Persistent Mullerian Duct Syndrome

Khondrion receives FDA clearance of IND application for pivotal Phase 3 clinical trial of sonlicromanol for the treatment of primary mitochondrial disease 52-week Phase 3 trial to investigate potential of novel, brain-penetrant redox-modulator with anti-inflammatory properties, in adult patients with most common genetic defect causing primary mitochondrial disease, m.3243A>GPrimary endpoints focused on most burdensome and frequently occurring effects of disease – chronic fatigue and muscle weakness – supported by significant and clinically relevant patient benefits achieved by sonlicromanol in its integrated Phase 2b program NIJMEGEN, the Netherlands – 14 November 2024: Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial disease (PMD), today announced that it has received clearance from the U.S. Food and Drug Administration (FDA) for its Investigational New Drug (IND) application for sonlicromanol. The IND supports the initiation of a pivotal Phase 3 trial in adult patients with PMD due to the m.3243A>G mutation, the most common genetic defect causing PMD. The company expects to initiate the trial in 2025. Sonlicromanol, Khondrion’s lead proprietary drug candidate, is a potentially disease-modifying first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD. The Company’s multicenter Phase 2b program, recently published in the scientific journal Brain, highlighted strong patient benefits from sonlicromanol in multiple outcome measures. That program’s 52-week extension study, which continued to treat some patients out to 78 weeks, demonstrated durable improvements among patients receiving sonlicromanol in several relevant domains, including chronic fatigue and muscle weakness, two of the most burdensome symptoms of PMD as described by patients. The drug candidate’s potential to treat these aspects of disease will be further investigated in the upcoming Phase 3 trial. The 52-week double-blind, randomized, placebo-controlled, multi-center, parallel-group Phase 3 trial is expected to enroll 150 adult patients with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G variant. For this study, Khondrion has selected the Neuro-QoL Fatigue short form questionnaire and the Five Times Sit-to-Stand test as its two independent primary endpoints. These outcome measures, assessing patients’ most burdensome and frequent effects of disease (chronic fatigue and muscle weakness), have encouragingly shown clinically meaningful and statistically significant (p-value of 0.004 and 0.0161, respectively) results in the 52-week open-label extension part of the Phase 2b program. Further details of the Phase 3 trial’s design can be found on ClinicalTrials.gov here. Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said: “The FDA’s clearance of our IND application for a pivotal Phase 3 trial marks another important milestone for Khondrion’s development of sonlicromanol, a disease-modifying therapy for primary mitochondrial disease that is so desperately needed by PMD patients. We look forward to sharing progress of our clinical program including its expected initiation next year.” Sonlicromanol: one of the most advanced drug candidates in development for PMDSonlicromanol has been investigated in four clinical trials, three in adult PMD patients with m.3243A>G, as well as in the first wave of a six-month Phase 2 study in children with genetically confirmed PMD suffering from motor symptoms. Encouragingly, seven patients in the Netherlands, who elected to participate in a named patient program following completion of the Phase 2b open label extension study out to 78 weeks, have been receiving sonlicromanol for more than two and a half years, thus confirming the drug’s favorable safety profile. Khondrion is initially focusing the development of sonlicromanol on PMD patients with the m.3243A>G variant, which is the most common genetic defect causing multi-systemic PMD and has an estimated prevalence of 4.4:100,000. There are currently no approved therapies for PMD associated with the m.3243A>G variant. The Company’s longer-term objective is to make sonlicromanol widely available for the broader PMD patient community. PMDs are the most prevalent inherited neurometabolic disorders, estimated to affect at least 1 in 4,300 which translates into approximately 65,000 people in the US alone. Khondrion’s wholly-owned, proprietary drug candidate has received orphan drug designation in the US and Europe and has also been granted a rare pediatric disease designation. – ENDS – Notes to editors About KhondrionKhondrion is a clinical stage biopharmaceutical company developing therapies for patients with primary mitochondrial disease (PMD). The company’s lead asset, sonlicromanol, is a potentially first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD. One of the most advanced, disease-modifying drug candidates for mitochondrial disease in development, sonlicromanol has been tested in three clinical trials in patients with m.3243A>G PMD, as well as in the first wave of a 6-month Phase 2 study in children with genetically confirmed PMD and who suffer from motor symptoms. Sonlicromanol has been granted orphan drug designations for the treatment of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Leigh disease and patients with maternally inherited diabetes and deafness (MIDD) in Europe, and for all inherited mitochondrial respiratory chain disorders in the U.S. It has also been granted a rare pediatric disease designation in the US for the treatment of MELAS. Sonlicromanol and other compounds from Khondrion’s proprietary library have the potential to be developed for a wide range of diseases and conditions with the aim of benefiting patients whose daily lives are severely impacted by mitochondrial impairment. For more information visit www.khondrion.com. About Primary Mitochondrial DiseaseMitochondrial disease occurs when mitochondria, found within all cells of the human body except erythrocytes, and responsible for producing the energy necessary for cells to function, are defective. This can result in a wide range of serious and debilitating illnesses occurring shortly after birth or later in life. Signs and symptoms of these can include cognitive problems, learning disabilities, blindness, deafness, heart failure, diabetes, fatigue, intolerance to exercise, muscle weakness and gait problems, and stunted growth. Originally referred to as MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), primary mitochondrial disease associated with the m.3243A>G variant in the mitochondrial genome is now considered to include a spectrum of phenotypes including classic MELAS, MIDD syndrome (maternally inherited diabetes mellitus and deafness), MP (mixed phenotypes) and CPEO (chronic progressive external ophthalmoplegia). Learn more. Forward-looking statementsThis press release may contain certain forward-looking statements regarding, among other things, the results, conduct, progress and timing of the company’s clinical trials and presentation of data from clinical trials for sonlicromanol. Although the company believes its expectations are based on reasonable assumptions, all statements other than statements of historical fact included in this press release about future events are subject to (i) change without notice and (ii) factors beyond the company’s control. These statements may include, without limitation, any statements preceded by, followed by or including words such as “target,” “believe,” “expect,” “aim,” “goal,” “intend,” “may,” “anticipate,” “foreseen,” “estimate,” “plan,” “project,” “will,” “can have,” “likely,” “potential,” “should,” “would,” “could” and other words and terms of similar meaning or the negative thereof. Forward-looking statements are subject to inherent risks and uncertainties beyond the company’s control that could cause the company’s actual results, performance or achievements to be materially different from the expected results, performance or achievements expressed or implied by such forward-looking statements. Except as required by law, the company assumes no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. Contacts: Khondrion BVProf. Dr. Jan Smeitink, CEOE-mail: info@khondrion.comTel: +31-24-7635000www.khondrion.com ICR Healthcare David Daley, Kris LamEmail: khondrion@icrhealthcare.com 1 Excluding data from two subjects whose baseline duration in the 5xSST test was below the envisaged threshold criteria to be used for analysis of the 5xSST test endpoint in the Phase 3 trial

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