CNM-Au8 Shows Significant Long-Term Survival Improvement in HEALEY ALS Platform Trial

Merit Cudkowicz, MD

Newly announced long-term follow-up data from Regimen C of the HEALEY ALS platform trial (NCT04297683) assessing the investigational agent CNM-Au8 (Clene Nanomedicine) in patients with amyotrophic lateral sclerosis (ALS) showed a decreased risk of mortality for up to 133 weeks in treated patients compared with placebo-treated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.¹ Overall, these findings suggest that CNM-Au8 continues to show benefit in patients with ALS over a long period of time.

Among 59 CNM-Au8-treated participants, investigators observed a statistically significant 49% decreased risk of mortality compared with PRO-ACT matched patients on placebo through long-term follow-up (HR, 0.510; 95% CI, 0.263-0.987; P = .046). In a pooled analysis of the HEALEY ALS platform trial and the phase 3 RESCUE-ALS study (NCT4098406) treatment with the agent resulted in a statistically significant 59% decreased risk of mortality compared with PRO-ACT matched placebo patients (HR = 0.406; 95% CI, 0.220-0.749; P = .004).

“Improved survival status is an important measure of drug effect. We previously reported a benefit for decreased risk of death or permanent assisted ventilation and delayed time-to-clinical-worsening events associated with CNM-Au8 30mg from the double-blind period, and we are pleased to see these data from our long-term follow-up as further support of a survival signal in our HEALEY ALS platform trial,” principal investigator Merit Cudkowicz, MD, chair, neurology department, Massachusetts General Hospital and director, Sean M Healey & AMG Center for ALS, said in a statement.¹

The HEALEY ALS platform trial is an ongoing multi-center, randomized, double-blind, placebo-controlled clinical trial program aimed to investigate the efficacy and safety of several investigational products such as CNM-Au8 in patients living with ALS. Enrollment for regimen C of CNM-Au8 began in the summer of 2020. In the study, participants received AMX0035 or placebo along with ALS standard-of-care for a 24-week period followed by an open-label extension. Of those who completed the double-blind period, 92% opted to continue on with 30 mg of CNM-Au8.

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“I am also happy to see how helpful a shared open-source dataset such as PRO-ACT is to the field to analyze data from the OLE portions of clinical trials. We encourage all companies working in ALS to contribute their data to PRO-ACT once their trial is complete. I want to also thank all the patients with ALS who are part of clinical trials and are helping the community find new treatments,” Cudkowicz said in a statement.¹

In the new HEALEY ALS analysis, participants originally randomized to 30mg of CNM-Au8 were compared with matched placebo participants derived from the PRO-ACT dataset. The dataset is obtained from 29 completed phase 2 and phase 3 clinical trials in ALS. Collected records from more than 11,600 patients with ALS were standardized across trials and gathered to establish the PRO-ACT database. Therefore, the database offers an insightful and validated surrogate of survival status from past participants in ALS clinical trials with long-term follow-up.

Investigators reported no serious adverse events in relation to CNM-Au8, with reported adverse effects as transient and predominantly mild-to-moderate in severity. This study analysis adds to over 500 estimated years of collective exposure of CNM-Au8 across trials in ALS, multiple sclerosis, Parkinson disease as well as in the Expanded Access Protocol programs showing no observed safety signals.

“To show such profound survival improvement using the HEALEY ALS platform trial data set alone and a pooled HEALEY and RESCUE data set is remarkable, and helps confirm the survival benefit seen in the prespecified secondary endpoint. Clene is extremely gratified to see this consistent long-term survival data from the HEALEY ALS platform trial OLE, with a continued clean safety profile, adding to the totality of the survival evidence,” Benjamin Greenberg, MD, head of medical at Clene, said in a statement.¹

At the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, James Berry, MD, MPH, director of the Massachusetts General Hospital ALS Care Center, presented findings of the survival analyses of CNM-Au8 from both the RESCUE-ALS trial and the HEALEY ALS platform trial.2 At the meeting, Berry sat down with NeurologyLive® for an interview to provide an overview of the analyses and explain the significance of the findings for patients with ALS. He also talked about the differences in treatment responses observed in terms of the safety profile with the treatment. Additionally, he spoke about the next steps in research with CNM-Au8 including what should be studied further in future trials.

REFERENCE
1. Clene Reports Significant Long-Term Survival Improvement From CNM-Au8 Treatment in HEALEY ALS Platform Trial Compared to PRO-ACT Historical Controls. News Release. Published September 25, 2023. Accessed September 25, 2023. https://invest.clene.com/news-releases/news-release-details/clene-reports-significant-long-term-survival-improvement-cnm-au8
2. Berry J, Maragakis N, Paganoni S, et al. Evidence for Survival Benefit in ALS with CNM-Au8 Treatment Across Three Study Populations. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts.