Persistent Mullerian Duct Syndrome

CAMBRIDGE, Mass., March 27, 2023 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage biopharmaceutical company on a mission to develop treatments for serious diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to zagociguat (previously CY6463) for the treatment of mitochondrial diseases. Zagociguat is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious diseases that involve the CNS. In an open-label, 29-day study in patients with MELAS*, zagociguat treatment was associated with improvements in multiple disease-relevant biomarkers: mitochondrial function, inflammation, cerebral blood flow, functional brain connectivity, and visually evoked brain activation. These data coupled with data from preclinical studies in cells from mitochondrial disease patients and in zebrafish disease models support the potential of zagociguat as a treatment for MELAS/mitochondrial diseases. “Orphan drug designation underscores the FDA’s recognition of zagociguat’s potential promise as a first-ever therapy for patients with MELAS, a rare, genetic mitochondrial disease,” said Peter Hecht, Ph.D., Chief Executive Officer of Cyclerion. “Cyclerion is working expeditiously to advance this potential treatment to help address the immense unmet needs of patients with MELAS, a patient population in desperate need of therapies.” The FDA's Orphan Drug Designation program provides orphan status to drugs defined as those intended for the treatment, diagnosis or prevention of rare diseases that affect fewer than 200,000 people in the United States. Orphan drug designation qualifies the sponsor of the drug for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and seven-year marketing exclusivity upon FDA approval. About MELAS MELAS is a complex orphan disease affecting multiple organ systems, including the CNS, with different degrees of severity, and no approved therapies. MELAS, one of the most common primary mitochondrial diseases (PMDs), is caused by mitochondrial DNA mutations resulting in large clusters of familial cases. It is estimated that about 1 in 4,300 individuals has a mitochondrial disease, and ~80% of individuals with mitochondrial disease have CNS symptoms. The unmet need in MELAS is immense, symptoms can affect virtually any organ and cause intense fatigue, muscle weakness, and pain in addition to neurological manifestations, including stroke-like episodes, encephalomyopathy, seizures, and headaches. Life expectancy is estimated at ~17 years from onset of CNS symptoms. The disease impedes the individual’s ability to live independently and leads to social isolation and overall reduced quality of life.   About Zagociguat Zagociguat is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious diseases that involve the CNS. 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 mitochondrial function, neuronal function, inflammation, 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. 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 may have broad therapeutic potential as a treatment to improve cognition and function in people with serious diseases that involve the CNS, including mitochondrial diseases. About Cyclerion Therapeutics Cyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments for serious diseases. Cyclerion’s portfolio includes novel sGC stimulators that modulate a key node in a fundamental signaling network in both the CNS and the periphery. The multidimensional pharmacology elicited by the stimulation of sGC has the potential to impact a broad range of diseases. Zagociguat is a CNS-penetrant sGC stimulator that has shown rapid improvements across a range of endpoints reflecting multiple domains of disease activity, including mitochondrial disease-associated biomarkers. CY3018 is a CNS-targeted sGC stimulator in preclinical development that preferentially localizes to the brain and has a pharmacology pro suggests its potential for the treatment of neuropsychiatric diseases and disorders. Praliciguat is a systemic sGC stimulator that is licensed to Akebia and being advanced in rare kidney disease. Olinciguat is a vascular sGC stimulator that the Company intends to out-license for cardiovascular diseases. For more information about Cyclerion, please visit and follow us on Twitter (@Cyclerion) and LinkedIn ( ). 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. The forward-looking statements include risks and uncertainties, including, but not limited to, being able to complete clinical studies for zagociguat for the treatment of mitochondrial diseases, including submitting additional regulatory applications in other countries; ability to demonstrate effectiveness of zagociguat in treating mitochondrial disease in patients; ability to maintain and expand related intellectual property portfolio; and statements regarding the timing of regulatory filings regarding development programs. 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. * MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes syndrome) Investors and Media Inquiries Cyclerion Investor Relations Phone: 857-327-8778 Email: info@cyclerion.com

First in human clinical study provides proof-of-concept for mitochondrial augmentation therapy platform, which enables use of healthy mitochondria to improve mitochondrial function and mitigate effects of large-scale mitochondrial DNA (mtDNA) deletion syndromes Study showed improved quality of life measures in children with Pearson Syndrome and Kearns-Sayre Syndrome spectrum No treatment-related adverse effects reported in study WOBURN, Mass. and HAIFA, Israel, Dec. 21, 2022 (GLOBE NEWSWIRE) -- Minovia Therapeutics, a clinical-stage global biotechnology company, today announced that the findings of the first clinical use of mitochondrial augmentation therapy (MAT) platform to treat pediatric patients with primary mitochondrial diseases have been published in Science Translational Medicine. The study was conducted in collaboration with global leaders in the field of hematology and primary mitochondrial disease at Sheba Medical Center (Tel Hashomer, Israel). Single, large deletions in mitochondrial DNA (mtDNA) can lead to a variety of devastating diseases, including Pearson Syndrome and Kearns-Sayre Syndrome (KSS). These mtDNA deletion syndromes are sporadic, uncurable and ultimately fatal. Pearson syndrome is a bone marrow failure disease that usually begins in infancy. In addition to presenting with sideroblastic anemia, patients are characterized by exocrine pancreas dysfunction. About half of patients die in infancy or childhood, while many who survive go on to develop KSS, a progressive multisystem disorder. “These findings demonstrate that mitochondrial augmentation therapy is feasible in children with mitochondrial DNA deletion syndromes and that autologous CD34+ cells augmented with mitochondria derived from maternal blood may potentially deliver some functional improvement for patients living with these debilitating diseases for which there are no available therapies,” said Elad Jacoby, M.D., Ph.D., Hemato-oncology Pediatric department, Sheba Medical Center. MAT is designed to rescue mitochondrial function and metabolic activity in diseased cells through enrichment with healthy mitochondria. This builds upon Minovia’s previous demonstration that MAT provides long-term functional benefit in an immunocompromised mouse model, and that mitochondria can transfer between hematopoietic stem cells (HSCs) in vivo (Jacoby et al 2021). Preclinical studies showed that hematopoietic stem and progenitor cells (HSPCs) can transfer normal mitochondria to hematopoietic and non-hematopoietic cells and improve disease features (Rocca et al., 2017). Minovia is developing MAT to treat Primary Mitochondrial Diseases such as Pearson syndrome, as well as other mitochondrially-related sideroblastic anemias. The Company’s lead investigational candidate, MNV-101 (MNV-BM-BLD), has been granted the Fast-Track, Orphan Drug and Rare Pediatric Disease designations by the U.S. Food and Drug Administration. The latest study reported results from six patients ranging from 2 to 7 years of age: four with Pearson syndrome and two with KSS spectrum. All six patients suffered from significant failure to thrive and advanced multi-organ disease, which was either immediately or potentially life-threatening, requiring multiple ongoing supportive care interventions. Key Findings No treatment-related adverse events were reported. Adverse events related to the leukapheresis procedure were managed with standard medical care. Adverse events that occurred following treatment were expected due to the patient’s underlying disease and resolved spontaneously or with appropriate treatment. Higher levels of normal mitochondrial DNA were observed in the blood of four out of six patients, indicating a reduction of mitochondria with large DNA deletions. Clinical improvement in aerobic function was observed in some patients, and five of six patients experienced weight gain. Quality of life measurements showed improvement in most patients. Changes in the general well-being of children and physical activity were reported, along with increased time spent awake and in play. A series of aerobic and endurance tests were performed on two patients. Both patients demonstrated improvement in leg muscle strength and endurance at 6 and 12 months post treatment. One patient, who at baseline was unable to walk any distance, was able to walk 10 meters at 12 months and had improvement on the 30-second sit-to-stand test. Another patient demonstrated improvement in muscle function in some tests and a sustained improvement in others, including the six-minute walk test and sit-to-stand capacity at 6 and 12 months. “We are tremendously encouraged by evidence of improvement to the