Korsana Biosciences, Inc 8-K, filed Sep 30, 2021
Korsana Biosciences, Inc. (KRSA)
8-K
2021-09-30
For: 2021-09-30
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April 08, 2026
About this 8-K
Korsana Biosciences, Inc filed this 8-K on September 30, 2021.
Items reported
- Item 7.01: Regulation FD disclosure
- Item 9.01: Financial statements and exhibits
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): September 30, 2021
(Exact name of registrant as specified in its charter)
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(State or other jurisdiction of incorporation)
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(Commission File Number)
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(IRS Employer Identification Number)
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(Address of principal executive offices, including Zip Code)
Registrant’s telephone number, including area code: (857 ) 327-8778
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
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Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
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Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
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Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
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Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
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Securities registered pursuant to Section 12(b) of the Act:
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Title of each class
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Trading Symbol(s)
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Name of each exchange on which registered
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(Nasdaq Global Select Market)
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of
the Securities Exchange Act of 1934 (§240.12b-2 of this chapter). Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised
financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
| Item 7.01. |
Regulation FD Disclosure.
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On September 30, 2021, Cyclerion Therapeutics, Inc. (the “Company”) released an updated corporate presentation (the “Corporate Presentation”). The
Corporate Presentation includes clinical study progress updates related to the development of CY6463, the Company’s first-in-class, CNS-penetrant soluble guanylate cyclase (sGC) stimulator for the treatment of neurological diseases associated with
cognitive impairment. The Company announces and the Corporate Presentation states that (1) first patients have been enrolled in a Phase 1b study in Cognitive Impairment Associated with Schizophrenia (CIAS); (2) enrollment remains ongoing in a Phase
2a study in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), and that topline clinical results are now expected in H1 2022; and (3) patient screening is underway in a Phase 2a study in Alzheimer’s disease with
vascular pathology (ADv).
Beginning on September 30, 2021, the Company intends to use the Corporate
Presentation, or portions thereof, in one or more meetings with investors. The Corporate Presentation is attached as Exhibit 99.1 to this Current Report on Form 8-K, is incorporated by reference herein and is posted on the Company’s website, www.cyclerion.com.
The information set forth in and incorporated by reference into this Item 7.01 is being furnished pursuant to Item 7.01 of Form 8-K and shall not be
deemed “filed” for purposes of Section 18 of the Securities and Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, and it shall not be deemed incorporated by reference in any filing under the
Securities Act of 1933 or the Exchange Act, whether made before or after the date hereof, except as expressly provided by specific reference in such a filing. By filing this Current Report on Form 8-K and furnishing the information in and
incorporated by reference into this Item 7.01, the Company makes no admission as to the materiality of such information. The information contained in the presentations is summary information that is intended to be considered in the context of the
Company’s filings with the Securities and Exchange Commission (the ‘SEC’) and other public announcements that the Company makes, by press release or otherwise, from time to time. The Company undertakes no duty or obligation to publicly update or
revise the information contained in this report, or incorporated by reference herein, although it may do so from time to time as its management believes is appropriate or as required by applicable law. Any such updating may be made through the
filing of other reports or documents with the SEC, through press releases, by updating its website or through other public disclosure.
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This report and the Corporate Presentation may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as
amended, and Section 21E of the Exchange Act. Our forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential changes in circumstances, assumptions, and uncertainties, including
statements about the anticipated timing of release of topline results of our clinical trials; the progression of our discovery programs into clinical development; and the business and operations of the Company. We may, in some cases use terms such as
“predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these
forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include the
risks listed under the heading “Risk Factors” and elsewhere in our 2020 Form 10-K filed on February 25, 2021, and our subsequent SEC filings including the Form 10-Qs filed on April 30, 2021 and July 29, 2021. Investors are cautioned not to place
undue reliance on these forward-looking statements. These forward-looking statements (except as otherwise noted) would speak only as of the respective dates of this report and the webcast, and the Company undertakes no obligation to update these
forward-looking statements, except as required by law.
| Item 9.01 |
Financial Statements and Exhibits
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(d)
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Exhibit No.
