Slide 1: Clene Announces Statistically Significant ALS Biomarker Results Supporting Accelerated Approval Pathway for CNM-Au8
CLENE ANNOUNCES STATISTICALLY SIGNIFICANT ALS BIOMARKER RESULTS SUPPORTING ACCELERATED APPROVAL PATHWAY FOR CNM-Au8® NIH-Sponsored EAP and HEALEY ALS Platform Trial Data 1
Slide 2: Forward Looking Statements
Forward Looking Statements This presentation contains “forward-looking statements” within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended, which are intended to be covered by the “safe harbor” provisions created
Slide 3: FDA Guidance | Substantiation of NfL Biomarker Effect May Support Survival Analyses
FDA Guidance | Substantiation of NfL Biomarker Effect May Support Survival Analyses “If you are able to provide substantiation of the effects on NfL, we would be willing to consider whether the 24-week data from the HEALEY Platform Trial and the post-hoc analyses on long-term survival are capable of
Slide 4: FDA Guidance | Regulatory Path for Accelerated Approval
FDA Guidance | Regulatory Path for Accelerated Approval Excerpted FDA Letters to Clene NIH-Sponsored EAP HEALEY Ex-Placebo Other Supportive NfL Change to CNM-Au8 NfL Change Biomarkers “…analysis of change from “…analysis of change “..the Division noted that baseline for NfL at 24 weeks from baseline
Slide 5: ALS Disease-Relevant Biomarkers | What are NfL & GFAP?
ALS Disease-Relevant Biomarkers | What are NfL & GFAP ? Neurofilament Light Chain (NfL) Structural protein of neuronal axons NfL is released as a sensitive biomarker of neuroaxonal injury when axons are damaged or degenerate in ALS Elevated NfL levels strongly correlate with faster ALS progres
Slide 6: High NfL and GFAP Levels Are Associated with Mortality Risk in ALS
High NfL and GFAP Levels Are Associated with Mortality Risk in ALS High NfL Levels are Significantly Associated High GFAP Levels are Significantly Associated with ALS Mortality with ALS Mortality (Upper Quartile vs. Lower Quartiles) Multivariate Cox HR (1 SD Rise in Log10 NfL): 2.99, 95% CI: 1.7–5.4
Slide 7: Substantiation of NfL Biomarker Effect May Support Acceptance of Survival Analyses (NIH-EAP)
Substantiation of NfL Biomarker Effect May Support Acceptance of Survival Analyses (NIH-EAP) 7
Slide 8: NIH-EAP Interim NfL Analyses | Full Analysis Set
NIH-EAP Interim NfL Analyses | Full Analysis Set ANSWER ALS Matched Controls | Participant Flow NIH-EAP (EAP04) ANSWER ALS (AALS) NIH-EAP AALS Enrolled ALS Pts. Enrolled ALS Pts. (n=183, 100%) (n=854, 100%) • Missing BL NfL (n=19) • No NfL Collection (n=112) • Missing Post-BL NfL (n=10) • Missing BL
Slide 9: Significant NfL AUC Difference Across All Matched Participants
Significant NfL AUC Difference Across All Matched Participants Full Analysis Set | Comparison to AALS Matched Controls at W36 Full Analysis Set | All Matched Participants NfL Change vs. AALS Matched Controls AUC Difference | Ln(NfL pg/mL)*Week Model covariates are the same as those used for propensi
Slide 10: Significant NfL AUC Difference Across All Matched Participants
Significant NfL AUC Difference Across All Matched Participants Bulbar Onset | Comparison to AALS Matched Controls at W36 Bulbar Onset | All Matched Participants NfL Change vs. AALS Matched Controls AUC Difference | Ln(NfL pg/mL)*Week Model covariates are the same as those used for propensity matchin
Slide 11: Primary Efficacy for NfL Analysis | Non-Bulbar Population
Primary Efficacy for NfL Analysis | Non-Bulbar Population NfL Reduction Non-Significant in Non-Bulbar AALS Matched Participants Non-Bulbar Onset (Limb, Thoracic) | All Matched Participants NfL Change vs. AALS Matched Controls AUC Difference | Ln(NfL pg/mL)*Week Model covariates are the same as those
Slide 12: Significant NfL Decline | All, Bulbar, Younger, Riluzole-Treated
Significant NfL Decline | All, Bulbar, Younger, Riluzole-Treated Comparison to AALS Matched Controls | Prespecified Subgroups Model covariates are the same as those used for propensity matching: (i) Baseline Ln(sNfL), (ii) Sex, (iii) Riluzole Treatment, (iv) delta-FS, (v) Bulbar Onset, (vi) Age, and
Slide 13: Substantiation of Additional Biomarker Effects to Support Survival Analyses
Substantiation of Additional Biomarker Effects to Support Survival Analyses 13
Slide 14: ALS Disease-Relevant Biomarkers | What are NfL & GFAP?
ALS Disease-Relevant Biomarkers | What are NfL & GFAP ? Neurofilament Light Chain (NfL) Structural protein of neuronal axons NfL is released as a sensitive biomarker of neuroaxonal injury when axons are damaged or degenerate in ALS Elevated NfL levels strongly correlate with faster ALS progres
Slide 15: HEALEY NfL and GFAP Biomarker Effects Are Consistent
HEALEY NfL and GFAP Biomarker Effects Are Consistent Biomarker Changes from Baseline to End of the Double-Blind Period (W24) Neurofilament Change Glial Fibrillary Acidic Protein (GFAP) Change Plasma NfL GMR 95% CI p-value Plasma GFAP GMR 95% CI p-value W24 LS Mean 0.905 0.822 – 0.996 p = 0.0403 W24
Slide 16: NIH-EAP NfL and GFAP AUC Decline is Also Consistent
NIH-EAP NfL and GFAP AUC Decline is Also Consistent Concordant Effect on NfL and GFAP AUC Change AUC Period N Pearson r p-value Concordance Week 0 – 24 AUC 115 0.911 p < 0.001 80.9% Week 0 – 36 AUC 115 0.919 p < 0.001 78.3% Week 0 – 48 AUC 115 0.941 p < 0.001 78.3% NfL and GFAP AUC Change Ln(NfL pg/
Slide 17: Plasma NfL & GFAP Change are Closely Correlated in Placebo Participants in the HEALEY
Plasma NfL & GFAP Change are Closely Correlated in Placebo Participants in the HEALEY ALS Platform Trial CNM-Au8 Placebo | Week 8 CNM-Au8 Placebo | Week 24 Pearson R 95% CI p-value Pearson R 95% CI p-value r = 0.525 0.232 to 0.730 p = 0.0012 r = 0.516 0.215 to 0.727 p = 0.0018 17 Data on File, Clene
Slide 18: Similar NfL and GFAP Reduction in Ex-Placebo to CNM-Au8 Population
Similar NfL and GFAP Reduction in Ex-Placebo to CNM-Au8 Population Only 31 Participants (Underpowered but with Comparable Treatment Difference) pNfL GMR 95% CI p-value pGFAP GMR 95% CI p-value OLE W28 Difference 0.885 0.737 – 1.063 p = 0.1854 OLE W28 Difference 0.859 0.717 – 1.029 p = 0.0966 Prespec
Slide 19: NfL & GFAP AUC Decline | Thresholds for Survival Analyses
NfL & GFAP AUC Decline | Thresholds for Survival Analyses Change from Baseline During the 24-Week Double-Blind Period CNM-Au8 30 mg AUC Change Thresholds (Nested Groups) 1. Any AUC Decline (n=34, 60%) 2. AUC Decline < Median (n=29, 50%) 3.AUC Decline < 33rd Percentile (n=19, 33%) 4. AUC Decline < 25
Slide 20: NfL & GFAP AUC Decline Associated with Improved Survival
NfL & GFAP AUC Decline Associated with Improved Survival AUC Decline through the 24-Week Double-Blind Period (Post Hoc) ~80% Risk Reduction Cox Hazard Ratio Model Full Analysis Set vs. RGA Controls to End of OLE Cox HR AUC Change Threshold p-value (95% CI) ~37% 0.191 AUC Decline < 25th Percentile p=
Slide 21: Increased NfL is Associated with the Risk of Death in ALS
Increased NfL is Associated with the Risk of Death in ALS 21
Slide 22: NfL Change Significantly Impacts ALS Survival
This means: This means: NfL Change Significantly Impacts ALS Survival Joint-Model of NfL Change and Survival | APST Dataset Association of NfL Change and Mortality Risk Joint-Model Hazard Ratio Exp (0.339) = 1.40 ALS Longitudinal NfL Association Hazard Ratio p-value & Mortality Dataset Factor (SE) (
Slide 23: Long-Term Survival Evidence from the HEALEY ALS Platform Trial
Long-Term Survival Evidence from the HEALEY ALS Platform Trial Original CNM-Au8 30 mg vs. Original Placebo to CNM-Au8 vs. Concurrently Randomized Controls Concurrently Randomized Controls (Regimen A) (Regimen A) 23
Slide 24: Survival Analysis Periods | CNM-Au8 30 mg
Survival Analysis Periods | CNM-Au8 30 mg Analysis Anchored by Time to Treatment Discontinuation | Median = Month 16 Analysis Intervals • Month 12 o Prespecified Timepoint in RGC HEALEY OLE SAP • Median Discontinuation Time o 50% Discontinuation at Month 16 24 Data on File, Clene Nanomedicine, Inc.
Slide 25: CNM-Au8 30 mg Survival vs. RGA Controls | Analysis Populations
CNM-Au8 30 mg Survival vs. RGA Controls | Analysis Populations Full Analysis Set (FAS) Comparable Risk Set (CRS) All Randomized Participants Filters At-Risk for Comparable Baseline Disease Severity • Ln(NfL) > 3.5 • TRICALS Risk Score (-2.5 to -6.5) Population CNM-Au8 30 mg Regimen A FAS n = 59 (100
Slide 26: Improved Long-Term Survival vs. Regimen A Controls at 1-Year
Improved Long-Term Survival vs. Regimen A Controls at 1-Year Significant Survival Difference at Month 12 Full Analysis Set Comparable Risk Set Month 12 | Prespecified OLE Timepoint Month 12 | Prespecified OLE Timepoint 73% 77% Risk Reduction Risk Reduction Prespecified HEALEY survival covariates inc
Slide 27: Results | Improved Long-Term Survival vs. Regimen A
Results | Improved Long-Term Survival vs. Regimen A CNM-Au8 30 mg vs. Regimen A Concurrent Controls (Post Hoc) | Month 16 Full Analysis Set Comparable Risk Set Month 16 | Median Treatment Discontinuation Month 16 | Median Treatment Discontinuation 52% Risk Reduction 64% Risk Reduction Prespecified H
Slide 28: Improved Long-Term Survival in Ex-Placebo to CNM-Au8
Improved Long-Term Survival in Ex-Placebo to CNM-Au8 Significant RMST Benefit vs. Regimen A at 12-Months Post Treatment Initiation & Beyond Ex-Placebo to Active Treatment Ex-Placebo to Active Treatment 12-Months | Post-CNM-Au8 Treatment Initiation To End of the Open Label Extension 51% Risk Reductio
Slide 29: FDA Guidance for Accelerated Approval
FDA Guidance for Accelerated Approval To be accepted as a surrogate for accelerated approval, the biomarker must have: 1. Treatment of serious condition; address unmet medical need 2. Meaningful benefit over available therapy on surrogate endpoint (e.g., a biomarker like NfL or GFAP) reasonably like
Slide 30: Next Steps
Next STEPS Type C Meeting Request Submitted Meeting to Consider Biomarker & Overall Survival Evidence Meeting Anticipated during 1st Quarter 2026 Currently Readying NDA for Submission 30
Slide 31: Clene Announces Statistically Significant ALS Biomarker Results Supporting Accelerated Approval Pathway for CNM-Au8
CLENE ANNOUNCES STATISTICALLY SIGNIFICANT ALS BIOMARKER RESULTS SUPPORTING ACCELERATED APPROVAL PATHWAY FOR CNM-Au8® NIH-Sponsored EAP and HEALEY ALS Platform Trial Data 31
Slide 32: Appendix
Appendix QB siucear sejoen 8 se pccene
Slide 33: Beyond HEALEY | RESCUE-ALS Improved Long-Term Survival
Beyond HEALEY | RESCUE-ALS Improved Long-Term Survival ALS Propensity Matched Controls from Australian MiNDAUS and PRO-ACT CNM-Au8 30 mg vs. ALS MiNDAUS CNM-Au8 30 mg vs. ALS PRO-ACT Model covariates included variables associated with mortality risk: (i) sex, (ii) site of symptom onset (bulbar vs. n
Slide 34: Beyond HEALEY | EAP01-02 Improved Long-Term Survival
Beyond HEALEY | EAP01-02 Improved Long-Term Survival ALS Propensity Matched Controls CNM-Au8 30 mg vs. ALS Natural History Consortium CNM-Au8 30 mg vs. All Available ALS Match Sets Combined Model covariates included variables associated with mortality risk: (i) sex, (ii) site of symptom onset (bulba