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Item 7.01 Regulation FD Disclosure.
On July 28, 2022, Cyclerion Therapeutics, Inc. (the "Company") announced topline data from its CY6463 Cognitive Impairment Associated with Schizophrenia (”CIAS”) study. Copies of the press release and CIAS clinical data presentation are being furnished as Exhibit 99.1 and Exhibit 99.2, respectively to this Current Report on Form 8-K.
The information contained in Item 7.01 of this Current Report on Form 8-K, Exhibit 99.1 and Exhibit 99.2 attached hereto is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
(d)
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Description |
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Press Release of Cyclerion Therapeutics, Inc. dated July 28, 2022 |
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CIAS Clinical Data Presentation of Cyclerion Therapeutics, Inc., dated July 28, 2022 |
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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: July 28, 2022 |
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/s/ Anjeza Gjino |
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Name: |
Anjeza Gjino |
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Chief Financial Officer |
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Exhibit 99.1
Cyclerion Therapeutics Announces Positive Topline Clinical Data for CY6463 in
Patients with Cognitive Impairment Associated with Schizophrenia (CIAS)
Study data demonstrate positive effects of CY6463 on cognition and inflammation after two weeks of dosing in patients with stable schizophrenia on standard of care
Oral, once-daily CY6463 was well tolerated, with no reports of serious adverse events (SAEs) or treatment discontinuation due to adverse events (AEs)
Data demonstrate the translation of sGC multi-dimensional pharmacology and the therapeutic potential of amplifying sGC signaling in the CNS and support the further development of oral, once-daily CY6463
Company to discuss data during live webinar today at 8:00 a.m. EDT
CAMBRIDGE, Mass., July 28, 2022 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function, today announced positive topline data from its clinical study of CY6463 for the treatment of Cognitive Impairment Associated with Schizophrenia (CIAS) in individuals with stable schizophrenia on a stable, single, atypical antipsychotic regimen. Data from the 14-day, double-blind, randomized, placebo-controlled, multiple-ascending-dose study demonstrate that once-daily CY6463 was safe and well tolerated, with no reports of serious adverse events (SAEs), severe adverse events (AEs), or treatment discontinuation due to AEs. Study data demonstrate a strong effect on cognitive performance after two weeks of 15mg once-daily dosing. A broad positive movement on inflammatory biomarkers was also observed. These signals on exploratory endpoints provide further evidence of the pro-cognitive and anti-inflammatory effects of CY6463 observed in preclinical studies and prior clinical trials.
“Cognitive impairment is a central debilitating, and untreated facet of schizophrenia, and there is a significant need for a treatment option that improves cognition,” said Steven E. Hyman, M.D., Core Member of the Broad Institute, Director of the Stanley Center for Psychiatric Research at the Broad Institute, and new member of Cyclerion’s Board of Directors. “I am encouraged by the promising
cognition signals observed after only two weeks of CY6463 dosing in patients with stable schizophrenia. These data demonstrate the therapeutic potential of amplifying sGC signaling in the CNS, including positive effects on cognition and inflammation, and support further development of CY6463 in diseases characterized by cognitive impairment.”
CY6463 is a positive allosteric modulator of soluble guanylate cyclase (sGC) that amplifies endogenous nitric oxide (NO) signaling, a pathway that has been linked to schizophrenia.
The clinical study enrolled 48 participants with stable schizophrenia with no more than moderate positive symptoms and on a stable, single, atypical antipsychotic regimen. Topline results include:
“This is the second clinical study successfully demonstrating safety, pharmacokinetics, and therapeutic activity in a patient population where previous drug development has been very challenging,” said Andreas Busch, Ph.D., Chief Scientific Officer at Cyclerion Therapeutics. “These exciting results confirm previous clinical and preclinical findings, adding to a strong data package that supports the advancement of CY6463 in CNS diseases where cognition is impaired, including CIAS and MELAS. We are eager to build on the momentum from these positive data and continue to assess opportunities to accelerate development, refine patient selection, and improve endpoint assessment.”
“The data emerging from this CIAS study, coupled with the recently reported CY6463 MELAS clinical study data, demonstrate positive multi-dimensional therapeutic activity and favorable safety and tolerability in two distinct patient populations,” said Peter Hecht, Ph.D., Chief Executive Officer of Cyclerion. “These data present a path and opportunity forward for Cyclerion’s first-in-class, CNS-penetrant sGC stimulator to yield multiple breakthrough CNS therapeutics across patient populations in need of novel treatment options. We continue to explore potential partnerships with parties who share our vision for the broad therapeutic potential of sGC in treating CNS disorders.”
Webinar Information
The Company will discuss these positive topline clinical data during a live webinar on Thursday, July 28th at 8:00 a.m. EDT, including a live Q&A. The live event can be accessed by visiting the investors' section of the Cyclerion website at https://ir.cyclerion.com/news-events/event-calendar. An archived replay will also be available on the Cyclerion website.
About the CIAS Study
The CIAS trial (NCT04972227) was an in-center, randomized, placebo-controlled, multiple-ascending-dose study of oral, once-daily CY6463 in 48 adults aged 18-50 who were diagnosed with stable schizophrenia with no more than moderate positive symptoms and on a stable, single, atypical antipsychotic regimen. The primary objective of the study was to assess the safety and tolerability of 15, 30 and 60 milligram, once-daily, oral doses of CY6463 over 14 days. The secondary objectives included pharmacokinetics and exploratory pharmacodynamic effects. The study was not powered for hypothesis testing.
About Schizophrenia and CIAS
Schizophrenia is a chronic brain disorder that affects how patients think, feel, and behave, which may result in hallucinations, delusions and/or disordered behavior that impairs daily functioning. Cognitive impairment is a core, debilitating, and untreated symptom of schizophrenia, with nearly all patients suffering from some cognitive deficits. There are currently no approved therapies that specifically improve cognitive deficits.
About CY6463
CY6463 is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious CNS diseases. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway is a fundamental mechanism that precisely controls key aspects of physiology throughout the body. In the CNS, the NO-sGC-cGMP pathway regulates diverse and critical biological functions including neuronal function, neuroinflammation, cellular bioenergetics, and vascular dynamics. Although it has been successfully targeted with several drugs in the periphery, this mechanism has yet to be fully leveraged
therapeutically in the CNS, where impaired NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of many neurodegenerative and neuropsychiatric diseases and other disorders associated with cognitive impairment. As an sGC stimulator, CY6463 acts as a positive allosteric modulator to sensitize the sGC enzyme to NO, increase the production of cGMP, and thereby amplify endogenous NO signaling. By compensating for deficient NO-sGC-cGMP signaling, CY6463 and other sGC stimulators may have broad therapeutic potential as a treatment to improve cognition and function in people with serious CNS diseases.
About Cyclerion Therapeutics
Cyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function. Cyclerion’s lead molecule is CY6463, a novel, first-in-class, CNS-penetrant, sGC stimulator that modulates a key node in a fundamental CNS signaling network. The multidimensional pharmacology elicited by the stimulation of sGC has the potential to impact a broad range of CNS diseases. 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).
Forward Looking Statement
Certain matters discussed in this press release are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should”, “positive” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding the potential for CY6463 in the treatment of CNS diseases, including CIAS and MELAS, the potential for any successful development of CY6463, the sufficiency of our resources and other abilities to pursue the development of CNS, and other trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, our ability to continue with sufficient liquidity and capital resources to pursue our business plan regarding CY6463 or any other product (including without limitation our ability to fund additional clinical trials); our ability to successfully demonstrate the efficacy, safety and therapeutic effectiveness of CY6463; the success, timing and cost of our ongoing or future clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation and completion of the trials, futility analyses and receipt of interim results, which are not necessarily indicative of or supported by
the final results of our ongoing or subsequent clinical trials; any results of clinical studies not necessarily being indicative of or supported by the final results of our ongoing or subsequent clinical trials;; the timing of and our ability to pursue, obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates; the potential for the CY6463 clinical trial to provide a basis for approval for treatment of MELAS and CIAS; the Company’s ability to successfully defend its intellectual property or obtain necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s product candidates, if approved; and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstance.
