CNM-Au8 / Clene - LARVOL DELTA

Other Promising ‘Pipeline-in-a-Product’ Indications Advancing in 2026 (GlobeNewswire) - "In our MS program, we plan to build on our 2025 momentum as we incorporate FDA feedback to finalize our Phase 3 clinical trial design focused on cognition in MS as an adjunct to standard of care therapies. We view CNM-Au8 as a potential 'pipeline in a product,' with the initial ALS indication serving as the foundation for a much larger clinical development pipeline within the neurodegenerative field."

New P3 trial • Multiple Sclerosis

Our Commitment to the ALS Community Remains Unwavering (GlobeNewswire) - "CNM-Au8 is well known to many of these ALS stakeholders. CNM-Au8 is also well known to the regulators within the FDA, and we look forward to presenting our robust body of evidence supporting CNM-Au8 to them in later in this first quarter of 2026. We expect the totality of our biomarker, survival, and bioanalytic evidence supporting CNM-Au8, coupled with the favorable tolerability profile of the drug and the significant unmet need in ALS, will be extremely compelling in our upcoming discussions with the FDA for consideration of the accelerated approval pathway."

Clinical data • Amyotrophic Lateral Sclerosis

Next Regulatory Steps and 2026 Catalysts (GlobeNewswire) - "Our discussions have culminated in an in-person Type C FDA meeting scheduled by the end of this quarter to discuss the data in our extensive briefing package submitted in late 2025. We expect to receive the FDA minutes from this meeting early in the second quarter, with the Company ready to submit a New Drug Application (NDA) to the FDA for CNM-Au8 via an accelerated regulatory pathway in the second quarter of 2026. FDA acceptance of this NDA and issuance of a Prescription Drug User Fee Act (PDUFA) date for regulatory decision under the accelerated approval pathway could occur in the second half of 2026, with potential approval for commercial launch in 2027."

FDA approval • FDA filing • Launch US • Amyotrophic Lateral Sclerosis

Confirmatory Phase 3 RESTORE-ALS Trial Planned to Begin Later in 2026 (GlobeNewswire) - "To confirm the survival benefit observed with CNM-Au8 30 mg treatment across several Phase 2 trials and to meet FDA requirements for the accelerated approval pathway, we are planning to dose the first patient in our confirmatory Phase 3 RESTORE-ALS trial later this year. The study will be a double-blind, placebo-controlled Phase 3 trial evaluating the effects of CNM-Au8 on survival and clinical worsening events in ALS. The trial design protocol has already been discussed with and reviewed by the FDA."

New P3 trial • Amyotrophic Lateral Sclerosis

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Recruiting | Sponsor: Merit E. Cudkowicz, MD | Active, not recruiting ➔ Recruiting | Trial primary completion date: Nov 2027 ➔ Jul 2027

Enrollment open • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

New Exploratory Biomarker Findings: CNM-Au8 Induced IGFBP7 Decline was Strongly Associated with Improved Survival (The Manila Times) - "IGFBP7 decline was strongly associated with improved survival with responders, defined as a cumulative AUC IGFBP7 reduction during the 24-week double-blind period, demonstrating 78% mortality risk reduction compared to concurrently randomized controls (n=38 of 56 evaluable; HR: 0.22, 95% CI: 0.07-0.71, p=0.012; 3 events in 38 responders vs 28% mortality in controls)...Notably, the decline in IGFBP7 levels has emerged as a plausible ‘mechanistic hub’ in a coordinated biomarker response....Together, these data suggest that lower IGFBP7, whether achieved genetically or pharmacologically, may help protect against ALS progression."

P2/3 data • Amyotrophic Lateral Sclerosis

Clene...announced that the U.S. Food and Drug Administration (FDA) has granted Clene an in-person Type C Meeting later this quarter. (The Manila Times) - "Clene has now submitted its pre-meeting briefing package to the FDA, which includes previously announced statistically significant reductions in neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) from the HEALEY ALS Platform Trial and NIH-sponsored Expanded Access Program (EAP) with linked survival evidence (announced December 2025), and new analyses demonstrating that the NfL reductions observed with CNM-Au8 treatment may predict clinical benefit in patients with ALS."

