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WASHINGTON & OXFORD, England--( BUSINESS WIRE )--Perspectum announced two research studies that were recently published, bringing hope to people with metabolic dysfunction-associated steatohepatitis (MASH). This research affirms the utility of quantitative MRI imaging as an alternative to liver biopsy in some clinical trials and in patient care management. The first study shows how noninvasive quantitative MRI scans can identify disease accurately and reproducibly. Perspectum’s second study , looks at participants in three multicenter clinical trials showing that changes in MRI biomarkers predict the biopsy changes in these patients, and thus identifies who are likely to respond to drug treatment. Specifically, a reduction of 80ms in cT1 predicted histological response. Rezdiffra was approved by FDA in March 2024, and is the first therapeutic for patients with MASH. There is a strong pipeline of MASH drugs under development in the U.S. with anticipated approval over the next few years. Eli Lilly’s tirzepatide in Metabolic dysfunction-associated steatotic liver disease (MASLD) published results in the New England Journal of Medicine in June 2024, showing a significant reduction in cT1 and liver fat over 52 weeks. Noninvasive tests (NITS) that can reliably monitor changes in liver health will reduce the need for liver biopsy -- currently used as the “gold standard” primary endpoint in MASH clinical trials. However, this new research recently reported may help pharmaceutical companies and regulatory entities have more options to consider; primarily, NITS may be used more as means to measure change in disease and monitor patient progress noninvasively. Perspectum’s CEO, Dr. Rajarshi Banerjee, commented, “Liver biopsy is not a safe or accurate way of assessing liver disease. Quantitative MRI is far safer, more scalable and authorized for clinical use. With more published data, the argument for replacing liver biopsy with quantitative MRI both in clinical practice and in clinical trials becomes stronger.” Dr. Naim Alkhouri, Chief Medical Officer, Chief of Transplant Hepatology, and Director of the Fatty Liver Program at Arizona Liver Health and the study’s lead author said, “Establishing a threshold for cT1 reduction that can predict histologic improvement in terms of MASH resolution and fibrosis improvement will have great implications for the field and may help replace the need for liver biopsy in MASH clinical trials in the future.” Dr. Banerjee concluded that, “With the continued support of the liver disease community of stakeholders, more studies and findings such as these may see pharmaceutical companies reconsider their approach to monitoring patients in clinical trials.” About LiverMultiScan LiverMultiScan is an established, FDA cleared technology that addresses a critical unmet need for noninvasive techniques to diagnose and monitor patients with chronic liver diseases such as nonalcoholic steatohepatitis, autoimmune hepatitis, or viral hepatitis. LiverMultiScan uses a noninvasive multiparametric magnetic resonance imaging (MRI) scan to accurately assess signs of liver disease by simultaneously quantifying liver disease activity and severity (using a proprietary MRI metric, cT1), fat, and iron content, offering a comprehensive picture of liver health. About the FDA-Supported Study This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [U01FD006880] totalling $249,940 with 100 percentage funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. About Perspectum Perspectum, a global medical technology company with offices in the U.K., the U.S., the EU, and Singapore, delivers leading digital technologies that help clinicians provide better care for patients with chronic metabolic disease, multi-organ diseases and cancer. With a strong focus on precision medicine using advanced imaging and genetics, our vision is to empower patients and clinicians through quantitative assessments of health enabling early detection, diagnosis, monitoring, and targeted treatment. With a diverse team of physicians, biomedical scientists, engineers and technologists, Perspectum offers a way to manage complex health problems at scale. For additional information, please visit: Perspectum.com and LinkedIn

