MELAS Syndrome

Khondrion appoints Jasper Levink as Chief Financial and Business Officer NIJMEGEN, the Netherlands – 11 September 2024: Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial diseases, today announces the appointment of Jasper Levink MSc, as Chief Financial and Business Officer, effective immediately. Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said: “We are delighted to welcome Jasper to the Khondrion Leadership Team as our new Chief Financial and Business Officer. His financial and business development experience will be extremely important as we continue to execute our strategy, progressing our late stage candidate, sonlicromanol, alongside the development of our pipeline and expansion of our clinical capabilities.” Jasper Levink, Chief Financial and Business Officer at Khondrion, added: “I am excited to be joining Khondrion at a pivotal time in its development, helping to drive the Company’s mission of bringing clinically meaningful medicines to patients living with devastating mitochondrial diseases. After the successful completion of four clinical trials of sonlicromanol and with preparations underway for registrational phase 3 studies, I am eager to bring my financial, operations and business development experience to the accomplished team and to work with medical and patient communities to leverage the transformational potential of sonlicromanol for people living with primary mitochondrial diseases.” Mr. Levink has over a decade of experience in business development and finance in biotech. Earlier roles include Partner and Managing Director at ttopstart, a boutique consulting company dedicated to business development and finance in biotech, and CBO at LenioBio, a German biotech pioneering the first eukaryotic cell-free protein expression platform. Recently he has taken up the role of CEO at SixtyFour Therapeutics, an early-stage biotech company developing therapies against autoimmune diseases. He will combine that role with his contributions to Khondrion. – Ends – Contacts: Khondrion BVProf. Dr. Jan Smeitink, CEOE-mail: info@khondrion.com Tel: +31-24-7635000www.khondrion.com ICR Consilium David Daley, Kris Lam Email: khondrion@icrhealthcare.com About KhondrionKhondrion is a clinical stage biopharmaceutical company developing therapies for patients with m.3243A>G primary mitochondrial diseases. The company’s lead asset, sonlicromanol, is a brain- penetrant, reductive and oxidative distress modulator with anti-inflammatory properties. 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 primary mitochondrial disease, as well as in the first wave of a 6-month Phase 2 study in children with genetically-confirmed primary mitochondrial diseases and who suffer from motor symptoms. 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. 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 mitochondrial disease Mitochondrial disease occurs when mitochondria, found within all cells of the human body 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 occuring 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. Orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders, MIDD (maternally inherited diabetes and deafness), LHON (Leber's hereditary optic neuropathy) and other respiratory chain/ oxidative phosphorylation disorders, are all examples of mitochondrial disease.

- Independent committee confirms FALCON study is powered for potential success with both alternative endpoints passing futility- -Committee confirms strong safety profile of KL1333- - Abliva to host conference call and webcast on Friday 19 July at 4:30 pm CET / 10:30 am ET – July 18, 2024 -- Abliva AB (Nasdaq Stockholm: ABLI), a clinical-stage company developing drugs for the treatment of rare and severe primary mitochondrial disease, today announced a positive outcome of the interim analysis for FALCON, the potentially registrational study evaluating KL1333 in patients with primary mitochondrial disease. The study evaluates fatigue and myopathy as alternative independent primary endpoints, only one of which is required for a successful study readout. The independent Data Monitoring Committee (DMC) recommended continuing the study without modification. The favorable recommendation by the DMC to continue the FALCON study with a total of 180 patients validates the overall study design and confirms the strong safety profile of KL1333. The DMC has reviewed the 24-week interim data from the Wave 1 patient cohort. In their analysis, the independent group conducted a pre-specified analysis of the conditional power of the two primary endpoints after 24 weeks of dosing. Both endpoints passed futility and the DMC recommended to include a total of 180 patients, increasing the probability of a positive readout upon completion of the full study. The DMC emphasized that KL1333 has a strong safety profile. No safety concerns or drug-related serious adverse events (SAEs) were seen after 24 weeks of dosing. The interim analysis was conducted by an independent committee to maintain the rigor of a blinded study. Statistical significance across the two primary endpoints will be evaluated at the conclusion of the full study. “We are pleased with the positive outcome of the interim analysis as it highlights the positive risk-benefit of KL1333, de-risking the full study, increasing our confidence in KL1333’s novel mechanism of action and the FALCON study design” said Ellen K. Donnelly, Chief Executive Officer of Abliva. “There are currently no approved therapies for mitochondrial disease and with over 85,000 people affected across the US and Europe, we believe KL1333 is well-positioned to address this high unmet medical need and reach blockbuster potential in key geographies. KL1333 has the potential for an expedited path to market and we are committed to rapidly advancing this important medicine towards approval, with plans to start the final wave of FALCON study recruitment in the second half of 2024.” Abliva will host an investor call on Friday, July 19, 2024, at 10:30 AM ET / 4:30 PM CET, to discuss the positive outcome of the interim analysis for FALCON. A live question and answer session will follow the formal presentation. To register, click here. If you would like to ask a question during the live Q&A, please submit your request to questions@lifesciadvisors.com. FALCON is a Phase 2, global, randomized, placebo-controlled, potentially registrational trial evaluating the safety and efficacy of KL1333 in adult patients with primary mitochondrial disease who experience consistent, debilitating fatigue and myopathy. Patients with mitochondrial DNA mutations who meet the eligibility criteria are randomized 3:2 to receive KL1333 (50mg-100mg) or placebo twice daily for 48 weeks. The two alternate primary endpoints assess chronic fatigue (using the PROMIS Fatigue Mitochondrial Disease Short Form) and muscle weakness (using the 30 second Sit-to-Stand test), the most common and debilitating disease expressions in mitochondrial disease patients. Primary mitochondrial disease affects the ability of cells to convert energy. The disease can manifest itself very differently depending on the organs impacted and the number of dysfunctional mitochondria in that organ. Historically viewed as clinical syndromes, our knowledge about the various mutations underlying mitochondrial disease has increased, improving our ability to identify and treat these patients. It is estimated that 125 people per million have primary mitochondrial disease. It often presents in early childhood and leads to severe symptoms, such as mental retardation, fatigue, myopathy, heart failure and rhythm disturbances, diabetes, movement disorders, stroke-like episodes, and epileptic seizures. Abliva’s lead candidate, KL1333, has been designed to treat chronic fatigue and myopathy (muscle weakness) in genetically confirmed adult patients with primary mitochondrial disease. Diagnoses can include MELAS-MIDD and KSS-CPEO spectrum disorders as well as MERRF syndrome. The drug candidate is intended for long-term oral treatment. KL1333 has the ability to restore the ratio of NAD+ and NADH, and thus leads to the formation of new mitochondria and improved energy levels. In a cohort of mitochondrial disease patients in a Phase 1a/b study, the patients who received KL1333 showed both improvements in symptoms of fatigue as well as functional improvements. KL1333 is currently being evaluated in a global, potentially registrational, Phase 2 study (the FALCON study) and has received orphan drug designation in both the USA and Europe as well as Fast Track designation in the USA. Abliva discovers and develops medicines for the treatment of mitochondrial disease. This rare and often very severe disease occurs when the cell’s energy provider, the mitochondria, do not function properly. The company has prioritized two projects. KL1333, a powerful regulator of the essential co-enzymes NAD⁺ and NADH, has entered late-stage development. NV354, an energy replacement therapy, has completed preclinical development. Abliva, based in Lund, Sweden, is listed on Nasdaq Stockholm, Sweden (ticker: ABLI). For more information, please visit www.abliva.com. Subscribe to our news and follow us on LinkedIn and YouTube. The content above comes from the network. if any infringement, please contact us to modify.