FDA event • Amyotrophic Lateral Sclerosis

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Active, not recruiting | Sponsor: Merit E. Cudkowicz, MD | Trial completion date: Apr 2026 ➔ Aug 2028 | Trial primary completion date: Jul 2025 ➔ Nov 2027

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

An Open-Label Extension for the Phase 2 Study in Early Symptomatic Amyotrophic Lateral Sclerosis Patients on Stable Background Therapy to Assess Bioenergetic Catalysis With CNM-Au8 to Slow Disease Progression in ALS (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: Clene Nanomedicine | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

REPAIR-MS: 31P-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Multiple Sclerosis. (clinicaltrials.gov) - P2 | N=33 | Completed | Sponsor: Clene Nanomedicine | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Multiple Sclerosis

CNM-Au8 Strengthens Overall Survival Signal in the HEALEY ALS Platform Trial Open-Label Extension Period (GlobeNewswire) - "CNM-Au8 30 mg treatment demonstrated statistically significant improved survival across both the FAS and CRS populations based on a Cox proportional hazard model and restricted mean survival time (RMST) analyses...In the FAS population: 1-year Cox proportional hazard ratio: 0.2723, 95% CI: 0.0961 – 0.7719, p=0.0144 → 73% reduction in risk of death...In the CRS population: 1-year Cox proportional hazard ratio: 0.229, 95% CI: 0.07 – 0.752, p = 0.0151 → 77% reduction in risk of death."

Biomarker • Clinical data • Amyotrophic Lateral Sclerosis

Among placebo-treated participants who transitioned to CNM-Au8 in the HEALEY ALS Platform Trial OLE, NfL trajectories generally showed decline or stabilization compared to increases observed during the double-blind period. (GlobeNewswire) - "With only relatively few ex-placebo participants (n=31), these analyses had limited power, but the relative decline compared to the double-blind period showed comparable GMR differences (OLE Week 28 GMR: 0.885, 95% CI: 0.737 – 1.063, p=0.185). These findings are consistent with the NfL effects previously published for CNM-Au8 vs. placebo during the 24-week double-blind period (Week 24 GMR difference: 0.905, 95% CI: 0.822 – 0.996, p=0.040)."

Biomarker • Clinical data • Amyotrophic Lateral Sclerosis

Additional disease-relevant biomarker effects on GFAP were identified with statistically significant declines observed during the double-blind period in the HEALEY ALS Platform Trial… (GlobeNewswire) - "GFAP increase in ALS is a marker of harmful reactive astrogliosis, astrocytic injury, and degenerative processes that contribute to motor neuron loss. High GFAP levels are associated with a statistically significant increase in mortality risk in ALS patients. In comparison, placebo participants demonstrated increases across both NfL and GFAP biomarkers during the 24-week double-blind period. Consistent with these findings, in the matched NIH-EAP population, the magnitude and timing of NfL and GFAP reduction were closely correlated (Pearson’s r >0.85....demonstrating concordant effects for NfL and GFAP in the HEALEY ALS Platform Trial and NIH-EAP participants."

