CNM-Au8 Reduces Neurofilament Light and Improves Survival in ALS, HEALEY-ALS Open-Label Extension Data Suggests

James Berry, MD

Clene Nanomedicine recently announced positive data from the open-label extension (OLE) phase of the HEALEY-ALS trial, with results showing that treatment with investigational CNM-Au8 resulted in reduced plasma neurofilament light (NfL) levels and improved survival among patients with amyotrophic lateral sclerosis (ALS).¹

In the trial, 161 patients with ALS were randomly assigned to 30 mg CNM-Au8, 60 mg CNM-Au8, or placebo as adjunct to standard of care for a 24-week treatment period. Following the double-blind period, all patients were given the choice to enter the OLE. After 76 weeks of treatment, investigators observed a 16% (95% CI, 2-28) reduction in NfL in those randomized to the 30 mg active group vs those initially randomized to placebo (P = .023). For more context, over the original 24-week period, investigators observed a 10% relative reduction in this biomarker (P = .040).

"As consensus is building that neurofilament is an important biomarker reasonably likely to predict clinical benefit, it is important to see NfL continue to decrease during long-term follow-up, and correlate with time to event clinical outcomes in the Clene regimen of the double-blind and OLE portions of the HEALEY ALS Platform Trial," James Berry, MD, associate professor of neurology, chief of the Motor Neuron Disorder Division, and director of the Neurological Clinical Research Institute at Massachusetts General Hospital, said in a statement.

Using a mixed model with repeat measures and least squared means on a natural log (Ln) scale, the 76-week change in NfL levels for 30 mg of CNM-Au8 were –0.075 (SE, 0.053) vs +0.098 (SE, 0.056) for those originally on placebo. Combined analyses of both the 30 and 60 mg doses of CNM-Au8 demonstrated nominally significant reductions in plasma NfL, with a difference of LS Means on a Ln Scale of –0.144 (SE, 0.066; P = .029).

The impact of CNM-Au8 on NfL, a key marker of neurodegeneration, could be considered noteworthy as this biomarker has been considered reasonably likely to serve as a surrogate of effect on clinical end points. Most notably, in April 2023, the FDA approved Biogen’s tofersen (Qalsody), an antisense oligonucleotide, as the first therapy for SOD1 mutation-mediated ALS, based on reductions in NfL as a surrogate biomarker.²

Additional OLE findings from HEALEY-ALS showed that under an assumption of constant common treatment effect, treatment with CNM-Au8 demonstrated a 60% decreased risk of long-term all-cause mortality in those originally randomized to active treatment vs those originally randomized to placebo. These long-term survival analyses included the prespecified rank-preserving structural failure time model (RPSFTM) and adjusted for the estimated benefit after switching to CNM-Au8 (Cox HR, 0.40; 95% CI, 0.19-0.85; P = .017).

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"These long-term results provide additional promising evidence that CNM-Au8 may offer more time to people living with ALS," principal investigator Merit Cudkowicz, MD, chair neurology department, director of the Sean M. Healey & AMG Center for ALS at Mass General Hospital, said in a statement.¹ "The survival analyses using RPSFTM is a well-recognized method that has been used to estimate cross-over effects in another recent ALS trial, as well as oncology and other rare diseases. Additional analyses of the open label data are underway."

These survival analyses further add to previously announced data in September 2023, which showed that CNM-Au8 improved survival when compared with placebo-treated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. Among 59 CNM-Au8-treated participants, investigators observed a statistically significant 49% decreased risk of mortality compared with PRO-ACT matched patients on placebo through long-term follow-up (HR, 0.510; 95% CI, 0.263-0.987; P = .046). In a pooled analysis of the HEALEY ALS platform trial and the phase 3 RESCUE-ALS study (NCT4098406) treatment with the agent resulted in a statistically significant 59% decreased risk of mortality compared with PRO-ACT matched placebo patients (HR = 0.406; 95% CI, 0.220-0.749; P = .004).³

To investigate the role of NfL in the incidence of ALS clinical worsening events, the pooled population of the HEALEY-ALS Platform and RESCUE-ALS trials were stratified by baseline plasma NfL levels by quartile (<51 pg/mL, 51-76 pg/mL, >76-114 pg/mL, and >114 pg/mL). Worsening events included death, tracheostomy, feeding tube placement, and initiation of assisted ventilation.

For each treatment group during the double-blind periods, results showed that treatment with the CNM-Au8 delayed occurrence of such worsening events in the highest risk NfL quartiles. In such participants, the apparent benefit of CNM-Au8 30 mg was enhanced (Cox HR, 0.25; 95% CI, 0.11-0.61; P = .003). Investigators also observed nominally significant reduced rates in time to death or permanently assisted ventilation, as well as all-cause mortality.

REFERENCES
1. Clene reports reduction in biomarker plasma neurofilament light (NfL) levels and improved survival with CNM-Au8 treatment from HEALEY ALS Platform trial long-term open-label extension. News release. December 21, 2023. Accessed January 3, 2024. https://www.globenewswire.com/news-release/2023/12/21/2799888/0/en/Clene-Reports-Reduction-in-Biomarker-Plasma-Neurofilament-Light-NfL-Levels-and-Improved-Survival-With-CNM-Au8-Treatment-From-HEALEY-ALS-Platform-Trial-Long-Term-Open-Label-Extensio.html
2. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed January 3, 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene
3. Berry J, Maragakis N, Paganoni S, et al. Evidence for Survival Benefit in ALS with CNM-Au8 Treatment Across Three Study Populations. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts.