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CLNN (NASDAQ)
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2 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 by those laws. Clene’s forward-looking statements include, but are not limited to, statements regarding our or our management team’s expectations, hopes, beliefs, intentions or strategies regarding our future operations. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “will,” “would,” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. Forward-looking statements in this presentation may include, for example, statements about our drug candidate’s trial results and potential impact on disease states, and other factors detailed under “Risk Factors” in our most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q. These forward-looking statements represent our views as of the date of this presentation and involve a number of judgments, risks and uncertainties. We anticipate that subsequent events and developments will cause our views to change. We undertake no obligation to update forward-looking statements to reflect events or circumstances after the date they were made, whether as a result of new information, future events or otherwise, except as may be required under applicable securities laws. Accordingly, forward-looking statements should not be relied upon as representing our views as of any subsequent date. As a result of a number of known and unknown risks and uncertainties, our actual results or performance may be materially different from those expressed or implied by these forward-looking statements. Some factors that could cause actual results to differ include our substantial dependence on the successful commercialization of our drug candidates, if approved, in the future; our inability to maintain the listing of our common stock on Nasdaq; our significant net losses and net operating cash outflows; our ability to demonstrate the efficacy and safety of our drug candidates; the clinical results for our drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; our ability to achieve commercial success for our drug candidates, if approved; our ability to obtain and maintain protection of intellectual property for our technology and drug candidates; our reliance on third parties to conduct drug development, manufacturing and other services; our limited operating history and our ability to obtain additional funding for operations and to complete the licensing or development and commercialization of our drug candidates; the impact of epidemics, pandemics, and the ongoing conflicts between Ukraine and Russia and Israel and Hamas on our clinical development, commercial and other operations; changes in applicable laws or regulations; the effects of inflation; the effects of staffing and materials shortages; the possibility that we may be adversely affected by other economic, business, and/or competitive factors; and other risks and uncertainties set forth in “Risk Factors” in our most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this presentation, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and you are cautioned not to rely unduly upon these statements. All information in this presentation is as of the date of this presentation. The information contained in any website referenced herein is not, and shall not be deemed to be, part of or incorporated into this presentation.
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3 • Q 2 Focused on Improving Mitochondrial Health and Protecting Neuronal Function to Treat Neurodegenerative Diseases THE PROBLEM • The World Health Organization predicts neurodegenerative diseases will become the second-most prevalent cause of death within the next 20 years. • A therapeutic breakthrough is urgently needed. • In neurodegenerative diseases, impaired mitochondrial activity and compromised cellular metabolism can lead to neuronal death. A NEW APPROACH • Clene is pioneering catalytic nanotherapeutics to treat neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease and multiple sclerosis. • By targeting the improvement of mitochondrial function via the nicotinamide adenine dinucleotide pathway, Clene’s first-in-class drug, CNM-Au8, is pioneering a new way to restore and protect neuronal function.
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4 Building the Clinical Case for Neuroprotection & Remyelination Proprietary Nanotherapeutic Manufacturing Strong IP: 150+ granted patents PLUS Trade Secrets Growing Body of Clinical Evidence Across ALS and MS Supports CNM-Au8 Therapeutic Potential to Treat Neurodegenerative Diseases Data on File, Clene Nanomedicine, Inc.
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5 What is CNM-Au8® ? Nanocrystal suspension Orally administered (or by feeding tube) Targets energy metabolism and oxidative stress Blood-brain-barrier penetrant CNM-Au8 Nanocrystal Suspension 60 mL per bottle (once daily) >100 Trillion Nanocrystals per 60 mL dose (at 30 mg) CNM-Au8 Attributes: Data on File, Clene Nanomedicine, Inc.
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6 CNM-Au8® | Surface Catalysis Supports Mitochondrial Function Mitochondrial Function Neuronal Survival And Function CNM-Au8 Nanocrystal Catalysis NAD+ Reactive Oxygen Species (ROS) Robinson et al. Sci Rep. 2020 Feb 11;10(1):1936. Wang et al 2023, Small. 2023 Sep 28:e2304082. Acts as an electron donor/receiver
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7 Safety Review • Over 800 participant-years of exposure to CNM-Au8 • CNM-Au8 long-term treatment duration up to 5.1 years • TEAEs (treatment-emergent adverse events) predominantly assessed as mild-to-moderate severity, and transient • No related SAEs (serious adverse events) related to CNM-Au8 across all clinical programs • No temporal association of increasing TEAE or SAE incidence based on exposure duration • ‘No Adverse Effect Level’ (NOAEL) findings across all toxicology studies up to maximum feasible dose Data on File, Clene Nanomedicine, Inc.
