Universität Ulm

研究人员利用哮喘和类风湿性关节炎动物模型，证实了糖皮质激素的抗炎作用在多大程度上取决于衣康酸。 可的松（cortisone）和其他相关的糖皮质激素（glucocorticoids）在抑制过度免疫反应方面非常有效。但在此之前，人们对它们如何做到这一点却知之甚少。 如今，在一项新的研究中，来自柏林夏里特医学院、埃尔兰根大学和乌尔姆大学的研究人员对它们的分子作用机制进行了更详细的探索。他们报告说，糖皮质激素能重塑免疫细胞的代谢，激活身体对炎症的天然“刹车”。这些发现为开发副作用更小、更轻的抗炎药物奠定了基础。 相关研究结果于2024年4月10日在线发表在Nature期刊上，论文标题为“Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids”。 糖皮质激素家族的一员——可的松，实质上是以皮质醇形式自然存在于人体内的一种应激激素。当机体面临压力时，会释放皮质醇来优化对压力的响应，它会调节糖和脂肪代谢，同时影响血压、呼吸频率和心率等生命指标。在较高剂量下，皮质醇还能抑制免疫系统的活动，这使得合成的糖皮质激素衍生物因其卓越的抗炎效果，得以广泛应用于免疫介导性炎症性疾病的治疗，成为全球应用最广泛的药物之一。 然而，糖皮质激素的作用并不局限于基因层面，还深刻地改变了细胞的能量代谢途径，这也正是其潜在副作用的根源，如长期大量使用可能导致高血压、骨质疏松、糖尿病和体重增加等问题。 糖皮质激素不仅影响基因，也影响细胞能量来源 为了开发副作用更小、更轻的抗炎药物，柏林夏里特医学院风湿病学与临床免疫学系主任Gerhard Krönke教授及其团队对糖皮质激素的免疫抑制机制进行了深度剖析。 Krönke教授指出，以往的研究虽已揭示糖皮质激素能够激活多种细胞内众多基因，但这并不能完全阐明其强大的免疫抑制效能。他们的新研究则证实了糖皮质激素不仅调控免疫细胞基因表达，更直接影响细胞的能量中心——线粒体，这一对细胞代谢的改变对于糖皮质激素的抗炎效果至关重要。 化剑为犁 在这项新研究中，研究人员聚焦于巨噬细胞，这是一种承担清除病毒、细菌等外来入侵者重任的免疫细胞，同时也是某些免疫介导性炎症性疾病发生的关键因素。通过实验室环境下的实验，他们观察了从实验小鼠体内提取的巨噬细胞对炎症刺激的反应，以及添加糖皮质激素后的效果。研究发现，除了基因表达的调控外，糖皮质激素还显著逆转了由炎症刺激所引发的细胞代谢变化。 图片来自Nature, 2024, doi:10.1038/s41586-024-07282-7 Krönke说，“当巨噬细胞进入‘战斗’模式时，它们会将它们的细胞能量转用于战斗。它们的线粒体不再提供能量，而是产生打击入侵者所需的成分。糖皮质激素逆转了这一过程，关闭了‘战斗’模式，可以说是化剑为犁。一种名为衣康酸（itaconate）的微小分子在其中发挥着特别重要的作用。” 衣康酸介导糖皮质激素的抗炎作用 衣康酸是人体线粒体内自然产生的一种抗炎物质。巨噬细胞在被激活的早期就会产生这种物质，这样炎症反应就会在一段时间后消退。然而，产生这种天然免疫“制动器”需要足够的燃料。当细胞的能量工厂正在准备战斗时，情况就不再是这样了，因此衣康酸的产生会在一段时间后减少到停止。对于正常的短期炎症，这个时机是有效的，因为在此期间免疫反应也已经减弱。 衣康酸是人体线粒体自然产生的具有抗炎作用的物质，巨噬细胞在激活初期会大量生成衣康酸，以此确保炎症反应在适当的时间逐渐消退。然而，在长时间炎症刺激下，线粒体因战斗模式的持续而无法提供充足的燃料来维持衣康酸的生成，导致其分泌逐渐减少直至停止，而这可能造成慢性炎症的持续存在。糖皮质激素通过重新编程线粒体功能，促进了巨噬细胞内衣康酸的生成，从而恢复了其抗炎效果。 寻找新的活性物质 研究人员利用哮喘和类风湿性关节炎动物模型，证实了糖皮质激素的抗炎作用在多大程度上取决于衣康酸。糖皮质激素对不能产生衣康酸的动物没有作用。那么，如果衣康酸介导了可的松的免疫抑制作用，直接给动物服用衣康酸而不是糖皮质激素不就可以了吗？ Krönke解释说，“不幸的是，衣康酸并不是一种特别理想的抗炎药物，因为它不稳定，而且由于它的高反应性，如果全身给药，可能会产生副作用。除此之外，我们认为人体内的过程要比小鼠体内的过程复杂一些。因此，我们的计划是寻找新的合成化合物，它们在重塑免疫细胞内的线粒体代谢方面与糖皮质激素一样有效，但副作用更小，也不那么严重。”（生物谷 Bioon.com） 参考资料： Jean-Philippe Auger et al. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids. Nature, 2024, doi:10.1038/s41586-024-07282-7. Study in Nature unlocks how cortisone inhibits inflammationhttps://www.fau.eu/2024/04/10/news/research/study-in-nature-unlocks-how-cortisone-inhibits-inflammation/

Cortisone and other related glucocorticoids are extremely effective at curbing excessive immune reactions. But previously, astonishingly little was known about how they exactly do that. Researchers have now explored the molecular mechanism of action in greater detail. As the researchers report, glucocorticoids reprogram the metabolism of immune cells, activating the body's natural 'brakes' on inflammation. These findings lay the groundwork for development of anti-inflammatory agents with fewer and less severe side effects. Cortisone and other related glucocorticoids are extremely effective at curbing excessive immune reactions. But previously, astonishingly little was known about how they exactly do that. A team of researchers from Charité -- Universitätsmedizin Berlin, Uniklinikum Erlangen and Ulm University have now explored the molecular mechanism of action in greater detail. As the researchers report in the journal Nature, glucocorticoids reprogram the metabolism of immune cells, activating the body's natural "brakes" on inflammation. These findings lay the groundwork for development of anti-inflammatory agents with fewer and less severe side effects. The glucocorticoid cortisone is actually naturally present in the body as cortisol, a stress hormone. The organism releases cortisol to improve the body's responses to stress. Cortisol intervenes in sugar and fat metabolism and affects other parameters, including blood pressure and respiratory and heart rate. At higher doses, it also inhibits the activity of the immune system, which makes it useful for medical purposes: Due to their excellent efficacy, synthetic glucocorticoid derivates that inhibit inflammation, even more than the natural substance present in the body, are used to treat a wide range of immune-mediated inflammatory diseases. They are among the most widely used medications of all. Glucocorticoids affect not only genes, but also cellular energy sources However, glucocorticoid-based medications also have side effects, especially at higher doses and when administered for longer periods. These side effects are related to the other effects of the body's own cortisol. They include high blood pressure, osteoporosis, diabetes, and weight gain. With the aim of developing anti-inflammatory agents with fewer and less severe side effects, a team of researchers led by Prof. Gerhard Krönke, director of the Department of Rheumatology and Clinical Immunology at Charité, has now conducted a closer study of how the immunosuppressive effects of glucocorticoids exactly works. "It was previously known that glucocorticoids activate a number of genes in different cells of the body," Krönke explains. "But through this mechanism, they mainly activate the resources present in the body. This does not adequately explains its strong immunosuppressive effect. In our study, we have now been able to show that glucocorticoids affect more than just the gene expression in immune cells. It also affects the cell´s powerhouses, the mitochondria. And that this effect on cell metabolism is in turn crucial to the anti-inflammatory effects exerted by glucocorticoids." Swords to plowshares For the study, the research team focused on macrophages, a type of immune cell responsible for eliminating intruders such as viruses and bacteria. These cells can also play a role in the emergence of immune-mediated inflammatory diseases. The researchers studied how these immune cells -- derived in this case from mice -- responded to inflammatory stimuli in a laboratory setting and what effects additional administration of a glucocorticoid had. The researchers observed that in addition to its effect on gene expression, glucocorticoids had a major effect in reversing changes in the cell metabolism that had been initiated by the inflammatory stimuli. "When macrophages are put into 'fight' mode, they redirect their cellular energy into arming for a fight. Instead of supplying energy, their mitochondria produce the components needed to fight intruders," Krönke says, describing the processes involved. "Glucocorticoids reverse the process, switching the 'fight' mode back off and turning swords into plowshares, so to speak. A tiny molecule called itaconate plays an especially important role in this." Itaconate mediates anti-inflammatory effect of glucocorticoids Itaconate is an anti-inflammatory substance that the body naturally produces inside its mitochondria. Macrophages produce it early on when they are activated so that the inflammatory reaction will subside after a certain period. Generation of this natural immune "brake," however, requires sufficient fuel. When the cell´s powerhouses are arming up for a fight, that is no longer the case, so itaconate production dwindles to a halt after a while. With normal, short-term inflammation, this timing is effective because the immune response has also subsided in the meantime. "With a persistent inflammatory stimulus, the drop-off in itaconate production is an issue because there is then no immune 'brake' even though the immune system is still running on all cylinders, eventually contributing to chronic inflammation," explains Dr. Jean-Philippe Auger, a scientist at the Department of Medicine 3 -- Rheumatology and Immunology at Uniklinikum Erlangen and the first author of the study. "This is where glucocorticoids intervenes. By reprogramming the mitochondrial function, they ramp up the formation of itaconate in the macrophages, restoring its anti-inflammatory effect." The search for new active substances Using animal models for asthma and rheumatoid arthritis, the researchers were able to demonstrate how much the anti-inflammatory effect of glucocorticoids depends on itaconate. Glucocorticoids had no effect in animals that were unable to produce itaconate. So, if itaconate mediates the immunosuppressant effect of cortisone, wouldn't it be possible to administer itaconate directly, instead of glucocorticoids? "Unfortunately, itaconate isn't a particularly good candidate as an anti-inflammatory drug, because it's unstable, and due to its high reactivity, it could cause side effects if administered systemically," Krönke explains. "Aside from that, we assume the processes in humans to be a bit more complex than those in mice. So our plan is to look for new synthetic compounds that are just as effective as glucocorticoids at reprogramming the mitochondrial metabolism inside immune cells, but have fewer and less severe side effects."

PRESS RELEASE AB SCIENCE ANNOUNCES THAT HEALTH CANADA HAS GRANTED ELIGIBILITY FOR RECONSIDERATION REQUEST FOR MASITINIB IN AMYOTROPHIC LATERAL SCLEROSIS Paris, 3 April, 2024, 6pm CET AB Science SA (Euronext - FR0010557264 - AB) today announces that Health Canada has granted eligibility for reconsideration request for masitinib in amyotrophic lateral sclerosis (ALS). The reconsideration process will re-examine, with new assessors, the decision based on information that was included in the original submission. A Notice of Deficiency-Withdrawal (NOD/w) was issued on February 19, 2024 by Health Canada regarding the New Drug Submission (NDS) for masitinib in the treatment of ALS. The intention to submit a reconsideration request was based on the arguments summarized in the press release dated 26 February 2024. Health Canada and AB Science have held a meeting to discuss the reconsideration process. AB Science is working closely with the agency to facilitate the review of masitinib conditional approval in ALS. AB Science has 45 days to file the reconsideration request. The pivotal argument is on the treatment of missing data. Various sensitivity analyses show that study AB10015 was successful at week 48 when masitinib missing data are imputed as a placebo, which is recognized as a highly conservative methodology for missing data imputation (i.e., jump-to-reference). Rerandomization calculation, which ignores whether the data distribution is linear or not, was also successful. Furthermore, the Combined Assessment of Function and Survival (CAFS) analysis showed a p-value of 0.078, even though study AB10015 was not powered for this endpoint. A related time-to-event endpoint, Progression Free Survival (PFS), did show significant improvement in favor of masitinib. Additionally, in the subgroup of patients with ‘ALS prior to any loss of function’, a logically defined cohort based on masitinib’s mechanism of action, a long-term median overall survival (OS) benefit of +22 months (p=0.0192) was observed. Professor Albert Ludolph, MD, PhD, Medical Director of the Neurology Department of at the University of Ulm, and principal investor of masitinib confirmatory study in ALS commented that, “The recent failure of numerous phase 2 or 3 programs, including registered drugs such as AMX0035 (Amylyx) and oral edaravone (Ferrer), as well as investigational drugs such as TUDCA (the TUDCA-ALS consortium), reldesemtiv (Cytokinetics) and the RIPK1 inhibitor SAR443820 (Sanofi), have dashed the community's hopes of benefiting from new therapeutic advances and have effectively set us back with riluzole being the only treatment with a proven modest effect in the overall ALS population. We should learn from theses failures. First, that demonstration of efficacy over a 24-week period is not predictive of efficacy over a 48-week period, which is the adequate duration to demonstrate a disease modifying effect in ALS. Second, that a 48-week study inevitably generates a large number of missing data. This situation is not unique to masitinib. It is a real challenge in the evaluation of efficacy and we are at risk of overlooking promising compounds. Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration”. About AB ScienceFounded in 2001, AB Science is a pharmaceutical company specializing in the research, development and commercialization of protein kinase inhibitors (PKIs), a class of targeted proteins whose action are key in signaling pathways within cells. Our programs target only diseases with high unmet medical needs, often lethal with short term survival or rare or refractory to previous line of treatment. AB Science has developed a proprietary portfolio of molecules and the Company’s lead compound, masitinib, has already been registered for veterinary medicine and is developed in human medicine in oncology, neurological diseases, inflammatory diseases and viral diseases. The company is headquartered in Paris, France, and listed on Euronext Paris (ticker: AB). Further information is available on AB Science’s website: www.ab-science.com. Forward-looking Statements - AB ScienceThis press release contains forward-looking statements. These statements are not historical facts. These statements include projections and estimates as well as the assumptions on which they are based, statements based on projects, objectives, intentions and expectations regarding financial results, events, operations, future services, product development and their potential or future performance. These forward-looking statements can often be identified by the words "expect", "anticipate", "believe", "intend", "estimate" or "plan" as well as other similar terms. While AB Science believes these forward-looking statements are reasonable, investors are cautioned that these forward-looking statements are subject to numerous risks and uncertainties that are difficult to predict and generally beyond the control of AB Science and which may imply that results and actual events significantly differ from those expressed, induced or anticipated in the forward-looking information and statements. These risks and uncertainties include the uncertainties related to product development of the Company which may not be successful or to the marketing authorizations granted by competent authorities or, more generally, any factors that may affect marketing capacity of the products developed by AB Science, as well as those developed or identified in the public documents published by AB Science. AB Science disclaims any obligation or undertaking to update the forward-looking information and statements, subject to the applicable regulations, in particular articles 223-1 et seq. of the AMF General Regulations. For additional information, please contact: AB ScienceFinancial Communication & Media Relations investors@ab-science.com Attachment CP Health Canada Reconsideration Eligibility VENG VF