Leigh Disease

21 November 2024 – The United Mitochondrial Disease Foundation’s (UMDF) venture philanthropy arm, The Mito Fund, has invested in Khondrion, a Netherlands-based clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial disease (PMD). Khondrion is currently preparing to initiate a Phase III study investigating the potential of its lead proprietary drug candidate, sonlicromanol, to treat adult patients with PMD due to the m.3243A>G mutation, the most common genetic defect causing multi-systemic PMD, which has an estimated prevalence of 4.4:100,000 impacting hundreds of thousands of patients worldwide. One of the most advanced drug candidates in development for PMD, sonlicromanol is a disease-modifying, potentially first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD. Its ongoing development is supported by compelling clinical data from Khondrion’s Phase IIb program, published earlier this month in the peer-reviewed scientific journal, Brain, showing strong patient benefits from sonlicromanol in multiple outcome measures of global health, quality of life, mood, fatigue, pain and balance control. "We believe sonlicromanol holds incredible potential for treating primary mitochondrial disease which impacts hundreds of thousands of people worldwide," said Dr. Philip Yeske, UMDF's Interim Managing Director and Science and Alliance Officer. "But it’s not just about numbers. The diseases associated with this mutation are devastating and remarkably progressive. The approval of this therapy would meet an urgent and unmet therapeutic need.” Said Khondrion’s Chief Executive Officer, Prof. Dr. Jan Smeitink: “Patients with primary mitochondrial disease currently have no treatment options available to them. Through our clinical trials to date, we see the great potential sonlicromanol may have on these patients, particularly on their most burdensome symptoms of chronic fatigue and muscle weakness. With the support and investment by the UMDF via The Mito Fund, we look forward to further progressing our clinical work on sonlicromanol at pace in our upcoming Phase III trial in adult patients with PMD.” Like all investments made by The Mito Fund, the Khondrion consideration went through a rigorous review process by UMDF’s Venture Philanthropy Investment Committee, an advisory group consisting of world-class experts in the areas of mitochondrial disease, pharmaceutical development, and private equity investments. After receiving the committee’s recommendation, the investment was then approved by UMDF’s full Board of Trustees. “From an investment perspective, there were several really attractive elements to the investment. First, sonlicromanol represents an innovative treatment for an underserved population. It’s also a mature clinical stage asset, which shortens the runway to approval,” said Dr. Yeske. “UMDF looks forward to partnering with Khondrion in advancing this investigational therapeutic in a patient-centric manner.” Launched in the summer of 2023, The Mito Fund is UMDF’s most ambitious effort to date to ramp up the development of mitochondrial disease treatments and cures. The fund’s venture philanthropy model is designed not only to financially support the development of the next generation of mitochondrial disease treatments, but also to leverage UMDF’s experience and network to accelerate the development process and lower the risk associated with entry into the field for a wide range of investors and researchers. This is the second official investment for The Mito Fund. In April 2024, the fund announced an investment in Pierrepont Therapeutics, Inc., which is working on a preclinical proprietary intracellular enzyme replacement therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE). Companies exploring the mitochondrial science space are encouraged to start a conversation about investment opportunities at www.themitofund.org. Proposals are accepted on a rolling basis. About UMDF For more than 25 years, The United Mitochondrial Disease Foundation (UMDF) has built a global network of patients, researchers, clinicians, institutions, and industry partners dedicated to fighting mitochondrial disease. Together with the mito community, UMDF is committed to a mission of funding the best science no matter where it is found in the world while at the same time providing critical education, advocacy, and support-focused programs and services to patient families. In the last year … Nearly 1,500 affected patients and families depended upon UMDF for support.More than 400 clinicians listened to UMDF’s Bench-to-Bedside seminars.UMDF advocates had more than 1,000 touchpoints with their congressional offices.UMDF provided hundreds of patients with no-cost genetic testing to help shorten the diagnostic journey. About Khondrion Khondrion 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, potentially 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 US. 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. Contacts: Khondrion BVProf. Dr. Jan Smeitink, CEOE-mail: info@khondrion.comTel: +31-24-7635000www.khondrion.com ICR Healthcare David Daley, Kris Lam, Tom DanielEmail: khondrion@icrhealthcare.com UMDF / The Mito FundAndy Dearth, Director of Marketing & CommunicationsEmail: Andy.dearth@umdf.org

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

NIJMEGEN, the Netherlands – 7 November 2024: Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial disease (PMD), today announced the publication of results from its integrated Phase 2b clinical development program of sonlicromanol in the peer-reviewed scientific journal, Brain. Sonlicromanol, Khondrion’s lead proprietary drug candidate, is a disease-modifying, potentially first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties, that targets key metabolic and inflammatory pathways underlying PMD. The Phase 2b program in adults with the most common genetic defect causing PMD, m.3243A>G, consisted of a 28-day, randomized, placebo-controlled, three-way cross-over, dose-finding study (27 patients), complemented by a 52-week, open-label extension study. Selected outcome measures based on the most burdensome symptoms experienced by patients, including muscle weakness, chronic fatiugue, pain and cognitive decline, were studied throughout the program. The paper’s researchers highlight strong patient benefits from sonlicromanol in multiple outcome measures of global health, quality of life, mood, fatigue, pain and balance control. In patients experiencing more severe symptoms at baseline, treatment effects from sonlicromanol were more pronounced, and longer-term treatment brought continuously improving patient benefits. Given that improvements were demonstrated in multiple domains frequently affected by PMD, such as the brain and muscle, treatment effects were established to be systemic. In line with previous completed clinical trials for sonlicromanol, the drug candidate showed excellent pharmacokinetics and a positive safety profile, well tolerated through 52 weeks. Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said: “The clinical significance of this comprehensive data set is considerable, providing strong evidence of the positive impact that sonlicromanol can offer to patients with primary mitochondrial disease, who currently have no treatment options available to them. To our knowledge, this is the first time a trial has shown clear reversal of the hallmark phenotypical symptoms in otherwise progressive mitochondrial disease.” “In undertaking this trial we were mindful of, but not daunted by, the challenges mitochondrial diseases present to clinical development. Beyond growing substantially our understanding of the long-term safety and efficacy potential of sonlicromanol, we are pleased that through this Phase 2b program we have made fundamental progress in further validating outcome measures that will support follow-up clinical research towards market authorization. Our sincere thanks to the patients and their families, the clinical study teams and the patient advocacy community, for their contributions to this program.” Learnings from the Phase 2b program, alongside data from Khondrion’s two earlier short-term safety and signal-seeking studies, have provided comprehensive insights to optimize the design – including the selection of primary and other endpoints – of the company’s planned pivotal 52-week Phase 3 study, which will further investigate the potential of sonlicromanol in adult m.3243A>G patients. – ENDS – Reference Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation. Jan Smeitink, Just van Es, Brigitte Bosman, Mirian CH Janssen, Thomas Klopstock, Grainne Gorman, John Vissing, Gerrit Ruiterkamp, Chris J. Edgar, Evertine J Abbink, Rob van Maanen, Oksana Pogoryelova, Claudia Stendel, Almut Bischoff, Ivan Karin, Mahtab Munshi, Anne Kümmel, Lydia Burgert, Christianne Verhaak, Herma Renkema https://doi-org.libproxy1.nus.edu.sg/10.1093/brain/awae277. 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 four 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 US. 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: https://www.khondrion.com/melas-syndrome/. 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 Lam, Tom Daniel Email: khondrion@icrhealthcare.com