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Description
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Corporate Presentation dated September 30, 2021
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2
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its
behalf by the undersigned hereunto duly authorized.
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Cyclerion Therapeutics, Inc.
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Dated: September 30, 2021
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By:
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/s/ Cheryl Gault
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Name:
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Cheryl Gault
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Title:
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Chief Operating Officer
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3
Exhibit 99.1
On a mission to develop treatments that restore cognitive function CORPORATE PRESENTATION
Safe harbor statement This document contains forward-looking statements within the meaning of Section
27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended.Our forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential
changes in circumstances, assumptions, and uncertainties, including statements about the anticipated timing of release of topline results of our clinical trials; the progression of our discovery programs into clinical development; and the
business and operations of the Company. We may, in some cases use terms such as “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “likely,” “will,” “should” or
other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from
those expressed or implied in such statement. Applicable risks and uncertainties include those related to the possibility that any results of operations and financial condition of the Company reported are preliminary and subject to final audit
and the risks listed under the heading “Risk Factors” and elsewhere in our 2020 Form 10-K filed on February 25, 2021, and our subsequent SEC filings. Investors are cautioned not to place undue reliance on these forward-looking statements. These
forward-looking statements (except as otherwise noted) speak only as of the date of this report, and the Company undertakes no obligation to update these forward-looking statements, except as required by law.
On a mission to develop treatments that restore cognitive function Tapping into a fundamental CNS
signaling pathway with CY6463, a first-in-class, CNS-penetrant sGC stimulator Executing biomarker-guided development strategy in well-defined populations with cognitive impairment Tackling the enormous burden and breadth of cognitive
impairment through an innovative portfolio of indications and molecules
Contents NO-sGC-cGMP is a fundamental CNS signaling pathway CY6463 translational pharmacology
clinical study results Advancing next-generation sGC stimulator program Pipeline centered around improving cognitive function Potential for patient impact: 3 studies underway Executing on our priorities
NO-sGC-cGMP is a fundamental CNS signaling pathway
CY6463 amplifies the fundamental NO-sGC-cGMP signaling pathway CY6463First-in-class BBB-permeable,
positive allosteric modulator of sGCAmplifies endogenous NO-sGC-CGMP signaling to address central aspects of disease pathophysiology Preclinical data and extensive academic work validate the crucial role of the NO-sGC-cGMP pathway in brain
physiology Synaptic plasticity Neuro-inflammation Bioenergetics Vascular function PKG, PDE, ion channels Downstream targets (e.g., CREB, BDNF) Important role in learning and memory
CY6463 improves endpoints relevant to cognition Young Control Aged Control Aged CY6463 R6/2 +
CY6463 46 nM R6/2 + CY6463 7 nM R6/2 WT Morphological plasticity In-vivo learning and memory Ex-vivo LTP Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 *p<0.05 vs. the
aged control group
CY6463 amplifies a fundamental CNS signaling pathway NO-sGC-cGMP pathway plays a critical role in brain
functionsGC stimulation with CY6463 amplifies NO-sGC-cGMP signalingMorphological, ex vivo and in vivo data demonstrate important role of sGC in synaptic plasticity, learning and memory, and 6463’s ability to restore deficits in these
