Mitochondrial Encephalomyopathies

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

DURHAM, N.C.--(BUSINESS WIRE)-- Precision BioSciences, Inc. (Nasdaq: DTIL), an advanced gene editing company utilizing its novel proprietary ARCUS® platform to develop in vivo gene editing therapies for sophisticated gene edits, including gene insertion, excision, and elimination, today announced it has received a Notice of Allowance from the U.S. Patent and Trademark Office (USPTO) for U.S. Patent Application No. 18/161,560, titled “Engineered Meganucleases That Target Human Mitochondrial Genomes.” Once issued, the patent arising from this application will have a standard expiration date in April 2042. The allowed composition of matter claims in this U.S. application encompass a mitochondria-targeted ARCUS nuclease (mitoARCUS) that is designed to specifically target, cleave, and eliminate mutant mitochondrial DNA comprising an m.3243A>G mutation. The m.3243A>G mutation is one of the most common pathogenic mitochondrial DNA mutations, differing from wild-type (normal) mitochondrial DNA by a single base change, and is associated with the development of a number of disorders, including primary mitochondrial myopathies that primarily affect skeletal muscle, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Precision recently announced PBGENE-PMM, the Company’s clinical candidate targeting mutant mitochondrial DNA, as a potentially first-in-class opportunity for treatment of m.3243 associated primary mitochondrial myopathy. Utilizing the claimed mitoARCUS nuclease, PBGENE-PMM is designed to target and eliminate mutant mitochondrial DNA, allowing for repopulation by wild-type mitochondrial DNA and restoration of mitochondrial function. “The high specificity and single component nature of Precision’s mitoARCUS nucleases are designed to enable specific elimination of mutant mitochondrial DNA while allowing the normal mitochondrial DNA to repopulate in the mitochondria and reestablish normal function,” said Jeff Smith, PhD, Co-Founder and Chief Research Officer at Precision BioSciences. “PBGENE-PMM holds the potential to deliver a one-time, transformative treatment for patients with primary mitochondrial myopathy.” Unlike CRISPR-based gene editing tools, mitoARCUS nucleases are able to gain access to mitochondria because they are small, single-component proteins that integrate DNA-binding and DNA-cleavage and do not require a nucleic acid, such as a guide RNA, for targeting. “The fact that mitoARCUS can be delivered directly to mitochondria, and has the specificity to distinguish a single base pair difference in the m.3243 A>G mutation, makes PBGENE-PMM a very important potential treatment candidate for patients suffering from m.3243 associated primary mitochondrial myopathy,” said Carlos Moraes, PhD, Esther Lichtenstein Professor of Neurology, and Cell Biology and Anatomy at the University of Miami Miller School of Medicine, and co-inventor of the allowed application. This U.S. application is jointly owned by Precision and the University of Miami, which has exclusively licensed the rights to the application to the Company. About Precision BioSciences, Inc. Precision BioSciences, Inc. is an advanced gene editing company dedicated to improving life (DTIL) with its novel and proprietary ARCUS® genome editing platform that differs from other technologies in the way it cuts, its smaller size, and its simpler structure. ARCUS is a highly precise and versatile genome editing platform that was designed with therapeutic safety, delivery, and control in mind. Using ARCUS, the Company’s pipeline is comprised of in vivo gene editing candidates designed to deliver lasting cures for the broadest range of genetic and infectious diseases where no adequate treatments exist. For more information about Precision BioSciences, please visit . About Mitochondria and Primary Mitochondrial Myopathy Mitochondria comprise multiple copies of a circular DNA referred to as mitochondrial DNA, which encodes for 13 subunits of the oxidative phosphorylation (OXPHOS) system, 2 rRNAs, and 22 tRNAs that are all necessary to support mitochondrial function. It is believed that a shift in mitochondrial DNA heteroplasmy toward wild-type (normal) may provide therapeutic benefit for patients, and not all mutant mitochondrial DNA must be eliminated to achieve improvements in symptoms. Rather, mutant mitochondrial DNA levels only need to be shifted below a disease threshold level. Mitochondrial diseases that arise from mutations in mitochondrial DNA are the most common hereditary metabolic disorder, affecting 1 in 4,300 people. Primary mitochondrial myopathy is characterized by severe fatigue and can affect skeletal muscle, and other high energy organs such as the brain, eyes, ears and heart. Primary mitochondrial myopathy currently lacks curative treatment and impacts approximately 50% of patients with mitochondrial disease. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The Company intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the expected safety, efficacy, and benefit of our gene editing approaches including editing efficiency and delivery methods, the suitability of ARCUS nucleases for gene insertion, excision, and elimination, including the elimination of mutant mitochondrial DNA, the clinical development, nomination, and goals of our PBGENE-PMM program, the potential for a shift in heteroplasmy toward wild-type mitochondrial DNA to restore mitochondrial function, and therapeutic potential of an ARCUS gene editing approach for the treatment of m.3243-associated mitochondrial diseases. The words “aim,” “anticipate,” “approach,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “goal,” “intend,” “look,” “may,” “mission,” “plan,” “possible,” “potential,” “predict,” “project,” “promise,” “pursue,” “should,” “target,” “will,” “would,” and other similar words or expressions, or the negative of these words or similar words or expressions, are intended to identify forward-looking statements, though not all forward-looking statements use these words or expressions. Forward-looking statements are based on management’s current expectations, beliefs and assumptions and on information currently available to us. These statements are neither promises nor guarantees, but involve number of known and unknown risks, uncertainties and assumptions, and actual results may differ materially from those expressed or implied in the forward-looking statements due to various important factors, including, but not limited to: our ability to become profitable; our ability to procure sufficient funding and requirements under our current debt instruments and effects of restrictions thereunder; risks associated with raising additional capital; our operating expenses and our ability to predict what those expenses will be; our limited operating history; the success of our programs and product candidates in which we expend our resources; our limited ability or inability to assess the safety and efficacy of our product candidates; our dependence on our ARCUS technology; the risk that other genome-editing technologies may provide significant advantages over our ARCUS technology; the initiation, cost, timing, progress, achievement of milestones and results of research and development activities, preclinical studies and clinical trials; public perception about genome editing technology and its applications; competition in the genome editing, biopharmaceutical, and biotechnology fields; our or our collaborators’ ability to identify, develop and commercialize product candidates; pending and potential liability lawsuits and penalties against us or our collaborators related to our technology and our product candidates; the U.S. and foreign regulatory landscape applicable to our and our collaborators’ development of product candidates; our ability to obtain orphan drug designation or fast track designation for our product candidates or to realize the expected benefits of these designations; our or our collaborators’ ability to obtain and maintain regulatory approval of our product candidates, and any related restrictions, limitations and/or warnings in the label of an approved product candidate; our or our collaborators’ ability to advance product candidates into, and successfully design, implement and complete, clinical trials; potential manufacturing problems associated with the development or commercialization of any of our product candidates; delays or difficulties in our and our collaborators’ ability to enroll patients; changes in interim “top-line” and initial data that we announce or publish; if our product candidates do not work as intended or cause undesirable side effects; risks associated with applicable healthcare, data protection, privacy and security regulations and our compliance therewith; the rate and degree of market acceptance of any of our product candidates; the success of our existing collaboration agreements, and our ability to enter into new collaboration arrangements; our current and future relationships with and reliance on third parties including suppliers and manufacturers; our ability to obtain and maintain intellectual property protection for our technology and any of our product candidates; potential litigation relating to infringement or misappropriation of intellectual property rights; our ability to effectively manage the growth of our operations; our ability to attract, retain, and motivate key executives and personnel; market and economic conditions; effects of system failures and security breaches; effects of natural and manmade disasters, public health emergencies and other natural catastrophic events; effects of COVID-19 pandemic and variants thereof, or any pandemic, epidemic or outbreak of an infectious disease; effects of sustained inflation, supply chain disruptions and major central bank policy actions; insurance expenses and exposure to uninsured liabilities; effects of tax rules; risks related to ownership of our common stock and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2023, as any such factors may be updated from time to time in our other filings with the SEC, which are accessible on the SEC’s website at and the Investors page of our website under SEC Filings at investor.precisionbiosciences.com. All forward-looking statements speak only as of the date of this press release and, except as required by applicable law, we have no obligation to update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.