Investors
Carlo Tanzi, Ph.D.
Kendall Investor Relations
ctanzi@kendallir.com
Media
Amanda Sellers
Verge Scientific Communications
asellers@vergescientific.com
Clinical Data Update from Study of CY6463 in CIAS Thursday, July 28, 2022 8:00 am EDT Exhibit 99.2
Safe harbor statement This presentation is for informational purposes only and is not an offer to sell nor a solicitation of an offer to buy any securities of Cyclerion Therapeutics, Inc. (the “Company”). This presentation includes or may include certain information obtained from trade and statistical services or sources, third party publications and other sources. The Company has not independently verified such information and there can be no assurance as to its accuracy. Certain matters discussed in this presentation are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “positive,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding the potential for CY6463 in the treatment of CNS diseases, including CIAS and MELAS, the potential for any successful development of CY6463, the sufficiency of our resources and other abilities to pursue the development of CNS, and other trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, our ability to continue with sufficient liquidity and capital resources to pursue our business plan regarding CY6463 or any other product (including without limitation our ability to fund additional clinical trials); our ability to successfully demonstrate the efficacy, safety and therapeutic effectiveness of CY6463; the success, timing and cost of our ongoing or future clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation and completion of the trials, futility analyses and receipt of interim results, which are not necessarily indicative of or supported by the final results of our ongoing or subsequent clinical trials; any results of clinical studies, not necessarily being indicative of or supported by the final results of our ongoing or subsequent clinical trials; the timing of and our ability to pursue, obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates; the potential for the CY6463 clinical trial to provide a basis for approval for treatment of MELAS and CIAS; the Company’s ability to successfully defend its intellectual property or obtain necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s product candidates, if approved; and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. Other important factors that could cause actual results to differ from those reflected in any forward-looking statements herein are described in the Company’s most recent Form 10-K as well as the Company’s subsequent filings with the Securities and Exchange Commission (the “SEC”). All of the Company’s development plans may be subject to adjustment depending on funding, recruitment rate, regulatory review, preclinical and clinical results, and other factors any of which could result in changes to the Company’s development plans and programs or delay the initiation, enrollment, completion, or reporting of clinical trials. In addition to the risks described above and in the Company’s filings with the SEC, other unknown or unpredictable factors could affect the Company’s results. No froward-looking statements can be guaranteed, and actual results may materially differ from such statements. The information in this presentation is provided only as of July 28, 2022, and the Company undertakes no obligation to update any forward-looking statements contained in this presentation on account of new information, future events, or otherwise, except as required by law.
