show a significant benefit for survival, a pre-planned more detailed analysis taking into account the complexity of ALS/MND revealed a statistically significant survival benefit in about 80% of the study participants who had lower levels of a cerebrospinal fluid (CSF) biomarker (phosphorylated neurofilament heavy chain protein – pNFH) 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%.
These findings provide encouraging evidence that modifying the immune system could be a useful strategy for altering ALS/MND progression. While IL2LD is not currently licensed for ALS/MND treatment, the MIROCALS results suggest that IL2LD should now be considered for development as a safe and well tolerated treatment for ALS, adding to the disease-modifying effect of riluzole.
The MIROCALS trial
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 randomised to receive either IL2LD 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 is a fatal condition the key (primary) measure of the effect of IL2LD at the end of the trial was survival.
The MIROCALS project sponsored by the University Hospital of Nîmes (France) was coordinated by Dr Gilbert Bensimon, University Hospital of Nîmes, Sorbonne University of Paris and Assistance Publique-Hôpitaux de Paris, France, and Professor P Nigel Leigh, Brighton and Sussex Medical School, Universities of Brighton and Sussex, UK. The MIROCALS Consortium included prestigious research institutions, medical centres and logistical organisations, across the UK, France, Italy, Sweden and Ireland. The Partnership included researchers from the University Hospital of Nîmes, Assistance Publique-Hôpitaux de Paris (AP-HP), Brighton and Sussex Medical School, King’s College London, Queen Mary University of London, the University of Sheffield, Humanitas Institute of Milan and the University of Gothenburg, with biobanking expertise from Généthon, and logistical support from WGK Ltd and ICON plc. Additional grants from UK charity funder, the Motor Neurone Disease Association, were supported by the J P Moulton Charitable Foundation and the Garfield Weston Foundation. The clinical trial involved 7 ALS/MND Centres in the UK (6 in England, 1 in Scotland) and 10 in France.
Funded by awards from the European Commission H2020 programme, The Programme Hospitalier pour la Recherche Clinique (PHRC, French Health Ministry) and a number of UK and French charitable organisations, the trial aimed to explore the potential of interleukin-2 as a treatment for ALS/MND.
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 (IL2LD) have been found to specifically reduce inflammation by increasing the number of white blood cells known as regulatory T cells (Tregs) in the blood.
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 IL2LD, was 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 Brighton and Sussex Medical School, added: "This trial provides very promising evidence that IL2LD 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 My Name’5 Doddie Foundation, MND Scotland, AFM-Téléthon France, and Association pour la Recherche sur la SLA who have contributed to supporting the trial and the ongoing work.”
Future directions
In 2023, ILTOO Pharma was granted the exclusive license of the MIROCALS trial data by the MIROCALS Consortium and has engaged in the process of regulatory approval of IL-2LD for ALS treatment. “ILTOO Pharma is committed to promoting IL-2LD as a novel therapeutic approach for ALS,” said Professor José Achache, Chairman of ILTOO Pharma. “The MIROCALS study represents an important step forward for ILTOO Pharma, which is engaged with regulatory authorities, patient’s associations and the scientific community to accelerate the next phases of development towards market approval in ALS.
About ALS/MND
ALS/MND affects around 45,000 people in Europe at any one time. It attacks the nerves that control movement (motor nerves) so muscles no longer work, but does not usually affect the senses (sight, sound and feeling).
ALS/MND usually progresses relentlessly but at different rates in different people. Eventually it can leave people unable to move, talk and breathe.
About a quarter of people with ALS die within a year of developing symptoms and more than half within two to three years of diagnosis. However, some people with ALS/MND live for 10 years or longer.
Care involves coordinated support from health professionals and social services help with psychological and emotional adjustment, and expert advice and intervention on communication aids, nutrition, and breathing difficulties.
Although one drug, riluzole, has been shown to slow the progression of the disease a little, there is still no cure. The fundamental cause of ALS/MND is not yet understood.