Background

CNM-Au8 is a preparation of pure elemental gold nanoparticles in a drinkable bicarbonate solution. The faceted crystals have a median diameter of 13 nm, slightly smaller than a ribosome. Their surfaces catalyze oxidation-reduction reactions, including the conversion of NADH to NAD+ (Huang et al., 2005). NAD+ is an essential cofactor for ATP generation and a cell metabolic sensor. The rationale for the therapeutic use of gold nanocrystals is that they may help ameliorate cellular-energy deficits and oxidative stress characteristic of multiple neurogenerative diseases.

Other gold nanoparticles have been reported to have reactive oxygen-scavenging, anti-oxidant, and anti-inflammatory activity, including in cell models of Aβ toxicity (e.g., Du et al., 2013; Li et al., 2017; Chiang et al., 2021). 

In a preclinical study, CNM-Au8 increased NAD+ and ATP concentrations in cultured neurons and glia, and promoted remyelination and recovery of motor function in two mouse models of multiple sclerosis (Robinson et al., 2020).

Findings

In 2015-2016, Clene ran a placebo-controlled Phase 1 study of single and multiple doses of CNM-Au8. It enrolled 86 healthy volunteers, who received 15, 30, 60, or 90 mg single doses, or the same daily doses for 21 days. In its communications, the company reported that drug-related adverse events were neural/gastrointestinal and mild, with none leading to study discontinuation.  

In July 2019, the U.S. FDA granted CNM-Au8 Orphan Drug Designation for ALS.

In December 2019, a Phase 2 trial called RESCUE-ALS began enrolling 45 ALS patients in two centers in Australia. Participants had to be within two years of symptom onset, or one year of diagnosis. They took 30 mg drug or a placebo once daily for 36 weeks. The primary endpoint was change from baseline to 36 weeks in an electrophysiological measure of motor neuron function, a biomarker that predicts ALS disease progression. Other endpoints included clinical measures of function, disease progression, and health care utilization. Participants who completed the trial could enter a 48-week open-label extension. For trial details, see Vucic et al., 2021. In November 2021, the company announced that the trial had missed its primary endpoint, but still claimed significant benefits on measures of progression and quality of life (press release). The drug was safe. In July 2022, Clene announced data from the open-label extension, claiming a 70 percent reduced risk of death in the patients who initially received CNM-Au8 compared to those who started on placebo (press release). Results were published after peer review (Vucic et al., 2023). 

In July 2020, a Phase 2/3 multicenter study began evaluating CNM-Au8 as part of Massachusetts General Hospital’s Healy ALS Trial Platform. This trial tests four experimental treatments in parallel under a single protocol at 54 locations in the U.S. In the CNM-Au8 arm of the trial, 161 ALS patients were randomized to 30 or 60 mg daily or matching placebo in a 3:1 ratio. The primary outcome was change in severity after 24 weeks, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes included respiratory function, muscle strength, and survival. The treatment phase finished in April 2022. Outside of this trial, an immediate access protocol is making the drug available to up to 30 patients at MGH.

In December 2019, two open-label pilot trials began to study CNS metabolic effects of CNM-Au8 in people with Parkinson’s disease and with relapsing-remitting multiple sclerosis. Conducted at the University of Texas Southwestern Medical Center, the studies each aimed to enroll 30 patients into a three-month course of 7.5 to 60 mg daily. The primary outcome was the brain’s NAD+/NADH redox ratio as measured by magnetic resonance spectroscopy imaging. The Parkinson’s study ended in June 2021 with 13 patients. A similar trial in 24 people with ALS was planned to start in April 2021, but was withdrawn before starting enrollment.

In March 2022, Clene registered an expanded access study for 15 ALS patients at three U.S. centers, but this was cancelled in June, before any patients were enrolled.

On October 3, 2022, Clene announced CNM-Au8 had failed to change the primary endpoint of functional decline at 24 weeks in the Healy ALS trial. Secondary endpoints of function, survival, and breathing capacity were also negative. The company claimed a potential survival signal at the 30 mg dose, where three patients on placebo died, compared to one on CNM-AU8 (press release). Additional survival data from a 52-week open-label extension is expected in mid-2023.

A placebo-controlled Phase 2 trial in people with MS showed improvements in vision and global neurological function (Nov 2022 press release). No clinical trial results with CNM-Au8 are published in peer-reviewed journals.

For details on CNM-Au8 trials, see clinicaltrials.gov.