Namodenoson

编者按伴随着肥胖的流行，代谢功能障碍相关脂肪性肝炎（MASH）已成为全球公共卫生领域的重要挑战。近期，随着瑞美替罗与司美格鲁肽的相继获批，MASH治疗领域正经历一场深刻变革。这不仅体现在治疗手段的日益丰富，更在于治疗理念的系统性升级——从以生活方式干预为主导的模式，逐步转向融合了精准靶向、全身代谢调控及个体化治疗的综合管理新阶段。为全面把握MASH治疗的最新进展，本文基于近期发表于Lancet. Gastroenterology & Hepatology的一篇综述，对该领域进行系统解读，从流行病学现状、关键治疗突破、临床实践挑战及未来发展方向等多个维度展开分析，以期为临床决策提供循证参考，助力患者管理的优化与提升。被忽略的“代谢性杀手”：从良性肝病到多系统健康威胁代谢功能障碍相关脂肪性肝炎（MASH）长期以来被视为一种良性的肝脏病变，初期往往无明显症状，导致患者及部分医务人员对其危害认识不足，诊断和治疗严重滞后。近年来，随着大规模流行病学研究和临床随访数据的积累，人们逐渐认识到MASH远非一种静止或无害的疾病，而是一个具有明确进展风险、影响多系统健康的“代谢性杀手”。根据近期流行病学调查数据，MASH已成为全球范围内影响最为广泛的慢性肝病之一。近三十年来，其患病率已上升超过50%，约38.2%的成年人群受到不同程度的影响，成为不容忽视的公共卫生问题。更为关键的是，MASH具有明确的进展风险。临床观察显示，约有20%的患者会由单纯脂肪变性发展为肝纤维化，而在这些患者中，又有约20%可能进一步进展为肝硬化或肝细胞癌（图1）。这种由代谢紊乱驱动、逐步恶化的病程，凸显了早期干预与全程管理的重要性。图1. MASH病程进展从预后角度看，MASH患者的主要死亡原因并非单一肝脏问题，而是多系统受累的综合体现：心血管疾病居首位，其次为肝外恶性肿瘤，肝脏相关并发症（如肝硬化失代偿）位列第三。这一死亡谱系清晰表明，MASH管理必须超越肝脏本身，采取兼顾代谢、心血管及肿瘤风险的综合治疗策略。在此背景下，肝纤维化分期已成为评估疾病风险、指导临床决策的核心指标。特别是处于F2及以上分期的高危MASH患者，其未来发生肝脏失代偿、肝癌等严重事件的风险显著升高，因此成为当前新药研发和临床试验的重点关注人群，也是临床实践中需要优先干预的目标群体。治疗新时代：双路径突破重构MASH治疗格局随着对MASH发病机制的深入理解，药物研发取得了突破性进展。2024～2025年间，瑞美替罗和司美格鲁肽相继获批用于MASH治疗，两者具有完全不同的作用机制（图2）。 图2. 瑞美替罗和司美格鲁肽对MASH不同的作用靶点1. 瑞美替罗： 肝脏靶向疗法2024年，全球首个专门针对MASH的药物——甲状腺激素受体β（THR-β）激动剂瑞美替罗获得FDA批准，标志着肝脏靶向治疗新时代的开启。瑞美替罗高度选择性地激活肝脏中的THR-β受体，通过优化线粒体功能，促进脂肪酸β氧化，从细胞层面逆转肝脏脂质堆积的病理过程。MAESTRO-NASH试验显示，为期12个月的瑞美替罗治疗后，患者实现了病理改善与生活质量改善的双重获益。肝脏组织学改善：MASH消退率达到25.9%～29.9%（安慰剂组仅9.7%），纤维化分期改善至少一个级别的患者比例为24.2%～25.9%（安慰剂组14.2%）。纤维化改善的患者同时报告了具有临床意义的生活质量提升，2. 司美格鲁肽：代谢重塑疗法2025年，胰高血糖素样肽-1（GLP-1）受体激动剂——司美格鲁肽获批用于MASH治疗，开启了通过代谢调控治疗肝脏疾病的新范式。司美格鲁肽通过系统性代谢调节发挥多重效应：一方面通过中枢性食欲抑制和延缓胃排空实现显著的体重减轻，另一方面通过改善胰岛素敏感性、调节脂质代谢等途径，从根源上改善导致MASH的代谢紊乱状态。 ESSENCE试验结果显示，经过72周治疗后，司美格鲁肽组在组织学改善方面表现出色：MASH消退且纤维化无恶化的比例高达62.9%（安慰剂组34.1%），纤维化改善且MASH无恶化的比例为37.0%（安慰剂组22.5%）。这两个药物的获批，代表了MASH治疗的两种不同但互补的策略路径：一是直接作用于肝脏的特异性靶向治疗，二是通过改善全身代谢状态间接获益的系统性治疗，共同构成了当前MASH药物治疗的基石。治疗策略多元化：从代谢调节到精准靶向的协同突破随着对MASH复杂发病机制的深入理解，其药物研发格局已从过去单一靶点的探索，演变为多靶点、多策略并行的多元化时代。这些进展主要聚焦于两大类创新路径：针对全身性代谢紊乱的代谢调节疗法与直接作用于肝脏病理核心的肝脏靶向疗法，并辅以新兴的基因靶向疗法，共同构成了从根源调控到病灶精准干预的协同突破体系。1.代谢调节疗法——调控全身性代谢紊乱此类疗法旨在纠正驱动MASH发生发展的全身性代谢失衡。多靶点肠促胰素受体激动剂：以Tirzepatide（GIP/GLP-1双重激动剂）和Retatrutide（GLP-1/GIP/胰高血糖素三重激动剂）为代表。它们超越了单一GLP-1受体激动剂的作用，通过协同激活多个肠促胰素通路，在强效降糖、减重的基础上，对肝脏脂肪代谢和炎症显示出更全面的调控潜力。例如，在SYNERGY NASH Ⅱ期研究中，替尔泊肽使高达62%的患者实现MASH缓解且纤维化无恶化。成纤维细胞生长因子21（FGF21）类似物：如Efruxifermin、Pegozafermin 和Efimospherin α。FGF21是调节能量代谢的关键激素。这些工程化类似物通过增强肝脏脂肪酸β-氧化、抑制脂肪新生、改善胰岛素敏感性等多重作用，在Ⅱ期临床试验中显著改善了MASH组织学活动和纤维化，目前均已进入Ⅲ期研究阶段。过氧化物酶体增殖物激活受体（PPAR）激动剂：以Lanifibranor为代表，能同时激活PPAR-α、PPAR-γ和PPAR-δ亚型。这种多重激活带来了协同效应：调节脂质代谢、改善胰岛素敏感性、抑制炎症并直接抗纤维化。在NATIVE IIb期研究中，拉尼法兰显示出较高的MASH缓解率和纤维化改善率。2. 