Steven Hyman, MD Director, The Stanley Center for Psychiatric Research, Broad Institute Board Member, Cyclerion Speakers & Agenda 1 Welcome & introductions A brief overview of CIAS and CY6463 CY6463 clinical data overview Clinical study design Clinical data summary Perspective on CY6463 Q&A 2 3 4 5 Jennifer Chickering, PhD Vice President, Clinical Strategy, Cyclerion Bruce Kinon, MD Vice President, Clinical Development, Cyclerion Peter Hecht, Ph.D. Chief Executive Officer, Cyclerion
Developing therapies to restore cognitive function NO-sGC-cGMP is a fundamental CNS signaling pathway Regulates mitochondrial function, inflammation, neuronal function, and cerebral blood flow CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure Promising signals observed in two distinct patient populations Strong safety and tolerability profile established in >150 participants In MELAS**: improvement in markers of mitochondrial function and inflammation, cerebral blood flow, and CNS functional connectivity In CIAS*: strong positive effect size on cognition; improvement in broad panel of inflammatory biomarkers *Cognitive impairment associated with schizophrenia (CIAS) **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Deficits in pathway linked to multiple CNS diseases Durable intellectual property with exclusivity to early 2040s
DISCOVERY IND-ENABLING PHASE 1* PHASE 1b/2a PHASE 2/3 CY6463 MELAS CIAS ADv Multiple under assessment CY3018 Multiple under assessment Advancing parallel clinical studies in priority populations *Two phase 1 studies were completed in healthy young and old (>65 years of age) volunteers confirming targeted CNS exposure and activity
Overview of CIAS And CY6463 Bruce Kinon, MD Vice President, Clinical Development, Cyclerion
Schizophrenia is one of the top 15 leading causes of disability worldwide1 21M worldwide, 2.7M in US with schizophrenia and growing Schizophrenia is associated with significant health, social, and economic concerns Over three quarters of the estimated US annual cost of schizophrenia ($281B in 2020) is attributable to indirect costs including costs due to unemployment and productivity loss2 Financial costs associated with schizophrenia are disproportionately high relative to other chronic mental and physical health conditions3 1 McGrath et al. Epidemiol Reviews 2008, 2 Societal Costs of Schizophrenia White Paper Schizophrenia & Psychosis Action Alliance 2021, 3 Global Burden of Disease Study The Lancet 2017
Core cognitive deficits are chief determinant of long-term disability in schizophrenia Vast majority of schizophrenia patients suffer with cognitive deficits Deficits overlap with measures of intelligence or IQ1 Cognitive function in schizophrenia may decline at rate of 1 IQ point every 1-2 years 2 As a group, patients with schizophrenia perform significantly worse than controls on almost all neuropsychological tests 3, 4 Impairments in memory, attention, reasoning and problem solving are worse in schizophrenia compared to bipolar disorder and major depressive disorder 5: 1 Kahn and Keefe JAMA Psychiatry 2013; 2 Jonas et al. JAMA Psychiatry; 3 Wilk et al. Schiz Res 2004; 4 Keefe et al. Schiz Res 2011; 5 Buchanan et al Schiz Bull 2005 Memory deficits Diminished reasoning Diminished social cognition Impaired executive function Impaired learning Reduced processing speed Attention deficits
Cognitive deficiencies are “neurocognitive rate-limiting factors” to optimal social and vocational functioning 1 Substantial correlation between functional capacity and cognitive performance in schizophrenia 2 Cognitive impairments, negative symptoms but not positive symptoms, are predictive, both cross-sectionally and longitudinally, of adaptive life skills in persons with schizophrenia 3 1 Green Am J Psychiat 1996; 2 Keefe et al. Schiz Res 2011; 3 McGurk et al. Schiz Res 2000
Current antipsychotic treatment does little to improve cognitive impairment No pharmacologic approaches to improve cognition have yet been successful to yield approved treatments Treatment innovation may depend on search for new disease targets that may mediate CIAS Increasing ability to participate fully in the community and live independently Functional recovery Improving cognition
