UNITED STATES
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): April 27, 2021
CYCLERION THERAPEUTICS, INC.
(Exact name of registrant as specified in its charter)
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Massachusetts
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001-38787
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83-1895370
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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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245 First Street, 18th Floor
Cambridge, Massachusetts 02142
(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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Common Stock, no par value
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CYCN
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The Nasdaq Stock Market LLC
(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. ☐
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Results of Operations and Financial Condition.
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On April 27, 2021, Cyclerion Therapeutics, Inc. (the “Company”) issued a press release and released an updated corporate presentation (“the Corporate Presentation”) as described in Item 7.01
below. The press release and presentation include information that the Company’s preliminary unaudited cash, cash equivalents and restricted cash balance as of March 31, 2021 was approximately $45 million and that the Company expects average monthly
cash use for the foreseeable future to be approximately 50 percent that of 2020.
The foregoing information constitutes unaudited and preliminary estimates that (i) represent the most current information available to management as of the date of the press release and
presentation, (ii) are subject to completion of financial closing and procedures that could result in significant changes to the estimated amounts, and (iii) do not present all information necessary for an understanding of the Company’s financial
condition as of, and its results of operations for the quarter ended, March 31, 2021. Accordingly, undue reliance should not be placed on such estimates.
The information set forth in this Item 2.02 is being furnished pursuant to Item 2.02 of Form 8-K and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934,
as amended (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, as amended (the “Securities Act”), or under the Exchange
Act, whether made before or after the date hereof, except as expressly provided by specific reference in such a filing.
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Regulation FD Disclosure.
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On April 27, 2021, the Company provided a corporate update. A copy of the Company’s press release of the same date summarizing the corporate update is attached hereto as
Exhibit 99.1. The information set forth in the press release is incorporated by reference herein. The press release contains hypertext links to information on the Company’s website. The information on the Company’s website is not incorporated by
reference into this Current Report on Form 8-K and does not constitute a part hereof.
In connection with the corporate update described above, the Company released the Corporate Presentation. Beginning on April 27, 2021, the Company intends to use
the Corporate Presentation, or portions thereof, which provides updates on its business activities, in one or more meetings with investors. The Corporate Presentation is attached hereto as Exhibit 99.2, is incorporated by reference herein and is
posted on the Company’s website, www.cyclerion.com. The Company plans to use its website to disseminate future updates to the presentation and may not necessarily file or furnish a Current Report on
Form 8-K alerting investors if the presentation is updated.
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 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 or under 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 Item 7.01 in this report, the press release or the presentation available on the Company’s website. The information contained in the press release and presentation 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.
Forward-Looking Statements
This report, the press release and the presentation may contain forward-looking statements within the meaning of Section 27A of the Securities Act 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 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.
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| Item 9.01. |
Financial Statements and Exhibits.
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(d) Exhibits.
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Exhibit No.
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Description
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Press Release dated April 27, 2021
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Corporate Update Presentation dated April 27, 2021
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SIGNATURES
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: April 27, 2021
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By:
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/s/ Anjeza Gjino
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Name:
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Anjeza Gjino
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Title:
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Chief Financial Officer
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Exhibit 99.1
Cyclerion Therapeutics Hosted Webinar to Discuss Pipeline Progress
Provided updates on development strategy and execution for CY6463, a first-in-class, CNS-penetrant sGC stimulator, including IND clearance from FDA in ADv and ongoing MELAS
program
Introduced new CY6463 clinical program in CIAS with key insights from neuropsychiatric key opinion leader, Andreas Reif, M.D.
Announced new development candidate, CY3018, a differentiated, next-generation CNS-penetrant sGC stimulator
CAMBRIDGE, Mass., April 27, 2021 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage biopharmaceutical company on a mission to
develop treatments that restore cognitive function, hosted a webinar today to provide clinical updates for its first-in-class, CNS-penetrant soluble guanylate cyclase (sGC) stimulator CY6463 in Alzheimer’s Disease with Vascular pathology (ADv) and
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS). Supported by recent clinical and preclinical data, Cyclerion also discussed the potential for CY6463 to treat Cognitive Impairment Associated with Schizophrenia
(CIAS), with key insights from Dr. Andreas Reif on the role of the sGC pathway in the disease. In addition, Cyclerion introduced its latest development candidate CY3018, a differentiated, next-generation, CNS-penetrant sGC stimulator.