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8 RESCUE-ALS RESCUE-OLE HEALEY ALS Platform HEALEY OLE Expanded Access Protocols ALS Participant Demographics Early-to-Mid-Stage (n=45) Early-to-Mid-Stage (n=36) Mid-to-Late-Stage (n=161; Regimen C) Mid-to-Late-Stage (n=134) Real-World Experience (~300) Duration 36-weeks Up to 234 weeks 24-weeks Up to 133 weeks Over 5.0 years Primary/ Secondary Endpoints 1. MUNIX % change 2. MUNIX total change 2. FVC (% predicted) NA 1. ALSFRS-R adj. by death 2. CAFS 2. SVC (% predicted) 2. Time to Death or PAV NA NA Survival -- vs. ALS natural history controls vs. ALS natural history controls Delayed Time to Clinical Worsening Not routinely collected Preserved Function (ALSFRS-R) -- -- in NfL Responders Progression Biomarkers ↓ p75 (trend) Not routinely collected NfL ↓ NfL ↓ GSH, GSH/GSSG ↑ NAD, NAD+/NADH ↑ Safety >800 Years of Participant Exposure without Identified Safety Signals across ALS, MS, and PD Despite Missed Primary Endpoints, Concordant Survival Outcomes with CNM-Au8 Treatment in ALS are Promising Data on File, Clene Nanomedicine, Inc.
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9 Time to Event | Survival During the Double-Blind Period HEALEY ALS Platform Trial CNM-Au8 30 mg (Full Analysis Set | All Shared Placebo) Time to Death or PAV* Time to Death Prespecified covariates included: age, months from symptom onset, pre-treatment ALSFRS-R slope (delta-FRS), riluzole treatment, edaravone treatment. One placebo FAS participant had PAV at BL, so is excluded from the left figure (Time to Death or PAV). 94% Risk Reduction 94% Risk Reduction *PAV=Permanently Assisted Ventilation
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10 Time to Event | Improved Survival During the OLE to Month 12 HEALEY ALS Platform Trial CNM-Au8 30 mg Time to Death or PAV Time to Death Prespecified covariates included: age, months from symptom onset, pre-treatment ALSFRS-R slope (delta-FRS), riluzole treatment, and edaravone treatment. 62% Risk Reduction 78% Risk Reduction
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11 Vucic et al. EClinicalMedicine. 2023 Jun 8;60:102036. Data on File, Clene Nanomedicine, Inc. 71% Risk Reduction 74% Risk Reduction Prespecified covariate risk adjustments included: (i) time from symptom onset, (ii) pre-baseline ALSFRS-R slope, (iii) riluzole use, (iv) edaravone use, and (v) age. PAV defined as continuous ventilatory support (>23 hr/day) by tracheostomy or NIV for at least 7-days CNM-Au8 | Delayed Time to Clinical Worsening Events Concordant in Double-Blind Periods of Two Independent Phase 2 Trials Delayed Time to Clinical Worsening Prespecified Exploratory Clinical Composite Endpoint Delayed Time to Clinical Worsening Prespecified Exploratory Clinical Composite Endpoint
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12 NfL: Neurofilament light chain. Benatar et al. Brain. 2023 Jul 3;146(7):2711-2716. NfL is a Key Biomarker of Disease Progression in ALS Patients Neurofilament Light (NfL) Neurofilament Light Chain (NfL) Protein Cytoskeletal proteins that provide structure and support for the cell and are highly specific for neurons Axonal damage: high NfL levels are associated with axonal damage High NfL in ALS: predicts greater risk of disease progression
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13 Mixed Model Repeat Measure analyses: HEALEY covariates included time from symptom onset, pre-treatment ALSFRS-R slope, background edaravone and riluzole, and interaction by week. Plasma NfL Decline During Double-Blind & Long-Term Treatment HEALEY ALS Platform Trial Double-Blind & Open Label Extension Open Label ExtensionDouble-Blind Period
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14 Evidence Linking Plasma NfL with CNM-Au8 Clinical Benefit Plasma NfL Burden At Baseline Plasma NfL Decline At Week 24 Time to Death or PAV to Month 12 Week 52 post-baseline was a prespecified time point for OLE analyses 1 Plasma NfL Decline At Week 24 2
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15 Greatest Benefit in Participants with Highest Baseline NfL Burden | Death or PAV HEALEY ALS Platform (Through Month 12) | Upper Tertile & > Median HEALEY | Upper NfL Tertile By Baseline Plasma NfL Prespecified HEALEY covariates included: age, months from symptom onset, pre-treatment ALSFRS-R slope (delta-FRS), riluzole treatment, edaravone treatment. Analyses are post hoc. HEALEY | NfL > Median By Baseline Plasma NfL 83% Risk Reduction 84% Risk Reduction
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16 Evidence Linking Plasma NfL with CNM-Au8 Clinical Benefit Plasma NfL Burden At Baseline Plasma NfL Decline At Week 24 1 2 Time to Death or PAV to Month 12 Week 52 post-baseline was a prespecified time point for OLE analyses
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17 Proportion of Participants Demonstrating NfL Decline at Week 24 End of Double-Blind Data on File, Clene Nanomedicine, Inc.
