MELAS Syndrome

NIJMEGEN, Netherlands, Nov. 1, 2023 /PRNewswire/ -- Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial diseases, today announced that the United States Patent and Trademark Office and the European Patent Office have granted patents covering the use of Khondrion's lead compound sonlicromanol as an [mPGES-1 inhibiting] anti-inflammatory agent. Sonlicromanol works in three distinct ways by modulating oxidative and reductive distress, along with anti-inflammatory properties. The compound is currently under investigation for its effectiveness in treating adult patients diagnosed with primary mitochondrial disease due to the m.3243A>G mutation in their mitochondrial DNA. This mutation is linked to various conditions such as classical MELAS and MIDD syndromes, CPEO, and mixed phenotypes. Sonlicromanol targets the key underlying mechanisms shared by many mitochondrial diseases, including high levels of reactive oxygen species, disrupted redox metabolism, and inflammation induced by PGE2. Research has demonstrated that sonlicromanol acts as a selective inhibitor of microsomal Prostaglandin E-synthase 1 (mPGES-1), contributing to its anti-inflammatory impact. Preclinical studies conducted in other disease models with elevated levels of cellular mPGES-1, such as particular prostate cancer cells, have displayed encouraging outcomes. These findings suggest a wider range of potential applications for sonlicromanol beyond its initial focus on primary mitochondrial diseases. "The distinctive triple mode of action of sonlicromanol has the potential to play an important role not just in primary mitochondrial diseases but also in in a range of rare and more prevalent disorders," said Prof. dr. Jan Smeitink, Chief Executive Officer at Khondrion. "This US and European patent issuance significantly strengthen our intellectual property portfolio and stands as a crucial step in the broader development of sonlicromanol." The US patent titled "Compounds as mPGES-1 inhibitors" was issued as U.S. patent No. 11,672,787 on June 13, 2023. Its European equivalent was granted on October 19, 2023 as EP 18808288. About Khondrion Khondrion is a clinical stage biopharmaceutical company developing therapies for patients with inherited mitochondrial diseases. Based on proprietary science and a deep biological understanding of mitochondrial dysfunction, the company is advancing its lead drug candidate sonlicromanol. Sonlicromanol is a first-in-class, oral small molecule targeting key underlying mechanisms of primary mitochondrial disease based on its uniquely differentiated triple mode of action: reductive distress modulation to help restore the cell's metabolism, oxidative distress modulation preventing ferroptotic cell death, and selective mPGES-1 inhibition resulting in anti-inflammatory effects. Based on the favourable benefit-risk profile shown across the clinical studies performed so far, Khondrion is finalizing the design of a global Phase 3 study which is currently foreseen to start in H2 2024. The compound has been granted orphan drug designations for the treatment of MELAS, Leigh disease and patients with maternally inherited diabetes and deafness (MIDD) in Europe, and for all inherited mitochondrial respiratory chain disorders in the US. It has also been granted a Rare Pediatric Disease designation in the US for the treatment of MELAS. Ongoing preclinical research of sonlicromanol shows potential broader applications of the drug in other rare diseases and more common disorders. For more information visit . About mitochondrial disease Mitochondrial disease is caused by defective mitochondria, which are present in all cells of the human body and are responsible for generating the energy necessary for cells to function. This can lead to a wide range of serious and debilitating illnesses that can appear shortly after birth or later in life. Signs and symptoms of these conditions may include issues with thinking, learning difficulties, blindness, deafness, heart failure, diabetes, fatigue, intolerance to exercise, muscle weakness walking difficulties, and stunted growth. Orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders including MIDD (maternally inherited diabetes and deafness), and other respiratory chain / oxidative phosphorylation disorders, are all examples of mitochondrial disease. MELAS spectrum disorders are some of the most frequently observed primary mitochondrial diseases, in which all patients are characterized by an underlying point mutation (m.3243A>G) in the maternally inherited MT-TL1 gene. Forward-looking statements This 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 BV Prof. Dr. Jan Smeitink, CEO E-mail: [email protected] Tel: +31-24-7635000 LifeSpring Life Sciences Communication, Amsterdam Leon Melens E-Mail: [email protected] Tel: +31-6-53816427 Logo - SOURCE Khondrion

