The purpose of the study was to investigate the concept of “glucagon resistance” in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. We asked if a disruption of the glucagon-mediated suppression of hepatic amino acid (AA) catabolism is present in individuals with MASLD compared with individuals with obesity but no MASLD. Contrary to expectations, we found no disruption of the glucagon-stimulated suppression of plasma AA concentration, which disputes the hypothesis that MASLD causes resistance to glucagon.

2024-12-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats

Article

作者: Azouz, Amany A ; Khalaf, Marwa M. ; Ezz-Eldin, Yousra M. ; El-Din Ewees, Mohamed Gamal ; Khalaf, Marwa M ; Azouz, Amany A. ; Ezz-Eldin, Yousra M

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, p.o.) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.

2024-11-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Liver-specific thyroid hormone receptor-β agonism alleviates alcoholic steatohepatitis (ASH) in mice

Article

作者: Tewari, Archana ; Sinha, Rohit A ; Raza, Sana ; Sinha, Rohit A. ; Gupta, Pratima ; Rajak, Sangam ; Yadav, Abhishek ; Shahi, Ambuj

Alcoholic steatohepatitis (ASH) represents a critical stage in alcoholic liver disease (ALD), which significantly increases the risk of developing alcoholic hepatitis and cirrhosis. Currently, corticosteroids and alcohol abstinence remain the only available strategy to prevent or reverse ASH progression with no FDA approved drug therapy till date. Given the notable pathological similarities between ASH and metabolic dysfunction-associated steatohepatitis (MASH), repurposing drugs approved for MASH presents an attractive therapeutic approach to treat ASH. In this context, we evaluated the efficacy of Resmetirom, a recently approved drug for MASH, in a mouse model of ASH. Our findings demonstrate that Resmetirom, a liver-specific thyroid hormone analog, not only reduces hepatic steatosis but also markedly alleviates liver injury, oxidative stress, and inflammation associated with ASH. In summary, this study provides a proof-of-concept for the potential use of MASH drugs in treating ASH and establishes a foundation for future testing and clinical trials of Resmetirom, in patients with ASH.

