This blog is part of the ‘Highlights from Perth’ collection of articles, where you can read about the content of some of the talks and posters presented at the 30th International Symposium on ALS/MND in Perth.
With this years International Symposium on ALS/MND now behind us, it is time to reflect on some of the news that was presented by researchers.
Researchers are invited to present their work as either a platform (oral) presentation or as a poster. Results and updates from several clinical trials of potential new treatments for MND were presented as posters, and some of these have also found their way into various online news articles. This blog will look at some of these results and their potential as new treatments for MND.
Ibudilast (MN-166): Phase 2 clinical trial
MediciNova’s experimental therapy, ibudilast (MN-166), may be most effective as a treatment for MND in people who are less than 18-months from symptom onset, researchers announced.
Ibudilast is a small molecule that targets three particular proteins in cells, and is thought to reduce levels of inflammatory molecules in the body while increasing levels of neurotrophic factors, which support the growth and survival of both developing and mature motor neurons.
The new analysis is taken from data collected in a Phase 2 clinical trial designed to study the safety and effectiveness of ibudilast as an add-on treatment to riluzole. Fifty-one people with MND, at different stages of disease, were randomly assigned to either six months of treatment with ibudilast or a placebo.
Initial analysis of data from this trial did not show a difference in disease progression between the treatment and placebo groups, as measured by ALSFRS-R scores (ALSFRS-R is a standard measure of functional decline) after six months of treatment, despite promising results from a previous trial. This was attributed to participants being at different stages of disease at the beginning of the trial.
On reanalysis of the data, where participants were split into those with a short MND history (less than 600 days since symptom onset) and those with a long MND history (more than 600 days since symptom onset), the researchers found that those with a short MND history had slower progression after six months of treatment, as measured by ALSFRS-R scores, than those who had received a placebo. This suggests that ibudilast is more effective in people with a short MND history.
A Phase 2b/3 clinical trial is due to begin recruiting shortly to test the effectiveness of ibudilast in people with MND who are less than 18-months since symptom onset. Two hundred and thirty people with MND will be randomly assigned to either the ibudilast group or the placebo group and will be assessed over 12 months of treatment. The trial will be followed by an open-label extension phase, meaning that all participants will be given the opportunity to receive ibudilast.
Levosimendan: LEVALS and REFALS Phase 2 and 3 clinical trials
Researchers from Orion Corporation presented new data on levosimendan’s mechanism of action and potential biomarkers of MND progression in four posters.
Levosimendan is a small molecule that acts on increasing calcium sensitivity in both heart and skeletal muscle fibres and was originally developed by Orion to treat acute heart failure. Because levosimendan can improve function of skeletal muscle, including those that control breathing, Orion has been evaluating the potential of the drug in preserving lung function and delaying the need for ventilation support in people with MND.
Previous studies have shown that levosimendan improves lung muscle function, blood circulation in the brain and reduces cell death, and that it has antioxidant and anti-inflammatory properties. These have all been associated with the development of MND, suggesting that levosimendan may also act on underlying mechanisms of disease as well as having an effect on skeletal muscle function. Researchers concluded that these effects should be confirmed in further studies.
Another of Orion’s posters focused on their research to identify biomarkers of MND progression in the LEVALS Phase 2 clinical trial. This involved 66 people with MND who were randomly assigned to the levosimendan or placebo groups. To identify potential biomarkers of disease progression lab data, ALSFRS-R and slow vital capacity (SVC) scores were assessed during the trial and in an open-label extension period. SVC is the maximum volume of air that can be slowly inhaled or exhaled in a given position and is used to assess lung function.
Results showed that levels of creatinine – a muscle biomarker – dropped significantly over time in people with MND in line with the decline of muscle function. Other muscle markers, and proteins associated with liver function, were also significantly associated with ALSFRS-R and/or SVC scores. Researchers found that participants treated with levosimendan showed improvement in several of these markers suggesting that some could be potential biomarkers of MND progression and response to treatment.
The remaining two Orion posters gave updates on the current Phase 3 REFALS trial, which is evaluating the effectiveness of oral levosimendan in preserving lung function in almost 500 people with MND, over 48 weeks of treatment. This will be followed by an open-label extension study to assess the long-term safety and effectiveness of the drug.
AMX0035: CENTAUR Phase 2 trial
Updated results from the CENTAUR Phase 2 trial show that Amylyx’s investigational oral treatment, AMX0035, significantly slowed progression in people with rapidly advancing MND compared to those participants who received a placebo, as measured by ALSFRS-R scores.
AMX0035 is a combination therapy that includes two small molecules – tauroursodeoxycholic acid (TUDCA for short) and sodium phenylbutyrate, which aims to preserve motor function rather than treat the root cause of MND. Both of these molecules block stress signals within the mitochondria (which provide cells with energy) and the endoplasmic reticulum (which is involved in making proteins), therefore preventing cell death.
The trial compared the effectiveness of AMX0035 to a placebo in 132 people with MND over a 24-week period, followed by an open-label extension study. This trial is expected to finish soon. More detailed results will be published in due course.
Reldesemtiv: FORTITUDE-ALS Phase 2 trial
Treatment with oral reldesemtiv appears to slow the deterioration of function, including breathing capacity and muscle strength in people with MND – regardless of whether they are taking riluzole or edaravone.
Reldesemtiv is a fast skeletal muscle tropin activator, intended to slow the decline in muscle and physical function in people with MND and spinal muscular atrophy (SMA).
The study, which has now finished, assessed the effects of reldesemtiv on respiratory function and other measurements of muscle function in 458 people with MND, who were randomly assigned to either the treatment group or placebo group, over 12 weeks of treatment.
Using ALSFRS-R and SVC scores, participants taking reldesemtiv did not progress as quickly as those taking placebo, with greater effects becoming more evident over time. Despite a constant trend toward slower disease progression, the differences in ALSFRS-R and SVC scores between the drug and placebo groups was not statistically significant (statistical significance is the likelihood that a relationship between two or more variables is caused by something other than chance). However, the new analyses shows that reldesemtiv’s effect on overall disability, respiratory function and muscle strength is maintained whether or not patients are already being treated with riluzole or edaravone. If these effects can be confirmed in a Phase 3 trial, reldesemtiv will likely be useful when taken with existing treatments.
Reldesemtiv is being developed by Cytokinetics in collaboration with Astellas.
On 18 December Cytokinetics announced that the US Food and Drug Administration (FDA) has granted orphan drug status to reldesemtiv for the treatment of MND. Orphan drug status is given to drugs intended for treatment of chronic or life-threatening diseases that are considered rare – known as orphan diseases. MND is considered to be an orphan disease in the USA and Europe. You can read more about what orphan drug status means in our Information Sheet H: Accessing unapproved drugs.
Results from Phase 2 trials should be viewed with ‘cautious optimism’. There have been many drugs tested at Phase 2 that have not stood up to Phase 3 scrutiny. However, it is encouraging that investment in research investigating potential new treatments continues around the world. We will follow these, and other, clinical trials with interest and will report on results as soon as they are published.
Find out more about the topics discussed in Perth at the Symposium on our Periodic table of MND Research at www.mndassociation.org/symplive.