endpoints
CY6463 Translational Pharmacology Study Results
CY6463 showed rapid and persistent improvements in multiple independent biomarkers associated with
cognitive impairment In a 15-day study in 24 healthy elderly subjects CY6463 demonstrated: Increased alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) reaction time Reduced neuroinflammatory
biomarkers Rapid onset (<15 days) Effect increased with ageBiomarkers linked to AD and aging
Phase 1b translational pharmacology study designed to evaluate CNS activity *due to COVID restrictions,
12 subjects completed only period 1 Healthy elderly population (≥65 years) Objectives washout CY6463 QD CY6463 QD Placebo Placebo 15 days 15 days 24 subjects completed period 1 12 subjects completed both periods* Safety and
tolerabilityPharmacokinetics Target engagementCNS activity
CY6463 showed rapid improvement in biomarkers of cognition Increased alpha and gamma power Faster
saccadic eye movement reaction time Improved N200 latency Alpha power: CY6463 vs. placebo Day 15 Improvement Age (years) Untreated CY6463 treated Time (ms) Time
(sec) p=0.0216 Placebo CY6463 p=0.0216 Improvement 0.02 0.00 -0.02 -0.04 Reduced neuroinflammatory biomarkers In a 15-day study in 24 healthy elderly subjects, CY6463 demonstrated:
Pipeline centered around improving cognitive Function
CY6463 data point to potential in cognition Preclinical CNS pharmacology Potential to improve
cognitive function Neuronal function Neuro-inflammation Bioenergetics Vascular function Increased posterior alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) andreaction time Reduced
neuroinflammatory biomarkers in CSF Clinical CNS pharmacology* *In a 15-day study in 24 healthy elderly subjects
Cognitive impairment is a debilitating facet of many CNS diseases Neurodegenerative Alzheimer’s
Disease Parkinson’s Dementia Lewy Body Dementia Neuropsychiatric Major Depressive Disorder Bipolar Disorder Autism Cancer/chemotherapy-induced cognitive impairment Traumatic brain
injury Stroke Event-related Mitochondrial Leigh Syndrome Kearns-Sayre Syndrome ADv ongoing CIAS ongoing MELAS ongoing ~2M ~35M ~13M ~5M Orphan Orphan Orphan ~21M ~150M ~27M ~10M ~21M (US) ~12M ~5M (US) Represents
approximate prevalence of patients with cognitive impairment associated with other CNS diseases, worldwide in millions, except where noted as US prevalence References on file.
Biomarker-guided development strategy in well-defined populations with cognitive impairment ADv |
Alzheimer’s Disease with vascular pathology (ADv) CIAS | Cognitive Impairment Associated with SchizophreniaMELAS | Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes MELAS ADv Neurodegenerative Parallel studies
in distinct populations Efficient, signal-seeking studies inform larger and longer studies Disease-relevant biomarkers accelerate and guide development Improving Cognition Neuropsychiatric CIAS Mitochondrial Disease Significant
additional opportunities Translation of insights across programs increases odds of success
Potential for patient impact: our priority indications
DISCOVERY IND-ENABLING PHASE 1* PHASE 1b/2a PHASE
2 CY6463 MELAS ADv CIAS Multiple under assessment CY3018 Multiple under assessment Advancing parallel, signal-seeking, exploratory studies in priority patient
populations *Two phase 1 studies were completed in healthy young and old (>65 years of age) volunteers confirming targeted CNS exposure and activity
Growing patient population, devastating impact, limited treatments Biomarker-guided development
strategy: ADv Exploratory Phase 2Near-term impact on disease-specific biomarkers and cognition Larger, longer studies symptomatic trialsfocused on cognition Initial approval expected on surrogate, symptomatic or functional endpoints Standard
of carefor patients with ADv Potential for disease modification and expansion into broader AD Today Tomorrow Future Alzheimer’sDisease VascularDementia ADv
ADv study ongoing 20 Exploratory, signal-seeking study to evaluate safety, tolerability,
and pharmacodynamic effects (EEG, MRI, neuroinflammatory biomarkers, cognition) Once-daily CY6463 vs. placebo12 weeks30 participants Confirmed AD pathology (PET, CSF)2+ cardiovascular risk factorsMild-moderate subcortical small-vessel disease