“To deliver on our mission to develop treatments that restore cognitive function, we are harnessing the momentum and insights from our preclinical and clinical data on the fundamental role of the NO-sGC-cGMP pathway in
central nervous system diseases,” said Peter Hecht, Ph.D., Chief Executive Officer of Cyclerion. “Following the science, we see the potential to unlock significant opportunities across a number of patient populations with cognitive impairment, who
are in desperate need of new therapeutic options.”
Key Webinar Highlights
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Modulating a fundamental CNS signaling pathway: sGC stimulators amplify the power of the nitric oxide‐soluble guanylate cyclase‐cyclic guanosine monophosphate pathway
(NO-sGC-cGMP) signaling to address central aspects of disease pathophysiology. Preclinical data from CY6463 and extensive academic work validate the crucial role of the sGC pathway in brain physiology. Clinical data from the recent
translational pharmacology study confirm the ability of CY6463 to impact brain oscillations, neuroinflammation and neurophysiological function.
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CY6463 Updates
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Disease-relevant, biomarker-guided pipeline strategy: The company is advancing parallel, signal-seeking, exploratory studies in
well-defined patient populations with cognitive impairment including neurodegenerative, neuropsychiatric, and mitochondrial diseases. CY6463 targets sGC, a proven druggable target, in critical brain regions and cell types linked to cognition
and has demonstrated an impact on multiple biomarkers associated with cognition in previous Phase 1 studies.
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ADv clinical trial initiation: The U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for CY6463 in ADv, and the Company
anticipates beginning to enroll patients in a 12-week Phase 2a clinical trial in patients with ADv by mid-2021, barring any COVID-19 related delays. This exploratory study is designed to evaluate safety, tolerability, and pharmacodynamic
effects including impact on disease-relevant biomarkers.
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MELAS clinical trial advancement: This study is enrolling more slowly than initially projected, primarily due to COVID-19. Data from the exploratory 29-day open-label
Phase 2a pilot study in patients with MELAS are now expected by year end 2021.
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Potential to treat CIAS with novel mechanism: Neuropsychiatric key opinion leader and expert in the neurobiology of nitric oxide and its relation to psychiatric
disorders, Andreas Reif, M.D., Chair, Department of Psychiatry, University Hospital Frankfurt, discussed the sGC pathway and its role in cognitive function and CIAS. Reduced NO-sGC-cGMP signaling is linked to cognitive dysfunction in
schizophrenia. Stimulation of sGC by CY6463 to amplify NO-sGC-cGMP signaling is a potential first-in-class approach for the treatment of CIAS. Cyclerion is planning to initiate a Phase 1b signal-seeking study in CIAS to evaluate safety and
near-term impact on disease-relevant biomarkers.
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CY3018, a differentiated, next-generation CNS-penetrant sGC stimulator: Cyclerion shared information on the latest development candidate, CY3018. Preclinical data show
increased CNS-exposure, with significantly increased cerebrospinal fluid (CSF) to plasma ratio, compared to CY6463. This increased CNS distribution is mirrored by a higher level of pharmacological activity in the CNS relative to the
periphery. The company is advancing CY3018 through IND-enabling development.
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“We are using insights from our preclinical and clinical data to tap into a fundamental CNS signaling pathway with CY6463 – our first-in-class, CNS-penetrant sGC stimulator,” said Andy Busch, Ph.D., Chief Scientific
Officer at Cyclerion. “We are excited by the data from our CY6463 translational pharmacology study that demonstrated rapid improvement in biomarkers associated with cognition and reflect CY6463’s multidimensional pharmacology. These data are leading
us to explore opportunities in cognition through the sGC pathway.”
Cash, cash equivalents, and restricted cash balance on March 31, 2021 was approximately $45 million, as compared to approximately $58 million on December 31, 2021. As of April 2021, Cyclerion has substantially
streamlined its operating model to invest more fully in its priority opportunities in cognition and expects average monthly cash use for the foreseeable future to be approximately 50 percent that of 2020.
Webinar Replay Information
A replay of the event can be accessed by visiting the investors’ section of the Cyclerion website at https://ir.cyclerion.com/news-events/event-calendar.
About Cyclerion Therapeutics
Cyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function. Cyclerion’ is advancing novel, first-in-class, CNS-penetrant, sGC stimulators
that modulate a key node in a fundamental CNS signaling pathway. The multidimensional pharmacology elicited by the stimulation of sGC has the potential to impact a broad range of CNS diseases. The most advanced compound, CY6463 has shown rapid
improvement in biomarkers associated with cognitive function and is currently in clinical development for Alzheimer’s Disease with Vascular pathology (ADv) and Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) and
Cognitive Impairment Associated with Schizophrenia (CIAS). Cyclerion is also advancing CY3018, a next generation sGC stimulator.
For more information about Cyclerion, please visit https://www.cyclerion.com/ and follow us on Twitter (@Cyclerion) and LinkedIn (www.linkedin.com/company/cyclerion).
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Forward Looking Statement
This press release 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 press release, and Cyclerion undertakes
no obligation to update these forward-looking statements, except as required by law.
Investors
Carlo Tanzi, Ph.D.
Kendall Investor Relations
ctanzi@kendallir.com
Media
Amanda Sellers
Verge Scientific Communications
asellers@vergescientific.com
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Exhibit 99.2
ON A MISSION TO DEVELOP TREATMENTS THAT RESTORE COGNITIVE FUNCTIONCORPORATE PRESENTATION
APRIL 2021
Safe harbor statement 2 © 2021 Cyclerion Therapeutics, Inc 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 2 © 2021 Cyclerion Therapeutics, Inc
Contents NO-sGC-cGMP is a fundamental CNS signaling networkCY6463
translational pharmacology study results Pipeline centered around improving cognitive function Potential for patient impact: our priority indications Next-generation sGC stimulator programExecuting on our priorities 2 © 2021 Cyclerion
Therapeutics, Inc
NO-sGC-cGMP IS A FUNDAMENTAL CNS SIGNALING PATHWAY
6 © 2021 Cyclerion Therapeutics, Inc 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 pathophysiologyPreclinical 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
7 © 2021 Cyclerion Therapeutics, Inc CY6463 improves endpoints relevant to
cognition Aged Control Aged CY6463 R6/2R6/2 + CY6463 7 nM R6/2 + CY6463 46 nM WT Morphological plasticityYoung Control 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 10 30 50 70 1.0 1.5 2.0 2.5 Time
(min) Normalized fEPSP amplitude CY6463 vs WT, p = 0.9811 CY6463 vs R6/2, p =
0.0017 10 30 50 70 1.0 1.5 2.0 2.5 Time
(min) Normalized fEPSP amplitude CY6463 vs WT, p = 0.0389 CY6463 vs R6/2, p = 0.265 *p<0.05 vs. the aged control group
8 © 2021 Cyclerion Therapeutics, Inc 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 powerimproved 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 10 © 2021 Cyclerion Therapeutics, Inc
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 11 © 2021 Cyclerion Therapeutics, Inc 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
12 © 2021 Cyclerion Therapeutics, Inc CY6463 showed rapid improvement in biomarkers of
cognition Faster saccadic eye movement reaction time Alpha power: CY6463 vs. placebo Day 15 Improvement Age (years) Untreated CY6463treated Time (ms) Time
(sec) p=0.0216 Placebo CY6463 p=0.0216 Improvement 0.02 0.00 -0.02 -0.04 TNFR2 MMP3 PARC
(CCL18) MCP1 PAI1 TIMP1 C3 A2M -30 -20 -10 0 10 20 30LS % Mean Difference with 95% CI CSF Biomarkers Reduced neuroinflammatory
biomarkersLS % Mean Difference from Placebo at Day 15 In a 15-day study in 24 healthy elderly subjects, CY6463 demonstrated:Increased alpha and gamma power Improved N200 latency
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) and reaction time Reduced
neuroinflammatory biomarkers in CSF Clinical CNS pharmacology* *In a 15-day study in 24 healthy elderly subjects 14 © 2021 Cyclerion Therapeutics, Inc
Cognitive impairment is a debilitating facet of many CNS
diseases Neurodegenerative Alzheimer’s Disease Lewy Body DementiaParkinson’s Dementia Neuropsychiatric Major Depressive Disorder Bipolar DisorderAutism Traumatic brain injury StrokeCancer/chemotherapy-induced cognitive
impairment Event-related 15 © 2021 Cyclerion Therapeutics, Inc Mitochondrial Leigh SyndromeKearns-Sayre Syndrome ADv ongoing CIAS ongoing MELAS ongoing ~2M~35M~13M~5M Orphan OrphanOrphan ~21M~150M~27M~10M ~21M (US)~12M~5M
(US) References on file.Represents approximate prevalence of patients with cognitive impairment associated with other CNSdiseases, worldwide in millions, except where noted as US prevalence
Biomarker-guided development strategy in well-defined populations with cognitive
impairment ADv | Alzheimer’s Disease with vascular pathology (ADv)CIAS | Cognitive Impairment Associated with Schizophrenia MELAS | Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes MELAS ADv
Neurodegenerative Neuropsychiatric CIAS Mitochondrial Disease Significant additional opportunities Improving CognitionParallel studies in distinct populationsEfficient, signal-seeking studies inform larger and