肝脏靶向疗法——直击肝脏病理核心这类药物旨在直接干预肝脏内导致脂肪变性、炎症和纤维化的特定分子通路。脂质合成关键酶抑制剂：Denifantast为靶向脂肪酸合酶（FASN），抑制肝脏内从头脂肪合成的最后关键步骤，减少毒性脂质（如棕榈酸酯）的积累，从而减轻脂毒性和炎症；ION224是一种靶向二酰基甘油O-酰基转移酶2（DGAT2）的反义寡核苷酸。DGAT2是甘油三酯合成的关键酶，抑制其活性可直接减少肝细胞内的脂肪堆积。新型肝脏内通路调节剂：ZSP1601通过提高肝细胞内环磷酸腺苷（cAMP）水平，抑制肿瘤坏死因子（TNF）等促炎因子产生，调节肝脏炎症和代谢；Namodenoson（A3腺苷受体激动剂）在临床前模型中显示出抗脂肪变性、抗炎和抗纤维化作用，其机制可能与调控Wnt/β-catenin和NF-κB通路有关；Microtirilant（选择性糖皮质激素受体调节剂/盐皮质激素受体拮抗剂）通过增加极低密度脂蛋白（VLDL）产生促进肝脏脂质流出，在早期试验中能快速降低肝脏脂肪含量。3. 基因靶向疗法——探索精准医疗前沿基于全基因组关联研究发现的MASH强遗传风险因素，针对特定基因的疗法正在开发中，代表了真正的精准医疗方向。AZD2693针对高风险基因PNPLA3**（尤其是p.I148M变异）的反义寡核苷酸。该变异与肝脏脂肪堆积增多和纤维化风险升高相关。AZD2693旨在沉默该风险基因的表达，目前正在针对携带该纯合变异的MASH患者进行IIb期研究（FORTUNA试验）。ARO-HSD一是种靶向HSD17B13基因的RNA干扰疗法。功能丧失性HSD17B13变异被认为具有保护作用，能降低MASH和纤维化风险。该疗法旨在降低肝脏中HSD17B13的表达，目前正在F3-F4期纤维化患者中进行IIb期研究（HORIZON试验）。简而言之，当前MASH的治疗策略已呈现出前所未有的多元化与协同性。研发管线涵盖了从调控全身代谢到精准靶向肝脏病灶，再到修正个体遗传风险的多个层面。这种“系统调控”与“局部靶向”相结合、“广谱干预”与“精准打击”相补充的策略，反映了现代肝病治疗理念的深刻演进，有望为具有不同主导病理机制、代谢特征和遗传背景的MASH患者，提供更为个体化、高效且持久的治疗方案。未来的治疗格局很可能是一种基于患者特征的组合拳模式，而非单一药物的治疗。从理念到实践：MASH治疗面临的新挑战与应对策略随着MASH治疗进入药物时代，临床实践面临着一系列新的挑战，这些挑战的解决将直接影响患者的短期治疗效果和长期预后。挑战1. 如何精准识别患者？在药物可及性提升的背景下，如何准确识别能从治疗中获益的目标人群——特别是F2-F3期纤维化的“MASH高危患者”——成为首要挑战。肝活检作为诊断金标准，在临床实践中应用受限。专家共识建议采用“两步法或多步法决策”：首先使用FIB-4、NFS等血清学模型进行初步筛查；对于无法确定诊断的患者，进一步结合肝脏弹性测定（如VCTE、MRE）或血清生物标志物（如ELF评分、Pro-C3）进行风险分层。值得注意的是，不同种族的检测阈值可能存在差异，因此需要建立不同种族特异性的评估标准。挑战2. 如何监测治疗反应？ 目前药物获批均基于短期的组织学改善，但长期临床结局数据尚未完善。如何有效地监测患者的治疗反应成为了另外一个挑战。目前临床主要依赖复合替代终点监测体系，具体包括：代谢指标：体重变化、血糖控制改善；血清生物标志物：ALT、AST等肝酶下降，特定纤维化标志物（如Pro-C3）变化；影像学评估：通过MRI-PDFF监测肝脏脂肪含量减少（通常认为减少≥30%有临床意义），通过弹性成像评估肝脏硬度改善；组织学改善（如可行）：MASH消退、纤维化分期逆转。挑战3. 如何对特殊人群进行管理？ MASH相关肝硬化患者的治疗面临着一系列特殊挑战：- 病理机制复杂化：肝硬化阶段的病理生理过程可能不同于早期MASH，疗效存在不确定性；- 治疗应答延迟：可能需要在更长疗程（如96周甚至更久）后才能观察到纤维化改善；- 评估标准调整：组织学改善的门槛更高，可能需要结合无创检测（如ELF评分变化≥0.5）与临床结局指标（如失代偿事件减少）进行综合判断。尽管MASH相关肝硬化的临床治疗挑战重重，但研究数据带来希望：即使在肝硬化阶段，纤维化逆转仍与肝脏相关事件风险降低显著相关。近期针对代偿期肝硬化患者的临床试验显示，部分患者可在较长时间治疗后实现纤维化改善和非侵入性标志物好转，这为这一难治人群的治疗提供了可能性。结语：从治疗突破到健康重塑目前MASH的治疗领域正在经历着深刻变革。瑞美替罗和司美格鲁肽的获批不仅是单一药物的成功，更代表着MASH治疗理念的根本转变——从单纯生活方式干预转向靶向药物与代谢调控相结合的精准治疗。在可见的未来，MASH管理将呈现三大发展趋势：治疗策略的整合化（药物干预、生活方式调整和共病管理协同推进）、临床实践的个体化（基于遗传特征、代谢表型和疾病阶段的定制方案），以及诊疗体系的系统化（从筛查诊断到长期随访的全病程管理）。这一转变不仅将改善肝脏组织学结局，更重要的是通过综合干预策略，全面降低心血管风险，优化代谢健康，最终提升患者的整体生活质量和长期预后。然而，机遇总与挑战并存。当前临床实践仍面临精准患者识别、疗效动态监测和特殊人群管理等诸多难题。解决这些挑战需要医学界、科研机构和公共卫生体系的协同努力：持续开展高质量临床试验积累循证医学证据，建立完善的诊疗标准和质控体系，发展先进的无创诊断和监测技术。展望未来，随着更多创新药物的问世和治疗方案的优化，MASH的治疗将不再局限于肝脏本身，而是成为代谢健康综合管理的重要组成部分。我们期待通过多学科协作和创新突破，为全球数亿MASH患者带来更有效的治疗选择，真正实现从“治疗疾病”到“促进健康”的医学理念升华。最终，MASH治疗的成功将不仅体现在肝活检报告的改善，更将体现在患者更长的健康寿命、更高的生活质量和更全面的代谢健康。这是现代医学对复杂代谢性疾病认识的深化，也是精准医疗理念在肝病领域的生动实践。参考文献：Li, Wenhao et al. “Current and emerging therapeutic landscape for metabolic dysfunction-associated steatohepatitis.” The lancet. Gastroenterology & hepatology vol. 11,2 (2026): 150-162. doi:10.1016/S2468-1253(25)00260-2声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。（来源：《心肾代谢时讯》编辑部）

Namodenoson Provided Clinical Stabilization as a Potential Bridge to Transplant in Advanced Liver Failure Ramat Gan, Israel, Feb. 05, 2026 (GLOBE NEWSWIRE) -- Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CANF), a biotechnology company developing a pipeline of proprietary small molecule drugs targeting oncological and inflammatory diseases, today announced that a patient with advanced decompensated liver cirrhosis who was treated with Namodenoson subsequently underwent a successful liver transplantation. The patient received Namodenoson treatment under a compassionate use framework while suffering from liver disease and complications consistent with decompensated cirrhosis. Throughout the treatment period, Namodenoson contributed to clinical stabilization, allowing the patient to remain a suitable candidate for liver transplantation until a compatible donor organ became available, ultimately resulting in a successful, life-saving liver transplantation. While this is a single case, the outcome suggests a potential supportive role for Namodenoson in patients with severe liver dysfunction awaiting transplantation. Due to the ongoing shortage of donor organs, many patients with decompensated cirrhosis deteriorate rapidly and, tragically, do not survive long enough to receive a suitable transplant, highlighting the importance of therapies that may help maintain stability during this critical period. Namodenoson is an orally bioavailable A3 adenosine receptor (A3AR) agonist with anti-inflammatory and anti-fibrotic properties, which has demonstrated a favourable safety pro previous clinical studies. The drug is currently being evaluated in advanced liver diseases, including MASH and hepatocellular carcinoma. “This case represents an encouraging clinical observation in a patient with advanced liver disease,” stated Prof. Ohad Etzion, Chief of Gastroenterology and Liver Diseases at Soroka Medical Center in Israel. “Although individual cases must be interpreted with caution, the ability to maintain clinical stability in such a fragile patient population is highly meaningful. We believe these findings support the continued clinical development of Namodenoson in liver disorders where treatment options remain extremely limited.” In 2017, an estimated 10.6 million people globally were affected