Background
Clene is a biopharmaceutical company developing nanotherapeutics seeking to treat failure in cellular energy production. Their lead candidate is CNM-Au8, an oral liquid aimed at enhancing energy production in neurons and oligodendrocytes (cells that support neurons by helping to conduct signals efficiently). CNM-Au8 is reported by the company to also increase resistance to oxidative stress and decrease the levels of potentially toxic misfolded proteins. CNM-Au8 is currently being tested in clinical trials as a potential treatment to slow progression of ALS/MND.
Trial Design & Results
On November 2, 2021, Clene announced the results from their phase 2 RESCUE-ALS clinical trial. The study was a randomized, placebo-controlled, trial of 45 participants, dosed daily with 30mg, and evaluated over 36 weeks. The primary outcome for this clinical trial was percent change in a measure called MUNIX, which estimates the number of motor neuron/muscle connections. There were several other secondary and exploratory outcomes.
There was no significant change between treated and placebo groups for MUNIX, forced vital capacity or ALSFRS-R at 36 weeks. However, this trial was small and trends in each of these measures favoring CNM-Au8 suggest that a larger trial, better powered to see subtle, but potentially meaningful effects, would be valuable. Some exploratory endpoints, including a responder analysis, defined here as someone with less than a six-point decline in the ALSFRS-R over 36 weeks, demonstrated a difference for CNM-Au8 over placebo, as did the quality of life ALSSQOL-SF score. Further exploratory endpoints around disease progression as measured by death or initiation of tracheostomy, non-invasive ventilation (NIV) or gastrostomy tube, and observed versus predicted survival over 96 weeks (including an open label extension), both favored CNM-Au8 as well.
In a peer-reviewed publication of RESCUE-ALS (2023), extended survival analyses through at least 12 months following the end of the double-blind period reported a notably lower risk of all-cause mortality among participants originally randomized to CNM-Au8 compared with placebo (hazard ratio 0.408). These survival findings were exploratory and were not pre-specified primary outcomes of the trial and therefore should be interpreted with caution. While open-label extension data provide additional longer-term observations, these data are not randomized and do not establish treatment efficacy.
CNM-Au8 is, to date, well tolerated without any significant safety concerns.
CNM-Au8 was subsequently tested in the HEALEY Platform Trial, where 161 participants were randomized to 30 mg CNM-Au8, 60 mg CNM-Au8, or placebo, with a 3:1 treatment to placebo ratio, and followed over 24 weeks. The data were reported in a 2025 peer-reviewed publication of the HEALEY Platform Trial and showed the primary endpoint, which assessed disease progression using a combined measure of function and survival, was not met. Secondary endpoints, including the Combined Assessment of Function and Survival joint rank test (CAFS) and respiratory functions measured by slow vital capacity (SVC), were also not met.
Exploratory analyses of survival were also reported. However, the number of deaths or permanently assisted ventilation events over the 24-week period was small, with differences between treatment and placebo groups based on very few events. As a result, analyses describing large percentage reductions in risk are highly sensitive to small changes in event numbers. One fewer event in the placebo group or one additional event in the treatment group would substantially alter these estimates, and such findings should therefore be interpreted with caution and only used for hypothesis generation for future studies
Exploratory analyses related to clinical outcomes and biomarkers were also undertaken. No significant change in exploratory time-to-event outcomes (including events such as initiation of non-invasive ventilation, gastrostomy tube placement etc.) was seen. A small difference in neurofilament light change (NfL) levels was seen although as a post-hoc analysis this is again considered hypothesis generating rather than indicative of a true biological effect and requires further study.
At this time, Clene announced their intent to pursue a multi-national 300 participant, Phase 3 clinical trial and has described plans for a confirmatory Phase 3 RESTORE-ALS trial of CNM-Au8, with dosing anticipated to begin in the first half of 2026. Such a trial will be critical to determining whether any signals seen in the RESCUE-ALS and HEALEY trials, as well as biomarker findings reported from the NIH EAP, can be confirmed in a larger, more definitive study.
In early 2026, Clene announced the FDA has granted them an in-person Type C meeting during the first quarter of 2026 to discuss support for a New Drug Application (NDA) filing under the accelerated approval pathway. This is based on additional biomarker data from the EAP programs from the RESCUE and Healey trials. Clene have proposed through analyses of large ALS patient datasets that even modest reductions in NfL are associated with improved survival. Across cohorts, the NfL reduction observed with CNM-Au8 treatment (approximately 9–10%) was associated with an approximately 8–13% lower risk of death, while larger NfL reductions were associated with proportionally greater survival benefit—a clinically meaningful benefit in a rapidly progressive disease with median survival of 2–4 years. This data has not been published so cannot be scrutinized by researchers.
Following the meeting, the FDA noted that “NfL could potentially serve as a reasonably likely surrogate endpoint to support (an) accelerated approval.” The FDA has requested that Clene provide additional information in its NDA, including to support a connection between the reported magnitude of reduction in NfL and clinical benefit, which Clene is preparing and will include in the submission. Clene are still planning on undertaking a Phase 3 confirmatory study for CNM-Au8, which they intend to commence in the first quarter of 2027.
Summary
The Scientific Advisory Council (SAC) believes that there is insufficient evidence at this time to conclude that CNM-Au8 provides any benefit to people with ALS and looks forward to the outcomes of any NDA application and the planned Phase 3 clinical trial that will provide clearer evidence for/against its efficacy.
International Alliance of ALS/MND Associations
April 2026
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