CY6463 is an sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling NO-sGC-cGMP is a fundamental CNS signaling pathway Pathway machinery is broadly expressed (neurons, glial cells, and vasculature) Deficits linked to multiple CNS diseases CY6463 is a positive allosteric modulator (PAM) that amplifies endogenous NO signaling Robust preclinical data demonstrate potential to address multiple aspects of CNS disease Mitochondrial function Inflammation Neuronal function Cerebral blood flow PKG, PDE, ion channels Downstream targets (eg, CREB, BDNF)
NO-sGC-cGMP dysfunction is implicated in CIAS pathophysiology CY6463 improved dendritic spine morphology, increased LTP, increased gamma EEG power, and improved cognitive performance in preclinical models11 Compromised prefrontal and hippocampal NO signaling is implicated in cognitive deficits in schizophrenia8; reduced cGMP in CSF observed in schizophrenia9,10 Network analysis of pathways, protein-protein interactions, and genetics link NO-sGC-cGMP signaling to schizophrenia1,2,3,4,5,6,7 1Docherty 2015, 2Freudenberg 2015, 3Shinkai 2002, 4Bernstein 2011, 5Reif 2006, 6O’Donovan 2008, 7Weber 2014, 8Issy 2018, 9Gattaz 1983, 10Ebstein 1976, 11Correia 2021
Targeting sGC is a promising therapeutic approach in CIAS where new therapies are greatly needed 0 +0.6 +0.2 +0.4 Nearly all people with schizophrenia (98%) have cognitive deficits Core cognitive deficits are chief determinant of long-term disability in schizophrenia NO-sGC-cGMP is a fundamental CNS signaling pathway with dysfunction implicated in CIAS pathophysiology CY6463 is a positive allosteric modulator of sGC that amplifies endogenous signaling, offering a promising therapeutic approach to the treatment of CIAS
CY6463 CIAS Clinical study Jennifer Chickering, PhD Vice President, Clinical Strategy, Cyclerion
Study to assess effects of once-daily CY6463 on safety, PK, PD, and cognition in CIAS on standard of care In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check in Check out Follow up Dosing 6 7 8 Day Randomized, double-blind, placebo-controlled, multiple-ascending-dose, in-clinic study Eligibility 18-50y with DSM-5 schizophrenia Stable, moderate symptomatology On stable, single atypical antipsychotic background regimen Baseline 4 dose cohorts (12 participants/cohort) Randomized 8 active/4 placebo Escalation based on safety 15 mg, 30mg, and 60 mg (2 cohorts) Placebo pooled for analyses
Assessments of safety, PK, cognition, and PD CNS/PD Safety Adverse events, BP/HR, ECGs, PANSS, clinical labs Extrapyramidal sx (AIMS, BARS, SAS), C-SSRS, other vitals, PEs PK Plasma concentrations of CY6463 and associated pharmacokinetics Cognitive performance battery Cognition Inflammation biomarkers (plasma) EEG: resting-state qEEG, ERPs, sleep BP, blood pressure; HR, heart rate; ECG, electrocardiography; PANSS, Positive and Negative Syndrome Scale; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; SAS, Simpson Angus Scale; C-SSRS, Columbia Suicide Severity Rating Scale; PE, physical exam; qEEG, quantitative electroencephalography; ERP, event-related potential Conducted at Hassman Research Institute, Dr. Elan Cohen (PI), and Collaborative Neuroscience, Dr. David Walling (PI)
Enrolled cognitively impaired, chronic schizophrenia population on standard of care Baseline characteristics Total study population (N=48) Sex – male, n (%) 47 (97.9) Race, n (%) Black/African-American 38 (79.2) White 10 (20.8) Hispanic/Latino, n (%) 11 (22.9) Age in years, mean (SD) 36.7 (7.75) BMI, mean (SD) 29.5 (5.06) Years since diagnosis, mean (SD) 15.1 (7.83) PANSS, mean (SD) 54.9 (7.19) Cognitively impaired at baseline consistent with chronic schizophrenia Means ~0.5 to 2 SDs lower than those of age-matched controls from normative database Single, antipsychotic background regimen, stable ≥ 8w; n (%) Risperidone 21 (43.8) Aripiprazole 13 (27.1) Quetiapine 9 (18.8) Paliperidone 3 (6.3) Olanzapine 2 (4.2)