引言骨分泌蛋白，称为骨因子，调节骨代谢和全身稳态。然而，关于真正的骨因子和它们的细胞来源是什么以及它们是如何被调节的基本问题仍然不清楚。2024年4月3日，南方医科大学白晓春、邹志鹏及中国科学院深圳先进技术研究院陈棣共同通讯在Cell Metabolism在线发表题为“An integrated multi-omics analysis reveals osteokines involved in global regulation”的研究论文，该研究分析了骨骼和骨骼外组织、成骨细胞(OB)条件培养基、骨髓上清(BMS)和血清，以寻找基础骨因子和那些对衰老和机械加载/卸载有反应的骨因子。通过整合RNA-seq、scRNA-seq和蛋白质组学方法的数据，该研究确定了375个候选骨因子及其对衰老和机械动力学的响应变化。此外，分析了它们在骨中的细胞来源和它们促进的器官间通讯(骨-脑、肝和主动脉)。值得注意的是，衰老的OBs分泌脂肪酸结合蛋白，使衰老向血管平滑肌细胞(VSMCs)传播。综上所述，该研究确定了以前未知的候选骨因子，并在它们之间建立了一个动态的调控网络，从而为进一步研究它们的系统作用提供了宝贵的资源。骨因子是指由骨产生和释放的一组细胞因子或肽，它们随后发挥自分泌、旁分泌和/或内分泌作用。骨是一种高度动态和代谢活跃的组织，在整个生命过程中经历不断的重塑以保持其强健的结构和功能，这一重塑过程涉及破骨细胞骨吸收和成骨细胞骨形成的协调作用。骨细胞(包括OBs细胞、破骨细胞、骨细胞、软骨细胞和骨髓基质细胞[BMSCs])之间广泛的分子通讯是精确调节骨形成和吸收的基本机制。OBs分泌多种骨因子，包括巨噬细胞集落刺激因子(M-CSF)，RANKL/OPG、SEMA3A和WNT5a调节破骨细胞的发生。此外，OBs分泌WNT4以自分泌方式促进骨形成，并以旁分泌方式抑制破骨细胞形成和吸收。骨细胞产生SOST抑制OB分化并促进破骨细胞分化。另一方面，破骨细胞分泌诸如CT-1、S1P、EphrinB2和SEMA4D等骨因子这些骨因子作用于OBs和骨细胞，影响成骨。此外，转化生长因子-β (TGF-β)调节破骨细胞OB串扰，将OB祖细胞募集到骨吸收部位，并促进骨形成。模式图（Credit: Cell Metabolism）近几十年来，骨生物学的重大进展揭示了骨的内分泌功能。骨源性FGF23调节肾脏中磷酸盐稳态的发现首次确立了骨作为内分泌器官的地位骨钙素促进胰岛素分泌和胰腺β细胞增殖，增加男性生育所需的睾酮生物合成，并修复神经变性导致的认知缺陷。另一个有趣的发现是OBs衍生的脂钙素-2 (LCN2)通过下丘脑的黑素皮质素4受体抑制食物摄入并调节葡萄糖水平。还报道了一系列调节骨髓微环境和造血的骨因子，如OBs衍生的CXCL9和骨细胞衍生的白细胞介素(IL)-34。这些发现表明骨因子在骨代谢和全身稳态中起重要作用。然而，现有的研究是有限的，缺乏整合。目前，对于骨因子的基本特征，如存在什么骨因子，从哪类骨细胞分泌骨因子，以及它们如何受环境因素的调节等，还缺乏全面的认识。此外，多组学方法提供了对生物学和疾病更全面的理解，使新的诊断和治疗靶点得以确定。该研究使用大量和单细胞转录组学和蛋白质组学进行了综合分析，以确定可能有助于骨代谢和全身稳态的骨因子。还鉴定了基础骨因子、衰老相关骨因子、机械反应性骨因子和OBs分泌骨因子(OBKs)，定位了它们在骨中的细胞来源，并分析了这些骨因子在器官间的通讯。孟德尔随机化(MR)分析显示，低骨密度(BMD)可能是动脉粥样硬化性心血管疾病(ASCVD)的潜在因果危险因素。衰老OBs分泌脂肪酸结合蛋白3 (FABP3)，使衰老向血管平滑肌细胞(VSMCs)扩散。总的来说，该研究建立了一个影响骨重塑和全局稳态的骨因子动态网络，为深入研究提供了宝贵的资源。原文链接https://doi.org/10.1016/j.cmet.2024.03.006责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace In one of the year’s most highly anticipated decisions, the FDA approved Madrigal Pharmaceuticals’ resmetirom Thursday as the first-ever therapy for metabolic dysfunction-associated steatohepatitis. Resmetirom, which will be marketed as Rezdiffra, is indicated for the treatment of patients with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis, along with diet and exercise, according to the FDA's press release. Speaking with BioSpace ahead of the decision, experts said the approval could signal a sea-change in the diagnosis and treatment of MASH. Resmetirom met its two primary endpoints in the MAESTRO-NASH Phase III trial, significantly improving disease resolution and liver fibrosis. The data, published last month in The New England Journal of Medicine, show that NASH resolved in 25.9% of patients who received an 80-mg dose of resmetirom and 29.9% of those taking 100 mg, with no worsening of fibrosis. This was compared to 9.7% of patients in the placebo group. Resmetirom targets thyroid hormone receptor beta (THR-β), which helps maintain liver homeostasis. THR-β agonists have been shown to improve lipid metabolism. “This is a huge area and affects millions of patients,” Rajarshi Banerjee, CEO of Perspectum, which supported Madrigal’s clinical trials, told BioSpace prior to the decision. “There are no effective approved therapies, and so Madrigal’s resmetirom, even though it has limited efficacy, would be an important first.” The Future MASH Market Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), affects 5.3 out of every 1000 people worldwide, according to a 2021 article published in MDPI. In the U.S., the disease accounts for 18% of all hepatocellular carcinoma cases. Rohan Palekar, CEO of the biotech 89bio, which is developing therapies for the treatment of liver and cardiometabolic diseases, told BioSpace that this is likely an underestimate. “Right now, if someone walks into the clinic who is obese and diabetic, physicians counsel them on diet and lifestyle but don’t necessarily work them up for MASH, because they don’t have a medication to give them,” Palekar explained. “Once we have one approved drug, I believe the diagnosis of MASH will increase.” The same is true for the MASH precursor, fatty liver or MAFLD (metabolic dysfunction-associated fatty liver disease), he said. “There is a greater unmet need than we know.” 89bio is developing pegozafermin, which aims to prolong the biological activity of fibroblast growth factor 21 (FGF21), for MASH. FGF21 regulates multiple metabolic pathways and cellular processes. The company earlier this week initiated its Phase III clinical trial program with the ENLIGHTEN-Fibrosis study, which will evaluate pegozafermin in non-cirrhotic MASH patients with fibrosis stage F2-F3. A second trial, ENLIGHTEN-Cirrhosis, which will assess the drug in patients with compensated cirrhosis (F4), is expected to begin in the second quarter of 2024. “We think a pretty dramatic change is on the way for the recognition and treatment of MASH,” Palekar said. “People may remember when the first lipid-lowering agents came out, it took time for awareness and education to catch