The results of the MIROCALS clinical trial into the effects of low dose interleukin-2 (IL-2) on people with MND have now been published in The Lancet along with an accompanying independent commentary which provides additional context and perspective. The paper is a scientific one so we’re taking this opportunity to explain the science in what we hope is a more digestible way.
Interleukin-2 (IL-2) and MND
Interleukin-2 (IL-2) is a protein that our bodies produce naturally to help us regulate our immune systems and control inflammation. Some decades ago, researchers developed a man-made version of IL-2 in the hope that it could be used to treat a number of diseases, and it was first used clinically as a cancer treatment in the 1990s. Because inflammation is thought to contribute to MND progression, researchers decided to test whether a low dose of IL-2 could be an effective treatment for MND.
The MIROCALS trial
To test whether IL-2 could help delay MND progression, researchers recruited 220 people in the UK and France, all recently been diagnosed with MND.
Half of the participants were given low dose IL-2, and the other half were given a placebo (a “dummy” treatment with no active ingredient). Neither the participants nor their clinicians knew which group they were in. The researchers then tracked all participants over 21 months.
The idea was that if a higher proportion of those taking IL-2 were still alive after 21 months compared to those on the placebo, that would suggest IL-2 was responsible for them living longer.
What did the top-line results show?
By the end of the 18 months, 69 of the 110 people who had been taking IL-2 were still alive, compared to 61 of the 110 people on the placebo. However, the difference was too small to be confident this wasn’t just down to chance.
So, while IL-2 might be the reason more people taking it were still alive after 21 months, the results fall short of being compelling evidence. Detailed analysis of this result showed that it is not statistically significant, meaning that the difference between the groups could simply be down to chance and, if the trial was repeated, you would be equally as likely to get the opposite result.
So, the trial did not meet its primary aim of showing that IL-2 is an effective treatment for MND.
Delving into the data
As well as looking at the overall results, after the trial, the researchers wanted to split the participants’ data into different groups to see if there was a subset of people that might be benefiting from the drug.
The level of a protein found in spinal fluid called phosphorylated neurofilament heavy chain (pNFH) was used to divide the participants into groups. The level of this biomarker protein that a person has gives an indication of the speed of their MND progression. Higher levels of pNFH is a sign a person’s MND is progressing more quickly; lower levels suggest slower disease progression.
Splitting the trial participants into different groups based on pNFH level would mean the researchers could look at the effect of IL-2 in more detailed scenarios.
There were 154 people with lower levels of the neurofilament biomarker. This was 70% of the total trial participants. There were 47 people (21% of the trial population) with the higher levels of the biomarker and the remaining 19 people (9%) had a level of pNFH that was too low to be measured.
High pNFH (fast progressing MND group)
In the group with high pNFH, fast progressing MND, a higher proportion of people taking IL-2 died – 20, compared with 13 on the placebo. Seven out of 20 (35%) people who took the placebo were alive at the end of the trial compared with seven out of 27 (26%) people who took low-dose IL-2. This raises the question of whether IL-2 may be causing harm to people with high pNFH levels. However, this difference is not statistically significant and could be down to chance. But it will be important to understand and rule this out in future research.
Low pNFH (slower progressing MND group)
In the group of participants with slower progressing MND, the researchers found that people taking IL-2 were more likely to be alive at the end of the trial – 55 out of 76 (72%) compared with people taking the placebo – 42 out 78 people (54%).
The statistical analysis reported that this difference is statistically significant.This suggests that the drug may provide a benefit to people with MND who have a low level of pNFH (slower progressing MND).
Dividing the participants into fast and slow progressors according to pNFH revealed some difference between placebo and IL-2 when examining ALSFRS-R
The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a tool used to monitor the progression of disability in people with MND. It measures the severity of MND using 12 categories, each with a maximum of four points, giving a maximum of 48 for full function. On average, someone with MND might expect to lose approximately one point per month.
Measuring the ALSFRS-R of participants in a clinical trial can therefore give an indication of any potential effects of a treatment through changes in an individual’s score and by comparison of average change in score between treatment and placebo groups.
Looking at everyone in the MIROCALS trial, there was no significant difference in the progression between people who were taking IL-2 and people who were taking the placebo.
However, dividing the participants according to their initial pNFH into fast and slow progressors revealed that in the low pNFH group, with slow progressing MND, the median rate of ALSFRS-R change per month was a drop of 1.06 points for people on placebo and 0.82 points per month for people on low dose IL-2. The difference between drug and placebo is a statistically significant difference of 23% which suggests that IL-2 may be having an effect on the MND progression of this slow progression group.
The change in ALSFRS-R of 0.82 points per month in the low dose IL-2 group does show that their MND was still progressing.
Neurofilament levels; What effect did low-dose IL-2 have on biomarkers of nerve damage during the trial?
Neurofilament is a marker of nerve damage, and can be useful to monitor throughout a clinical trial to see if a drug is having an effect on MND. Neurofilament appears in the blood and spinal fluid as motor neurones become damaged and break down. So, if a treatment is having a beneficial effect, neurofilament levels are expected to lower, as less damage is happening to neurones.
In the MIROCALS trial, pNFH (phosphorylated neurofilament heavy chain) was measured in samples of spinal fluid taken at regular intervals. No treatment-associated change in pNFH levels was detected. Further research would be needed to see if low-dose IL-2 does have an impact on nerve damage.
Summary
While some of the results seem promising, the results from the MIROCALS trial are complex.
Overall the data suggests that IL-2 is not an effective treatment for all people with MND. It may have a benefit for people with MND who have slower disease progression although the same analysis suggests that low-dose IL-2 may not be beneficial to people with MND with faster MND progression.
Given the complexity of the findings. We have asked the UK MND Clinical Studies Group to evaluate the results and provide guidance and advice to us and the MND community on next steps.
