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WE ENVISION A FUTURE WHERE THE BOUNDARIES OF NEURODEGENERATIVE DISEASES ARE TRANSCENDED, WHERE INDIVIDUALS NOT ONLY SURVIVE BUT THRIVE 2023 ANNUAL REPORT
FOCUSED ON IMPROVING MITOCHONDRIAL HEALTH AND PROTECTING NEURONAL FUNCTION TO TREAT NEURODEGENERATIVE DISEASES THE PROBLEM Neuronal decline, a natural part of aging, is intensi ed in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where energy de cits worsen the dysfunction. The World Health Organization forecasts neurodegenerative diseases to rank as the second-most prevalent cause of death within the next 20 years, underscoring the urgent need for therapeutic advancements.1 Impaired mitochondrial activity and compromised cellular metabolism in these diseases contribute to neuronal death, highlighting the critical role of addressing energetic de cits in developing treatments. A NEW APPROACH Clene is pioneering catalytic nanotherapeutics to treat neurodegenerative diseases, such as ALS, multiple sclerosis (MS) and Parkinson s disease (PD). By targeting the improvement of mitochondrial function via the nicotinamide adenine dinucleotide pathway, Clene s rst-in-class drug, CNM-Au8 , is pioneering a new way to restore and protect neuronal function. 1 Gammon, K. Neurodegenerative disease: Brain windfall. Nature 515, 299 300 (2014). https://doi.org/10.1038/nj7526-299a
EVIDENCE OF CNM-AU8 THERAPEUTIC POTENTIAL TO TREAT ALS Improved Survival and Delayed Time to Clinical Worsening From Two Phase 2 ALS Trials and Real-World Evidence through EAPs ALS Patient Demographics Duration RESCUE-ALS & HEALEY ALS Double Blind Trial Period RESCUE-ALS & HEALEY ALS Open Label Extensions (OLEs) TWO EXPANDED ACCESS PROGRAMS (EAPs) Early-toLate-Stage Early-toLate-Stage Real-World Experience n=206 n=170 n=256 Up to 36 weeks Up to 173 weeks Over 4 years Survival Delayed Time to Clinical Worsening Not routinely collected Progression Biomarkers Safety NfL* NfL* >600 years of subject exposure without identi ed safety signals across ALS, MS, and PD *Neuro lament light RESCUE-ALS, a Phase 2 multi-center, randomized, double-blind, parallel-group, placebo-controlled trial, examined the efficacy and safety of CNM-Au8 in 45 patients with early early ALS conducted in Australia. Subjects were randomized 1:1 to receive either active treatment with CNM-Au8 (30 mg) or placebo in addition to their current standard of care over a 36-week treatment period. For more information, please see ClinicalTrials.gov Identi er: NCT04098406. 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 in people living with ALS. Subjects were randomized 3:1 to receive active treatment or placebo for the 24-week double-blind treatment period followed by the option to enroll in the OLE in which all subjects receive active drug. For more information, please see ClinicalTrials.gov Identi er: NCT04297683. EAP01 with Massachusetts General Hospital (MGH), started in 2019 to offer people with ALS access to Clene s investigational drug CNM-Au8. EAP02 with MGH and 17 centers across the United States, started in 2023, is ongoing. This EAP was initiated to allow people with ALS who were participants in the Healey ALS Platform Trial continued access to CNM-Au8 once the long-term extension of the regimen ended.
EVIDENCE OF CNM-AU8 THERAPUETIC POTENTIAL TO TREAT MULTIPLE SCLEROSIS IMPROVEMENT in LONG-TERM FUNCTION, VISION and COGNITION with CNM-Au8 treatment observed in up to 3 years of follow up VISIONARY-MS, a Phase 2 trial designed to investigate the protection or improvement of neurological function in stable relapsing remitting MS participants with chronic optic neuropathy treated with CNM-Au8 Patients Stable background therapy Stable relapsing remitting MS with chronic optic neuropathy 92% on effective immunomodulatory disease-modifying therapies (DMTs) Participants & Trial Duration Double Blind Period Long Term Extension (LTE) 48 weeks N=73 Additional 96 weeks N=55/69 (80%) Low Contrast Vision Cognition & Working Memory Neurological Function (low contrast vision, cognition, upper extremity function, and walking speed) MRI Biomarkers VEP: Visual evoked potential DTI: Diffusion tensor imaging Safety Improved axonal integrity Improved axonal integrity Preservation of white matter integrity Preservation of white matter integrity >600 years of subject exposure without identi ed safety signals across ALS, MS, and PD Clinicians noted that observed clinical improvements for participants with stable disease, over and above background immunomodulatory DMTs, are unprecedented. VISIONARY-MS was a Phase 2 multi-center, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of CNM-Au8 (15 mg or 30 mg daily) versus placebo over 48 weeks of double-blind treatment. The primary outcome was low contrast letter acuity (LCLA) improvement. Global neurological improvement, measured by the modi ed Multiple Sclerosis Functional Composite (mMSFC) including vision, cognition, upper extremity function, and walking speed assessment was the secondary outcome. In the double-blind portion of the trial, 73 participants were randomized, with 55 of 69 eligible (80%) participants continuing in the LTE. For more information, see ClinicalTrials.gov Identi er: NCT03536559.
2024 CLENE PRIORITIES 01 02 Advance regulatory agency discussions with FDA and EMA for CNM-Au8 path forward in ALS Launch Global Phase 3 ALS Trial 04 03 Expand collaboration with advocacy groups and people living with ALS Pursue opportunities for MS clinical development with a focus on high unmet need
 • shareholder letter icon 4/16/2024 Letter Continued (Full PDF)
 • stockholder letter icon 3/29/2023 CLNN Stockholder Letter
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CLNN Shareholder/Stockholder Letter Transcript:

WE ENVISION A FUTURE WHERE THE
BOUNDARIES OF NEURODEGENERATIVE
DISEASES ARE TRANSCENDED,
WHERE INDIVIDUALS NOT ONLY
SURVIVE BUT THRIVE
2023
ANNUAL
REPORT

FOCUSED ON IMPROVING MITOCHONDRIAL
HEALTH AND PROTECTING NEURONAL FUNCTION
TO TREAT NEURODEGENERATIVE DISEASES
THE PROBLEM
    Neuronal decline, a natural part of aging, is intensi   ed
in neurodegenerative diseases such as amyotrophic
lateral sclerosis (ALS), where energy de   cits worsen
the dysfunction.
    The World Health Organization forecasts
neurodegenerative diseases to rank as the
second-most prevalent cause of death within the next
20 years, underscoring the urgent need for
therapeutic advancements.1
    Impaired mitochondrial activity and compromised
cellular metabolism in these diseases contribute to
neuronal death, highlighting the critical role of
addressing energetic de   cits in developing treatments.
A NEW APPROACH
    Clene is pioneering catalytic nanotherapeutics to treat
neurodegenerative diseases, such as ALS, multiple
sclerosis (MS) and Parkinson   s disease (PD).
    By targeting the improvement of mitochondrial
function via the nicotinamide adenine dinucleotide
pathway, Clene   s    rst-in-class drug, CNM-Au8  , is
pioneering a new way to restore and protect neuronal
function.
1 Gammon, K. Neurodegenerative disease: Brain windfall. Nature 515, 299   300 (2014). https://doi.org/10.1038/nj7526-299a

