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)

Massachusetts
001-38787
83-1895370
(State or other jurisdiction of incorporation)
(Commission File Number)
(IRS Employer Identification Number)

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:

  ☐
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
  ☐
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
  ☐
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
  ☐
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class
Trading Symbol(s)
Name of each exchange on which registered
Common Stock, no par value
CYCN
The Nasdaq Stock Market LLC
(Nasdaq Global Select Market)

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 2.02.
Results of Operations and Financial Condition.

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.

Item 7.01.
Regulation FD Disclosure.

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.

(d) Exhibits.

Exhibit No.
Description


Press Release dated April 27, 2021


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.
Cyclerion Therapeutics, Inc.



Dated: April 27, 2021
By:
/s/ Anjeza Gjino


Name:
Anjeza Gjino


Title:
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


 •
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.

1


 •
CY6463 Updates


o
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.


o
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.


o
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.


o
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.


•
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
[email protected]

Media
Amanda Sellers
Verge Scientific Communications
[email protected]


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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 (10M)  CY6463 (0.1M)    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