up. Now everybody gets their LDL [cholesterol] checked and gets on a statin if it’s elevated.” He sees a similar trajectory for MASH and MAFLD. The Treatment Landscape Already, some of the unmet need in MASH can be met by GLP-1 anti-obesity drugs, said Mayank Mamtani, head of healthcare research at B. Riley Securities. “The unmet need is simply not the same as it was before the weight loss drugs came along,” he told BioSpace. “I would argue that the anti-obesity drugs have the same benefit as resmetirom [in MASH].” Moreover, Mamtani said, weight loss drugs such as Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound, might be less expensive. While a weight loss drug can cost $15,000 per year, Madrigal’s drug may cost between $30,000 and $40,000 annually. Still, there are “multiple molecules out there” with potential to treat MASH specifically, Mazen Noureddin, who recently established the Houston Research Institute, told BioSpace. “I hope this will be the first in a series of approvals,” he said of resmetirom. As more drugs hit the market, Noureddin envisions that different pharmaceuticals will be combined to treat MASH. “In a perfect world, resmetirom will be combined with other molecules, such as those targeting semaglutide,” the GLP-1 analog that forms the basis of Wegovy and Zepbound, he said. Anti-obesity drugs can be effective in earlier stages of MASLD, he added, but because some of them have “little antifibrotic effect, they will be combined with strong antifibrotics." Mamtani said he hopes the greenlight of resmetirom will lead the way for other approvals that act directly on fibrosis. He specifically cited pegozafermin and Akero Therapeutics’ exfruxifermin, both FGF21 analogs, as examples. “That’s the holy grail to help people who are very close to liver failure,” he said. “It will just take a lot of time and capital to generate that data.” Ultimately, treatment of MASH may have a huge impact on patients’ health and physicians’ treatment practices because of the ways it can overlap with cardiovascular medicine, Banerjee predicted. “Liver disease can cause liver failure, but it is more likely to cause heart disease, including heart failure, atrial fibrillation and heart attacks,” he said. However, he added, “Liver disease is a modifiable cardiovascular risk factor, like high cholesterol, diabetes and smoking. It can be reversed. This is why MASH matters to cardiologists and internists, even if it is asymptomatic—treat it, and you could potentially stop heart attacks like statins do.” The Diagnostic Conundrum One of the biggest challenges facing the MASH field is how to identify, define and measure the disease and improvements in it, including primary endpoints to be met in clinical trials. In a paper published in Nature on March 9, Noureddin and colleagues address both the challenges and opportunities in MASH diagnosis and treatment. Currently, liver biopsy is the gold standard, but it has drawbacks. At 89bio, Palekar said, liver biopsies were performed at the start of the Phase IIb ENLIVEN 48-week clinical trial, then again at week 24. Because pathologist interpretations on the degree of fibrosis can vary, each biopsy was sent to three separate pathologists. “At least two out of three had to agree,” he explained. Another problem with biopsies is that the liver is a large organ, Palekar noted, and a biopsy can only capture a small slice of it. In addition, “patients don’t like biopsies, and they present risks, such as bleeding.” Moreover, once medications are approved and available, liver biopsy would be impractical and too expensive for routine clinical use, Palekar said. Currently, two large consortiums, the U.S.-based Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) and the European Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS), are working to establish noninvasive markers and clinical endpoints for MASH and non-alcoholic fatty liver disease. These can include MRI imaging to quantify the amount of fat and fibrosis in the liver, ultrasound and blood biomarkers such as liver enzyme levels. In addition, Banerjee said, Perspectum is working on a proprietary marker called cT1, which the company hopes will predict clinical outcomes even better than liver biopsy. For now, those in the field appear to be optimistic. “2024 is going to be a happy year for MASH,” Noureddin said. “I think we’re going to see the movement to replace liver biopsy with noninvasive markers. I’m excited we are going to be able to give our patients options.” Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.