Clene Presents NfL Biomarker Data for CNM-Au8 in ALS, Plans NDA Filing for Accelerated Approval
核心洞察
CNM-Au8-treated ALS patients whose neurofilament light chain (搜索) (NfL) declined or stabilized had a 38% lower risk of death versus controls (HR 0.621; p=0.037) in the HEALEY platform trial.
A causal principal stratum analysis preserving randomization showed a 41% lower death risk in predicted NfL responders on CNM-Au8 30 mg (HR 0.593; p=0.026).
CNM-Au8 30 mg patients had a 74% lower 12-month death risk versus concurrent controls (p=0.0124), with an average survival gain of nearly six months at four years.
Clene Inc. (搜索) (Nasdaq: CLNN) announced new biomarker analyses demonstrating that CNM-Au8-treated amyotrophic lateral sclerosis (搜索) (ALS) patients whose neurofilament light chain (搜索) (NfL) levels declined or stabilized experienced significantly improved survival and functional outcomes. These findings will be included in the company's planned New Drug Application (NDA) seeking accelerated approval, with submission expected in early Q4 2026.
The analyses address questions raised by the U.S. Food and Drug Administration during a March 2026 Type C meeting, where the agency acknowledged that NfL — a recognized blood marker of nerve-cell injury — has established prognostic value in ALS and could potentially serve as a reasonably likely surrogate endpoint to support accelerated approval.
Survival Benefit Concentrated in NfL Responders
In the HEALEY ALS Platform Trial, participants randomized to CNM-Au8 30 mg had a 74% lower risk of death after 12 months of follow-up compared with concurrently randomized controls from other regimens (p = 0.0124). Among participants whose NfL declined or stabilized, the survival benefit was pronounced: a 38% lower risk of death over the full follow-up period (HR 0.621, 95% CI 0.397–0.972; p = 0.037), with the average survival gain reaching nearly six months (177 days) at four years of follow-up (Day 1,463; p = 0.012).
By contrast, participants whose NfL increased did not demonstrate a statistically significant difference in survival benefit at any measured timepoint.
These findings were replicated in RESCUE-ALS, a smaller nine-month placebo-controlled Phase 2 trial. Among the 22 CNM-Au8-treated participants whose NfL response could be classified, the 11 whose NfL declined or stabilized had a 76% lower adjusted risk of death compared with the 11 whose NfL increased (HR 0.24; p = 0.008), with median survival of 43.5 months versus 19.9 months (log-rank p = 0.040). NfL responders in RESCUE-ALS also had a 69% lower risk of death compared with propensity-matched real-world ALS controls (HR 0.31; 95% CI 0.13–0.76; p = 0.011).
Functional Improvements on Combined Measures
NfL responders in HEALEY scored significantly better than concurrently randomized controls on the Combined Assessment of Function and Survival (CAFS). The least-squares mean difference was 62.6 (95% CI 5.3–119.9; p = 0.032) when combining ALSFRS-R with survival, and 86.3 (95% CI 30.3–142.2; p = 0.003) when combining Slow Vital Capacity (SVC, % predicted) with survival.
On death-imputed analyses — which score participants zero after death, capturing survival and function jointly — the advantage reached 7.0 points on the ALSFRS-R (p < 0.0001) and 15.6 points on SVC (% predicted; p = 0.004) at Week 52. Participants whose NfL increased showed no statistically significant difference on any of these measures.
Causal Evidence from Principal Stratum Analysis
To address the observational nature of post-treatment NfL-based grouping, Clene conducted a principal stratum analysis that classified every participant — treated and control — by pre-treatment characteristics alone, preserving the randomized comparison. The survival benefit of CNM-Au8 30 mg was concentrated in the predicted NfL-responder stratum: a 41% reduction in the hazard of death (HR 0.593, 95% CI 0.374–0.940; p = 0.026) and approximately 3.4 months of survival gain at Day 878 (p = 0.004). No statistically significant difference was observed in the predicted NfL-increase stratum (HR 1.199, 95% CI 0.643–2.239; p = 0.568).
"This is the strongest causal evidence in the planned NDA package that the CNM-Au8 30 mg treatment benefit operates through a mechanism related to NfL response," the company stated.
The specificity of the NfL finding was confirmed through four negative controls — sex, body mass index change, glial fibrillary acidic protein change, and Tau change — each substituted for NfL and run through the identical analysis. All four analyses were null for both composite functional benefit and survival, whereas the NfL analysis was positive on both measures.
NfL Reduction Magnitude and Clinical Benefit
As previously reported in JAMA (Berry et al., 2025), plasma NfL declined in CNM-Au8-treated participants and increased in placebo recipients over the 24-week double-blind period of HEALEY, with a least-squares mean difference of −0.100 on the natural log scale (SE 0.048; p = 0.040). Larger differences were observed in faster progressors (−0.144; p = 0.014) and in participants with above-median baseline NfL (−0.150; p = 0.031).
In prespecified analyses of two ALS observational cohorts — the German/Austrian APST (1,671 evaluable) and the U.S. ANSWER ALS (380 evaluable) — none of whose participants received CNM-Au8, a 10% decline in NfL was associated with a 6% to 10% reduction in the hazard of death (p < 0.0001 and p = 0.001, respectively), independent of baseline NfL level.
Safety Profile and Regulatory Path Forward
CNM-Au8 has demonstrated a consistent safety and tolerability profile across clinical trial and expanded access programs totaling more than 1,280 collective participant-years of treatment as of July 31, 2026, including more than 1,100 participant-years in ALS. As of August 10, 2026, no serious adverse events have been assessed as related to CNM-Au8, and no safety signals have been associated with long-term use.
"ALS is a heterogeneous disease, and it matters that a biomarker signal, NfL decline or stabilization, marks the patients in whom CNM-Au8 appears to be providing the greatest benefit," said Ben Greenberg, Head of Medical at Clene. "The FDA's accelerated approval of another drug for SOD1-ALS (搜索) established that a reduction in NfL can be reasonably likely to predict clinical benefit in a defined ALS population."
Rob Etherington, President and CEO of Clene, added: "Observing the NfL biomarker-to-clinical-benefit relationship replicated in two independent trials, and NfL's prognostic value confirmed in more than 2,000 patients who never received CNM-Au8, is exactly the kind of evidence that gives us confidence in what we're submitting to the FDA."
Clene's planned Phase 3 confirmatory trial, RESTORE-ALS, will evaluate the NfL biomarker relationship prospectively, using baseline NfL level as a prospective enrollment stratification factor with prespecified NfL-stratified analyses.
The company noted that these biomarker analyses are post hoc and exploratory; neither the HEALEY nor RESCUE-ALS trial met its prespecified primary efficacy endpoint, no adjustment was made for multiple comparisons, and reported p-values are nominal. The FDA has made no determination regarding the acceptability of NfL as a surrogate endpoint for CNM-Au8.