Strong safety, tolerability, and PK profile extended in participants with schizophrenia on standard of care Well tolerated across all dose levels on top of antipsychotic regimen Mostly mild adverse events (AEs), all AEs resolved No SAEs, no severe AEs, no dropouts due to AEs Most common AE was headache, all but 1 mild No signals on clinical labs, vital signs, ECGs, PANSS, SAS, AIMS, BARS, C-SSRS Once-daily pharmacokinetics as expected, consistent with previous studies Approximately dose proportional exposure Low intersubject variability Accumulation (~3x) similar across dose levels At or near steady state by Day 13 *Based on visual assessment ~ steady state* Mean (SD) trough conc. (ng/mL) Study day SAE, serious adverse event; ECG, electrocardiography; PANSS, Positive and Negative Syndrome Scale; SAS, Simpson Angus Scale; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; C-SSRS, Columbia Suicide Severity Rating Scale
Characterizing effects of CY6463 on cognitive performance In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check-in Check-out Follow-up 6 7 8 MCCB; Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery Effect size=(Mean CFB CY6463 – mean CFB placebo)/pooled SD MMRM (mixed-effect model repeated measure) analysis with change from baseline as the response variable, treatment, time point, and treatment-by-visit interaction as fixed effects and the respective baseline value as the covariate with an appropriate variance-covariance structure. Baseline Steady state Content validity vs MCCB with reduced burden Composite scores for general cognition and cognition domains Analysis – change from baseline CY6463-treated vs placebo-treated Focus - effect size (standardized mean difference) CY6463 vs placebo Executive function Attention Memory General cognition Cogstate Schizophrenia Battery
Promising cognition signal after only 2 weeks of once-daily dosing with 15mg CY6463 0.44 0.15 0.44 Attention 0.60 Executive function 0.44 Memory 0.60 General cognition Day 14 Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD; means are least square means from MMRM (mixed-effect model repeated measure) analysis with change from baseline as the response variable, treatment, time point, and treatment-by-visit interaction as fixed effects and the respective baseline value as the covariate with an appropriate variance-covariance structure. 1Angst 2017, 2Leucht 2012. Strong positive effect on general cognition at steady-state Effect size of ≥0.3 considered clinically relevant in the context of neuropsychiatry1,2 Higher doses did not show an effect on general cognition on Day 14 15mg results on cognition supported by sensitivity analyses 15mg dose also showed broad positive effects in recently completed MELAS study Effect size ≥0.30 ≥.20 to .29 -.19 to .19 -.29 to -.20 <=-0.30 Legend
Increase in cognition signal over time Increasing effect size with time on treatment Consistent with pharmacokinetics of CY6463 Benefit expected to be durable and increase with chronic treatment based on: Experience with approved, peripherally active sGC stimulators Multi-dimensional sGC stimulator pharmacology 0.44 0.15 0.44 Exec fn Memory Attn 0.60 General cognition Day 14 0.27 -0.32 0.18 Exec fn Memory Attn 0.16 Day 2 0.12 0.06 0.54 Exec fn Memory Attn 0.31 General cognition Day 7 General cognition Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD; means are least square means from MMRM (mixed-effect model repeated measure) analysis with change from baseline as the response variable, treatment, time point, and treatment-by-visit interaction as fixed effects and the respective baseline value as the covariate with an appropriate variance-covariance structure. Effect size ≥0.30 ≥.20 to .29 -.19 to .19 -.29 to -.20 <=-0.30 Legend
CY6463 shows strong cognition signal over placebo after only 2 weeks of dosing Intervention N Treatment duration Test Effect size Reference CY6463 15mg sGC stimulator 8 active, 16 placebo 2 weeks CSB 0.60 Current study BI 425809 10mg GlyT1 inhibitor ~85 active, 170 pbo 12 weeks MCCB 0.34 Fleishhacker et al, 2021, Phase 3 ongoing Encenicline 0.27mg α7 partial agonist ~ 105/arm 12 weeks CSB 0.26 Keefe et al, 2015 GSK239512 H3R antag./inverse agon. ~20/arm 7 weeks CSB 0.29 Jarskog et al, 2015
