Long-term treatment with Clene Nanomedicine’s CNM-Au8 was associated with improved survival among patients with amyotrophic lateral sclerosis from 2 clinical trials.
According to a new announcement, Clene Nanomedicine has submitted new biomarker and efficacy data of its investigational agent CNM-Au8 to the FDA for the treatment of amyotrophic lateral sclerosis (ALS). These new data, which included results from post hoc analyses of the HEALEY ALS platform trial (NCT04297683) and the RESCUE-ALS phase 2 trial (NCT04098406), supplements the initial findings previously discussed with the agency in late 2023.
In its announcement, Clene noted that these data are intended to be a guide for the planned FDA Type C interaction with the agency, which the company anticipates to happen in the third quarter of 2024. Ultimately, the parties will discuss a path toward an accelerated approval.1
CNM-Au8 neurofilament light (NfL) responders, who were defined by investigators as participants that showed consistent and sustained NfL reductions, comprised nearly half of all patients treated with the ALS agent in both trials. These CNM-Au8 NfL responders demonstrated a 28% mean reduction in NfL levels compared with baseline. Notably, NfL levels continued to increase in CMN-Au8 NfL non-responders in HEALEY ALS and RESCUE-ALS (all doses; geometric mean ratio difference at week 76 post-baseline, 0.57; 95% CI, 0.50–0.64; P <.00001).
“We believe that the new data recently presented to the FDA demonstrates that the significant and reproducible survival benefit associated with CNM-Au8 treatment is supported by biomarker results. These results also establish a link between the observed survival benefits and CNM-Au8’s dual mechanism of action and ALS disease improvements," Rob Etherington, CEO at Clene, told NeurologyLive®. "We want individuals living with ALS, their caregivers, and the broader ALS community to know that we remain deeply committed to pursuing possible regulatory pathways to make this potentially life-saving treatment available."
In new analyses of the trials, CNM-Au8 NfL responders showed extended survival compared with propensity matched controls from the PRO-ACT database (HR, 0.504; 95% Wald CI, 0.28–0.904; covariate adjusted, P = .022). Moreover, the agent improved survival of CNM-Au8 NfL responders compared with CNM-Au8 NfL non-responders (HR, 0.350; 95% CI, 0.188–0.649; covariate adjusted, P = .0009).
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Additional findings revealed that CNM-Au8 NfL responders demonstrated a significantly less decline in ALS Functional Rating Scale (ALSFRS-R) total score and in the respiratory subdomain score of the ALSFRS-R compared with CNM-Au8 NfL non-responders at week 64, 76, 88, and 100 visits post-randomization (P <.01). In addition, this group showed improvements compared with CNM-Au8 NfL non-responders starting at week 48 (P <.10) and all later timepoints with significance reached at weeks 88 and later (P <.05) in the combined assessment of function and survival ranks clinical outcomes.
Researchers observed that long-term treatment with CNM-Au8 30 mg, independent of NfL responder status, was associated with an improvement in survival among participants from RESCUE-ALS and HEALEY ALS using updated long-term follow-up of survival status compared with propensity matched controls from the PRO-ACT database, the ALS/MND Natural History Consortium (NHC), and the Australian MiNDAUS registry. The company noted that matching methods and covariates were prespecified and performed by an independent statistician.
In HEALEY ALS, long-term treatment with CNM-Au8 30 mg displayed a 57% decreased in risk of all-cause mortality compared with PRO-ACT propensity matched controls (HR, 0.431; 95% CI, 0.276-0.672; covariate adjusted, P = .0002). Also, long-term treatment with the agent showed a 48% decreased risk of all-cause mortality compared with ALS NHC propensity matched controls (HR, 0.519; 95% CI, 0.347-0.776; covariate adjusted, P = .0014).
In RESCUE-ALS, long-term treatment with CNM-Au8 30 mg revealed a 70% decreased risk of all-cause mortality in comparison with PRO-ACT propensity matched controls (HR, 0.311; 95% CI, 0.142-0.682; covariate adjusted, P = .0035). It also had a 51% decreased risk of all-cause mortality compared with MiNDAUS propensity matched control (HR, 0.487; 95% CI, 0.287-0.824; covariate adjusted, P = .0074).
“The strong safety profile of CNM-Au8, with its NfL biomarker response now linked to survival evidence, and new information on mechanisms of action support proceeding to a confirmatory phase 3 clinical trial and regulatory discussions on approval pathways,” principal investigator Merit Cudkowicz, MD, chair of the neurology department at Massachusetts General Hospital and director of the Sean M Healey & AMG Center for ALS, said in a statement.1
The company also noted they data provided to the agency included an association of responses between CNM-Au8 mechanism responders and CNM-Au8 NfL responders, where the connection between the 2 responders links the mechanism of action to NfL reductions. Additionally, biomarkers of oxidative stress revealed consistent improvement after CNM-Au8 treatment with an enhancement of activity associated with the duration of treatment. Overall, Clene noted that these data support a dual mechanism of action of neuronal metabolic support and reduced oxidative stress.
In the submission, Clene also provided further mechanistic data from preclinical models that showcased improvement of neuronal integrity and survival where CNM-Au8 significantly reduced the release of NfL from damaged motor neurons axons. In over 650 patient years of safety data, the company noted that the agent continues to demonstrate a safety profile, with no serious adverse events as related to the treatment reported by investigators to date.
