ALS Agent CNM-Au8 Displays Survival Benefit and Delay of Clinical Worsening in 2 Year Follow-Up

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New data from the ongoing phase 2 RESCUE-ALS (NCT04098406) open-label extension (OLE) trial investigating CNM-Au8 (Clene Nanomedicine) demonstrated survival improvement and improved time to clinical worsening among patients with amyotrophic lateral sclerosis (ALS) treated with the agent.1 These findings produced by using the rank-preserving structural failure time model (RPSFTM), a well-recognized method to estimate crossover treatment effects in ALS trials, are cut from the 24-month long-term data of RESCUE-ALS as of July 2023.

At the conclusion of the data cutoff point, findings showed a median survival benefit of 19.3 additional months among 45 patients with ALS in comparison with placebo (CNM-Au8 median survival, 34.2 months; placebo-adjusted median survival, 14.9 months). Notably, the results displayed a 75% decreased risk of long-term all-cause mortality in patients who originally started treatment with CNM-Au8 compared with placebo after adjusting for benefit received by placebo following the switch to CNM-Au8 (HR = .252; 95% CI, 0.106-0.597; bootstrap log-rank P <.001).

“This new data include open label participants treated with CNM-Au8—42% of whom remain alive up to 3.5 years from randomization and up to 6.6 years from the onset of ALS symptoms, a profoundly meaningful milestone for people living with this devastating disease,” Benjamin Greenberg, MD, head of medical at Clene Nanomedicine, said in a statement.1 “A median survival improvement of 19.3 months provides people living with ALS, their families, and caregivers more time that is so invaluable, and adds to the totality of data we are seeing in our ALS clinical program.”

The RESCUE-ALS trial was a 36-week phase 2 randomized, placebo-controlled, and double-blinded study of CNM-Au8 treatment in patients with early sporadic ALS, with an open-label extension that further evaluated safety and efficacy. Participants (n = 45) from RESCUE-ALS were randomly assigned using a ratio of 1:1 and received 30 mg of CNM-Au8 or the placebo every day over the course of 36 weeks for the double-blind period of the trial.

Following the double-blinded portion, 36 patients entered the long-term open-label extension, including 20 participants originally treated with CNM-Au8 during the blinded period and 16 placebo-treated participants who were subsequently switched to CNM-Au8 during the beginning of the OLE. Survival status outcomes following treatment were available for all of the enrolled participants.

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Findings in the OLE showed a 52% decreased risk of ALS clinical worsening events, which were defined as the first occurrence of death, tracheostomy, assisted ventilation, or feeding tube placement, (HR: 0.48; 95% CI, 0.23-1.0; log-rank P = .049) in patients originally treated with CNM-Au8 versus original placebo. There was a median survival benefit of 10.1 months when not accounting for the improvement by placebo-treated participants who switched to CNM-Au8 at the beginning of the OLE (CNM-Au8 median survival, 34.2 months; placebo median survival, 24.1 months). Notably, in the same analysis, there was a 46% decreased risk of all-cause mortality in patients originally treated with CNM-Au8 compared with those originally treated with placebo (HR: 0.54; 95% CI, 0.25-1.1, log-rank P = .09).

“The data that continues to be received from the RESCUE-ALS open label extension study is truly impressive, and now shows consistently significant decreased risk of death greater than 70% using two different long-term analysis models,” trial clinical advisor Matthew Kiernan, PhD, DSc, Bushell Chair of Neurology at University of Sydney said in a statement.1 “The survival benefit across treatment arms is linked to less worsening of disease, as experienced by ALS patients. At the same time, the further safety data confirms that CNM-Au8 is well tolerated in ALS patients.”

In the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) data, findings showed a 70% decreased risk of long-term mortality in those originally treated with CNM-Au8 compared with matched placebo participants (Cox adjusted HR = .300; 95% CI, 0.09-0.79; P= .03).2 The PRO-ACT database contains approximately 12,000 patients with ALS recorded from several completed clinical trials, making it the largest publicly available repository of merged ALS trial data.

The collective research of CNM-Au8, spanning over 475 years in clinical trials and Expanded Access Protocol programs, showed no observed safety signals across investigations for ALS, multiple sclerosis, and Parkinson disease. Additionally, there have been no serious adverse events reported in relation to CNM-Au8 and the adverse events that have been observed with CNM-Au8 have been recorded as transient and predominantly mild-to-moderate in severity.1

REFERENCES
1. Clene Reports Significantly Improved Survival Benefit of 19.3 Months and Significantly Delayed Clinical Worsening in Rescue-Als Open-Label Extension Two Year Follow-Up. News Release. Clene Nanomedicine. Published August 29, 2023. Accessed August 30, 2023. https://invest.clene.com/news-releases/news-release-details/clene-reports-significantly-improved-survival-benefit-193-months
2. Atassi N, Berry J, Shui A, et al. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014;83(19):1719-1725. doi:10.1212/WNL.0000000000000951



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