EVIDENCE OF CNM-AU8
THERAPEUTIC POTENTIAL TO TREAT ALS
Improved Survival and Delayed Time to Clinical
Worsening From Two Phase 2 ALS Trials and
Real-World Evidence through EAPs
ALS Patient
Demographics
Duration
RESCUE-ALS
& HEALEY ALS
Double Blind
Trial Period
RESCUE-ALS
& HEALEY ALS
Open Label
Extensions (OLEs)
TWO EXPANDED
ACCESS
PROGRAMS
(EAPs)
Early-toLate-Stage
Early-toLate-Stage
Real-World
Experience
n=206
n=170
n=256
Up to 36 weeks
Up to 173 weeks
Over 4 years
Survival
Delayed Time to
Clinical Worsening
Not routinely
collected
Progression
Biomarkers
Safety
NfL*
NfL*
>600 years of subject exposure without identi   ed
safety signals across ALS, MS, and PD
*Neuro   lament light
RESCUE-ALS, a Phase 2 multi-center,
randomized, double-blind,
parallel-group, placebo-controlled trial,
examined the efficacy and safety of
CNM-Au8 in 45 patients with early
early ALS conducted in Australia.
Subjects were randomized 1:1 to receive
either active treatment with CNM-Au8
(30 mg) or placebo in addition to their
current standard of care over a
36-week treatment period. For more
information, please see
ClinicalTrials.gov Identi   er:
NCT04098406.
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 in people living with
ALS. Subjects were randomized 3:1 to
receive active treatment or placebo for
the 24-week double-blind treatment
period followed by the option to enroll
in the OLE in which all subjects receive
active drug. For more information,
please see ClinicalTrials.gov Identi   er:
NCT04297683.
EAP01 with Massachusetts General
Hospital (MGH), started in 2019 to offer
people with ALS access to Clene   s
investigational drug CNM-Au8.
EAP02 with MGH and 17 centers across
the United States, started in 2023, is
ongoing. This EAP was initiated to
allow people with ALS who were
participants in the Healey ALS Platform
Trial continued access to CNM-Au8
once the long-term extension of the
regimen ended.

EVIDENCE OF CNM-AU8 THERAPUETIC
POTENTIAL TO TREAT MULTIPLE SCLEROSIS
IMPROVEMENT in LONG-TERM FUNCTION, VISION
and COGNITION with CNM-Au8 treatment observed
in up to 3 years of follow up
VISIONARY-MS, a Phase 2 trial designed to investigate the protection or
improvement of neurological function in stable relapsing remitting MS
participants with chronic optic neuropathy treated with CNM-Au8
Patients
Stable background
therapy
Stable relapsing remitting MS with chronic optic neuropathy
92% on effective immunomodulatory disease-modifying
therapies (DMTs)
Participants &
Trial Duration
Double Blind Period
Long Term Extension (LTE)
48 weeks
N=73
Additional 96 weeks
N=55/69 (80%)
Low Contrast Vision
Cognition &
Working Memory
Neurological Function
(low contrast vision,
cognition, upper extremity
function, and walking speed)
MRI Biomarkers
VEP: Visual evoked potential
DTI: Diffusion tensor imaging
Safety
Improved axonal integrity
Improved axonal integrity
Preservation of white
matter integrity
Preservation of white
matter integrity
>600 years of subject exposure without identi   ed
safety signals across ALS, MS, and PD
Clinicians noted that observed clinical improvements for participants with stable
disease, over and above background immunomodulatory DMTs, are unprecedented.
VISIONARY-MS was a Phase 2
multi-center, randomized, double-blind,
placebo-controlled trial evaluating the
efficacy and safety of CNM-Au8 (15 mg
or 30 mg daily) versus placebo over 48
weeks of double-blind treatment. The
primary outcome was low contrast
letter acuity (LCLA) improvement.
Global neurological improvement,
measured by the modi   ed Multiple
Sclerosis Functional Composite
(mMSFC) including vision, cognition,
upper extremity function, and walking
speed assessment was the secondary
outcome. In the double-blind portion of
the trial, 73 participants were
randomized, with 55 of 69 eligible
(80%) participants continuing in the
LTE. For more information, see
ClinicalTrials.gov Identi   er:
NCT03536559.

2024 CLENE PRIORITIES
01
02
Advance regulatory
agency discussions
with FDA and EMA
for CNM-Au8 path
forward in ALS
Launch Global
Phase 3 ALS Trial
04
03
Expand
collaboration with
advocacy groups
and people living
with ALS
Pursue opportunities
for MS clinical
development with
a focus on high
unmet need



shareholder letter icon 4/16/2024 Letter Continued (Full PDF)
 

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