- MIROCALS (Modifying Immune Response and Outcomes in ALS) is a phase 2b randomised placebo-controlled trial investigating the efficacy and safety of a low dose interleukin 2 (ld IL2) in people with amyotrophic lateral sclerosis (ALS)
- 220 participants were recruited in 17 ALS Centres and France, randomised to either ld IL2 or placebo for 18 months and followed for up to 21 months
- The results provide encouraging evidence, from a randomised placebo-controlled drug trial, in support of immune system modification and neuroinflammation as viable targets for altering ALS disease progression.
The MIROCALS (Modifying Immune Response and Outcomes in ALS) Trial Consortium - which includes scientists from the University of Sheffield - have today announced the top-line results from the phase 2b trial of a low dose Interleukin-2 (ld IL2) in patients with Motor Neurone Disease (MND).
The results were presented on the opening day of the MND Association’s 33rd International Symposium.
The MIROCALS trial, conducted in 17 clinics across the UK and France, in collaboration with eight leading research groups in the UK, France, Italy and Sweden, tested whether low doses of IL2 can alter aspects of the immune system associated with inflammation in the central nervous system, which is believed to play an important role in the speed at which MND progresses - also known as amyotrophic lateral sclerosis (ALS).
Following a 12-week run in period while starting treatment with riluzole (the accepted standard drug treatment), a total of 220 people with MND attending 17 specialist clinics in the UK and France were randomised in equal proportion to receive subcutaneous injections of low-dose interleukin-2 or placebo for a period of 18 months, with the primary outcome to demonstrate a treatment-related decrease in the rate of death.
The treatment was well tolerated, with adverse events recorded as mostly mild to moderate, occurring across both active treatment and placebo arms. Effective target engagement, measured by elevation in plasma regulatory T cells (Tregs) was also demonstrated, confirming the results of a previous pilot study which showed that IL2 decreases inflammatory markers in the blood).
The primary unadjusted analysis of survival showed a small (19 per cent) but not statistically significant decrease in the risk of death at 21 months.
The primary core biomarker (CSF pNFH) revealed a highly significant association between CSF pNFH levels and survival. Furthermore, pre-planned analysis of efficacy adjusted on the level of CSF pNFH at randomisation showed a significant effect in favour of IL2 on disease progression and survival.
CSF pNFH measurements were critical in the context of developing a ‘personalised medicine approach’ by defining groups of participants with different responses to IL2. According to CSF pNFH levels, in about 20 per cent of the population no significant treatment effect could be detected in these rapidly progressive patients all with high CSF pNFH levels.
However, 80 per cent of the population had low to moderate CSF pNFH levels, correlating with less aggressive disease progression and for these patients there was a significant decrease in the risk of death of over 40 per cent.
Dame Professor Pamela Shaw, Sheffield Principal Investigator of the study and Director of the Sheffield Institute for Translational Neuroscience (SITraN), and National Institute for Health and Care Research (NIHR) Sheffield Biomedical Research Centre said: "MND is such a cruel disease and any research which brings forward a new treatment approach is very important. The results of this pioneering drug trial of low dose interleukin 2 are complex but encouraging and highlight the importance of reducing the inflammation which occurs in the nervous system as motor neurons are becoming injured.
“This treatment approach may slow down disease progression at least in some patients. Life expectancy for patients with MND is usually between two-three years from onset of symptoms, so being able to reduce the speed of progression of debilitating symptoms would make a tremendous difference to patients and their families.
“To be part of the international team of clinicians and scientists working on the study for the past five years has been an honour. Huge thanks are due to the patients, supported by their families and friends, and who allowed us to test this experimental treatment. I hope that the results of the MIROCALS trial represent an important step towards an effective new therapy for MND."
Dr Gilbert Bensimon, Lead Investigator and Project Co-ordinator, Centre Hospitalier Universitaire de Nîmes (CHU) said: “While the primary unadjusted survival analysis was not significant, the pre-planned adjusted analysis - an approach recommended by the US Food and Drug Administration - shows a positive effect of IL2 on survival.
“Furthermore, a joint rank analysis of survival and function also showed significant benefit with IL2 compared to placebo. These results indicate that IL2 does have a beneficial effect in ALS, but clearly further studies are needed to see if this effect can be enhanced by different treatment schedules and by exploiting the insights we have gained by integrating CSF pNFH and other biomarkers into the trial design.
“Peripheral changes in immune processes and their knock-on impact on central neuroinflammation have emerged as exciting targets for therapy development. MIROCALS is the first large scale randomised placebo-controlled trial to demonstrate ‘proof of principle’ in relation to IL2 with the potential to translate into clinical benefit for people living with this devastating condition.”
An important feature of the MIROCALS trial is the attention devoted to the rigorous collection and analysis of blood and cerebrospinal fluid samples through the course of the study to confirm the relevance of emerging disease biomarkers, whilst seeking to identify novel biomarkers and therapeutic targets for future drug development.
“A key strength of MIROCALS has been the collaboration of leading European research groups in immunology, biomarker development and genomics,” said Professor Nigel Leigh, co-lead and chief trial investigator, of Brighton and Sussex Medical School.
“There remain many questions to address, but the wealth of data and samples accumulated are supporting ongoing research to better understand the factors that drive ALS disease progression. These will hopefully open the door to new therapeutic avenues and more personalised approaches to treatment, to deliver even more positive outcomes in future trials.”
Additional analysis of samples and data, maintained in a central biobanking facility in France, are being performed across various MIROCALS consortium laboratories in the UK, Italy, and Sweden, with further findings to be announced in the coming months.
“ALS is a relentlessly progressive and devastating disease that robs people of their independence and ultimately their lives,” said Dr Brian Dickie, Director of Research for the UK-based Motor Neurone Disease Association.
“Taking part in clinical trials requires a significant commitment from people with ALS and we are so grateful of everyone who volunteered for this important and ground-breaking study.”
Dr Bensimon added: “There is still work to be done with sample analysis to understand the beneficial biological effects that we believe are occurring, as well as addressing issues around drug formulation and administration. But the priority will be the discussion with drug regulatory agencies on the next steps to hopefully add this promising treatment to the ‘tool kit’ of therapeutic options available to the medical and patient community.”