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18 Long-Term Survival Benefit in Participants with Any NfL Decline at 24-Weeks HEALEY ALS Platform (Through Month 12) | Time to Death or PAV Time to Death or PAV In Participants with NfL Decline at Week 24 Prespecified covariates included: age, months from symptom onset, pre-treatment ALSFRS-R slope (delta-FRS), riluzole treatment, edaravone treatment. Post hoc analyses. Hazard Ratio for Death or PAV At 12 Months Post-Baseline 91% Risk Reduction
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19 Evidence Supporting Long-Term Survival Benefit Clinical Trial Populations Real World Expanded Access Protocols Long-Term All-Cause Mortality 1 2 PRO-ACT, ALS Natural History Consortium (ALS NHC), ANSWER-ALS Propensity Matched Controls
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20 Improved Long-Term Survival | HEALEY ALS Platform & Pooled ALS Trials CNM-Au8 30 mg Original Randomization vs. Propensity Matched Controls Data on File, Clene Nanomedicine, Inc. HEALEY | Optimal Variable Ratio Matching Prespecified Matching Methodology 36% Risk Reduction 33% Risk Reduction Pooled ALS Trials | Optimal Variable Ratio Matching
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21 Long-Term Survival | Real-World Expanded Access Protocols CNM-Au8 30 mg vs. Propensity Matched Controls (Pooled PRO-ACT, ALS NHC, ANSWER-ALS) Data on File, Clene Nanomedicine, Inc. EAP Matching | Optimal Variable Ratio (Prespecified) 31% Risk Reduction • Propensity Matching: Variable Optimal Ratio Matching Minimizes global distance of the logit score by assessing the overall set of matches when choosing individual matches • Pooled Control Set: PRO-ACT, ALS Natural History Consortium (ALS NHC), ANSWER-ALS o Widest possible universe for control matches o 1:3 (active:control) match • Narrow Logit Caliper Width: 0.1 • Matching Covariates: BMI, Sex, Bulbar Onset, Months from Symptom Onset, Onset Age, Diagnostic Delay (Months), ALSFRS-R Pre- Treatment Slope, ALSFRS-R Total Score, Vital Capacity (% predicted), VC (% predicted) Pre-Treatment Slope, TRICALS Risk Score • Survival Cox Proportional HR Model Covariates: Bulbar Onset, (ii) Onset Age, (iii) Sex, (iv) BMI, (v) Pre- treatment ALSFRS-R slope, (vi) ALSFRS-R Total Score, (vii) Diagnostic Delay (in months), (viii) Vital Capacity (% predicted), (ix) Pre-Treatment Vital Capacity Slope, and (x) TRICALS Risk Score
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22 Improved CNM-Au8 30 mg Long Term Survival vs. Regimen A Concurrent Controls Consistent Baseline Severity (Filters Baseline Imbalances) RESTORE-ALS (Core Inclusion Criteria) All Randomized (Full Analysis Set) Prespecified HEAELY survival covariates included: age, months from symptom onset, pre-treatment ALSFRS-R slope (delta-FRS), riluzole treatment, edaravone treatment. No difference in Regimen A long term survival active vs. placebo; 78% of participants across both groups received standard ALS background therapy (riluzole, edaravone, or both) at baseline 28% Risk Reduction 44% Risk Reduction 49% Risk Reduction Post hoc analyses compared survival in participants who received CNM-Au8 30 mg (Regimen C) to those of Regimen A, a large concurrent control group vs. CNM-Au8 treatment using the same randomization criteria established within the HEALEY master protocol
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23 Core Design Elements Change in Low Contrast Letter Acuity (LCLA) 1° 2° Change in modified MS Functional Composite (mMSFC) • Enrolled stable relapsing remitting MS participants with chronic optic neuropathy on background DMTs • 92% treated with background DMTs (inc 53% monoclonal antibodies, 32% oral) • n=73 of 150 planned (~50%) study ended prematurely due to COVID-19 pandemic enrollment challenges • Modified ITT (mITT) Analysis Population; Pre-specified statistical threshold set at p=0.10 • CNM-Au8 Open Label Extension (OLE) for original active and placebo continued for up-to-96 weeks Phase 2 Study: 48-Week Placebo-Control Treatment Period 2:1 Randomization (Active [15mg, 30 mg]: Placebo) LCLA9HPT SDMT T25FWT Data on File, Clene Nanomedicine, Inc.