longer studiesDisease-relevant biomarkers accelerate and guide developmentTranslation of insights across programs increases odds of success 16 © 2021 Cyclerion Therapeutics, Inc
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 18 © 2021 Cyclerion Therapeutics, Inc *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 trials focused on cognitionInitial approval expected on surrogate, symptomatic or functional
endpoints Standard of care for patients with ADvPotential for disease modification and expansion into broader AD Today Tomorrow Future Alzheimer’s Disease Vascular Dementia ADv 19 © 2021 Cyclerion Therapeutics, Inc
ADv study expected to initiate in mid-2021 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 PartnershipCollaborating with Dr. Andrew
Budson at Boston University on a study to examine the relationship between ERP/EEG and cognitive measures indementias Collaborations 20 © 2021 Cyclerion Therapeutics, Inc
Biomarker-guided development strategy: MELAS Exploratory Phase 2 Near-term impact on
disease-specific biomarkers Larger, longer symptomatic trials focused on cognition and stroke-like-episodesPotential for accelerated approval with predictive biomarker Transformative therapy for patients with MELASPotential for expansion into
additional mitochondrial diseases Today Tomorrow Future MELAS is a serious orphan disease, with significant CNS impact, no approved treatments 21 © 2021 Cyclerion Therapeutics, Inc
MELAS study underway; data expected late 2021 Objectives Exploratory, signal-seeking
study to evaluate safety, tolerability, and pharmacodynamic effects (MRI, biomarkers) Study design 29-day open labelOnce-daily CY6463Up to 20 adults (targeting 12 completers) Patient targeting Genetically confirmed mitochondrial disease
with neurological features of MELASElevated 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 UniversityPreclinical collaboration with Dr. Marni Falk at CHOP to elucidate the role of sGC in mitochondrial disease models 22 © 2021 Cyclerion Therapeutics, Inc
Biomarker-guided development strategy: CIAS Exploratory Phase 1b Safety + 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 23 © 2021 Cyclerion Therapeutics, Inc
CIAS study expected to initiate in 2H 2021 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-blindedOnce-daily CY6463Approximately 50 participants
across sequential cohorts Patient targeting Psychiatrically stable adults with schizophreniaOn stable antipsychotic regimen 24 © 2021 Cyclerion Therapeutics, Inc
NEXT GENERATION sGC STIMULATOR PROGRAM
26 © 2021 Cyclerion Therapeutics, Inc Rat
Cyno 0 2 4 6 CSF : Plasma Ratio CY6463 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 CY3018 CY6463 0.0 0.5 1.0 1.5 Relative Pharmacology% change (gamma : BP)
EXECUTING ON OUR PRIORITIES
28 © 2021 Cyclerion Thera*pePutrieclsi,mInicnar 2021: executing on our
priorities Clinical and pre-clinical ADv Ph2 study start mid-2021MELAS Ph2 study data by year end 2021CIAS Ph2b study start in 2H 2021Advancing CY3018, NextGen development candidate Partnerships Explore CNS collaborationsPraliciguat
out-license Capabilities and capital Grow external CNS network and augment core team CNS expertiseReduced monthly cash use to ~50% that of 2020Q1 2021 ending cash balance of ~$45M* * Preliminary, unaudited unrestricted cash, cash
equivalents and restricted cash balance as of March 31, 2021
29 © 2021 Cyclerion Therapeutics, Inc 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 andtranslational pharmacology studies, references
PRECLINICAL DATA
CY6463 demonstrated beneficial effects in preclinical studies across multiple domains
associated with cognitive disease IM P RO V ED Cerebral Blood FlowIncreased blood flow in areas associated with memory and arousal by fMRI BOLD imaging ENH A NCED Cellular BioenergeticsIncreased ATP and restored gene expression in cells
from patients with mitochondrial diseases IM P RO V ED Neuronal FunctionEnhanced memory & spine density in aged animals; increased LTP in neurodegenerative models; affected qEEG spectra RED UCED Neuro- inflammationDecreased markers of
LPS-induced neuroinflammation (ICAM1, VCAM1, IL6) invitro 32 © 2021 Cyclerion Therapeutics, Inc
CY6463 improved neuronal functionRestored hippocampal long-term potentiation to wild-type
levels in a mouse neurodegenerative
