SALT LAKE CITY, Utah — Clene Inc. and its wholly owned subsidiary Clene Nanomedicine Inc., a clinical-stage biopharmaceutical company focused on improving mitochondrial health and protecting neuronal function to treat neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), today reported new data from the 12-month long-term open label extension (OLE) of the CNM-Au8® treatment arm in the HEALEY ALS Platform Trial.
Long-Term Plasma NfL Biomarker Findings from Regimen C (CNM-Au8) in the HEALEY ALS Platform Trial Open Label Extension (OLE)
Plasma neurofilament light chain (NfL), a blood-based biomarker associated with neurodegeneration, declined by 16% (95% CI: 2% to 28%) from baseline to 76 weeks of treatment in the HEALEY ALS Platform Trial Open Label Extension (OLE) in participants randomized to CNM-Au8 30 mg relative to participants initially randomized to placebo (p=0.023). CNM-Au8 was associated with a 10% relative reduction in plasma NfL over the 24-week double-blind treatment period of the HEALEY ALS Platform Trial (p=0.040). This effect on NfL appears durable over the long-term follow-up period.
NfL, a key biomarker of neurodegeneration, is released from neurons following axonal injury, especially in people living with ALS, where higher levels of NfL have been found to predict more rapid decline in clinical function and increased mortality risk. Biomarkers such as NfL that are considered reasonably likely to serve as surrogates of effects on clinical endpoints have recently been used to support an FDA approval of a drug for the treatment of ALS.
The post hoc NfL results are based on analyses of plasma NfL collected from participants in the HEALEY OLE who were treated with CNM-Au8 for up to 76 weeks compared to participants treated with placebo for 24 weeks prior to crossing over to active treatment.
CNM-Au8 30mg treatment reduced plasma NfL levels compared to baseline: Mixed Model with Repeat Measures (MMRM), Least Squared Means on a Natural Log (Ln) Scale for the 76-week change from baseline of plasma NfL: CNM-Au8 = -0.075 (SE: 0.053); placebo = +0.098 (SE: 0.056); CNM-Au8 30mg vs. original placebo difference of LS Means on a Ln Scale = -0.173 (SE: 0.076), p=0.023. Combined analyses of both CNM-Au8 doses (30mg and 60mg) also demonstrated nominally significant reductions in plasma NfL, CNM-Au8 vs. placebo difference of LS Means on a Ln Scale = -0.144 (SE: 0.066), p=0.029.
Participants were treated with CNM-Au8 in the OLE for as long as 2.6 years from original randomization, providing long-term data on treatment effects in people living with ALS.
James D. Berry MD, Associate Professor of Neurology, Chief of the Motor Neuron Disorder Division and Director of the Neurological Clinical Research Institute at Massachusetts General Hospital commented, “As consensus is building that neurofilament is an important biomarker reasonably likely to predict clinical benefit, it is important to see NfL continue to decrease during long-term follow-up, and correlate with time to event clinical outcomes in the Clene regimen of the double-blind and OLE portions of the HEALEY ALS Platform Trial.”
Long-Term Survival Improvement from Regimen C (CNM-Au8) in the HEALEY ALS Platform Trial Open Label Extension (OLE)
Long-term survival analyses included the prespecified rank-preserving structural failure time model (RPSFTM) to account for the effects of CNM-Au8 in participants randomized to placebo who crossed-over to treatment with CNM-Au8. Under an assumption of a constant common treatment effect from CNM-Au8, treatment with CNM-Au8 demonstrated a 60% decreased risk of long-term all-cause mortality in participants originally randomized to treatment with CNM-Au8 compared to those originally randomized to placebo, after adjusting for the estimated benefit received after switching to CNM-Au8 (Cox HR= 0.40, 95% CI: 0.19 to 0.85; p-value= 0.017).
The RPSFTM analysis estimates the survival gained by receiving active treatment using the data from all study participants and then subtracting the estimated benefit from ex-placebo participants switched to CNM-Au8 during the OLE to provide a comparison of CNM-Au8 versus placebo across the entire study period.