quality of life and well-being of the children treated with MAT, including clinical improvements in aerobic function, weight gain and increased strength and endurance," said Natalie Yivgi Ohana, Ph.D., co-founder and CEO of Minovia. "We believe these findings lay important groundwork for further development of MAT and future clinical trials to demonstrate the effectiveness and safety of MAT in patients with primary mitochondrial disorders and other diseases. Our excellent collaboration with the clinicians and teams at the Sheba Medical Center, as well as with patient advocacy groups, will enable us to accelerate the clinical development plans for Pearson Syndrome patients." About Primary Mitochondrial Diseases (PMD) and Mitochondrial Dysfunction Primary Mitochondrial Diseases (PMDs) are chronic, genetic disorders that occur when mitochondria fail to produce enough energy for the body to function properly. Mitochondrial diseases affect about one in 5,000 people globally and can be sporadic or inherited and onset can occur at any age. Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. Mitochondrial dysfunction also plays an important role in more prevalent diseases, such as Alzheimer’s disease, muscular dystrophy, amyotrophic lateral sclerosis and diabetes. About Minovia Minovia Therapeutics is a clinical-stage global biotechnology company committed to the discovery and development of novel approaches to treating diseases caused by mitochondrial dysfunction. Minovia’s Mitochondrial Augmentation Therapy (MAT) platform is designed to extend and enhance human lives by restoring mitochondrial function using autologous stem cells enriched with healthy, functional mitochondria. This unique approach capitalizes on the natural ability of mitochondria to transfer between cells. The company’s initial clinical focus is on primary mitochondrial diseases, such as Pearson syndrome, a fatal pediatric disease, and hematological disorders that include mitochondrial dysfunction. Minovia was founded by leading researchers in mitochondrial biology and is headquartered in Haifa, Israel, with operations in Massachusetts. For more information, visit . Contact: info@minoviatx.com Phone: +972-747033354

Recent positive MELAS clinical study data drive urgency to deliver potential first-ever therapy for patients with rare, genetic mitochondrial diseases Development programs prioritized and organization structured to align with mitochondrial disease-focused strategy Plans to meet with FDA in Q4 2022 to discuss MELAS development program CAMBRIDGE, Mass., Oct. 06, 2022 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN) today announced its mitochondrial disease-focused corporate strategic plan. Propelled by the positive data from the recently completed CY6463 Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) clinical study, the Company believes it has a unique opportunity to deliver the first-ever approved medicine for patients suffering from rare mitochondrial diseases, a family of debilitating, progressive, and ultimately fatal genetic diseases. “We are inspired by the recently reported clinical data generated in our MELAS study; there is a clear drug signal seen in objective measures of disease-relevant domains and the CY6463 safety profile has been favorable across all clinical studies to date. Motivated by these compelling data and by a patient population in desperate need of therapies, we are adapting our strategic mission, reprioritizing our development programs and focusing our people, resources, and capabilities to deliver this potential therapy to individuals living with mitochondrial diseases,” said Peter Hecht, Ph.D., Chief Executive Officer of Cyclerion. “We look forward to discussions with regulators later this year, and then sharing more detailed development plans early in the new year.” Pipeline, organization, and corporate development The company has been exploring the pharmacology of sGC stimulation with once-daily CY6463 in signal-seeking studies in three patient populations: MELAS, Cognitive Impairment Associated with Schizophrenia (CIAS), and Alzheimer's Disease with Vascular Pathology (ADv). Going forward, Cyclerion will focus future development of CY6463 on genetic mitochondrial diseases, concentrating first on development in MELAS, a rare disease where the company believes it has the capabilities to advance the program independently. MELAS: In an open-label, 29-day study in patients with MELAS, CY6463 treatment was associated with improvements in multiple disease-relevant biomarkers: mitochondrial function, inflammation, cerebral blood flow, functional brain connectivity, and visually evoked brain activation. These data coupled with data from preclinical studies in cells from mitochondrial disease patients and in zebrafish disease models support a focus on MELAS/mitochondrial diseases for CY6463. The Company is currently preparing to