Noninsulin-Dependent Diabetes Mellitus With Deafness

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.

Khondrion announces sonlicromanol Phase IIb progress supporting Phase III development in MELAS spectrum disorders Sonlicromanol for MELAS spectrum disorders – a rare, progressive primary mitochondrial disease – to move into a Phase III registrational study supported by favourable benefit-risk profileBoth randomised placebo-controlled Phase IIb study and ongoing Phase IIb open label extension study show statistically significant and/or clinically meaningful results in multiple outcome measures with acceptable safety profileThough 28-day Phase IIb study did not meet primary endpoint of the attention domain score of cognitive functioning, the study demonstrated positive treatment effects in several other cognition and mood-related secondary endpointsPositive results on cognition, mood, quality of life, pain, fatigue and balance control were observed after up to 52 weeks sonlicromanol treatmentTopline data to be presented today by Khondrion’s CEO, Prof. Dr. Jan Smeitink, at Wellcome’s Mitochondrial Medicine - Therapeutic Development Conference, Cambridge, UK NIJMEGEN, the Netherlands – 22 November 2022: Khondrion, a clinical stage biopharmaceutical company discovering and developing therapies targeting primary mitochondrial diseases, today provides an update from (A) the 28-day double-blind, randomised, placebo-controlled, three-way cross-over KHENERGYZE Phase IIb study in 27 patients, and (B) the ongoing, open label extension KHENEREXT Phase IIb study (7 patients up to 52 weeks) (both studies jointly the “Phase IIb programme”). Sonlicromanol, Khondrion’s wholly-owned lead asset, is being investigated in the Phase IIb programme in adult patients with MELAS spectrum disorders as genetically confirmed by the m.3243A>G mutation in the mitochondrial DNA. In line with previous studies, sonlicromanol was found to be safe and well tolerated in the Phase IIb programme, with no serious adverse effects. The overall evaluation of the shorter and longer term data from the programme shows patient benefits in several domains (cognition and mood, pain, fatigue and balance control) and marked improvements in global health and quality of life assessments, supporting sonlicromanol’s progression into Phase III clinical development in patients with MELAS spectrum disorders. In line with expectations in these slowly progressing rare diseases, analysis of the data shows more pronounced treatment effects after 52 weeks. These longer-term patient data are, therefore, instrumental in providing valuable insights for the design of the upcoming Phase III trial. Dr. Mirian Janssen, one of the principal investigators, Radboud Centre for Mitochondrial Medicine (Nijmegen, the Netherlands), said: ‘’I am encouraged by these promising results, especially the improvement in quality of life measurements and NMDAS score over a longer period. The fact that the study-patients wish to continue using sonlicromanol and their personal motivation are also positive signs. I have had the privilege to work closely with many of these patients for many years and I am pleased to observe tangible improvements in those patients who have now been treated with sonlicromanol for 52 weeks. I praise Khondrion for its pursuit of mitochondrial disease innovation, care to the patients in its trials and commitment to this development programme.” Phase IIb programme results A. KHENERGYZE Phase IIb study in m.3243A>G MELAS spectrum disorders (adults) Patients (n=27) treated with sonlicromanol (50 mg and 100 mg bid) for 28 days did not achieve a statistically significant improvement in the attention domain score of cognitive functioning, as assessed by the computerised Cogstate visual identification test, compared to those who received placebo.Post-hoc analyses of the Phase IIb study data showed positive trends in several other cognition and mood-related secondary endpoints as well as in other domains including fatigue.More specifically, statistically significant and clinically meaningful treatment effects versus placebo were obtained, amongst others for the Beck Depression Inventory (BDI, 100 mg bid, p=0.01) and the Cognitive Failure Questionnaire (CFQ, 100 mg bid, p=0.007).The totality of data suggests better effectiveness of the 100 mg bid dose relative to 50 mg bid.Acceptable safety profile confirmed. B. KHENEREXT Phase IIb open label extension study (ongoing) An interim analysis from the ongoing Phase IIb open label extension study, examining the long-term safety and a broad set of efficacy parameters of sonlicromanol (100 mg bid) in patients who completed the KHENERGYZE Phase IIb study, confirmed the positive results shown in the Phase IIb study on BDI and CFQ over a longer period of time in a first cohort of 7 patients who received sonlicromanol for 52 weeks.On the widely-used NMDAS score, specifically developed and validated to assess disease severity of adult patients with primary mitochondrial disease, the majority of subjects showed a meaningful improvement with a decrease up to 6 points after 52 weeks. In a Natural History Study conducted by De Laat et al. (J Med Genet 2021), it was observed that the NMDAS score in patients with m.3243A>G increased on average with 0.47 points per year, representing disease deterioration.Regarding other global health and quality of life related outcome measures, like RAND SF36 and EQ-5D-5L, the majority of patients overall who were affected for these parameters at baseline showed clinically meaningful responses, while both the clinician- and patient-reported global impression of change improved in the majority of patients in an otherwise progressive disease.In addition, the interim analysis showed marked improvements in multiple other outcome measures, including pain (Short-form McGill Pain Questionnaire), fatigue (Neuro-QoL short form) and balance control (Mini-Balance Evaluation Systems Test), with various endpoints showing statistically significant and/or clinically meaningful treatment effects.Acceptable safety profile confirmed. Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion, said: “These results are an important milestone for Khondrion. While sonlicromanol’s effect on the primary endpoint within a 28-day period was insufficient in the Phase IIb trial, we believe the broader results from the Phase IIb programme, now up to 52 weeks, provide unequivocal evidence of the positive clinical impact and important patient benefit that sonlicromanol can provide. We are particularly encouraged by the positive signals on overall disease severity, mood, cognition, fatigue, balance and pain, all belonging to the most burdensome symptoms patients experience in their daily lives, as mentioned in UMDF’s Voice of the Patient Report 2019. We look forward to discussing our plans with European and U.S. regulators in the near future, ahead of the initiation of the Phase III registrational trial which is currently foreseen in late 2023. “I would like to express my heartfelt gratitude to each of the patients, and their families who have played a part in these studies, and to the patient advocacy groups, the clinical study teams in Nijmegen, Munich, Newcastle and Copenhagen, and Foundations and Governmental bodies for their special contributions to our research. And a huge thank you to the talented team at Khondrion for their continued hard work, furthering this field of research, and for their commitment to finding the new treatments that are so needed for patients.” A presentation of topline data from this sonlicromanol Phase IIb programme update will be given by Prof. Dr. Jan Smeitink today at Wellcome’s Mitochondrial Medicine – Therapeutic Development Conference, Cambridge, UK. The full data will be submitted for peer-reviewed publication. – ENDS – Notes to editors About the Phase IIb programme in adult patients with MELAS spectrum disorders KHENERGYZE – A 28-day double-blind, randomised, placebo-controlled, multi-centre, three-way cross-over Phase IIb study examining cognitive function in adult patients with a specific genetically confirmed DNA mutation in the mitochondrial transfer RNALeu(UUR) (MT-TL1m.3243A>G). This mutation is responsible for MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders, including classical MELAS, MIDD (maternally inherited diabetes and deafness) syndromes, and mixed phenotypes. Further details are available on clinicaltrials.gov (NCT04165239) and eudract.ema.europe.eu (2019-000599-40). KHENEREXT – An open-label extension study, enabling continued sonlicromanol treatment for patients who had completed the KHENERGYZE Phase IIb study and the collection of longer-term data. Alongside safety, the study also gathers a broad set of primary and secondary functional clinical outcome measures, including cognition, fatigue and motor-function related parameters. Further details are available on clinicaltrials.gov (NCT04604548) and eudract.ema.europe.eu (2020-000832-23). Additional pediatric study (ongoing) KHENERGYC – A placebo-controlled, double-blind Phase II study to explore the pharmacokinetics, safety and efficacy of sonlicromanol in children with a genetically confirmed primary mitochondrial disease and suffering from motor symptoms. The 6-month study, supported by Dutch Patient Foundations and an EFRO Grant (PROJ-00582), is investigating the effect of sonlicromanol in 24 children (from birth to 17 years) with genetically confirmed mitochondrial disease of which the gene defect is known to hamper the functioning of one or more oxidative phosphorylation system enzymes and who are suffering from motor symptoms. The study’s primary objective is to evaluate the effect of sonlicromanol on motor function using a range of validated, quantitative assessments including the Gross Motor Function Measure-88 and the Nine Hole Peg Test. Further details are available on clinicaltrials.gov (NCT04846036) and eudract.ema.europe.eu (2020-003124-16). 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 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. One of the most advanced disease-modifying drug candidates for mitochondrial disease in development, sonlicromanol has recently completed a Phase IIb study in adult patients with m.3243A>G MELAS spectrum disorders. In combination with interim 52-week data from the ongoing Phase IIb open-laben extension study, analysis of the results has shown marked improvements in multiple endpoints which merit further study in a Phase III registrational trial. Sonlicromanol is also studied in a 6-month Phase II 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 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. 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 characterised 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: info@khondrion.com Tel: +31-24-7635000 www.khondrion.com Consilium Strategic CommunicationsDavid Daley, Melissa Gardiner, Kris LamE-mail: khondrion@consilium-comms.comTel: +44 20 3709 5700