Clene to Submit Application for CNM-Au8 as Potential ALS Treatment

According to a recent company update, Clene Nanomedicine plans to submit a new drug application (NDA) in the first quarter of 2026 for its investigational, first-in-class, nanocatalytic, bioenergetic agent CNM-Au8 as a treatment for amyotrophic lateral sclerosis (ALS). The company is planning to request an additional type C meeting with the FDA to discuss data for the submission, which is expected to be through the accelerated approval pathway.¹

CNM-Au8 is an oral suspension of clean-surfaced faceted gold nanocrystals designed as a bioenergetic/neuroprotective therapy for neurodegenerative diseases. The agent aims to restore energetic homeostasis and reduce oxidative stress in neurons and glia, with preclinical models showing remyelination and neuroprotection in demyelinating and ALS models. Within its ALS program, the drug has been tested in the phase 2 RESCUE-ALS trial (NCT), HEALEY-ALS platform study, and through an expanded access program.

Clene’s second Type C meeting with the FDA focused on the long-term survival signal seen with CNM-Au8 30 mg in the HEALEY ALS Platform Trial, with the agency reiterating that meaningful improvement in ALS-specific biomarkers—not survival alone—will be required to support an accelerated approval submission, with survival potentially serving as confirmatory evidence. To increase the strength of the dataset, the FDA recommended pursuing additional analyses of ALS-relevant biomarkers, including further evaluation of CNM-Au8’s effects on neurofilament light chain (NfL) across the NIH-sponsored expanded-access program and the HEALEY Platform Trial.

"The three potential biomarker paths that could be leveraged to increase the persuasiveness of our ALS data, as outlined by the FDA, include: a) the NfL analysis of our ongoing NIH-sponsored Expanded Access Program (EAP); b) additional ALS disease-specific biomarker changes (in addition to NfL) from the HEALEY ALS Platform Trial; and c) NfL analysis of subjects in the open-label extension (OLE) of the HEALEY ALS Platform Trial who were initially treated with placebo during the placebo-controlled portion of the trial and then received CNM-Au8 during the OLE," Rob Etherington, president and chief executive officer at Clene, said in a statement.¹

He added, "The Company anticipates completing these data analyses shortly which could support the filing of an NDA using the accelerated approval pathway."

RESCUE-ALS

RESCUE-ALS was a randomized, double-blind, placebo-controlled phase 2 study of patients with early-stage ALS, testing the efficacy and safety of 30 mg CNM-Au8 daily plus background riluzole for 36 weeks. The study’s primary end point, mean percent change in summed motor unit number index (MUNIX), was not met.²

Overall, there was no significance difference between the CNM-Au8 group and placebo on MUNIX score percent change LS mean difference: 7.7%, 95% CI: −11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: −56.4 to 94.0), or forced vital capacity (FVC) change (LS mean difference: 3.6, 95% CI: −12.4 to 19.7). Despite this, exploratory and longer-term analyses suggested a 60% or so reduction in all-cause mortality at 12 months in the extension (HR, .408 [95% Wald CI: .166-1.001; log-rank P=.0429), and quality of life improvements (ALSQOL-SF).^3,4

HEALEY-ALS

Within this large-scale platform trial, CNM-Au8, or regimen C, was evaluated over a 24-week period, using change in ALS Functional Rating Scale (ALSFRS-R) as the primary outcome. Published in JAMA, findings showed no significant benefit on ALS disease progression over 24 weeks vs shared placebo on the primary outcome and other clinical measures.⁵

Since that publication, Clene has presented post-hoc survival analyses pooling data from RESCUE-ALS and HEALEY, suggesting a strengthened survival signal for the medication. Across the full analysis set, patients receiving 30 mg CNM-Au8 showed a median survival of 951 days compared with 753 days in the Regimen A comparator group, a gain of 198 days (6.5 months), alongside a covariate-adjusted restricted mean survival time benefit of 124 days (95% CI, 3–245; P = 0.045). These findings remained robust across multiple sensitivity analyses that incorporated additional covariates—including baseline serum NfL levels, background ALS therapies, and the TRICALS risk score—further supporting the observed survival advantage.⁶

Ongoing Phase 3 Trial

CNM-Au8 is expected to be submitted through the accelerated approval pathway, thus needing a confirmatory phase 3 trial to support its clinical benefit. The confirmatory trial, dubbed RESTORE-ALS, is expected to begin dosing in the first half of 2026. This large-scale, global, event-driven study is anticipated to include 690 patients randomized 2:1 to either CNM-Au8 30 mg or placebo for a period of 108 weeks.⁷

RESTORE-ALS will use delayed time to death or death equivalent (PAV) as the primary end point, calculated through a covariate adjusted cox proportional hazard model. Randomization for the study is stratified by plasma neurofilament light levels (<95 pg/mL vs >95 pg/mL), modified 6-factor TRICALS risk score (<4.1 vs >4.1), and use of background ALS therapy (riluzole or edaravone vs none). Some of the secondary end points include combined assessment of function & survival, Composite ALS clinical worsening hierarchy, and joint-rank of time to death or PAV and ALSFRS-R change over 108 weeks.

REFERENCES
1. Clene Reports Third Quarter 2025 Financial Results and Recent Operating Highlights. News release. Clene Nanomedicine. November 13, 2025. Accessed November 14, 2025. https://www.globenewswire.com/news-release/2025/11/13/3187278/0/en/Clene-Reports-Third-Quarter-2025-Financial-Results-and-Recent-Operating-Highlights.html
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. The Lancet. 2023;60:102036. doi:10.1016/j.eclinm.2023.102036
3. Results from RESCUE-ALS Study Demonstrate Safety and Efficacy of CNM-Au8 for Treatment of ALS. Practical Neurology. September 20, 2023. Accessed November 14, 2025. https://practicalneurology.com/news/results-from-rescue-als-study-demonstrate-safety-and-efficacy-of-cnm-au8-for-treatment-of-als/2470296/
4. Glanzman R, Menon P, Huynh W, et al. RESCUE-ALS Trial Results: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of CNM-Au8 to Slow Disease Progression in ALS. Presented at: MDA Conference. https://www.mdaconference.org/abstract-library/rescue-als-trial-results-a-phase-2-randomized-double-blind-placebo-controlled-study-of-cnm-au8-to-slow-disease-progression-in-als/
5. Berry JD, Maragakis N, Macklin EA, et al. CNM-Au8 in Amyotrophic Lateral Sclerosis The HEALEY ALS Platform Trial. JAMA Neurol. 2025;333;(13):1138-1149.doi:10.1001/jama.2024.27643
6. Clene Demonstrates Strengthened ALS Survival Benefit with CNM-Au8® Treatment. News release. Clene Nanomedicine. March 12, 2025. Accessed November 14, 2025. https://invest.clene.com/news-releases/news-release-details/clene-demonstrates-strengthened-als-survival-benefit-cnm-au8r
7. Vucic S, Greenberg B, Rynders A, et al. RESTORE-ALS Phase 3 Clinical Trial Design. Accessed November 14, 2025. https://invest.clene.com/static-files/21ae9a48-c2e2-4c80-b8dc-1ebbf6c71a97#:~:text=Objective:%20to%20investigate%20the%20effects,5.