meet with FDA to discuss the CY6463 development program, including the next study and paths to registration in MELAS. CIAS: The company has presented encouraging CIAS exploratory study data, highlighted by the strong effect on cognitive performance after only 14 days. Cyclerion believes its next-generation development candidate, CY3018, has attributes that make it especially well suited for treating CIAS and other neuropsychiatric indications. Cyclerion is completing pre-IND activities for CY3018 and is looking to secure a partnership or other funding mechanism to develop the program in the future. ADv: Cyclerion recently capped enrollment of its ongoing ADv clinical study. This will further enable the Company to channel its resources to its most urgent priorities in MELAS. Data from the ADv study are expected in the first half of 2023. Learnings from this and previous CY6463 studies can be leveraged to optimize future potential Alzheimer’s Disease/Vascular Dementia studies. Organization: The Company’s workforce is being tailored to the mitochondrial disease-focused strategy, leading to a reduction of approximately 45%, to 16 full-time employees. The Company expects to take an aggregate charge for one-time employee-related costs of approximately $1.9 million that is expected to be incurred primarily in Q4 2022 and realize annual cash savings of approximately $4.1 million. Corporate Development: To support the Company’s mitochondrial disease-focused strategy, Cyclerion intends to leverage its other assets through out-licensing and partnerships, including CY3018 and two additional, oral, clinical-phase, peripherally targeted compounds, olinciguat and praliciguat, for which the Company has an extensive IP portfolio with long-duration exclusivity. Praliciguat has been licensed to Akebia for development in renal diseases and, if successful, will provide Cyclerion with development, regulatory, and commercial milestones as well as royalties. The Company will similarly seek an external partner to advance CY3018 in neuropsychiatric diseases and olinciguat in serious systemic diseases in return for a mix of upfront, milestone, and royalty payments as a source of non-dilutive capital. About MELASMELAS is a complex orphan disease affecting multiple organ systems, including the CNS, with different degrees of severity, and no approved therapies. MELAS, one of the most common primary mitochondrial diseases (PMDs), is caused by mitochondrial DNA mutations resulting in large clusters of familial cases. It is estimated that about 1 in 4,300 individuals has a mitochondrial disease, and ~80% of individuals with mitochondrial disease have CNS symptoms. The unmet need in MELAS is immense, symptoms can affect virtually any organ and cause intense fatigue, muscle weakness, and pain in addition to neurological manifestations, including stroke-like episodes, encephalomyopathy, seizures, and headaches. Life expectancy is estimated at ~17 years from onset of CNS symptoms. The disease impedes the individual’s ability to live independently and leads to social isolation and overall reduced quality of life.   About CY6463CY6463 is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious diseases that involve the CNS. 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 mitochondrial function, neuronal function, inflammation, 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. 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 may have broad therapeutic potential as a treatment to improve cognition and function in people with serious diseases that involve the CNS. About Cyclerion TherapeuticsCyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments for mitochondrial diseases, including MELAS. Cyclerion’s lead molecule is CY6463, a novel, first-in-class, CNS-penetrant sGC stimulator that modulates a key node in a fundamental signaling network. The multidimensional pharmacology elicited by the stimulation of sGC has the potential to impact a broad range of diseases that involve the CNS. CY6463 is currently in clinical development for MELAS where it has shown rapid improvement in multiple disease-relevant biomarkers. 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 StatementCertain 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 MELAS and other mitochondrial diseases, the potential for any successful development of CY6463, the sufficiency of our resources and other abilities to pursue the development of CY6463, 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 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 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 existing license agreement with Akebia and the ability to obtain any other 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. InvestorsCarlo Tanzi, Ph.D.Kendall Investor Relationsctanzi@kendallir.com MediaAmanda SellersVerge Scientific Communicationsasellers@vergescientific.com