on MRIMini mental state exam score (20-26) Objectives Study design Patient targeting Partially funded by the Alzheimer's Association’s Part the Cloud-Gates Partnership Collaborating with Dr. Andrew Budson at Boston University on a study to
examine the relationship between ERP/EEG and cognitive measures in dementias Collaborations
Biomarker-guided development strategy: MELAS Exploratory Phase 2Near-term impact ondisease-specific
biomarkers Larger, longer symptomatic trials focused on cognition and stroke-like-episodes Potential for accelerated approvalwith predictive biomarker Transformative therapy for patients with MELAS Potential for expansion into additional
mitochondrial diseases Today Tomorrow Future MELAS is a serious orphan disease, with significant CNS impact, no approved treatments
MELAS study ongoing; data expected 1H 2022 22 Objectives Exploratory, signal-seeking study to
evaluate safety, tolerability, and pharmacodynamic effects (MRI, biomarkers) Study design 29-day open label Once-daily CY6463Up to 20 adults (targeting 12 completers) Patient targeting Genetically confirmed mitochondrial disease with
neurological features of MELAS Elevated plasma lactate (disease biomarker) Sites and collaborations Study performed at centers of excellence for mitochondrial medicine: CHOP, MGH, Children’s National Hospital, Columbia University, Johns
Hopkins University Preclinical collaboration with Dr. Marni Falk at CHOP to elucidate the role of sGC in mitochondrial disease models
Biomarker-guided development strategy: CIAS Exploratory Phase 1bSafety + near-term impact on
disease-relevant biomarkers Larger, longer studies focused on biomarker-identified populations Standard of care adjunctive therapy Improve cognitive impairment and functional outcomes Today Tomorrow Future CIAS is a debilitating
and untreated facet of schizophrenia, with large and growing unmet need
CIAS study ongoing 24 Objectives Exploratory, signal-seeking study to evaluate safety, tolerability,
and pharmacodynamic effects (qEEG, ERP, digital cognitive performance battery) Study design 14-day in clinic, randomized, placebo-controlled, double-blinded Once-daily CY6463Approximately 60 participants across sequential cohorts Patient
targeting Psychiatrically stable adults with schizophreniaOn stable antipsychotic regimen
Next generation sGC stimulator program
Next generation sGC stimulator CY3018: selectively targeting the CNS Greater relative CNS
exposure Greater relative CNS pharmacology Greater CSF:plasma ratio for CY3018 translating into greater relative CNS pharmacologyCY3018 is progressing though IND-enabling developmentOngoing pharmacology studies to validate amenable CNS
indications CY3018 Data displayed as mean+ SEM, Relative pharmacology ratio: 1-hour post-dose with vehicle-subtraction
Executing on our priorities
2021: executing on our priorities 28 * Preliminary, unaudited unrestricted cash, cash equivalents and
restricted cash balance as of March 31, 2021 Clinical andpre-clinical ADv Ph2 study ongoingMELAS Ph2 study data expected H1 2022CIAS Ph1b study ongoingAdvancing CY3018, next-generation development candidate Partnerships Explore CNS
collaborationsPraliciguat out-license complete Capabilities and capital Grow external CNS network and augment coreteam CNS expertiseReduced monthly cash use to ~50% that of 2020Q2 2021 ending cash balance of ~$70M
On a mission to develop treatments that restore cognitive function Tapping into a fundamental CNS
signaling pathway with CY6463, a first-in-class, CNS-penetrant sGC stimulator Executing biomarker-guided development strategy in well-defined populations with cognitive impairment Tackling the enormous burden and breadth of cognitive
impairment through an innovative portfolio of indications and molecules
Appendices Preclinical, Phase 1 and translational pharmacology studies, references
Preclinical Data
CY6463 demonstrated beneficial effects in preclinical studies across multiple domains associated with
cognitive disease 32 Cerebral Blood FlowIncreased blood flow in areas associated with memory and arousal by fMRI BOLD imaging IMPROVED CellularBioenergeticsIncreased ATP and restored gene expression in cells from patients with