Biomarker • P2/3 data • Amyotrophic Lateral Sclerosis

Statistically significant decrease in NfL levels compared to matched ALS controls across the full analysis set (all evaluable matched participants) in the NIH-EAP (GlobeNewswire) - "The Week 36 AUC (area under curve) difference (SEM) of NfL (Ln(pg/mL)*Week) was: –0.0899 (0.0430), p = 0.0373, equivalent to a geometric mean ratio (GMR) difference of 0.914, 95% CI: 0.840 – 0.995. The effect size was similar to the NfL decline observed in the original double-blind phase of the HEALEY ALS Platform Trial: HEALEY W24 AUC GMR of 0.901, 95% CI: 0.845 – 0.959, p=0.0013 compared to the NIH-EAP W24 AUC GMR of 0.911, 95% CI: 0.836 – 0.993, p=0.0339. Multiple pre-specified supportive analyses in the NIH-EAP across the full analysis set at Week 24 and Week 48 confirmed the of the findings (p<0.05). Pre-specified subgroups showed significant effects in participants including those with an age younger than the median, on background riluzole treatment, and in participants with bulbar onset (p<0.05). In the primary analysis population in non-bulbar onset participants (i.e., predominantly limb onset), the Week 36 AUC NfL change was not significant (p=0.2085)."

Biomarker • Retrospective data • Amyotrophic Lateral Sclerosis

NfL and GFAP biomarker decline is associated with improved survival. (GlobeNewswire) - "Among participants treated in the HEALEY ALS Platform Trial with CNM-Au8 30 mg, participants with the greatest declines across both NfL and GFAP biomarkers during the double-blind period had the largest long-term overall survival improvement relative to all participants treated with CNM-Au8 30 mg (NfL and GFAP average AUC decline"

Biomarker • P2/3 data • Amyotrophic Lateral Sclerosis

Clene…announced it plans provide an update on its CNM-Au8 program in ALS, and to host an investor call and webcast at 8:30 am ET on Wednesday, December 3, 2025 (GlobeNewswire)

Clinical data • Amyotrophic Lateral Sclerosis

A comparison of baseline characteristics of decentralized and In-clinic participants enrolled in the CNM-Au8 EAP04 study (ALS-MND 2025) - "There were no clinically meaningful differences in baseline disease severity or progression risk between institutionally and remotely enrolled participants. These findings support the feasibility of decentralized models in ALS research and validate the integration of data from both enrollment pathways in future analyses. Expanding access through telehealth does not compromise clinical comparability, strengthening the case for broader DCT adoption in ALS trials."

Clene Reports…Recent Operating Highlights (GlobeNewswire) - "...As recommended by the FDA, Clene plans to request a Type C meeting with the FDA to review its data from these analyses, which meeting is expected to occur in the first quarter of 2026....The Company plans to submit a New Drug Application (NDA) in the first quarter of 2026 under an accelerated approval pathway. The Company expects to have the first patient dosed in the confirmatory Phase 3 RESTORE-ALS trial of CNM-Au8 in the first half of 2026."

FDA event • FDA filing • New P3 trial • Amyotrophic Lateral Sclerosis

A Phase 2, Open Label, Sequential Group, Investigator Blinded Study ofMagnetic Resonance Spectroscopy (to Assess the Effects ofCNM-Au8 for the Bioenergetic Improvement of Impaired Neuronal RedoxState in Multiple Sclerosis (REPAIR-MS) - Results (ECTRIMS 2025) - " REPAIR-MS cohort 1 included relapsing remitting MS, stable on natalizumab...Sguigna received personal compensation for consulting services from Genentech, EMD Serono, Horizon Therapeutics, Amgen, and Bristol Myers Squibb and has received research support from Genentech, Clene Nanomedicine, Zenas Biopharma, IPMSA through the NMSS, PCORI, DOD/CDMRP, and NIH/NIA through his institution... CNM-Au8 showed evidence of improved brain bioenergetics improvement in MS participants with an average percent increase in the NAD+/NADH ratio of 9.5% (p=0.0275). CNM-Au8 treatment was safe and well-tolerated with treatment emergent adverse events predominantly assessed as mild-to-moderate severity, and transient. This data buttresses the theory that bioenergetic failure contributes to neurodegeneration in MS."

