A major clinical trial has revealed that low-dose interleukin-2 (IL2LD) therapy may significantly extend survival in people with motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS). The landmark MIROCALS (Modifying Immune Responses and Outcomes in ALS) trial found the treatment to be safe and demonstrated a substantial survival benefit in a majority of participants.
Motor neurone disease affects approximately 45,000 people across Europe, attacking the nerves that control movement and causing progressive muscle failure. The condition is typically aggressive, with about 25% of patients dying within one year of symptom onset and more than half within two to three years of diagnosis.
Trial Design and Key Findings
The MIROCALS trial recruited 220 newly diagnosed MND/ALS patients between 2017 and 2019. All participants initially received riluzole (the standard treatment) before being randomized to receive either IL2LD or a placebo for 18 months in a double-blind setting.
While the primary analysis did not show a significant survival benefit across all participants, a pre-planned detailed analysis revealed a statistically significant survival advantage in approximately 80% of study participants. These individuals had lower levels of phosphorylated neurofilament heavy chain protein (pNFH) in their cerebrospinal fluid, a biomarker indicating a slower rate of motor neuron damage.
"In these people, the risk of death at the end of the study was reduced by over 40%," said Professor Dame Pam Shaw, Principal Investigator of the MIROCALS trial from the University of Sheffield's Institute of Translational Neuroscience.
The drug was well-tolerated with no excess side effects compared to placebo, addressing a critical safety concern for long-term treatment options.
Mechanism of Action
Interleukin-2 is a molecule known to regulate the immune system. The drug used in the trial, aldesleukin, is a manufactured human interleukin-2 that has previously been used at high doses to treat certain cancers.
Low doses of interleukin-2 work by specifically reducing inflammation through increasing the number of regulatory T cells (Tregs) in the blood. Previous research has suggested that inflammation in the central nervous system is linked to faster MND/ALS progression, while higher numbers of Tregs correlate with better survival outcomes.
Professor Timothy Tree from King's College London, one of the study's joint first authors, emphasized the significance of these findings: "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."
International Collaboration
The MIROCALS project was sponsored by the University Hospital of Nîmes (France) and coordinated by Dr. Gilbert Bensimon from the University Hospital of Nîmes and Professor Nigel Leigh from Brighton and Sussex Medical School.
The consortium included research institutions and medical centers across the UK, France, Italy, Sweden, and Ireland. In the UK, Sheffield Teaching Hospitals Foundation Trust was the second-highest recruiter, contributing 18 patients to the study.
"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," stated Dr. Bensimon. "Our findings underline the importance of the immune system as a target for treatments aimed at slowing the progression of this devastating condition."
Implications for Treatment Development
Professor Janine Kirby, Principal Investigator within the MIROCALS Consortium from the University of Sheffield, highlighted the broader implications: "Alongside more personalized gene therapies for MND/ALS, this trial offers significant evidence that modifying the immune system, specifically by providing a low-dose of IL-2, can benefit a broad range of people living with MND/ALS."
While IL2LD is not currently licensed for MND/ALS treatment, the MIROCALS results suggest it should be considered for development as a safe and well-tolerated treatment that could complement the disease-modifying effect of riluzole.
Path to Regulatory Approval
In 2023, ILTOO Pharma was granted the exclusive license of the MIROCALS trial data by the consortium and has begun the process of seeking regulatory approval for IL-2LD as an 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."
Future Research Directions
The data and biological samples donated by trial participants are now being used to advance understanding of ALS and help develop new therapies that can further slow disease progression.
Professor Leigh emphasized the importance of continued research: "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."
The trial was funded by awards from the European Commission H2020 programme, The Programme Hospitalier pour la Recherche Clinique (PHRC, French Health Ministry), and several UK and French charitable organizations including The Motor Neurone Disease Association, The My Name'5 Doddie Foundation, MND Scotland, AFM-Téléthon France, and Association pour la Recherche sur la SLA.