mitochondrial diseases ENHANCED Neuronal FunctionEnhanced memory & spine density in aged animals; increased LTP in neurodegenerative models; affected qEEG spectra IMPROVED Neuro- inflammationDecreased markers of LPS-induced
neuroinflammation (ICAM1, VCAM1, IL6) in vitro REDUCED
CY6463 improved neuronal function Restored hippocampal long-term potentiation to wild-type levels in a
mouse neurodegenerative model Wild type Disease Disease + CY6463 (46 nM) * Normalized fEPSPAmplitude Time (min) 10 30 50 70 1.0 5 2.0 2.5 ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular
Bioenergetics ImproveCerebral Blood Flow Hippocampal slices from symptomatic Huntington’s Disease (R6/2) mice incubated with CY6463 for 25-30 minutes before LTP inductionExtracellular field potentials recordings performed using
Multi-Electrode Array; **p<0.01 vs. Disease By acting directlyon the neurons,CY6463 could restore impaired neurotransmission
CY6463 increased qEEG gamma power No effect seen with PDE9 inhibitor Healthy awake rats were treated
with clinically relevant doses of CY6463 (3 mg/kg) or PDE9 inhibitor (10 mg/kg) Graph displays 1-2h post-dose, mean ± SEM ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow CY6463
isdifferentiated from PDE9 inhibitor, which showed no effect on gamma power Gamma Power Vehicle PDE9i CY6463 CY6463 + PDE9i
CY6463 and donepezil act independently to enhance qEEG signal Combination elicited additive increase in
gamma band power in healthy rats ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs Veh# p<0.05 CY6463 vs CY6463 +DonepezilHealthy rats orally administered CY6463
(10mg/kg), Donepezil (1mg/kg), or a combination. Graph displays 1-2h post-dose, mean ± SEM CY6463 may offer opportunity to enhance attention and cognitive performance alone and on top of standard of care Gamma
Power Vehicle Donepezil CY6463 CY6463 + Donepezil
CY6463 improved learning and memory in aged rats Increased rate of learning in aged rats treated with
CY6463 in Morris Water Maze Healthy aged male rats were administered CY6463 (10 mg/kg, p.o.) daily during Morris Water Maze training Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Young rat/Vehicle Aged rat/Vehicle Aged
rat/CY6463 *p<0.05 vs. Aged vehicle-treated ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow
CY6463 improved cognitive function in pharmacologically impaired rats ImproveNeuronal
Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Rat Novel Object Recognition *p<0.05 vs. VEH + MK-801 rats CY6463 acts downstream of NMDA receptor to reverse deficit induced by NMDA
antagonist (MK-801)
Mushroom spine density Restoration of spine density has potential to provide neuroprotectiveeffects and
improve synaptic function in neurodegenerative diseases CY6463 improved neuronal function Enhanced hippocampal spine density in aged animals treated with CY6463 Young Control Aged Control Aged CY6463 Control Young
CY6463 Control Aged * * ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs. Aged3-month old (young) or 16-month old (aged) healthy mice at study
initiationAged mice treated for 4 months with 1 mg/kg CY6463
CY6463 reduced neuroinflammation Inhibited in vitro LPS-induction of biomarkers of
neuroinflammation 39 *p<0.05 vs. control LPS-treated wellsCY6463 (10 µM) and DETA (30 µM) were incubated with SIM-A9 cells or rat brain 3D microtissues for 30 minutes before LPS (100 ng/ml) incubation and further incubated for 18-20h at
37oC before IL-6 quantification in the media Neuroinflammation in mouse microglial cells Neuroinflammation in rat brain 3D microtissues * ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral
Blood Flow CY6463 Control Control CY6463 Control Control * *
CY6463 enhanced cellular bioenergetics Increased ATP and restored decreased gene expression in cells
from patients with mitochondrial diseases 40 *p<0.05 vs. vehicle-treated wellsGM13740 Leigh Syndrome patient cells obtained from the Coriell Institute were treated for 24h before ATP quantificationTFAM: mitochondrial transcriptional factor
A, a key activator of mitochondrial transcription as well as a participant in mitochondrial genome replication. ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood
Flow TFAM Mitochondrial disease patient cells * * * *
CY6463 improved cerebral blood flow 41 Increased blood flow in areas associated with memory