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24 CNM-Au8 Demonstrated Vision and Global Neurological Improvement in Stable MS patients on DMTs Global Neurological Improvement Change in modified MS Functional Composite (mMSFC) Significantly Improved Vision Change in Low Contrast Letter Acuity (LCLA) Global neurological clinical improvement was driven by cognition, manual dexterity, and low contrast letter acuity Data on File, Clene Nanomedicine, Inc.
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25 Long-Term LCLA Improvement in LTE Participants Low Contrast Letter Acuity Original Active (CNM-Au8) Original Placebo Data on File, Clene Nanomedicine, Inc.
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26 CNM-Au8 Improved Information Signal Strength & Speed in the Visual Pathway Amplitude = Signal Strength Latency = Signal Speed From the Eye to Visual Cortex Increased VEP amplitude is associated with improved axonal integrity (more signal); Improved latency is associated with evidence of remyelination (faster conduction velocity) Data on File, Clene Nanomedicine, Inc. Visual Evoked Potentials Improved Amplitude Improved Latency LTE: LS mean difference vs. randomization baseline: # p<0.0001, *** p<0.001, ** p<0.01, *p<0.05, ^p<0.10
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27 Long-Term SDMT Improvement in LTE Participants Symbol Digit Modality Test | Working Memory & Cognition Original Active (CNM-Au8) Original Placebo Data on File, Clene Nanomedicine, Inc.
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28 CNM-Au8 Treatment Demonstrated MS Lesion Repair and Promoted Remyelination Data on File, Clene Nanomedicine, Inc. Advanced MRI Techniques T2 Lesion Myelin Water Fraction (Remyelination) T2 Lesion Axial Diffusivity (Axonal Integrity) LTE: LS mean difference vs. randomization baseline: # p<0.0001, *** p<0.001, ** p<0.01, *p<0.05, ^p<0.10
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29 Clinical LTE Changes Correlated with mf-VEP & MRI DTI Improvement MTR DTI Correlations (Post Hoc)mf-VEP Latency Correlations (Post Hoc) Data on File, Clene Nanomedicine, Inc.
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30 Clene | CNM-Au8 Path to Regulatory Approval MS FDA EOP2 meeting Clinical data up-to-3-yrs Non-active progressive MS VISIONARY-MS OLE Global MS Phase 3 Trial Protocol DesignREPAIR-MS Phase 2 Trial Readout ALS FDA Engagement Potential FDA ALS accelerated NDA submission* HEALEY ALS Biomarkers HEALEY ALS OLE ALSFRS/Clin Worsening Global RESTORE-ALS Phase 3 Trial Launch Clinical Data up-to-30 months Global ALS Phase 3 Trial Design Approval Amyotrophic Lateral Sclerosis (ALS) Data Readouts / Phase 3 Planning Multiple Sclerosis (MS) Planned Regulatory Potential ALS Accelerated FDA Approval (PDUFA)* Potential FDA ALS Advisory Committee 6mos. & OLE (up to 30 mos.)
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31 Evidence Supports CNM-Au8 Therapeutic Potential to Treat Neurodegenerative Diseases CNM-Au8® a gold nanocrystal suspension, in development as the first cellular energetic catalyst to remyelinate1 & protect neurological function Strong IP: 150+ patents on nanotherapeutic platform, plus trade secret protection Concordant Survival in two Phase2 trials, with NfL Biomarker in HEALEY >800 participant years of CNM-Au8 clinical exposure Demonstrated global neurological improvement in MS patients on adjunctive DMT standard of care As of March 31 2025, cash and equivalents on hand (unaudited): $9.8M Data on File, Clene Nanomedicine, Inc. 1Robinson et al. Sci Rep. 2020 Feb 11;10(1):1936.2https:/ /clinicaltrials.gov/ct2/show/NCT04414345. .
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©2025 Clene Inc. Version: 14 May 2025 Clene Inc. HQ & Clinical Development 6550 South Millrock Drive, Suite G50 Salt Lake City, UT 84121 R&D and Manufacturing 500 Principio Parkway, Suite 400 North East, MD 21901 32