Sonlicromanol

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

Transmition Electron microscopy of an epithelial cell showing mitochondria/courtesy of Dlumen/iStock They’re the powerhouses of the cell, generating energy for nearly every organ in the body. But when mitochondria are dysfunctional, the resulting power outage can cause devastation for children and adults with rare and ultra-rare diseases. One rare mitochondrial disease, Friedreich’s ataxia, saw its first approval in March when the FDA greenlit Reata Pharmaceuticals’ Skyclarys for adults and adolescents 16 and older. While this bodes well for adult diseases, there have not been many recent advances in treating pediatric mitochondrial diseases, said Jan Smeitink, CEO of Khondrion, a company developing symptomatic treatments for mitochondrial diseases. “The good thing is that, at least now, there is this huge interest in primary mitochondrial diseases, so more companies are working in the space,” he told BioSpace. “It’s also good to notice that different companies have compounds working on different targets.” Jan Smeitink A Glimmer of Hope in Pearson Syndrome One of these companies is Israel-based Minovia Therapeutics, which is developing a mitochondrial cell therapy for Pearson syndrome, a multisystem disease caused by single, large deletions in mitochondrial DNA (mtDNA). The mitochondria are the only place in the cell where there is DNA outside of the nucleus, Natalie Yivgi-Ohana, co-founder and CEO of Minovia, told BioSpace. This makes the organelle particularly vulnerable. “It’s exposed. It’s circular. It has no protections, no proofreading, so mutations just accumulate with time.” Pearson syndrome affects fewer than 1,000 people in the U.S., according to the Genetic and Rare Diseases Information Center. “Almost 50% of [patients] will die before the age of five, and the rest will just develop a multisystemic, terrible disease that affects almost every organ system,” Yivgi-Ohana elaborated. Patients experience neurodegeneration, muscular dysfunction, cardiac dysfunction and diabetes. “It’s almost like the whole body is collapsing.” Minovia’s Mitochondrial Augmentation Technology (MAT) platform involves extracting a patient’s hematopoietic stem cells, enriching them with healthy mitochondria from a donor and then infusing them back into the body. This allows the cell’s natural processes to select for the healthy versions of the organelles, Yivgi-Ohana said. Pearson syndrome is the only mitochondrial disease where bone marrow failure occurs, so “hematopoietic stem cells are very relevant to treat at least the hematopoietic environment of that patient,” Yivgi-Ohana said. Generally, mitochondria—and consequently­—mtDNA, is inherited only from the mother. But Pearson is usually caused by de novo mutations, enabling the mother to serve as a donor, she said. Natalie Yivgi-Ohana In a compassionate use study, seven young patients—four with Pearson syndrome and two with another primary mitochondrial disease, Kearns-Sayre syndrome (KSS)—were treated with MAT (MNV-101). Prior to treatment, all patients had potentially life-threatening symptoms, including advanced multi-organ disease, according to Minovia. Minovia extracted one unit of blood from the donor, isolated the mitochondria from the white blood cells and introduced them into the patient’s hematopoietic stem cells in the lab before re-injecting those into the patient. Treatment with MNV-101 was well-tolerated and resulted in normal mitochondrial DNA in the blood of four patients, which Minovia said indicated a reduction of mitochondria containing the disease-causing deletions. “The first few patients showed remarkable improvement and reversal of the disease,” Yivgi-Ohana said. She shared the story of a six-and-a-half-year-old boy who was confined to a baby stroller due to stunted growth, muscle weakness and fatigue. After treatment with MAT, “the first thing that we observed in this patient was a burst of energy in the waking hours of the day,” Yivgi-Ohana said. The baby stroller disappeared and the child started to walk and run. The boy continued to improve, and his kidney function stabilized for four years after treatment before beginning to deteriorate in the past two years, Yivgi-Ohana said. Based on this patient and eleven others who have been treated with MAT, she believes another dose of MNV-101 will be required. Leigh Syndrome and MELAS Spectrum Disorders Waltham, Mass.