Clinical • Late-breaking abstract • P2 data • CNS Disorders • Movement Disorders • Multiple Sclerosis • Parkinson's Disease

Clene Presents New Clinical Data at ECTRIMS 2025 Meeting Demonstrating CNM-Au8 Improves Brain Energy Metabolism in Multiple Sclerosis Patients (GlobeNewswire) - "The mean NAD+/NADH ratio in the brain was significantly increased following 12 weeks of treatment with CNM-Au8 in the full REPAIR population (+0.449 units, 95% CI: 0.093 to 0.805, p=0.0148; percent change: 8.65%, 95% CI: 2.6% to 14.7%, p=0.0006)...Baseline measures of working memory and cognitive processing speed, measured by the Symbol Digit Modalities Test, were significantly associated with average brain ATP levels (peak signal area average for α-ATP, β-ATP, γ-ATP; Pearson Correlation: ρ=0.542, p=0.0009)....CNM-Au8 treatment was safe and well tolerated with treatment emergent adverse events characterized as transient and predominantly mild-to-moderate in severity."

Late-breaking abstract • P2 data • Multiple Sclerosis

Clene Presents Preclinical Data Supporting CNM-Au8 for the Treatment of Parkinson’s Disease (GlobeNewswire) - "Improved mitochondrial health in familial PD: CNM-Au8 increased mitochondrial health (membrane potential) and mitochondrial volume, while reducing harmful reactive oxygen species (ROS) in fPD neurons. Similar, relatively milder effects were observed in sPD neurons. Reduced inflammation in sporadic PD: CNM-Au8 lowered levels of senescence-related inflammatory proteins, including CD40 and CXCL10, in sPD neurons, helping to reduce neuroinflammation that exacerbates PD progression."

Preclinical • Parkinson's Disease

Clene Inc. Advances Toward ALS Drug Approval… (City Buzz) - "The biopharmaceutical company plans to submit a New Drug Application for CNM-Au8 in ALS treatment by the end of 2025, representing a significant milestone for patients suffering from the progressive neurodegenerative disease."

FDA filing • Amyotrophic Lateral Sclerosis

CNM-Au8 for the treatment of MS (GlobeNewswire) - "The Company plans to hold an end-of-Phase 2 Type B meeting with the FDA in the third quarter of 2025. This meeting will review results from the Phase 2 VISIONARY-MS trial and discuss the planned Phase 3 study focusing on cognition improvement as an adjunct to standard-of-care MS therapies."

FDA event • New P3 trial • Multiple Sclerosis

CNM-Au8 for the treatment of ALS (GlobeNewswire) - "NfL change will be analyzed following 9 months of treatment (primary NfL analysis) and after 6 months of treatment (supportive NfL analysis). These analyses are intended to provide supportive data of the NfL change previously demonstrated in the HEALEY ALS Platform Trial double-blind period following 6 months of treatment with CNM-Au8. Clene expects to conduct the analysis of this NfL biomarker data early in the fourth quarter of 2025."

Trial status • Amyotrophic Lateral Sclerosis

Clene Provides Regulatory Update Following Constructive FDA Type-C Meeting on Neurofilament Biomarker Analysis Plan and Confirms Two Additional FDA Meetings (GlobeNewswire) - "Clene, Inc...and its subsidiary, Clene Nanomedicine, Inc...provided a regulatory update following a Type C meeting with the U.S. Food and Drug Administration (FDA), and announced two additional meetings scheduled with the FDA in the 3rd quarter of 2025...In the recently concluded Type C meeting, Clene discussed its proposed statistical analysis plan (SAP) for comparing neurofilament light (NfL) biomarker data from its ongoing NIH-sponsored Expanded Access Protocol (EAP), supporting nearly 200 people living with ALS treated with compassionate use of CNM-Au8, to matched ALS controls. The FDA provided constructive feedback on Clene’s proposed analysis methodology for assessing NfL change...The NfL analyses will be conducted early in the 4th quarter of 2025. If the findings demonstrate a clinically meaningful decline in NfL, they may support a new drug application (NDA) submission under the accelerated approval pathway, planned for the end of 2025."

FDA event • FDA filing • Amyotrophic Lateral Sclerosis • Multiple Sclerosis