Despite not meeting its primary and secondary end points, CNM-Au8 will continue to be evaluated in an open-label extension in HEALEY ALS and could potentially be offered in an expanded access protocol program.
Topline findings from the pivotal HEALEY ALS trial (master protocol; NCT04297683), the first-ever platform trial for amyotrophic lateral sclerosis (ALS), demonstrated that CNM-Au8 (Clene Nanomedicine) did not meet its primary and secondary end points; however, the therapy did show survival benefit on exploratory analyses.1
All told, over a 24-week period, treatment with the investigational gold nanocrystal suspension resulted in 2% (95% CI, –20 to 19) slowing of disease progression, demonstrated by scores on ALS Functional Rating Scale Revised (ALSFRS-R) adjusted for mortality. Prespecified survival analyses showed significant survival benefit for those in the 30-mg CNM-Au8 group, which the company noted warrants continued development. No survival benefit was observed for the 60-mg CNM-Au8 group, the larger of the 2 doses assessed.
"There remains a high unmet medical need for treatments for people living with ALS. The potential survival benefit with CNM-Au8 at 30 mg is encouraging. Additional prespecified exploratory analyses of both the RCT and open-label extension part of the study will be shared once available,” principal investigator Merit Cudkowicz, MD, MSc, director, Sean M. Healey & AMG Center for ALS, and chief of the Department of Neurology, Massachusetts General Hospital, said in a statement.1 "We are thankful to the many people who participated in this study. We will learn from these results and continue to use these data to inform future advances in ALS trial design."
The news comes less than a week after another ALS hopeful, Biohaven’s enzyme inhibitor verdiperstat, also failed to statistically differentiate itself from placebo in HEALEY ALS. In the CNM-Au8 regimen of the study, 161 participants with ALS were randomized to 30- or 60-mg CNM-Au8 or placebo as adjunct to standard of care. In addition to change in ALSFRS-R, investigators assessed secondary end points such as Combined Assessment of Function and Survival (CAFS) joint rank test, change in respiratory function as measured by slow vital capacity (SVC), and overall survival.
Across both CNM-Au8 groups, secondary end points showed no statistically significant change over the 24-week treatment. There were no drug-related serious adverse events or significant safety signals found in either group. The statistically significant survival results were statistically consistent for the 30-mg dose group between the regimen only and full analysis sets, which included shared placebo from other regimens participating in the platform trial.
"We are very pleased to see a survival benefit in a broad population of people who had already been living with ALS for up to three years. Importantly, this is the second phase 2 study demonstrating a survival benefit following CNM-Au8 treatment. CNM-Au8’s mechanism of enabling energy metabolism and efficiency may not be reflected in the slope of ALSFRS-R change after only 24 weeks of treatment," Robert Glanzman, MD, FAAN, chief medical officer, Clene, said in a statement.1 "These Healey ALS Platform Trial results support advancement of the CNM-Au8 30 mg dose. We look forward to discussions with US regulatory authorities at an End of Phase 2 meeting for our CNM-Au8 development program in ALS."
The survival findings were in line with data from the phase 2 RESCUE-ALS trial (NCT04098406), most recently presented at the 2022 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, held September 21-24, in Nashville, Tennessee. Specifically, ALS disease progression, which was defined in the study as occurrence of death, tracheostomy, noninvasive ventilation, and gastrostomy, had an absolute risk reduction of 55% (P = .0125).2
In addition, findings from RESCUE-ALS showed that the proportion of participants who experienced greater than or 6-point decline in ALSFRS-R was significantly reduced (Chi-square test, P = .035). Quality of life was improved, as demonstrated by a least-squares mean difference of 0.9 (95% CI, 0.2-1.6; P = .018) on ALS Specific Quality of Life-Short Form. Overall, there were no significant adverse events that occurred in the study. A larger study is underway to confirm efficacy of CNM-Au8 in ALS, as data from RESCUE-ALS have established safety of the treatment. Notably, percent change in the summated motor unit index scores for the abductor digit minimi, abductor pollicis brevis, tibialis anterior, and biceps brachii were not significant, with a least-squares mean difference of 7.7% (95% CI, –11.9 to 27.3; P =0.430).
Following the findings presented at AANEM, Michael Hotchkin, chief development officer, Clene, sat down to discuss them in detail. Watch below as he described the mechanistic function of CNM-Au8, and how it improves survival in ALS. Watch the video below to hear his takeaways.