model 10 30 50 70 1.0 5 2.0 2.5 Time
(min) Normalized fEPSPAmplitude 1. Wild type Disease Disease + CY6463 (46 nM) * Normalized fEPSP Amplitude Time (min) 10 30 50 70 1.0 5 2.0 2.5 ImproveNeuronal Function Reduce
Neuroinflammation 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 directly on the neurons,CY6463 could restore impaired neurotransmission 33 © 2021 Cyclerion Therapeutics, Inc
CY6463 increased qEEG gamma powerNo 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 Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood
Flow CY6463 isdifferentiated from PDE9 inhibitor, which showed no effect on gamma power Vehicle PDE9i CY6463 CY6463 +PDE9i 0 5 10 15 GammaPower Gamma
Power Vehicle PDE9i CY6463 CY6463+ PDE9i 34 © 2021 Cyclerion Therapeutics, Inc
CY6463 and donepezil act independently to enhance qEEG signalCombination elicited additive
increase in gamma band power in healthy rats ImproveNeuronal Function Reduce Neuroinflammation 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 Vehicle Donepezil IW-6463 IW-6463+Donepezil 0.0 0.5 2.0 2.5 rewo PmmaaG * * # Gamma 1.5Power1.0 Vehicle Donepezil CY6463 CY6463 +Donepezil 35 © 2021 Cyclerion Therapeutics, Inc
36 © 2021 Cyclerion Therapdeautiliycs, uInrcin CY6463 improved learning and memory in
aged ratsIncreased rate of learning in aged rats treated with CY6463 in Morris Water Maze 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 Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow
37 © 2021 Cyclerion Therapeutics, Inc CY6463 improved cognitive function in
pharmacologically impaired rats ImproveNeuronal Function Reduce Neuroinflammation 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) 0 20 80 VEH-SAL VEH + MK-801 Galantamine + MK-801 0.01mg/kg 0.1mg/kg 1mg/kg 40 60Recognition Index (% of time
exploring novel object) * * * * CY6463 (oral)+ MK-801
38 © 2021 Cyclerion Therapeutics, Inc Mushroom spine density Restoration of spine
density has potential to provide neuroprotective effects and improve synaptic function in neurodegenerative diseases CY6463 improved neuronal functionEnhanced hippocampal spine density in aged animals treated with CY6463 Young
Control Aged Control Aged CY6463 86420 Spines/10 μm of dendrite Control Young CY6463 Control Aged * * ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular
Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs. Aged3-month old (young) or 16-month old (aged) healthy mice at study initiation Aged mice treated for 4 months with 1 mg/kg CY6463
CY6463 reduced neuroinflammationInhibited in vitro LPS-induction of biomarkers of
neuroinflammation *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 Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral
Blood Flow CY6463 Control Control CY6463 Control Control * * 39 © 2021 Cyclerion Therapeutics, Inc
Vehicle Healthy CY6463 (10uM) 0.0 0.2 Normalized gene expression
0.4 0.6 0.8 * * TFAM CY6463 enhanced cellular bioenergeticsIncreased ATP and restored decreased gene expression in cells from patients with mitochondrial diseases *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 Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Vehicle AMPKactivator FCCP (10M) CY6463
(0.1M) 0 100 200 300 ATP(pmole/ug protein) * * TFAM Mitochondrial disease patient cells * * * * 40 © 2021 Cyclerion Therapeutics, Inc
CY6463 improved cerebral blood flowIncreased blood flow in areas associated with memory and
arousal by fMRI BOLD imaging Peripherally restricted sGC stimulator CNS-penetrant sGC stimulator CY6463 Cortical transition areas ThalamusVentral hippocampus Reticular activating system ImproveNeuronal
Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Healthy awake male rats treated with 0.3 mg/kg iv; image quantification 20-30 minutes post-dose 41 © 2021 Cyclerion Therapeutics, Inc
PHASE 1 STUDY RESULTS
43 © 2021 Cyclerion Therapeutics, Inc PHASE 1 (completed Jan. 2020)
Results CY6463 phase 1 showed CNS exposure, target engagement, PK, and safety 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, consistent with QD dosing CNS exposure confirmed Evidence of target engagement (blood pressure) Goals Achieved Study designThree stages:SAD MAD Food Interaction110 healthy young 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 powerimproved 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 45 © 2021 Cyclerion Therapeutics, Inc
