Clene Submits NDA Seeking Accelerated Approval for ALS Drug

Clene has submitted a New Drug Application (NDA) to the FDA seeking accelerated approval of CNM-Au8 for amyotrophic lateral sclerosis (ALS), the company announced. The filing follows more than 3 years of mixed trial results and evolving regulatory discussions with the agency.¹

Rob Etherington, president and CEO of Clene, said in a statement that the submission “represents an important achievement for Clene, CNM-Au8, and especially for people living with ALS.” He added, "We appreciate the FDA's constructive engagement throughout this process and look forward to working closely with the Agency during its review.”

The NDA seeks accelerated approval under the FDA's Subpart H pathway, based on reductions in plasma neurofilament light chain (NfL), a blood-based biomarker of neuronal injury, along with clinical outcomes data. Clene said it is simultaneously preparing a confirmatory phase 3 trial, which the company has said it intends to start in the first quarter of 2027.^1,7

Getting to this point required Clene to overcome 2 missed primary trial endpoints and, at one stage, an FDA finding that its data were insufficient to support filing.

RESCUE-ALS: a missed primary endpoint, but a signal on survival

CNM-Au8's clinical story began with RESCUE-ALS, a phase 2, randomized, double-blind, placebo-controlled trial that tested 30 mg of CNM-Au8 added to background riluzole over 36 weeks in early symptomatic ALS. The trial missed its primary endpoint, a measure of motor unit number index change, with a least-squares mean difference of 7.7% (95% CI, -11.9 to 27.3; P=.43) versus placebo.²

In a 12-month open-label extension, however, Clene reported an approximately 60% reduction in all-cause mortality among patients originally randomized to CNM-Au8 (hazard ratio, 0.408; 95% CI, 0.166-1.001; P=.0429), a finding that became central to the company's subsequent regulatory strategy.[2]

HEALEY ALS Platform Trial: a second miss, but more survival and biomarker data

CNM-Au8 was also tested as one of several investigational regimens in the HEALEY ALS Platform Trial, a multi-arm, multi-sponsor adaptive trial coordinated by Massachusetts General Hospital. In its 24-week randomized period, the regimen showed no significant benefit on the trial's primary outcome, a Bayesian model combining function and survival (disease rate ratio, 0.97; 95% CI, 0.783-1.175; posterior probability of benefit, 0.65), according to results published in JAMA.³

As with RESCUE-ALS, longer follow-up told a more favorable story. In a December 2023 analysis of the trial's open-label extension, Clene reported a 16% reduction in plasma NfL at 76 weeks among patients originally randomized to 30 mg CNM-Au8 (95% CI, 2-28; P=.023) and an estimated 60% reduction in long-term mortality risk (hazard ratio, 0.40; 95% CI, 0.19-0.85; P =.017).⁴

FDA's shifting guidance on the accelerated approval pathway

Clene spent much of 2024 trying to translate those exploratory findings into a regulatory pathway. Earlier in the year, the FDA told the company that the data in its briefing package were insufficient to support an NDA under accelerated approval. In August 2024, Clene submitted new post hoc analyses linking NfL reductions to survival benefit, relative to external propensity-matched control datasets, ahead of a planned meeting with the agency.⁵

Following an in-person meeting with FDA senior leadership in September 2024, the agency issued written guidance in December 2024 outlining what additional evidence, including survival and biomarker data from the company's expanded access programs, would be needed to support the accelerated approval pathway.⁶

A new regulatory path built on neurofilament light

The FDA's position solidified in a Type C meeting whose minutes Clene received in May 2026. The agency confirmed that the company's proposed data “may be capable of supporting the submission and review” of an NDA under the Subpart H accelerated approval pathway, based on NfL as a potential “reasonably likely surrogate endpoint.”⁷ That pathway mirrors the one the FDA used in April 2023 to approve tofersen (Qalsody) for SOD1-mutated ALS, the first ALS therapy cleared on the basis of NfL reduction as a surrogate biomarker.⁸

REFERENCES
1. Clene announces New Drug Application submission to FDA for CNM-Au8 for the treatment of ALS. News release. Clene. Published October 19, 2026. Accessed October 20, 2026. https://invest.clene.com/news-releases/news-release-details/clene-announces-new-drug-application-submission-fda-cnm-au8
2. Vucic S, Menon P, Huynh W, et al. Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open-label extension. eClinicalMedicine. 2023;60:102036. doi:10.1016/j.eclinm.2023.102036
3. Writing Committee for the HEALEY ALS Platform Trial, Berry JD, Maragakis NJ, et al. CNM-Au8 in amyotrophic lateral sclerosis: the HEALEY ALS Platform Trial. JAMA. 2025;333(13):1138-1149. doi:10.1001/jama.2024.27643
4. 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. Clene. Published December 21, 2023. Accessed October 20, 2026. https://invest.clene.com/news-releases/news-release-details/clene-reports-reduction-biomarker-plasma-neurofilament-light-nfl
5. Clene announces new CNM-Au8 biomarker and clinical efficacy data submitted to FDA in support of treatment for ALS. News release. Clene. Published August 6, 2024. Accessed October 20, 2026. https://invest.clene.com/node/10851/pdf
6. FDA provides roadmap for accelerated approval pathway through submission of additional CNM-Au8 biomarker data in ALS. News release. Clene. Published December 10, 2024. Accessed October 20, 2026. https://invest.clene.com/news-releases/news-release-details/fda-provides-roadmap-accelerated-approval-pathway-through
7. After successful FDA meeting, Clene filing accelerated approval NDA for ALS. News release. Clene. Published May 4, 2026. Accessed October 20, 2026. https://invest.clene.com/news-releases/news-release-details/after-successful-fda-meeting-clene-filing-accelerated-approval
8. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. Published April 25, 2023. Accessed October 20, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene