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

The HEALEY ALS Platform trial accelerates the path to new therapies for amyotrophic lateral sclerosis (ALS) by testing multiple investigational products concurrently and sequentially. Results of 4 regimens which had concluded the RCT period were shared at the AAN 2023 meeting: 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 the use of shared placebo data. Prof. Sabrina Paganoni (Massachusetts General Hospital, USA) said that the key to successfully launching this trial is working with multiple stakeholders: industry, FDA, patients, investigators, and foundations. The trial is composed of one (phase 2/3) protocol, over 70 enrolling sites, around 1300 participants, and a total of 7 treatments (“regimens”). 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 (3:1) to a shared placebo dataset, which is continuously expanding. Participants cannot choose the drug they may be assigned. Interim analyses are performed for early futility. There is a 24-week randomised placebo-controlled treatment (RCT) period, followed by an open-label extension. The primary endpoint of the RCT is a change in disease severity, measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Additional endpoints include 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 overall objective of the study 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 four regimens, of which she presented the results [1]. Regimen A is zilucoplan (0.3 mg/kg daily), a complement inhibitor targeting C5, a terminal complement activation pathway component. After the 4^th 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 BID), a myeloperoxidase inhibitor. It was well-tolerated but failed to show any differences in primary or secondary endpoints versus placebo. Like regimen A, it received a “no-go decision”.

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

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

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

 

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Posted on 28 April, 202314 May, 2023