Biomarker overview: qEEG frequency bands and their clinical
implications qEEG is quantitative electroencephalography, an objective method that measures electrical activity and brain wave patterns Band Frequency Hz associated withDelta 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 functionResting-state qEEG:subjects sit facing a featureless wall without movingrecorded with eyes
open and closed for 5 minutes each Associated with:Cognitive decline in aging and ADGenetic risk factors for AD (ApoE4)AD pathological protein levels(Aβ, tau)Improvement with approved AD treatments 46 © 2021 Cyclerion Therapeutics,
Inc
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 47 © 2021 Cyclerion Therapeutics, Inc
CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust
signal Footer CY6463 relative to placebo DAY 1baseline DAY 15change from baseline CY6463 Placebo Pre- Pre-dose 1 dose 2 Pre-dose 2 hr 3 hr 6 hr last dose post-dose post-dose post-dose Magnitude of improvement
equivalent to decline seen after 2 years of aging 48 © 2021 Cyclerion Therapeutics, Inc
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 Placebo CY6463 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 p = 0.0197%Placebo CY6463Posterior BL D15 BL D15Placebo CY6463 17% treatment effect • Similar increase in anterior over placebo alpha power observed(p=0.0752) 13/18 participants increase • Overall effect not driven with
CY6463, vs 5/18 with by outliersplacebo1 49 © 2021 Cyclerion Therapeutics, Inc
CY6463 treatment associated with trend improvement in gamma power Change in Closed-Eye
Gamma (25-45 Hz) Power Placebo CY6463Anterior (p = 0.081) Placebo CY6463Posterior (p = 0.1163) 200150100500 -50-100 Change from baseline (%) 50 © 2021 Cyclerion Therapeutics, Inc
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 51 © 2021 Cyclerion
Therapeutics, Inc
CY6463 improved N200 latency and effect increased with age Day 15 Improvement Age
(years) Time (ms) Effect of age on N200 latencyUntreated CY6463 treated Overall decrease in N200 latency for CY6463 treated vs untreated on day 15 (p<0.02)Effect more pronounced in older subjects 52 © 2021 Cyclerion
Therapeutics, Inc
65 to 69yn=10 ≥70 yn=14 p=0.016 CY6463 improved N200 latency, driven by response in
older subjects Greater decrease in ≥70y vs <70yDay 15 change from baseline Latency response was greater insubjects ≥70y vs 65-69y (p=0.016) Narrowing of variance in ≥ 70ysupports 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 53 © 2021 Cyclerion Therapeutics, Inc
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 amygdalaConsidered 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 54 © 2021 Cyclerion Therapeutics, Inc 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) 55 © 2021 Cyclerion
Therapeutics, Inc Improvement Mean change from baseline on day 15 post-dose 0.02 0.00 -0.02 -0.04 150 100 50 0
PAI1MCP1 PARC (CCL18)MMP3
TNFR2 TIMP1 C3 A2M LS % Mean Difference from Placebo at Day 15 LS % Mean Difference with 95% CI CSF Biomarkers CY6463 improved
neuroinflammatory biomarkers A2M and C3 are associated with pathological aging and Alzheimer’s Disease -30 -20 -10 0 10 20 30LS % Mean Difference from placebo at Day 15 (95% CI) 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 56 © 2021 Cyclerion
Therapeutics, Inc
RELEVANT REFERENCE PUBLICATIONS
Relevant reference publications (1 of 2) 58 © 2021 Cyclerion Therapeutics, Inc NO-sGC-cGMP
signaling in the CNSGarthwaite, John. “Nitric oxide as a multimodal brain transmitter.” Brain and neuroscience advances vol. 2 2398212818810683. 4 Dec. 2018Kleppisch 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) 59 © 2021 Cyclerion Therapeutics,
Inc 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 movements in dementia due to Alzheimer’s disease and mild cognitive impairment. Aging 2019, Vol.11, No.15James A. Sharpe & David H. Zackon (1987) Senescent Saccades: Effects of
Aging on Their Accuracy, Latency and Velocity, Acta Oto- Laryngologica, 104:5-6, 422-428ADvCortes-Canteli M, Iadecola C. Alzheimer’s Disease and Vascular Aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(8):942-951MELASEl-Hattab AW, Adesina
AM, Jones J, Scaglia F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116(1-2):4-12CIASKeefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37