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Clene Receives FDA Guidance on Accelerated Approval Pathway for CNM-Au8 in ALS, Plans Further Biomarker Analysis
Key Takeaways
- Clene aims to leverage expanded access program data to support CNM-Au8's effect on NfL decline for ALS accelerated approval.
- The company plans to submit an NDA in mid-2025, incorporating additional data and analyses.
The FDA recommended a follow-up meeting with Clene to further discuss the analyses needed to support the accelerated approval pathway for CNM-Au8 in amyotrophic lateral sclerosis.
Rob Etherington
(Credit: Clene)
A month after Clene’s recent meeting with the FDA and presentation of new data, the agency has provided written guidance to the company regarding a potential accelerated approval pathway for its investigational product CNM-Au8 in amyotrophic lateral sclerosis (ALS). Clene announced its intention to follow the FDA’s recommendations for CNM-Au8, expressing confidence in its ability to address the agency’s requests.1
Earlier this year, the company was initially advised that the data presented in its briefing package for the ALS agent was insufficient to support a new drug application (NDA) submission under the accelerated approval pathway. With the FDA’s recommendation, Clene will need to investigate whether additional data from the ongoing compassionate use expanded access programs (EAPs) can be leveraged to substantiate the effect of CNM-Au8 on neurofilament light chain (NfL) decline.
“We are incredibly grateful for the FDA’s willingness to consider how the available data from our expanded access programs may be able to support the existing clinical study data to allow for the review of an application for approval of CNM-Au8 for ALS via an accelerated regulatory pathway, and for the valuable feedback we have received to date,” Rob Etherington, president and CEO at Clene, said in a statement.1 “Together with the survival and supportive biomarker data generated thus far, the drug’s benign safety profile, and the emerging EAP NfL data, we look forward to continued discussions with the Agency. Clene plans to include the additional data in an NDA submission under the accelerated approval pathway in mid-2025. We remain dedicated to the ALS community and honored to help critically ill patients and their families.”
The company plans to provide evidence of NfL declines from participants in 3 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.
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“Having seen first-hand the potential benefits of CNM-Au8 in both its clinical and compassionate use EAP programs, I am grateful that the FDA has recognized the power of real-world experience for a drug in ALS, and is willing to consider how EAP data can help ALS drugs advance on regulatory pathways,” Jinsy A. Andrews, MD, MSc, FAAN, associate professor of neurology and the director of Neuromuscular Clinical Trials at Columbia University, said in a statement.1
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.
“It was my pleasure to assist Clene in these varied supportive analyses, including NfL biomarker data from participants in our trials. Given the limited therapeutic options for ALS and a high sense of urgency, I am grateful to participate in considering multiple paths forward in ALS,” Merit Cudkowicz, MD, chair, neurology department, Massachusetts General Hospital, director, Sean M Healey & AMG Center for ALS, said in a statement.1
In 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 of 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, 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). 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.