在一项新的研究中，来自Amgen子公司deCODE genetics的研究人员利用64806名冰岛人的谱系和序列数据，揭示了线粒体DNA（mtDNA）突变的速度和性质，以及其母体传播的特殊动态。这是迄今为止对人类生殖系 mtDNA突变及其在母子间传播规律的最大规模研究。 相关研究结果于2024年6月7日在线发表在Cell期刊上，论文标题为“The rate and nature of mitochondrial DNA mutations in human pedigrees”。 背景信息 线粒体作为细胞的能量工厂，其DNA仅能通过母系遗传。每个人的mtDNA副本数以万计，源于母体极少数mtDNA分子，经过生殖系瓶颈（germline bottleneck）筛选传递。当传递的mtDNA中存在大量有害突变时，可能导致多种严重疾病，如中风、2型糖尿病、肌肉疾病、视力和听力丧失。 大约每5000人中就有1人因已知的mtDNA突变而患病，而未知的有害突变可能带来更重的疾病负担。过往的系统发生学研究显示mtDNA的生殖系突变率约为常染色体的20倍，但这些研究可能低估了有害变异的频率，不过，这也凸显了大规模谱系研究的重要性，可以使我们全面掌握mtDNA的变异特点及其对健康的深远影响。 个体平均仅从母亲继承大约3个mtDNA单元？ 这项新的研究记录了 mtDNA 某些位置惊人的高突变性，其中包括导致 MELAS 综合征的著名 3243 位点有害 A>G 突变。该突变在 2548 个母系谱系中出现了 15 次，但由于对携带者的健康有严重影响，通常在几代后就消失了。 研究呈现了强有力的证据，证明母系谱系中存在对这类有害且短暂存活的mtDNA突变的自然选择机制。同时，研究还揭示了早期广泛的负选择现象，即在卵细胞成熟过程中丢弃功能低下的mDNA 分子。 研究进一步通过广泛的mtDNA突变传递分析，精确估算了个体平均仅从母亲继承大约3个mtDNA单元，这远低于先前研究的预估。 论文共同通讯作者Agnar Helgason指出，“值得注意的是，卵母细胞通常会携带数十万个mtDNA，但其中仅有大约三个mtDNA分子来自于母亲。这种急剧的瓶颈效应决定了生殖系mtDNA中的新突变能在短短几代内快速消失或固定，其部分原因肯定是卵母细胞发育过程中的一种选择过程，在这种过程中，带有有害突变的mtDNA分子被生殖系移除。” 图片来自Cell, 2024, doi:10.1016/j.cell.2024.05.022 论文共同通讯作者、deCODE genetics首席执行官Kári Stefánsson指出，该研究推进了我们对mtDNA基因组中核苷酸突变率巨大差异的理解，并揭示了即使在同一位置的不同等位基因间也存在这种差异。尽管某些疾病的高突变率使得它们易于被识别，但研究结果提示，仍有许多造成人类疾病负担的罕见致病mtDNA突变等待发现。 参考资料： Erla R. Árnadóttir et al. The rate and nature of mitochondrial DNA mutations in human pedigrees. Cell, 2024, doi:10.1016/j.cell.2024.05.022. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！