and arousal by fMRI BOLD imaging Peripherally restricted sGC stimulator CNS-penetrant sGC stimulator CY6463 Reticular activating system Thalamus Cortical transition areas Ventral hippocampus ImproveNeuronal
Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Healthy awake male rats treated with 0.3 mg/kg iv; image quantification 20-30 minutes post-dose
Phase 1 study results
Results CY6463 phase 1 showed CNS exposure, target engagement, PK, and safety PHASE 1
(completed) 110 healthy young Age range 18-63 Standard safety Identified safe and well-tolerated dose levels with steady-state CNS exposure in therapeutic target range* Linear, predictable PK, consistentwith QD dosing CNS exposure
confirmed Evidence of target engagement(blood pressure) GoalsAchieved Study designThree stages: SAD MAD Food Interaction PK (blood & CSF) Wide dose range tested Well tolerated at all dose levels,no safety signals May
be taken with or without food *Based on positive CNS pharmacology in multiple preclinical models
Translational Pharmacology Study Results
CY6463 showed rapid and persistent improvements in multiple independent biomarkers associated with
cognitive impairment In a 15-day study in 24 healthy elderly subjects CY6463 demonstrated: Increased alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) reaction time Reduction in neuroinflammatory
biomarkers Rapid onset (<15 days) Effect increased with ageBiomarkers linked to AD and aging
Biomarker overview: qEEG frequency bands and their clinical implications qEEG is quantitative
electroencephalography, an objective method that measures electrical activity and brain wave patterns Resting-state qEEG: subjects sit facing a featureless wall without movingrecorded with eyes open and closed for 5 minutes
each Band Frequency Hz associated with Delta 0-4 Deep sleep Theta 4-8 Waking/falling asleep, some with cognition Alpha 8-14 Passive wakefulnessAttention and cognitive processing Beta 14-30 Alert,
concentration Gamma 30-80 Higher cognitive function Associated with: Cognitive decline in aging and ADGenetic risk factors for AD (ApoE4)AD pathological protein levels (Aβ, tau)Improvement with approved AD treatments
CY6463 improved qEEG measures: significant increase in alpha power qEEG is quantitative
electroencephalography, an objective method that measures electrical activity and brain wave patterns CY6463 vs. baseline Significant increase in EEG alpha power No effect of placebo Placebo vs. baseline CY6463 vs. placebo change
(%) in alpha power on day 15
CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust
signal Footer DAY 1baseline DAY 15change from baseline CY6463 relative to placebo CY6463 Placebo Pre-dose 1 Pre-dose 2 Pre-doselast dose 2 hr post-dose 3 hr post-dose 6 hr post-dose Magnitude of improvement equivalent to
decline seen after 2 years of aging
CY6463 increased alpha power with high responder rate (>70%) 1. Includes all subjects. For CY6463
and pbo each: n=12 for period 1, n=6 for period 2 Increase in alpha powerDay 15 change from baseline in mean closed-eye alpha (8-12 Hz) Power Consistent individual treatment responsesPosterior Closed-Eye Alpha (8-12 Hz)
Power Placebo CY6463 Placebo CY6463 Posterior p = 0.0197 % 17% treatment effect over placeboSimilar increase in anterior alpha power observed (p=0.0752) 13/18 participants increase with CY6463, vs 5/18 with placebo1Overall effect not
driven by outliers Placebo CY6463 BL BL D15 D15
CY6463 treatment associated with trend improvement in gamma power Change in Closed-Eye Gamma (25-45
Hz) Power Placebo CY6463 Placebo CY6463 200 150 100 50 0 -50 -100 Anterior (p = 0.081) Posterior (p = 0.1163) Change from baseline (%)
Biomarker overview: event-related potential (ERP) Trial: 500 tones80% standard, 20%
deviant Deviant Standard ERP oddball paradigmSubjects wear EEG cap and headphones, hear tones with instruction to press a button upon deviant tones P300 N200 N200Stable component of ERP waveformStimulus
identification and distinctionAffected in aging, neurodegenerative and neuropsychiatric diseases with cognitive impairment, and other CNS diseases ParametersLatency: time after the stimulus to peak signalAmplitude: size of peak signal
CY6463 improved N200 latency and effect increased with age Day 15 Improvement Age
