The HEALEY ALS Platform Trial accelerates new therapies by testing multiple investigational products. Results of four regimens were shared at AAN 2023.
The HEALEY ALS Platform Trial is a perpetual adaptive phase 2/3 multi-regimen trial that allows for shared trial infrastructure and the use of shared placebo data. Sabrina Paganoni, MD, PhD, 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 a single phase 2/3 protocol, over 70 enrolling sites, approximately 1,300 participants, and a total of seven treatments regimens. Key inclusion criteria included sporadic or familial ALS, 3 years since 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. The 24-week randomized placebo-controlled treatment (RCT) period is followed by an open-label extension, and the primary endpoint is a change in disease severity, measured by the ALS Functional Rating Scale-Revised. Additional endpoints include respiratory function, muscle strength, survival, and safety. Dr. 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 patients with ALS patients were randomized within the first four regimens. Regimen A is zilucoplan (0.3 mg/kg daily), a complement inhibitor targeting C5, a terminal complement activation pathway component. After the 4th interim analysis, the trial was terminated for futility. No major safety concerns were identified. Dr. Paganoni stressed that this decision saved over 250 visits, plus 5 months of operational activities.
Regimen B is verdiperstat (600 mg twice a day), 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) favoring 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 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 and was associated with a reduction in neurofilament light levels in fast-progressing patients. A phase-3 trial is needed to confirm these results.
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