by decompensated cirrhosis, and the available treatment options remain scarce, especially for patients who have reached the advanced stages of the disease. Highlighting the urgent need for new therapies, the American Liver Foundation has stated that there are more patients in need of a liver transplant than available organs, with some patients waiting over five years for a transplant. The global liver cirrhosis treatment market is projected to grow from approximately $7.6 billion in 2024 to more than $15 billion by 2031. About Namodenoson Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson is currently being evaluated in a pivotal Phase III trial for advanced liver cancer, a Phase IIb trial for the treatment of Metabolic Dysfunction-associated Steatohepatitis (MASH), and in a Phase IIa study in pancreatic cancer. A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential expression may be one of the important factors that accounts for the excellent safety pro the drug. About Can-Fite BioPharma Ltd. Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CANF) is an advanced clinical stage drug development Company with a platform technology that is designed to address multi-billion-dollar markets in the treatment of cancer, liver, and inflammatory disease. The Company's lead drug candidate, Piclidenoson reported topline results in a Phase III trial for psoriasis and commenced a pivotal Phase III trial. Can-Fite's liver drug, Namodenoson, is being evaluated in a Phase III trial for hepatocellular carcinoma (HCC), a Phase IIb trial for the treatment of MASH, and in a Phase IIa study in pancreatic cancer. Namodenoson has been granted Orphan Drug Designation in the U.S. and Europe and Fast Track Designation as a second line treatment for HCC by the U.S. Food and Drug Administration. Namodenoson has also shown proof of concept to potentially treat other cancers including colon, prostate, and melanoma. CF602, the Company's third drug candidate, has shown efficacy in the treatment of erectile dysfunction. These drugs have an excellent safety pro experience in over 1,600 patients in clinical studies to date. For more information please visit: . Forward-Looking Statements This press release may contain forward-looking statements, about Can-Fite’s expectations, beliefs or intentions regarding, among other things, its product development efforts, business, financial condition, results of operations, strategies or prospects. All statements in this communication, other than those relating to historical facts, are “forward looking statements”. Forward-looking statements can be identified by the use of forward-looking words such as “believe,” “expect,” “intend,” “plan,” “may,” “should” or “anticipate” or their negatives or other variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical or current matters. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to known and unknown risks, uncertainties and other factors that may cause Can-Fite’s actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Important factors that could cause actual results, performance or achievements to differ materially from those anticipated in these forward-looking statements include, among other things, our history of losses and needs for additional capital to fund our operations and our inability to obtain additional capital on acceptable terms, or at all; uncertainties of cash flows and inability to meet working capital needs; the initiation, timing, progress and results of our preclinical studies, clinical trials and other product candidate development efforts; our ability to advance our product candidates into clinical trials or to successfully complete our preclinical studies or clinical trials; our receipt of regulatory approvals for our product candidates, and the timing of other regulatory filings and approvals; the clinical development, commercialization and market acceptance of our product candidates; our ability to establish and maintain strategic partnerships and other corporate collaborations; the implementation of our business model and strategic plans for our business and product candidates; the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates and our ability to operate our business without infringing the intellectual property rights of others; competitive companies, technologies and our industry; risks related to any resurgence of the COVID-19 pandemic and the war between Israel and Hamas; risks related to not satisfying the continued listing requirements of NYSE American; and statements as to the impact of the political and security situation in Israel on our business. More information on these risks, uncertainties and other factors is included from time to time in the “Risk Factors” section of Can-Fite’s Annual Report on Form 20-F filed with the SEC on April 14, 2025 and other public reports filed with the SEC and in its periodic filings with the TASE. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Can-Fite undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. Contact Can-Fite BioPharma Motti Farbstein info@canfite.com +972-3-9241114