Four potential treatments being trailed by Biohaven, Prilenia Therapeutics, Clene Nanomedicine and UCB for amyotrophic lateral sclerosis (ALS) have fallen short of their endpoints as part of a US-led platform trial.
All four trials, part of the Massachusetts General Hospital’s HEALEY ALS platform trial (NCT05136885), failed to show an impact on ALS disease progression. The platform trial is examining different regimens and therapeutic options for the condition that the US Centres for Disease Control (CDC) affected more than 30,000 people in 2018 alone.
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Biohaven’s myeloperoxidase inhibitor, verdiperstat, fell short when its Phase II/III trial (NCT04436510) in which 167 patients were randomised to verdiperstat or regimen-specific placebo, missed its primary efficacy endpoint. Additionally, there were no significant differences between active and placebo in the secondary endpoints such as a 24-week change in isometric muscle strength.
The Prilenia Therapeutics sigma-1 receptor agonist, pridopidine, missed its primary endpoint in its Phase II/III trial (NCT04615923) similarly seeing no impact on disease progression compared with placebo. The primary endpoint in that trial was a change from baseline through week 24 in ALS disease severity. Among the 162 patients randomised to receive the pridopidine regimen, 136 (84%) completed the trial. Similarly, there was no benefit in secondary endpoints.
Additionally, Clene Nanomedicine’s gold-based nanocrystal treatment, known as CNM-Au8, failed to reach the same endpoint of a 24-week change in disease baseline disease progression compared with placebo. Its multicentre, randomised, double-blind trial (NCT04414345) saw 90% of the 161 patients recruited finishing the trial but results suggested no benefit or harm in the use of CNM-Au8.
Lastly, the Belgium-based UCB’s complement C5 inhibitor zilucoplan failed the same endpoint after its trial (NCT04436497) was halted early due to futility.
Despite these disappointing results, both Prilenia Therapeutics’ pridopidine and Nanomedicine’s CNM-Au8 will move to Phase III trials. Investigators noted that in a pre-specified subgroup of patients with early-course ALS, pridopidine was associated with slower disease progression. Clene Therapeutics was given the green light for the Phase III RESTORE-ALS trial of CNM-Au8 in December 2024 based on earlier data showing signals of potential efficacy which is set to initiate in early 2025.
Meanwhile, zilucoplan and verdiperstat will not move to Phase III trials.
Speaking with Clinical Trials Arena, co-principal investigator for the Healey ALS platform trials Sabrina Paganoni, said: “The primary goal of this trial is to deliver robust go / no go decisions: by providing comprehensive data regarding dose, target engagement, biomarkers, and clinical outcomes the trial helps inform subsequent studies including target population and outcomes.
“Importantly, the ever-growing shared placebo group serves as a natural history study and will continue to provide learnings for the entire field in terms of novel biomarkers and outcome measures. The placebo data and samples from the first four regimens have been retired and will be shared with the scientific community in mid-2025 to help advance global ALS research.”
Results from all four regimen trials were published in the Journal of the American Medical Association on 17 February.
The news follows more than a month after both Denali Therapeutics, and AbbVie and Calico reported their candidates, DNL343 and fosigotifator respectively, failed to meet their endpoints in the HEALEY platform trial. Elsewhere in the field of ALS, the US Food and Drug Administration (FDA) has lifted a clinical hold on Amylyx Pharmaceuticals’ Phase I trial of AMX0114.
