Four more drugs in keenly watched ALS trial miss the mark

Four more experimental drugs for amyotrophic lateral sclerosis (ALS) have failed to hit the primary endpoint in the phase 2/3 HEALEY ALS basket trial, which is trying to accelerate the search for new therapies for the devastating neurodegenerative disease.

The four therapies – Biohaven's myeloperoxidase inhibitor verdiperstat, Prilenia Therapeutics' sigma-1 receptor agonist pridopidine, Clene Nanomedicine's gold nanocrystal therapy CNM-Au8, and UCB's complement C5 inhibitor zilucoplan – join Denali Therapeutics' DNL343 and AbbVie/Calico's fosigotifator, both eIF2B agonists, in failing to slow disease progression in the study.

There may be a silver lining, however, as two of them – pridopidine and CNM-Au8 – showed signs of activity on measure that may warrant testing in phase 3, according to their developers.

Despite the best efforts of drug developers, just a handful of disease-modifying drugs, such as Mitsubishi Tanabe's Radicava (edaravone) and generic drug riluzole, have been approved for ALS, and their benefits are limited. HEALEY ALS has been designed to allow multiple drug candidates to be tested in parallel in the hope of spotting potential new therapies in half the time and reducing the cost of clinical testing by a third.

The results of the four substudies have been published in separate papers in the journals JAMA, JAMA Neurology and JAMA Network Open, with all four drugs unable to show a significant change in disease severity from baseline through 24 weeks, measured using the ALSFRS-R scale.

That verdiperstat failed to move the needle does not come as a surprise, as Biohaven had acknowledged its failure to show efficacy in interim results reported in 2022 and the programme was subsequently shelved.

Likewise, the disappointing result with zilucoplan doesn't come entirely out of left field, as AstraZeneca's rare disease unit Alexion abandoned the development of its complement C5 inhibitor Ultomiris (ravulizumab) for ALS after it flunked the phase 3 CHAMPION-ALS trial in 2021.

Against that backdrop, glimmers of activity for pridopidine and CNM-Au8 could be considered a win, even though verdiperstat and zilucoplan will not be taken forward in ALS.

Prilenia has already filed pridopidine for approval in Europe as a treatment for Huntington's disease, another neurogenerative disorder, and has been working on the design of a phase 3 trial of the drug in ALS on the back of earlier data readouts from HEALEY ALS that pointed to improvements in rate of progression, dyspnoea, speech decline, and quality of life.

In the new update published in JAMA, there was no difference between pridopidine and placebo on the ALSFRS-R scale or survival, or on five secondary endpoints, but the drug did show a significant improvement on a couple of exploratory endpoints.

Whether that will be enough to warrant the investment in a full phase 3 trial remains to be seen, and, as yet, Prilenia hasn't disclosed any update on its plans in light of the JAMA paper.

There was also no significant improvement on primary and secondary endpoints with CNM-Au8 – an oral suspension of gold nanocrystals designed to increase energy production and utilisation by neurons – but there was an effect on levels of the neurofilament light chain (NfL) biomarker.

In December, Clene said the FDA had provided a "roadmap" for possible accelerated approval of CNM-Au8 based on NfL data from three compassionate-use expanded access protocols (EAPs) and HEALEY ALS, and said it intended to start a confirmatory trial (RESTORE-ALS) before submitting the drug.

Dr Ahmad Al Khleifat, senior research fellow at King's College London, who was not involved with HEALEY ALS, said that while the results "seem discouraging, they provide critical insights."

He suggested that there is merit in looking at biomarkers like NfL, rather than relying on survival and functional scores as primary outcome measures, pointing out that treatments like riluzole and tofersen have shown benefits only in later stages of ALS, so short-term trials could "overlook" the full impact of a drug.

"Extending trial durations or incorporating post-trial follow-ups could help capture these delayed effects and provide a clearer picture of treatment efficacy," commented Al Khleifat.

"Despite these challenges, platform trials continue to revolutionise ALS research, they hold immense potential to accelerate the discovery of effective therapies and bring new hope to the ALS community."

Other recent failures in the clinical pipeline include studies of Apellis' complement C3 inhibitor pegcetacoplan and Cytokinetics' fast skeletal muscle troponin activator (FSTA) reldesemtiv. On the plus side, Biogen's Qalsody (tofersen) became an option for patients with a specific genetic form of ALS associated with a mutation in the SOD1 gene in 2023.