This blog is part of our Symposium Spotlight series, where we’re looking back on some of the research that was presented at the 33rd International Symposium on ALS/MND. Today we’re taking a closer look into talks given as part of the Clinical Trials session to provide updates on 4 trials for MND/ALS.
Over the last year ALS/MND clinical trials have taken centre stage, with more trials than ever opening for recruitment in the UK, the news of promising results from some trials and the approval of drugs by some regulatory authorities. With the year coming to an end, we thought we would roundup some recent clinical trial updates that were presented at the 33rd International Symposium on ALS/MND.
Inflammation in the brain and the spinal cord is thought to contribute to MND progression. RNS60 is hoped to have anti-inflammatory properties, to help reduce this inflammation, as well cytoprotective properties, meaning it could help to protect cells from harmful agents which may be linked to ALS/MND.
A 24-week randomised, double-blind, placebo-controlled phase 2 trial was completed. This means that the participants were randomly assigned to either the RNS60 treatment group or the placebo (dummy drug) group for 24-weeks, and neither the participants nor those running the trial knew who was in which group. The primary outcome of the trial was measuring the effect of RNS60 on biomarkers, biological fingerprints of the disease, to see if the treatment was interacting in the body as thought. Other endpoints, such as the effect on function, survival and safety and tolerability of the treatment were also measured.
The results from the trial found that unfortunately there were no statistically significant differences between the treatment and the placebo on any of the biomarker measures or when measuring function using the ALSFRS-R. However, there were hints of promising trends when looking at Forced Vital Capacity (FVC), which is a measure of respiratory function. The researchers found that those who received the treatment had a reduced decline in respiratory function compared to those who received the placebo. The results from this trial support the need for additional trials to investigate the use of RNS60 in people living with ALS/MND further.
In MND/ALS it is thought that there might be problems with energy production within cells and this could mean that neurons don’t have the amount of energy they need to function as they should. CNM-Au8 is an oral liquid which contains gold nanocrystals and it may help to increase energy production which could improve the survival, function and communication of neurons in people with MND/ALS.
A phase 2 trial of CNM-Au8 was conducted in 45 people with MND/ALS and the participants were randomly assigned to either the placebo or CNM-Au8 group for 36 weeks. The primary outcome of the study was the change in a measure called the ‘Motor Unit Number Index’ (MUNIX), which is a quantitative neurophysiological measure that can be used to estimate the number of motor neuron and muscle connections. Other endpoints were also measured including respiratory function using forced vital capacity and disease progression using the ALSFRS-R. The trial did not meet it’s primary endpoint but there were positive trends suggesting that CNM-Au8 may be beneficial for MND/ALS as there were statistically significant reductions in ALS disease progression and ALSFRS-R score and there was also evidence for potential long-term survival benefit.
Participants on this trial were able to take part in the open label extension. This is where all participants could have CNM-Au8 regardless of whether they were previously in the CNM-Au8 or placebo group. They were followed up for up to 48 weeks to see if taking CNM-Au8 earlier and for longer led to an increased benefit. The open label extension data has suggested that CNM-Au8 may improve survival if it is taken for longer, as those who started on CNM-Au8 at the beginning of the trial were found to have a 70% reduction in risk of death compared to those who were originally on placebo.
These findings support the testing of CNM-Au8 in further trials to understand more about its effect on survival and a phase 3 trial is currently being planned. CNM-Au8 is also being tested as part of the Healey Platform Trial and we are looking forward to hearing more about the results of this in a session at the Symposium on Friday.
Several gene mutations have been found to be associated with the development of MND/ALS. One of these is a mutation in the SOD1 gene, which causes the production of a faulty SOD1 protein. The faulty protein misfolds in neurons in the brain and spinal cord and this is thought to contribute to the development of the disease. Tofersen is an antisense oligonucleotide which has been designed to target the genetic instructions for the faulty SOD1 protein and aims to reduce the amount being made.
The VALOR trial of Tofersen, a phase 3 randomised placebo-controlled trial, was completed in 108 participants. Participants were randomly assigned to either the Tofersen treatment group or the placebo group for 28-weeks. The primary outcome of this trial was measuring the effect of Tofersen on function using the ALSFRS-R. The results of the VALOR trial found that there were no significant differences in function between those on Tofersen and those on placebo. However, there were some promising signs that treatment with Tofersen did reduce SOD1 protein levels and also helped to decrease levels of a biomarker called Neurofilament light chain (a marker of neuron damage), suggesting a decrease in disease activity and progression.
After the 28-week trial, participants were invited to take part in an open label extension and were followed up for around 52 weeks to determine if talking the treatment for longer led to more of an effect. The results from the open label extension demonstrated that Tofersen may be effective if taken for a longer period of time. The open label extension showed that taking Tofersen for longer led to improvements or stabilisations in function, muscle strength and respiratory function. It has also been found that Tofersen may have a positive effect on body weight, with those who took Tofersen for longer either gaining weight or not losing any further weight. This suggests that Tofersen may be beneficial for people with SOD1 MND/ALS and a new drug application has been made to the FDA for Tofersen, with a decision expected by 25 April 2023.
Blog | 10 June 2022 | Charlotte Roy
VALOR Biogen’s Tofersen trial: a look at the open label extension data
Inflammation and immune system changes are thought to play a role in the progression of MND/ALS. A drug called Interleukin-2 (IL-2) has been found to increase the number of immune cells that reduce inflammation when given at low doses. It is hoped that a low dose of IL-2 could have an effect on disease progression for people with MND/ALS.
The MIROCALS (Modifying Immune Response and OutComes in ALS) trial, a phase 2 randomised placebo-controlled trial, was conducted in 220 participants from 17 MND/ALS centres in UK and France. Participants were followed for a preliminary 3 month ‘run in’ phase, before then being randomised to either IL-2 or a placebo for 18 months. The primary outcome of the trial was measuring the effect of IL-2 on survival and there were also a number of secondary outcomes, including changes in quality of life, function and biomarkers of MND/ALS in the blood and cerebrospinal fluid.
IL-2 was found to be safe and well tolerated, side effects were minimal across both treatment and placebo. When the whole trial population was analysed, treatment with IL-2 showed a modest decrease in risk of death for those on the treatment over the 21 months of the study, but this was found not to be statistically significant. However, when the survival analysis data was examined by subgrouping people using a particular biomarker they found a larger and statistically significant effect on survival for those who received the treatment. This effect equated to an over 40% decrease in the risk of death at 21 months for a large proportion (80%) of the overall trial population who received IL-2. Further analysis of the results is being conducted to understand how IL-2 affects the underlying biology of the disease. The lead researchers on the trial are prioritising discussions with drug regulatory bodies to determine next steps.
Blog | 05 December 2022 | Charlotte Roy
Breaking down the MIROCALS clinical trial results
We know how important being up to date on the latest trials is to the MND community so we will always endeavour to keep you updated with all the latest news and updates. For the latest information you can follow us on twitter, sign up to our research monthly newsletter or check out our latest news page.
Clinical trials and the results coming from them would not be possible without the dedication, generosity and commitment of the entire MND community. Each and every person who is involved in clinical trials is helping us get closer to effective treatments for MND, and hopefully a cure.