Merit Cudkowicz, M.D., Chair Neurology Department, Director, Sean M Healey & AMG Center for ALS at Mass General Hospital, Julianne Dorn Professor of Neurology Harvard Medical School, and the Principal Investigator of the HEALEY ALS Platform Trial, said, “These long-term results provide additional promising evidence that CNM-Au8 may offer more time to people living with ALS. The survival analyses using RPSFTM is a well-recognized method that has been used to estimate cross-over effects in another recent ALS trial, as well as oncology and other rare diseases. Additional analyses of the open label data are underway.”
Post-hoc Analysis Validates Association of NfL levels with Clinical Morbidity Outcomes and the Effects of CNM-Au8 in High Risk ALS Patients
To investigate the role of NfL in the incidence of ALS clinical worsening events, the pooled population of the HEALEY ALS Platform and the RESCUE-ALS trial were stratified by baseline plasma NfL levels by quartile (<51 pg/mL, 51 – 76 pg/mL, >76 – 114 pg/mL, and >114 pg/mL). The average number of ALS clinical worsening events including death, tracheostomy, feeding tube placement, and initiation of assisted ventilation were calculated for each treatment group (CNM-Au8 30 mg vs. placebo) during the double-blind periods. Results of these analyses suggested a beneficial effects of CNM-Au8 in delaying occurrence of clinical worsening events in the highest risk NfL quartiles.
In participants with the highest baseline plasma NfL levels (> median), the apparent benefit of CNM-Au8 30 mg was enhanced (Cox HR: 0.25, 95% CI: 0.11 to 0.61; p-value= 0.003). In the same post hoc analyses, nominally significant reduced rates of time to death or permanently assisted ventilation (PAV), and all-cause mortality, were also observed.
Benjamin Greenberg, M.D., Head of Medical at Clene, said, “The clinical correlation seen with plasma neurofilament change, as well as long-term survival using RPSFTM, provides further independent evidence to strongly support CNM-Au8 as a potential treatment for ALS. The concordance of these long-term biomarker and survival results with previously reported clinical outcomes from two Phase 2 ALS trials is encouraging. Additional biomarker and clinical data from the HEALEY ALS Platform Trial open-label extension periods have been collected and are undergoing analysis for expected results to be reported in the first quarter of 2024.”
About Clene
Clene Inc., (Nasdaq: CLNN) (along with its subsidiaries, “Clene”) and its wholly owned subsidiary Clene Nanomedicine Inc., is a late clinical-stage biopharmaceutical company focused on improving mitochondrial health and protecting neuronal function to treat neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease and multiple sclerosis. CNM-Au8® is an investigational first-in-class therapy that improves central nervous system cells’ survival and function via a mechanism that targets mitochondrial function and the NAD pathway while reducing oxidative stress. CNM-Au8® is a federally registered trademark of Clene Nanomedicine, Inc. The company is based in Salt Lake City, Utah, with R&D and manufacturing operations in Maryland.
About Healey ALS Platform Trial
The HEALEY ALS Platform Trial is a perpetual multi-center, randomized, double-blind, placebo-controlled Phase 2 program designed to evaluate the efficacy and safety of multiple investigational products in people living with ALS. This landmark platform trial tests multiple treatments utilizing a shared placebo group. 161 participants were randomized to 30 mg CNM-Au8, 60 mg CNM-Au8, or placebo as adjunct to standard of care for a 24-week treatment period. Active drug was offered to all participants who were eligible and elected to continue into the Open Label Extension (OLE). The primary outcome of the trial was the change in disease severity over time as measured by ALSFRS-R through 24 weeks accounting for mortality (analyzed using a Bayesian shared parameter model). Prespecified secondary efficacy endpoints included the Combined Assessment of Function and Survival joint rank test (CAFS), change in respiratory function as measured by slow vital capacity (SVC), and overall survival.
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