CCN4

Phase 1 study of MTX-463 initiated after FDA Clearance of IND IND-enabling studies completed for second antibody program with Phase 1 expected to start in Q3 Clinical Advisory Board (CAB) of global experts in fibrosis formed to advance clinical development New preclinical data to be presented at upcoming medical meetings on WISP-1 and EphrinB2 and their roles in Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis (SSc), respectively BOSTON, May 6, 2024 /PRNewswire/ -- Mediar Therapeutics, Inc., a biotechnology company advancing a portfolio of first-in-class therapies that halt fibrosis progression, today announced that, following FDA clearance of its investigational new drug (IND) application, the first cohort of participants has been dosed in a Phase 1 trial evaluating the safety and tolerability of MTX-463. MTX-463 is a first-in-class human IgG1 antibody designed to neutralize WISP-1-mediated fibrotic signaling to address IPF and other fibrotic diseases. The Phase 1 study for MTX-463 is designed to assess its safety at multiple dose levels, tolerability, and pharmacokinetics, while also assessing the ability of MTX-463 to engage its target, WISP-1. The trial is enrolling healthy participants and consists of staggered single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. "Advancing our first-in-class portfolio to the clinic is an important milestone for Mediar, and an exciting moment envisioned by our founders at Mass General Brigham and advanced by our team," said Mediar's Chief Executive Officer Rahul Ballal, Ph.D. "MTX-463 is the first of two programs to begin clinical trials this year and we look forward to initiating a second Phase 1 study with our first-in-class anti-EphrinB2 molecule, MTX-474, in the third quarter." As Mediar advances MTX-463 and MTX-474 into human studies, it will be guided by its clinical advisory board, comprising world renowned leaders in fibrosis across pulmonology, rheumatology, hepatology, and regulatory. "With the formation of our CAB, we bring together a wealth of experience and expertise to help advance the clinical development of our pipeline as we work to address the significant unmet need in fibrosis," said Mediar's Chief Medical Officer Jeff Bornstein, M.D. The newly appointed members of the clinical advisory board are: Flavia Castelino, M.D., Associate Professor of Medicine, Harvard Medical School, Division of Rheumatology, Massachusetts General Hospital Lara Dimick-Santos, M.D., Medical Director, CTI Clinical Trial & Consulting Services, former FDA medical reviewer Scott Friedman, M.D., Dean for Therapeutic Discovery, Fishberg Professor of Medicine, Director, Institute for Liver Research, Icahn School of Medicine at Mount Sinai Robert Lafyatis, M.D., Professor of Medicine, Division of Rheumatology & Clinical Immunology, University of Pittsburgh Medical Center Rohit Loomba, M.D., MHSc, Professor of Medicine, Chief of the Division of Gastroenterology and Hepatology, University of California San Diego Toby Maher, M.D., Ph.D., Professor of Medicine, Director of Interstitial Lung Diseases, University of Southern California Sydney Montesi, M.D., Assistant Professor of Medicine, Harvard Medical School, Pulmonary and Critical Care Medicine, Massachusetts General Hospital John Varga, M.D., Professor of Medicine, Chief of the Division of Rheumatology, University of Michigan In addition, new preclinical data supporting the application of MTX-463 in IPF will be presented at the 2024 American Thoracic Society (ATS) meeting in San Diego, May 17-22, 2024. Data supporting MTX-474 in Systemic Sclerosis (SSc) will be presented in an oral presentation at the Congress on the EPH/Ephrin System in Parma, Italy, May 16-17, 2024. About MTX-463 MTX-463 is a first-in-class human IgG1 antibody developed against WNT1-inducible signaling pathway protein-1 (WISP-1). WISP-1 is a secreted matricellular protein shown to have a relevant role in fibrosis progression, measurable in human blood, and correlates with disease severity. Initial data indicates that MTX-463 neutralizes WISP-1-mediated fibrotic signaling that spans several fibrotic indications and significantly reduced fibrosis in vitro and in preclinical mouse models. MXT-463 is currently in Phase 1 clinical evaluation to assess its safety and tolerability in healthy participants (NCT06401213). About MTX-474 MTX-474 is a first-in-class human IgG1 antibody designed to neutralize the EphrinB2 signaling that causes the onset and progression of fibrosis. Ephrin ligands and Eph receptors mediate biological processes involved in tissue fibrosis including cell migration, myofibroblast activation, and tissue remodeling. A growing body of evidence has implicated EphrinB2 in the fibrosis of the skin, lungs, and heart. Expression of EphrinB2 and its receptors are measurable in human blood and correlates with disease severity. Initiation of Phase 1 clinical studies for this program is anticipated in Q3-2024. About Mediar Therapeutics Mediar Therapeutics is pioneering a new approach to fibrosis treatment that halts the disease at a different source – the myofibroblast, the key pathogenic cell in fibrosis that drives scarring, disease progression, and ultimately organ failure. Mediar was founded based on a deep understanding of the complex science underlying fibrosis onset and progression. By combining novel targets with reliable, easily detectable blood biomarkers and familiar modalities, Mediar is derisking the path forward for fibrosis therapies in clinical development. For more information, contact [email protected] or follow us on LinkedIn. SOURCE Mediar Therapeutics

