Clene Inc. (CLNN) has announced that the U.S. Food and Drug Administration (FDA) has provided written guidance regarding a potential accelerated approval pathway for its investigational product, CNM-Au8, in the treatment of amyotrophic lateral sclerosis (ALS). This guidance follows Clene's recent meeting with the FDA and the presentation of new data, signaling a possible shift in the regulatory landscape for ALS therapies.
FDA's Recommendation and Clene's Plan
Initially, the FDA had advised Clene that the data presented in its briefing package for CNM-Au8 was insufficient to support a New Drug Application (NDA) submission under the accelerated approval pathway. However, following Clene’s presentation of additional data and analyses, the FDA has recommended that Clene investigate whether additional data from ongoing compassionate use Expanded Access Programs (EAPs) could be leveraged to substantiate the effect of CNM-Au8 on neurofilament light chain (NfL) decline.
Clene intends to follow the FDA’s recommendations, expressing confidence in its ability to address the agency’s requests. The company plans to provide evidence of NfL declines from participants in three ongoing FDA-authorized compassionate use EAPs and will meet with the agency in early 2025 to finalize the statistical analysis plan for these NfL biomarker evaluations. Additionally, Clene will conduct survival pharmacometric modeling to link NfL and other disease-specific biomarkers to clinical survival benefits and changes observed in phase 2 trial data. Further analyses of ALS-specific biomarkers will also be undertaken to demonstrate the pharmacodynamic activity of CNM-Au8.
Clinical Data and Biomarker Analysis
At the recent FDA meeting, Clene and ALS experts presented new data from prespecified and post hoc analyses of the HEALEY ALS Platform trial (NCT04297683) that highlighted the potential benefits of CNM-Au8 for patients with ALS. During the open-label extension to month 12 from the trial, researchers observed a 78% risk reduction in time to death (improved survival) compared with the placebo (covariate adjusted Cox hazard ratio (HR) = 0.224; 95% CI, 0.053-0.949; P = .042).
Additional post hoc evidence from the trial showed a significant association between baseline NfL burden and a survival benefit from CNM-Au8. For CNM-Au8-treated participants with the highest baseline Upper NfL tertile, investigators observed an 83% risk reduction in time to death or permanently assisted ventilation (PAV) through month 12 compared with placebo (covariate adjusted Cox HR = 0.174; 95% CI, 0.036-0.830; P = .0283). Similarly, an 84% risk reduction was observed in participants treated with CNM-Au8 with baseline NfL levels at least above the median through month 12 compared with placebo (covariate adjusted Cox HR = 0.155; 95% CI, 0.035-0.693; P = .0147).
Further findings in the analysis also showed a significant link between NfL decline and survival benefit in CNM-Au8-treated patients. Specifically, 57% of CNM-Au8 30 mg treated participants experienced a decline in NfL at week 24, the end of the double-blind phase of the HEALEY-ALS Platform Trial. Furthermore, there was a 91% risk reduction observed in time to death or PAV in participants with any level of NfL decline (or missing NfL data) at week 24, with follow-up through month 12 (covariate adjusted Cox HR = 0.0925; 95% CI, 0.22-0.382; P = .001).
Long-term survival data from real-world expanded access compassionate-use protocols also supported CNM-Au8's potential benefit. Findings in the analysis demonstrated a 31% risk reduction in participants who were unable to enter other ALS clinical trials because of advanced disease severity, when compared with propensity-matched controls pooled from 3 different natural history and clinical trial datasets (covariate adjusted Cox HR = 0.689; 95% CI, 0.529-0.898; P = .0059).
Safety Profile and Future Plans
Notably, after over 700 patient years of CNM-Au8 use, the company reported no significant safety concerns or safety trends identified and that no serious adverse events (SAEs) have been linked to CNM-Au8 treatment by any investigator to date.
Clene plans to initiate the confirmatory phase 3 RESTORE-ALS trial, with participant enrollment scheduled to begin prior to the submission of the NDA. The study is designed to evaluate the effects of CNM-Au8 on improved survival as the primary end point and delayed time to ALS clinical worsening events as the secondary efficacy end point.
Clene plans to include the additional data in an NDA submission under the accelerated approval pathway in mid-2025.