– Interviews Intended to Illuminate Experience of Living with MELAS, a Rare Mitochondrial Disease – – Findings to Support Data-driven Endpoint Selection for Phase 2b Study of Zagociguat in MELAS – CAMBRIDGE, Mass., Oct. 25, 2023 (GLOBE NEWSWIRE) -- Tisento Therapeutics, a privately held, clinical-stage biotechnology company developing novel medicines for diseases with significant unmet medical needs, today announced the initiation of a patient interview study to identify and describe the signs, symptoms, and health-related quality-of-life impacts of MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) that are most burdensome to adults and adolescents living with this rare mitochondrial disease. The interviews will inform the selection of clinical outcomes assessments and endpoint strategy for the company’s planned Phase 2b study of its investigational medicine, zagociguat, in MELAS. “At Tisento, patient perspectives are at the forefront of the decisions we make. This interview study is one way we will thoughtfully and intentionally listen to individuals with MELAS and take action in response,” said Peter Hecht, Ph.D., chief executive officer of Tisento. “The goal of the interview study is to ensure our Phase 2b study and all future studies are measuring the impact of zagociguat on the most meaningful aspects of the disease, as reported directly by people living with MELAS, and that our assessment tools are both comprehensive and relevant. We look forward to partnering with the patient community to finalize the endpoints for this clinical study of what could be the first treatment for this devastating disease.” “MELAS is a complex and little understood disease characterized by both neurological and systemic symptoms that impact patients’ health and lives in a myriad of ways,” said Philip Yeske, science and alliance officer at United Mitochondrial Disease Foundation. “The first step in improving quality of life for this community is to better understand what individuals with MELAS face on a daily basis. Tisento’s first-of-its-kind MELAS interview study will add to the scientific and clinical body of knowledge about this disease and ensure that their clinical research has been informed by the voices of those who are living with MELAS.” The interview study is expected to enroll approximately 20 adults and adolescents with MELAS and is designed to document the severity and frequency of MELAS symptoms, as well as gather descriptive information about the most salient aspects of these symptoms. Tisento plans to use the findings from the interviews to identify clinical outcomes assessments that may be used as clinical study endpoints to evaluate the efficacy of zagociguat for the treatment of MELAS. About MELASMELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) is a rare mitochondrial disease that affects multiple organ systems, especially organs that require significant energy like the brain and muscles. MELAS frequently causes severe and burdensome symptoms including chronic fatigue, cognitive dysfunction, muscle weakness, seizures, and stroke-like episodes. MELAS is also associated with shortened life expectancy. About ZagociguatZagociguat is a once-daily, oral, clinical-stage investigational medicine with the potential to positively impact both peripheral and central nervous system components of mitochondrial diseases. Zagociguat acts upon the central node of the nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic GMP (cGMP) pathway, which plays an essential role in fundamental physiological processes, such as mitochondrial function, inflammatory processes, cerebrovascular hemodynamics, and neuronal function. As a first-in-class, brain-penetrant sGC stimulator, zagociguat is intended to restore deficient NO-sGC-cGMP signaling in diseases where it is dysregulated, such as MELAS. In a Phase 2a study in patients with MELAS, zagociguat exhibited an excellent safety profile, exposure throughout the body including in the central nervous system, and improvements across key domains of MELAS disease pathophysiology including neuronal function, mitochondrial function, cerebrovascular hemodynamics, and inflammatory processes. About Tisento TherapeuticsTisento Therapeutics is developing novel medicines to treat diseases with significant unmet medical needs, beginning with MELAS and other genetic mitochondrial diseases. Ti sento means “I hear you” in Italian; our approach to innovation begins with listening first to patients and then channeling what we learn into decisive actions that shape our research and clinical programs. Tisento is guided by a high-caliber internal team of biopharma veterans and an extensive external network of expert physicians, patient advocacy groups, researchers, industry-leading vendors, and other close collaborators who we consider partners in our mission to develop meaningful treatments for mitochondrial diseases. Learn more at our website, www.tisentotx.com, or connect with us on LinkedIn (Tisento Therapeutics) or X (@tisentotx). Media Contact:Jessi Rennekamp, Astrior Communications Email: jrennekamp@tisentotx.com

Cyclerion Therapeutics had taken its lead drug candidate into the clinic, obtaining encouraging data in a rare disease. But the company was running out of cash to support that program and others in its pipeline. A key Cyclerion financial backer stepped in with a deal to acquire that asset and continue its development in a new biotech company. That startup, the mitochondrial diseases-focused Tisento Therapeutics, formally launched on Monday, nearly three months after the deal was first announced. Cambridge, Massachusetts-based Tisento is backed by $81 million in Series A financing. Tisento’s lead program is zagociguat, a small molecule previously known as CY6463 under Cyclerion. This drug is designed to penetrate the brain to stimulate soluble guanylate cyclase (sGC), an enzyme key to the nitric oxide signaling pathway. This pathway controls aspects of physiology throughout the body, including mitochondrial function. Cyclerion was developing zagociguat for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, a rare disease typically shortened to “MELAS.” This disorder affects the energy-producing components of cells called mitochondria and leads to central nervous system problems, cognitive impairment, fatigue, and muscle weakness. In mid-2022, Cyclerion announced data from an open-label Phase 1 study showing encouraging effects were observed on various aspects of MELAS in six of the eight patients in the study. Last October, Cyclerion announced it would hone its focus on mitochondrial disease, a strategy shift that led to the layoff of 45% of its staff. But cash continued to be problem. CEO Peter Hecht was part of a group that tried to buy some of Cyclerion’s assets to continue their development. The company’s independent board of directors unanimously turned down that proposal. This past March, in its report of 2022 financial results, Cyclerion reported a cash position totaling just $13.4 million. In May, Cyclerion announced a deal to sell zagociguat and another asset, the preclinical CY3018, for $8 million cash and another $2.4 million to cover employee and development expenses for zagociguat. Cyclerion also received a 10% equity stake in Tisento as well as the right to purchase additional equity in the future. Hecht, who is also CEO of Tisento, personally invested $5 million in Cyclerion. Tisento’s Series A financing includes participation of major Cyclerion shareholders, including Invus, Hecht, Polaris, and others. They are joined in the Tisento investor syndicate by Sanofi Ventures, Venrock, J. Wood Capital, and other unnamed investors. Meanwhile, Cyclerion says it now has enough cash to last into 2025. Errol De Souza, chair of Cyclerion’s board, said in a prepared statement that the company will continue an “externalized business model” in which it targets later-stage, de-risked CNS assets that can be quickly advanced in development. In parallel, the company will explore ways to advance its systemic sGC stimulator drugs. The remaining pipeline includes praliciguat, a systemic sGC stimulator that is licensed to Akebia Therapeutics and is in clinical development for treating rare kidney diseases. Olinciguat is a clinical-stage vascular sGC stimulator that the company intends to out-license for cardiovascular diseases. “We are very pleased to have found a good solution to advance our promising brain-penetrant sGC development programs on behalf of patients with significant unmet medical needs,” De Souza said. “In the midst of this extremely challenging financing climate for the biotech industry, we’re honored to partner with an excellent syndicate of investors.”