*仅供医学专业人士阅读参考骨髓是人体的造血器官，在这里，造血干细胞处于由间充质干细胞等细胞构成的造血微环境之中，进行自我更新和多能性分化。造血干细胞分化为髓系祖细胞和淋巴系祖细胞，进而分化为髓系免疫细胞、血小板、红细胞等髓系细胞以及淋巴系细胞，此过程即为造血。骨髓造血活性增强是各种慢性病的标志，伴随的则是造血干细胞的自我更新能力逐渐耗尽。法国巴黎西岱大学的Julie Helft及其同事们的最新研究表明，乳腺癌能够在保留其自我更新能力的情况下，诱导全身的造血干细胞向髓系细胞的分化。他们使用转录组学分析和原位成像技术，发现乳腺癌能够远程重塑骨髓造血微环境，诱导造血干细胞和间充质干细胞在转录水平和空间定位上发生变化，从而影响造血微环境中细胞间的交流与互作，增加髓系细胞的浸润，但不会导致造血干细胞功能衰竭。论文首页截图髓系细胞浸润通常与实体瘤患者预后较差以及疾病严重性相关，因此了解患癌期间骨髓造血的情况和机制，对于抗肿瘤治疗至关重要。在这项研究中，先是利用乳腺癌小鼠模型的组织学切片和单细胞RNA测序分析，Julie Helft等人发现，局限发生于乳腺的肿瘤能够诱导小鼠发生全身性的变化。与正常小鼠相比，乳腺癌小鼠的骨髓造血活性增强，从基因表达特征来看，造血干细胞的髓系分化潜力增加。提取小鼠的造血干细胞，在体外实验中通过特定条件培养或者给其它小鼠进行移植，可以更直观地观察到，相比于正常小鼠，乳腺癌小鼠来源的造血干细胞确实更容易向髓系细胞分化。不过令人意外的是，尽管已表现出更高的髓系细胞分化潜能，乳腺癌小鼠造血干细胞的自我更新能力并没有减弱，体外培养7小时后，其造血干细胞数量是正常小鼠的2倍。乳腺癌小鼠的造血干细胞功能没有减弱此外，研究者们发现ANGPT2、WISP1和OPG等调控骨组织稳态的蛋白质在乳腺癌小鼠血液中水平提高。于是，他们使用荧光探针来检测小鼠体内的骨骼生长情况，发现乳腺癌小鼠比正常小鼠的骨骼形成增加。进一步的小鼠肱骨成像结果显示，乳腺癌小鼠肱骨的血管形态发生变化，血管内皮细胞的直径、体积和长度减少，且间充质干细胞的定位异常。具体而言，乳腺癌小鼠的间充质干细胞不再分布在血管内皮细胞周围，远离血管，而是与造血干细胞“贴紧”。与正常小鼠相比，乳腺癌小鼠的间充质干细胞与造血干细胞之间距离缩小、相互作用增强，造血干细胞则在骨髓中分布不均。造血干细胞和间充质干细胞的分布特点也就是说，乳腺癌小鼠造血干细胞所处的骨内膜生态位被重塑。对于乳腺癌小鼠的间充质干细胞来说，不仅是迷失了定位，基因表达也发生改变，表达更多与成骨细胞特征相关的基因（Mmp13、Col1a1），与脂肪细胞分化相关的基因（Apoe、Adipoq）表达下调。而且与成纤维细胞、成骨细胞和血管内皮等其它骨髓基质细胞相比，间充质干细胞在转录水平上受到最显著的影响。另外，体外实验验证表明，乳腺癌小鼠来源的间充质干细胞能够促进造血干细胞的扩增和向髓系细胞的分化。这些表明间充质干细胞有助于乳腺癌诱导骨髓造血活性增强。间充质干细胞促进造血干细胞向髓系细胞分化Julie Helft等人表示，这项研究结果暗示着癌症与慢性病以不同机制影响髓系造血，他们将在未来进一步探索乳腺癌条件下间充质干细胞和造血干细胞之间的互作关系，并找到乳腺癌远程操控骨髓的机制。参考文献：[1]https://www.nature.com/articles/s41556-023-01291-w本文作者丨张艾迪

Mediar's new partnerships follow an $85 million series A closed in March. Mediar Therapeutics is tapping the business development well early, teaming up with Pfizer and WuXi Biologics as two assets near the clinic.  The fibrosis-focused biotech will be lent Pfizer’s assistance on R&D work, test development and IND-enabling studies for its first two assets, MTX-463 and MTX-474, according to an announcement Wednesday. Though financial details weren’t disclosed, the biotech says it will retain full decision-making authority and rights to both programs. China's WuXi will assist with providing drug substance for the trials and bolstering manufacturing capabilities. Both partnerships are a function of Mediar’s nearing clinical arrival, with the two assets expected to reach phase 1 trials next year. The first candidate, MTX-463, is a monoclonal antibody targeting WISP-1, a kind of protein that often operates in the extracellular matrix and regulates cell function. Elevated levels of the protein have been associated with fibrosis progression. MTX-474 targets EphrinB2, which similarly impacts disease progression.  Mediar is not just bolstering external efforts to support its clinical progress, however. Jeffrey Bornstein, M.D., is joining as chief medical officer, moving across from Eledon Pharmaceuticals where he held the same role. Before that, he was a leader in Takeda’s gastroenterology unit, elevating from executive medical director to VP and head of clinical science over a four-year span. He also spent more than six years combined at Biogen and Gilead.  With the latest partnerships and a clinical leader on board, all systems appear ready to go. Mediar previously took care of the necessary fundraising to afford this stage of development, inking $85 million from a series A back in March. Novartis’ venture fund and Soffinova co-led the round, with help from Bristol Myers Squibb and Pfizer.