CNM-Au8 / Clene - LARVOL DELTA

Clene…announced the closing of a registered direct offering of common stock to existing shareholders, including insiders, with total gross proceeds of $4 million (GlobeNewswire) - "The offering was made without a placement agent, underwriter, broker or dealer, and is expected to provide Clene with sufficient cash to fund its operations through mid-first quarter 2027, which is beyond the potential U.S. Food and Drug Administration (FDA) decision for accepting the New Drug Application (NDA) for review of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS) under the accelerated approval pathway. In addition, if the FDA accepts the NDA from Clene for review, the Company could potentially receive $6.7 million to $7.8 million in proceeds from common stock warrants issued in a January 2026 financing that could further extend the Company’s cash runway."

Financing • Amyotrophic Lateral Sclerosis

Clene Targets Early Q4 NDA Filing for CNM-Au8 in ALS (Yahoo Finance) - "The agency indicated that survival data alone would not support accelerated approval and wants evidence that the approximately 10% reduction in neurofilament light is clinically meaningful...Additional funding will be needed to support operations through NDA review and a potential approval decision."

FDA filing • Amyotrophic Lateral Sclerosis

Phase 3 Confirmatory Trial Will Evaluate the NfL Relationship Prospectively (The Manila Times) - "Clene’s planned Phase 3 confirmatory trial, RESTORE-ALS, is designed to evaluate the NfL biomarker relationship prospectively. The trial will use a patient’s baseline NfL level as a prospective enrollment stratification factor and will include prespecified, NfL-stratified analyses, building on the concordance evidence described here."

New P3 trial • Amyotrophic Lateral Sclerosis

Clinical Benefit Tracked NfL Response Across Phase 2 Trials (The Manila Times) - "These findings will be included in Clene’s planned New Drug Application (NDA) seeking accelerated approval....Participants whose NfL declined or stabilized lived significantly longer than concurrently randomized controls at every measured timepoint, showing an expanding survival benefit that reached nearly six months (177 days) at four years of follow-up (Day 1,463; p = 0.012). By comparison, participants whose NfL increased did not demonstrate a statistically significant difference in survival benefit at any timepoint....On CAFS, NfL responders scored significantly better than concurrently randomized controls on both function and breathing: a least-squares mean difference of 62.6 (95% CI 5.3-119.9; p = 0.032) combining ALSFRS-R with survival, and 86.3 (95% CI 30.3-142.2; p = 0.003) combining SVC (% predicted) with survival."

P2 data • Amyotrophic Lateral Sclerosis

Relationship between longer survival and NfL decline or stabilization also observed in RESCUE-ALS. (The Manila Times) - "Among the 22 CNM-Au8-treated participants whose NfL response could be classified, the 11 participants whose NfL declined or stabilized had a 76% lower adjusted risk of death than 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). In RESCUE-ALS, participants whose NfL declined or stabilized had a 69% lower risk of death than propensity-matched real-world ALS controls (MiNDAUS; HR 0.31; 95% CI 0.13-0.76; p = 0.011); those whose NfL rose did not differ significantly from the matched controls. Within the treated arm, NfL responders also scored significantly better on CAFS (rank difference +7.7, 95% CI 3.1-12.3; p = 0.002) compared to NfL non-responders."

P2 data • Amyotrophic Lateral Sclerosis

Antioxidant Nanozymes: From Rational Design to Biomedical Applications. (PubMed, Research (Wash D C)) - "Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure-activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes."

Journal • Review • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Oncology • Reperfusion Injury • CAT

IGFBP7 As A Nexus Biomarker Identifying A Coordinated Treatment Response Phenotype In ALS: Post-Hoc Exploratory Analysis From Regimen C Of The HEALEY Platform Trial (ENCALS 2026) - "Consistent survival associations were also observed for the multi-biomarker AUC W0-24 decline (>8 of the 14), Day 487 HR=0.24, p=0.017; Day 878 HR=0.47, p=0.019).Conclusion IGFBP7 functions as a nexus biomarker whose coordinated decline with 13 other neurodegeneration-related markers identifies an ALS treatment response phenotype. The striking correlation collapse in non-responders suggests IGFBP7 connectivity may distinguish genuine biological responders from non-responders to CNM-Au8 to inform enrichment strategies and therapeutic response in future ALS trials."

Biomarker • Retrospective data • CNS Disorders • IGFBP7

Nanomedicine in 2026: Illustrative Quantitative Analyses of EPR Heterogeneity, Clinical Trial Attrition, and Emerging Horizons for Active Nanotherapeutics. (PubMed, Int J Nanomedicine) - "We identify four important clinical advances: first Phase II data for hafnium oxide nanoparticle radioenhancers in inoperable lung cancer; logic-gated STING-agonistic nanoparticles for metastasis-specific immunotherapy; ultrasmall silica nanoparticles that remodel suppressive tumor microenvironments independent of a drug cargo; and CNM-Au8 gold nanocrystals advancing toward regulatory submission for amyotrophic lateral sclerosis...Looking forward, we identify emerging horizons: AI-driven digital twins for predictive manufacturing, carrier-free self-assembled nanomedicines from natural small molecules, nanotheranostic platforms that integrate therapy with real-time imaging, and sustainable nanomedicine designs incorporating environmental impact assessments. By bridging clinical reality with future potential, this review aims to inform researchers, clinicians, and regulatory stakeholders navigating the rapidly evolving landscape of nanomedicine."

Heterogeneity • Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Lung Cancer • Oncology • Solid Tumor

First Quarter 2026 and Recent Operating Highlights (The Manila Times) - "Clene intends to submit the New Drug Application (NDA) in the third quarter of 2026. Also, Clene plans to commence the confirmatory Phase 3 trial in the first quarter of 2027. The RESTORE-ALS trial is designed to investigate the effects of CNM-Au8 on improved survival (primary endpoint) and delayed time to ALS clinical worsening events (secondary efficacy endpoint)."

FDA filing • New P3 trial • Amyotrophic Lateral Sclerosis

Clene Announces $7 Million Underwritten Offering of Common Stock (GlobeNewswire) - "Clene expects to use the net proceeds from the offering, together with its existing cash, for expenses primarily related to general corporate purposes, as well as to fund the following: the preparation and filing of our New Drug Application (NDA) for our lead drug candidate, CNM-Au8; the conduct of and continued access to CNM-Au8 in our on-going expanded access protocols and future confirmatory Phase 3 clinical trial; manufacturing expansion; potential future commercialization efforts; and for additional early-stage research and development activities. The offering is expected to close on or about May 6, 2026, subject to the satisfaction of customary closing conditions."

Financing • Amyotrophic Lateral Sclerosis

After Successful FDA Meeting, Clene Filing Accelerated Approval NDA for ALS (The Manila Times) - "FDA stated that the 'proposed data may be capable of supporting the submission and review of an [NDA] under the accelerated approval pathway' for CNM-Au8 based on neurofilament light (NfL) biomarker data; FDA acknowledged NfL could potentially serve as a reasonably likely surrogate endpoint; Clene expects to submit an NDA for CNM-Au8 to the FDA in the third quarter of 2026...'We are committed to working with the Agency on this filing and are conducting the Phase 3 confirmatory study for CNM-Au8, which we intend to commence in the first quarter of 2027.'...The planned NDA submission will be supported by NfL biomarker and clinical data from the Phase 2 HEALEY ALS Platform Trial and its open-label extension, as well as the Phase 2 RESCUE-ALS Trial, and the NIH-sponsored Expanded Access Protocol for CNM-Au8."

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

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