(years) Untreated CY6463 treated Time (ms) Effect of age on N200 latency Overall decrease in N200 latency for CY6463 treated vs untreated on day 15 (p<0.02) Effect more pronouncedin older subjects
65 to 69yn=10 ≥70 yn=14 p=0.016 CY6463 improved N200 latency, driven byresponse in older
subjects Greater decrease in ≥70y vs <70yDay 15 change from baseline Latency response was greater in subjects ≥70y vs 65-69y (p=0.016) Narrowing of variance in ≥ 70y supports a drug effect In ≥ 70y, magnitude of improvement after 2
weeks of treatment with CY6463 represents ~10y age-related change in N200 latency Time (ms) 3.0 1.5 0.0 1.5
Biomarker overview: saccadic eye movement as an objective measure of attention and cognition Short,
fast, simultaneous tracking of both eyes in the same direction Brain areas involved include the frontal cortex, superior colliculus, substantia nigra, and amygdala Considered to be reflective of attention / arousal and influenced by
motivation, time on task, and task difficulty Sensitive to sedation, fatigue, and CNS depressants and cognitive enhancers, and is affected by aging Peak Velocity Amplitude Latency Duration T=0ms Eye Position Eye
Velocity https://www.liverpool.ac.uk/~pcknox/teaching/Eymovs/params.htm
CY6463 improved saccadic eye movement, an objective functional measure Decrease in saccadic reaction
time Increase in saccadic peak velocity Shorter saccadic reaction times and faster saccadic velocities indicate that CY6463 is improving CNS functional performance – motor output – in addition to CNS neurophysiologyCognitive enhancers (e.g.,
modafinil) also positively impact saccadic eye movements Time (sec) p=0.0216 Placebo CY6463 Placebo CY6463 p=0.0216 p=0.07 Improvement Velocity (deg/sec) Improvement Mean change from baseline on day 15
post-dose 0.02 0.00 -0.02 -0.04 150 100 50 0
CY6463 improved neuroinflammatory biomarkers A2M and C3 are associated with pathological aging
and Alzheimer’s Disease Alpha-2-macroglobulin (A2M) levels predict cognitive decline and development of AD; may lead to tau hyperphosphorylation Complement C3 (C3) colocalizes with Aβ plaques and tau tangles; involved in synaptic
remodeling and degeneration LS % Mean Difference from placebo at Day 15 (95% CI)
Relevant reference publications
Relevant reference publications (1 of 2) NO-sGC-cGMP signaling in the CNSCorreia S, et al. “The
CNS-penetrant soluble guanylate cyclase stimulators CY6463 reveals its therapeutic potential in neurodegenerative diseases.” Frontiers in Pharmacology. 2021;12(1014)Correia S, et al. “The CNS-penetrant soluble guanylate cyclase stimulators
CYR119 attenuates markers of inflammation in the central nervous system.” Journal of Neuroinflammation. 2021;18(1)Garthwaite, John. “Nitric oxide as a multimodal brain transmitter.” Brain and Neuroscience Advances vol. 2 2398212818810683.4 Dec.
2018 Kleppisch T, Feil R. cGMP signaling in the mammalian brain: role in synaptic plasticity and behaviour. Handb Exp Pharmacol. 2009;(191):549-79Ben Aissa M, Lee SH, Bennett BM, Thatcher GR. Targeting NO/cGMP Signaling in the CNS for
Neurodegeneration and Alzheimer's Disease. Curr Med Chem. 2016;23(24):2770-2788Hollas MA, Ben Aissa M, Lee SH, Gordon-Blake JM, Thatcher GRJ. Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery. Nitric Oxide. 2019 Jan
1;82:59-74qEEG spectral frequency analysisIshii et al. Healthy and Pathological Brain Aging: From the Perspective of Oscillations, Functional Connectivity, and Signal Complexity. Neuropsychobiology, 2018Babiloni, et al. Resting-state posterior
alpha rhythms are abnormal in subjective memory complaint seniors with preclinical Alzheimer's neuropathology and high education level: the INSIGHT-preAD study. Neurobiol Aging. 2020;90:43-59
Relevant reference publications (2 of 2) Event-related potential (ERP): MMN, N200 and P300Bennys K,
Portet F, Touchon J. Diagnostic value of event-related evoked potentials N200 and P300 subcomponents in early diagnosis of Alzheimer’s disease and mild cognitive impairment. J Clin Neurophysiol 2007;24:405–12Fruehwirt et al. Associations of
event-related brain potentials and Alzheimer’s disease severity: A longitudinal study. Progress in Neuropsychopharmacology and Biological Psychiatry 92 (2019) 31-38Saccadic eye movement (SEM)Wilcockson et al. Abnormalities of saccadic eye
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