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First-ever ALS platform trial reports on outcomes of 4 treatments

Presented by
Prof. Sabrina Paganoni, Massachusetts General Hospital, MA, USA
AAN 2023
HEALEY ALS Platform Trial

The HEALEY ALS Platform Trial accelerates the path to new amyotrophic lateral sclerosis (ALS) therapies by testing multiple investigational products concurrently and sequentially. Results of 4 regimens that had concluded the randomised controlled trial (RCT) period were shared: zilucoplan, verdiperstat, CNM-Au8, and pridopidine.

The HEALEY ALS Platform Trial (NCT04297683) is a perpetual, adaptive, phase 2/3, multi-regimen trial that allows for shared trial infrastructure and shared placebo data. Prof. Sabrina Paganoni (Massachusetts General Hospital, MA, USA) said the key to successfully launching this trial was working with multiple stakeholders: industry, FDA, patients, investigators, and foundations [1]. The trial is composed of 1 (phase 2/3) protocol, over 70 enrolling sites, around 1,300 participants, and a total of 7 treatments (i.e., zilucoplan, verdiperstat, CNM-Au, pridopidine, SLS-005, trehalose, ABBV-CLS-7262, and DNL343). Key inclusion criteria included sporadic or familial ALS at least 3 years after the onset of weakness and a slow vital capacity of no more than 50% of predicted.

Each regimen is compared with a shared, continuously expanding placebo dataset (3:1). Participants were not able to choose the drug they were assigned. Interim analyses performed for early futility. The RCT period was 24 weeks, followed by an open-label extension. The primary endpoint of the RCT was a change in disease severity, measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Additional endpoints included respiratory function, muscle strength, survival, and safety. Prof. Paganoni explained that the study also provides a unique opportunity to put new ALS biomarkers and outcome measures to the test: DNA (whole-genome sequencing), neurofilaments, home spirometry, and speech analysis. She added that the study’s overall objective is to provide a “go or no-go decision” for the clinical development of each regimen. A total of 653 ALS patients were randomised within the first 4 regimens, of which she presented the results.

Regimen A is zilucoplan (0.3 mg/kg daily), a complement inhibitor targeting C5, which is a terminal complement activation pathway component. After the 4th interim analysis, the trial was terminated for futility. No major safety concerns were identified. Prof. Paganoni stressed that this decision saved over 250 visits plus 5 months of operational activities.

Regimen B is verdiperstat (600 mg twice daily), a myeloperoxidase inhibitor, which was well-tolerated but failed to show differences in primary or secondary endpoints versus placebo. Like regimen A, it received a “no-go decision”.

Regimen C is CNM-Au8 (30 or 60 mg daily), an oral suspension of gold nanocrystals. The treatment was well-tolerated, but after 24 weeks, no significant differences were seen in ALS severity between the pooled CNM-Au8 and the placebo group. However, consistent trends in time to clinical events (i.e., clinical worsening, permanent assistant ventilation, or death) favouring CNM-Au8 30 mg were observed. A longer phase 3 trial is needed to confirm these findings and explore survival.

Regimen D is pridopidine (45 mg twice daily), a highly selective and potent sigma-1 receptor (S1R) agonist that was well tolerated. However, after 24 weeks no differences were found in primary or key secondary clinical endpoints compared with placebo. In exploratory and subgroup analyses, pridopidine improved speech function and was associated with a reduction in neurofilament-light (NfL) levels in fast-progressing participants. A phase 3 trial is needed to confirm these results.

  1. Paganoni S. Results from the first four regimens of the HEALEY ALS Platform Trial. PL5.003, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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