Research Directions

Unfortunately, there have been a number of early and late-stage clinical trial failures in the last couple of months. 

Healey Platform Trial

The HEALEY ALS Platform Trial is based in the US and is designed to test multiple potential therapies at once, improve the medication to placebo ratio and increase access for participants.  Recently, several trials have failed to produce positive outcomes after coming through the Healey Platform. 

• Two of the trials targeted the same molecule, eIF2B, a key regulator of the integrated stress response (ISR). The ISR appears to be overactive in MND, leading to the formation of stress granules containing TDP-43. The buildup of TDP-43 is harmful and leads to neuronal degeneration. The first was DNL343 from Denali Therapeutics (Regimen G of the trial) and the second is fosigotifator from Calico Life Sciences (Regimen F). In both cases, the trial was 6-months long and the drugs were shown to be safe and well-tolerated. However, in both cases primary or key secondary outcome measures were not achieved. Fosigotifator showed some minor changes in muscle strength at a higher dose, but no plans for taking either drug forward have been announced.
• CNM-Au8, produced by Clene Nanomedicine, is an oral suspension of catalytically active gold nanocrystals thought to boost energy production in neurons. As with all Healey Platform trials, the drug was tested for 6-months with the primary outcome to see if CNM-Au8 (Regimen C) slowed disease progression, as measured by the ALSFRS-R and survival. Unfortunately, no significant changes in ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised) or survival were seen. The therapy was generally safe, with no serious side effects reported. The company are looking to proceed with a larger Phase 3 trial based on additional data from extended access programs from this and previous CNM-Au8 studies. The final decision on the Phase 3 trial is yet to be announced. 
• Pridopidine (Regimen D) is thought to enhance the clearance of toxic proteins, increase energy production and reduce cellular stress and inflammation in neurons. The drug was tested over 6-months with ALSFRS-R and survival the primary outcomes. These primary outcomes were not met, and neither were the secondary outcomes. Further analysis did suggest pridopidine-treated patients retained better speaking abilities and that fast-progressing patients might have had a better response to the therapy. Prilenia, the company producing Pridopidine, have announced plans for a Phase 3 trial based on the speech and fast-progressor outcomes with details yet to be released. 
• Two other Healey trial arms trials, verdiperstat and zilucoplan, both failed and will not be taken further. Zilucoplan (Regimen A) is a complement C5 inhibitor designed to reduce neuroinflammation. Verdiperstat (Regimen B) is thought to reduce neuroinflammation and oxidative stress. 

Although we are seeing negative outcomes, the adaptive platform design of the HEALEY ALS Platform Trial has made it possible to test a new investigational product with efficient use of time and resources. Moving forward, the trial is updating its protocol to lengthen trials to 9-months. The first drug to go through this new protocol will be NUZ-001, formerly Monepantel, produced by the Australian company Neurizon, formerly  PharmAust. 

Other trial results

• Neuronata-R is a stem cell therapy for MND currently approved only in Korea following a Phase 2 trial. The producers, Corestem-Chemon, have now reported the outcomes of a larger Phase 3 trial. Unfortunately, this 12-month trial failed to demonstrate efficacy in functional change or survival and no further information is currently available.  
• In some more positive news, the evidence of tangible benefits of the SOD-1 targeting genetic therapy, Tofersen (Qalsody) produced by Biogen, continues to build. The results of a small study of a cohort of 7 patients who had been receiving the treatment for a duration ranging from 7 to 30 months has shown that all patients showed robust and sustained declines in neurofilament biomarkers (signals of neuron death). All patients also showed a stabilisation of ALSFRS-R scores i.e no decline, and even increases, in their functional independence measure motor score (FIM). The FIM measures a patient's ability to perform motor tasks like eating, grooming, bathing, dressing, transferring, and locomotion. As we see more patients with a SOD1 gene using this drug we hope to see more examples of good outcomes. 

Australian MND Research

• Andrew Eisen, Steve Vucic and Matthew Kiernan have presented an intriguing hypothesis that MND results from specific failure of the corticomotoneuronal system. The corticomotoneuronal system is a collection of neurons that control fine motor function and connect to all bulbar and spinal motoneurons, including those used in speech and respiration. Interestingly, the extent of this system in humans is not found in other species and this might provide an explanation of why mouse models have not proven to be good representations of human MND. These neurons, with their extensive network of connections, are particularly vulnerable to the factors considered to contribute to MND such as aging, environmental stress and lifestyle changes. Further studies that focus on this system in patients may show disease-related changes and identify ways to target these cells specifically. 
• Shyuan Ngo and her team at University of Queensland have completed a Phase 2 trial of the drug trimetazidine which targets the rapid weight loss and high metabolic rates seen in MND. The trial was open-label (i.e. all participants received the drug) and was designed to test the safety and tolerability of the treatment and to show if it could alter oxidative stress and energy expenditure markers in patients. Patients received oral trimetazidine for 12 weeks after an initial 4-week lead-in period. Results showed the drug was well-tolerated and there was a decrease in oxidative stress markers as well as a reduction in resting energy expenditure during the trial. A larger double-bind placebo-controlled trial is now planned that will look at the efficacy of the drug on MND progression.

Other MND Research

• Intravenous edaravone, marketed as Radicava, has been approved by the TGA for use in Australia and we are waiting for an announcement on availability following negotiations on pricing. A recent study has provided some additional evidence of potential effectiveness of intravenous edaravone. The study looked at insurance claims data for a 4-year period in the US and matched patients receiving edaravone with patients not using the drug. This sort of study is termed “real-world data” as it is not from a placebo controlled clinical trial but does reflect what happens in a more normal clinical setting outside of a clinical trial. The study of approximately 400 patients using Radicava showed fewer reported disease progression milestones and deaths during the first 2 years of therapy. This suggests that Radicava can provide some benefit for some patients. 
• The ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised) is used all over the world to measure functional change in MND patients. Assessment provides a number that reflects the level of physical function a person has at that time. The rate of change in those numbers can then indicate disease progression and identify if a patient is responding to treatment. However, we do not really know what number change is meaningful to the patients themselves. A study from the University of Sheffield in the UK compared ALSFRS-R score changes with asking participants to rate how their disease had progressed since their previous visit. This analysis produced a “minimal important difference (MID).” They used two different analysis methods to interpret the data, and they suggested a MID of either 3.8 or 2 points. Clearly more work is needed here to firm up those numbers, but this is an important issue. Treatments being tested are sometimes considered successful claiming a 1-point difference. Whether such changes are truly beneficial needs to be considered. 
• MND Australia is currently finalising a report looking at the economic and human burden of MND in Australia. As part of this report, we will be updating our estimates on the numbers of MND patients in Australia. A recent study has undertaken a similar analysis in the US. This US study estimated MND prevalence retrospectively from 2022 to 2024 and prospectively from 2025 to 2030 using the National ALS Registry. The analysis showed that, by 2030, MND cases will increase more than 10%, to 36,308. The largest increase occurs for the population ages 66 years and older, with a 25% increase in this cohort (from 16,349 cases in 2022 to 20,438 cases in 2030). It will be interesting to see how this data compares to the Australian figures when they are finalised.