–based IMEL Biotherapeutics aims to restore mitochondrial function with cell-based therapies to treat both genetic and age-related diseases. On the genetic side, IMEL is targeting Leigh syndrome, a severe neurometabolic disorder that affects children carrying certain mutations in their mtDNA. The company’s Mitochondrial Replaced Cells (MirC) technology allows it to deplete the dysfunctional mitochondria and replace them with healthy mitochondria, Silvia Noiman, founder, chair and CEO of IMEL, told BioSpace. Silvia Noiman IMEL is currently testing the MirC process in animal models resembling Leigh syndrome. Using the MirC process in stem cells and T cells from both animal models and healthy humans, IMEL has shown that it can replace almost 90% of the host cells’ dysfunctional mitochondria with functional organelles, Noiman said. She believes the technology “can be a game changer.” Noiman will expound on the age-related impacts of mitochondrial disorders at the Biomed Israel Conference, held this week in Tel Aviv. Mitochondrial disorders affect adults too. Khondrion has several therapies in development for these diseases. Its most advanced product is sonlicromanol for the treatment of cognitive dysfunction in adults with MELAS spectrum disorders. Classical MELAS spectrum disorders, including maternally inherited diabetes and deafness (MIDD) and mixed phenotypes, are most often caused by a mutation in the MT-TL1 gene in the mtDNA. The most oft-affected organs are the brain, muscles and pancreas, Smeitink said. Between Phase IIb and open-label extension studies, Smeitink said the company has good safety data for up to 78 weeks. Khondrion is currently discussing Phase III trial design with the FDA and European Medicines Agency. Sonlicromanol, a reductive and oxidative distress modulator with anti-inflammatory properties, aims to correct the outward manifestations of mutations in the cell lines of patients with mitochondrial diseases. Khondrion is also testing the drug for the treatment of mitochondria-based movement disorders in children. The Path Forward The mitochondrial disease space comprises approximately 300 neuro-metabolic genetic disorders, according to Khondrion. “The problem with mitochondrial diseases is that it’s not one disease. It’s hundreds and hundreds of diseases,” Mary Kay Koenig, pediatric neurologist and director of the Mitochondrial Center of Excellence at UTHealth Houston, told BioSpace. Gene replacement therapies and DNA modifications are focused on a very small proportion of the diseases, she said. For Smeitink, small molecule therapies are “the way to go” in treating mitochondrial diseases, at least for the next 10 years. He said gene and cell therapy also hold promise but “need a little bit more time as several obstacles first have to be overcome.” He pointed to vector design, targeted tissue tropism and efficient delivery, transgene expression and immunotoxicity. Yivgi-Ohana said that autologous hematopoietic stem cells are the most trusted cell therapy. She said that the riskiest part of such treatment is typically the preconditioning—clearing the bone marrow with chemotherapy to allow engraftment of cells in the bone marrow niche—but added that this is not done for Pearson patients because their bone marrow has low cellular content, meaning there is space in the bone marrow niche for engraftment of the augmented cells. Another primary challenge is phenotyping, Koenig said. “You can’t really find a treatment for something if you don’t understand what the natural history of it is, and I think . . . we’re still in the process of trying to understand [mitochondrial] diseases,” she said. “It makes it really hard to determine whether or not a drug is efficacious if you don’t know what’s supposed to happen to the patient” in the natural course of the disease. One initiative, The Leigh Syndrome Roadmap Project: A Natural History Study, is trying to address this challenge. The project, being run out of the Children’s Hospital of Philadelphia, aims to better understand the natural history of Leigh syndrome and determine proper endpoints for clinical trials, Koenig said. Currently, there are not many ongoing studies in mitochondrial diseases for children, Smeitink noted. While there are around 200 active trials for mitochondrial diseases listed on ClinicalTrials.gov as of May 2023, just 10 of these are for Leigh’s syndrome and two are for Pearson syndrome. “That is unfortunate,” he said. “But it will change, I’m sure.” Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn: and Twitter: @chicat08. The Biomed Israel conference paid for Heather McKenzie to travel to Israel to meet with Minovia Therapeutics in December 2022.