Welcome to the MNDRA research update. In this report we will highlight outcomes and advances from the MND research world that have caught our attention over the last few weeks.
RELYVRIO
Amylyx have now announced they will be withdrawing Relyvrio from the US and Canadian markets. They have stated they will be providing the drug free-of-charge to those patients in the US and Canada who wish to keep taking the drug but have not indicated how long this will continue.
We commend Amylyx for consideration of the MND community in making these extremely difficult decisions.
Although there are not many treatment options for MND patients, it is critical that those we have are based on strong data and a robust approval process. We recognise this will be a massive financial hit for the company but they have placed the wellbeing of the community over their own business.
A great tweet from Ammar Al-Chalabi captures some key thoughts: “What can we learn from the sad failure of the Amylyx Phoenix trial: 1. A trial is designed to answer a specific scientific question. 2. If it "appears" to answer a different, more desirable question, that does not mean it did.3. You can do a trial quickly, cheaply or well.”
TUDCA
The TUDCA-ALS consortium have announced the TUDCA-ALS study did not meet the ALSFRS-R primary endpoint and there were also no significant differences observed across secondary endpoints. This 18 month Phase 3 trial tested TUDCA, one of the main components of Relyvrio (AMX0035), on its own. Perhaps no surprise following the Relyvrio outcome but still disappointing.
Monepantel
PharmAust announced they received the final ethics approval for their Open-Label Extension (OLE) study of monepantel (MPL). This allows the remaining three patients to be enrolled at Macquarie University. It is good to see Open-Label Extension being included in more and more trials and it should really be a requirement for relentlessly progressing diseases such as MND.
Patients cannot afford to test a drug for a while then wait months or years for the outcomes – if a drug might work then their payback for helping out testing should be at least to continue to obtain any possible benefits!
Radicava/Edaravone
A decision from the PBAC on listing Edaravone on the PBS is due imminently.
“Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study” by van Unnik and others
We need to understand better how we can use “wearables” to better monitor and measure MND. Working out how we can use these devices would enable near-continuous collection of data in the home setting, potentially enhancing the detection of treatment effects or identify the best care and treatment interventions on a timelier basis.
This study from a group in the Netherlands looked at whether using a hip-worn accelerometer to measure movement could detect MND disease progression and correlate this with overall survival. They showed this approach could predict disease progression rates and produced data that was strongly associated with overall survival. This study suggests we should incorporate accelerometer-derived outcomes in clinical trials, which will allow us to test the utility of this data to be used as a reliable measure of disease progression.
“Deep learning modeling of rare noncoding genetic variants in human motor neurons defines CCDC146 as a therapeutic target for ALS” by Zhang and others
As we gather more and more genetic data on MND patients we need to use more complex approaches to extract new information and clues as to causes and new treatments for MND. In this study a team from the UK and the US combined data from almost 7000 individuals and used a highly computational “deep-learning” analysis to identify new gene changes associated with MND. They identified a previously unknown gene, CCDC146, that appeared to be “over-active” in MND. Inhibiting the activity of this gene in human neuron cells from MND patients rescued the MND symptoms in these cells. This suggests CCDC146 might be good candidate for further investigation but also highlights this computational approach as a good way to keep identifying new factors contributing to MND.
“The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications” by Iacoangeli and others
As in the study above, we spend a lot of time looking for single factors that contribute to MND. However, looking at how several different genetic factors may combine to produce larger effects has not been studied widely. This international consortium of researchers looked at how multiple gene defects might contribute to MND. They analysed genetic data from 6700 patients and 2400 controls and showed that in 6% of cases there were defects in multiple known MND genes in the same patient. They showed that people carrying multiple “hits” were more likely to develop MND but these multiple hits did not seem to affect disease outcomes such as age of onset or rate of progression. This suggests that multiple hits (oligogenicity) must considered in genetic counselling and testing by ensuring the use of comprehensive gene panels even when a potential pathogenic variant has already been identified. Such a complete genetic profile can also be very useful in the correct choice of therapy in all ALS patients.