Characterizing effects of CY6463 on plasma biomarkers of inflammation In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check-in Check-out Follow-up 6 7 8 InflammationMAP® v. 1.1, RBM Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD where means are from an ANCOVA (analysis of covariance) with change from baseline as the response variable, treatment group as the main effect, and the respective baseline value as the covariate Baseline Steady state Multi-Analyte Profile (MAP) – multiplexed immunoassay for a panel of inflammatory biomarkers Anti-inflammatory effects are well established for CY6463, preclinically and clinically Inflammation implicated in schizophrenia Analysis – change from baseline CY6463 group vs placebo group Focus – effect size (standardized mean difference) CY6463 vs placebo InflammationMAP® biomarker panel
Disease-relevant, anti-inflammatory effects for CY6463 15mg, consistent with CY6463 pharmacology Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD where means are from an ANCOVA (analysis of covariance) with change from baseline as the response variable, treatment group as the main effect, and the respective baseline value as the covariate; p-value not controlled for multiplicity RANTES (Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) 1Asevedo 2014; 2Carnossa 2022; 3Domenici 2019; 4Frydecka 2015; 5Frydecka 2018; 6Fu 2019; 7Lee 2017; 8Miller 2021; 9Miranda 2019; 10Momtazmanesh 2018; 11Peng, 2018; 12Potvin 2008; 13Stuart 2014; 14Syed 2021 Biomarker Abbrev Effect size Brain-Derived Neurotrophic Factor BDNF -0.83 Interleukin-2 IL-2 0.81 Interleukin-6 IL-6 -0.66 Interleukin-8 IL-8 -0.59 Interleukin-10 IL-10 -0.60 Interleukin-18 IL-18 -0.72 Stem Cell Factor SCF 0.73 T-Cell-Specific Protein-RANTES RANTES -0.62 Tissue Inhibitor of Metalloproteinases 1 TIMP-1 -0.59 Biomarkers highlighted showed: Change from baseline in CY6463 group Effect size >|0.5| Nominal p-value <0.2 All effects represent favorable directional improvement1-14
CY6463 shows cognition signal over placebo after only 2 weeks of dosing in CIAS 0 +0.6 +0.2 +0.4 Well tolerated, no safety signals, on top of stable, single antipsychotic regimen Dose-proportional, once-daily PK profile Robust cognition signal measured on instrument suitable for registration Disease-relevant, anti-inflammatory pharmacology
Perspective on CY6463 Steven Hyman, MD Director, The Stanley Center for Psychiatric Research, Broad Institute Member, Cyclerion Board of Directors
summary Peter Hecht, PhD Chief Executive Officer, Cyclerion
CY6463 pharmacology translating from preclinical to clinical, now in two patient populations Known aspects of sGC pharmacology CY6463 studies Mitochondrial function Inflammation Neuronal function Cerebral blood flow Preclinical Healthy elderly (CY6463 15mg) MELAS (CY6463 15mg) CIAS (CY6463 15mg) ADv (CY6463 15mg) TBD TBD TBD Not assessed Assessed, no effect observed
Developing therapies to restore cognitive function NO-sGC-cGMP is a fundamental CNS signaling pathway Regulates mitochondrial function, inflammation, neuronal function, and cerebral blood flow CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure Promising signals observed in two distinct patient populations Strong safety and tolerability profile established in >150 participants In MELAS**: improvement in markers of mitochondrial function and inflammation, cerebral blood flow, and CNS functional connectivity In CIAS*: strong positive effect size on cognition; improvement in broad panel of inflammatory biomarkers *Cognitive impairment associated with schizophrenia (CIAS) **Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Deficits in pathway linked to multiple CNS diseases Durable intellectual property with exclusivity to early 2040s
Q&A Moderated by Cheryl Gault, Chief Operating Officer, Cyclerion Key Takeaways NO-sGC-cGMP is a fundamental CNS signaling pathway CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure, strong safety profile and durable IP Promising signals observed in two distinct patient populations with CY6463 In CIAS: strong positive effect size on cognition; improvement in broad panel of inflammatory biomarkers In MELAS: improvement in markers of mitochondrial function and inflammation, cerebral blood flow, and CNS functional connectivity