项与 MASH(Repair) 相关的新闻（医药）

2024-12-02

·药事纵横

MASH百亿市场全景回顾

2024年3月，首个MASH药物Resmetirom获批，正式揭开了这一百亿级市场的序幕。在Q2-Q3期间，该药物实现了累计6000万美元的销售额，展现出强劲的市场潜力。同年10月，司美格鲁肽公布了针对MASH的F2-3患者群体的三期临床试验数据，并计划于明年提交上市申请。与此同时，FGF21和PPAR类药物也正在三期临床中快速推进，市场竞争日益激烈。面对这一充满机遇与挑战的市场，现有管线的临床数据有哪些亮点？未来的竞争格局将如何演变？治疗逻辑又会发生怎样的变化？一、疾病简介代谢功能障碍相关脂肪变性肝病（MAFLD）是一类肝脏中多余脂肪堆积（非酒精摄入）导致的疾病。脂肪在正常肝脏堆积超过5%的时候，形成非酒精性脂肪肝。随着疾病进展，肝脏产生炎症，导致不同程度纤维化或瘢痕的产生，进入代谢功能障碍相关脂肪性肝炎（MASH）。如果病情得不到有效控制，长期处于MASH状态可能导致肝硬化，并引发一系列严重并发症，如肝功能衰竭和肝细胞癌（HCC）。常见风险因素包括超重、代谢综合症、高胆固醇、高血压、高血糖、胰岛素抵抗/糖尿病、甲状腺功能低下等。二、流行病学 MAFLD在全球范围内的患病率高达 30%，已成为一种广泛存在的健康问题。而在MAFLD患者中，约 5.27% 的人群进一步发展为MASH。按照纤维化进展的不同阶段，MASH患者的分布情况如下：F0（无纤维化）占比 10%-15%，F1（轻度纤维化）占比 30%-35%，F2（中度纤维化）：占比 20%-25%，F3（重度纤维化）占比 15%-20%，代偿性肝硬化（F4C）占比 10%-15%，失代偿性肝硬化（F4D）占比 5%。研究表明，在未干预的情况下，每7年纤维化程度可能增加一个等级，尤其在进展至中重度纤维化（F3或F4）时，患者的死亡风险显著升高。此外，MAFLD和MASH常伴随多种代谢性并发症，显著增加患者的疾病负担与管理难度。以下是常见并发症及其发生率：肥胖最为普遍，发生率高达 51%-81%；心血管疾病（CVD）：发生率为 20%-50%；糖尿病发生率为 22%-43%。这些代谢性并发症不仅加速了肝病的进展，还进一步增加了全因死亡率。三、疾病评分系统在 MASH 的诊断和分级中，评分系统起着关键作用。目前，临床上广泛使用以下两种主要评分方法： 1. NAFLD活动评分（NAS）由美国国立卫生研究院NASH临床研究网络（CRN）提出，NAS评分是临床试验中最常用的系统，主要基于以下指标：NAS < 3分，定义为非MASH；NAS ≥ 4分：定义为 MASH NAS 3~4分，定义为 MASH可能。此外，NAS评分还结合肝纤维化分级（F0-F4），用以评估疾病的严重程度，F0-F1为轻度纤维化，F2-F4为中至重度纤维化。 2. SAF评分法 2012年，由欧洲脂肪肝研究小组提出的 SAF评分法，通过定量评估以下三项指标来诊断MASH：S（脂肪变性），A（炎症程度），F（纤维化程度）。当脂肪变性、肝细胞气球样变性和小叶炎症的评分均≥1时，即可确诊为MASH。尽管NAS和SAF评分在MASH诊断中表现出较高的一致性，但NAS评分系统存在低估风险，尤其对边缘病例（NAS 3~4分）的判定偏保守。研究显示，约50%的NAS“边缘性”患者在使用SAF评分后被确诊为MASH。因此，SAF评分法因其更全面的评估维度，在实际诊断中的应用正逐渐增加，成为更为敏感的MASH诊断工具。此外还有一些非侵入性的诊断评分方法。四、市场潜力 MASLD的经济负担巨大，已成为全球医疗体系的重要挑战。2016年数据显示，美国每年的直接医疗成本高达 1030亿美元，远超德国、法国和意大利三国总和的 277亿欧元，以及英国的 52.4亿英镑。未来10年，美国MASLD的总经济负担预计将达 1万亿美元，欧洲则为 3340亿欧元。2024年，首个MASH药物 Resmetirom 上市后展现了显著市场潜力，其Q2和Q3的销售额分别为 1400万美元和 4800万美元，累计 6200万美元，目标覆盖 31.5万名美国患者，截至Q3已有 6800名患者使用，并覆盖了 40%的顶级医生。当前其单片定价为 138.96美元，投行Evercore预测其峰值销售额可达 50亿美元。随着市场渗透加深、新药上市和治疗方案的完善，MASLD/MASH领域正迎来爆发式增长，未来潜力不可限量。五、监管要求美欧中监管机构都支持替代终点上市，其中FDA给出了加速批准和完全批准上市的具体路径。在终点的选择上，FDA和EMA略有不同。在美、欧、中三大地区的监管框架中，各机构均支持以替代终点作为上市审批的依据，这为MASH药物的开发提供了重要机遇。其中，FDA 明确制定了加速批准和完全批准的具体路径，为药物快速进入市场提供了便利。在终点选择方面，FDA和 EMA存在一定差异。六、现有治疗手段目前，治疗 MAFLD 主要依赖三种方式：生活方式干预、手术治疗和药物治疗。生活方式包括减少高热量食物摄入、运动等，手术包括减重手术和肝移植，药物治疗包含减肥、降血脂、降血压等多种药物。其中，国内外指南推荐MASH药物治疗选择如下：AALSD推荐使用维生素E、噻唑烷二酮类（吡格列酮）、GLP-1激动剂（利拉鲁肽, 司美格鲁肽，替尔泊肽）、sglt-2抑制剂进行治疗。中华医学会推荐使用以下一种肝损伤治疗药物，水飞蓟素（宾）、多烯磷脂酰胆碱、双环醇、甘草酸制剂（异甘草酸镁、复方甘草酸苷、甘草酸二铵等）、还原型谷胱甘肽等。 2024年3月，FDA加速批准了 Resmetirom用于治疗 F2-F3 纤维化的MASH患者，成为美国首个获批的MASH药物，但目前尚未列入指南推荐。从疾病严重程度来看，MASH无纤维化/轻度纤维化，依赖生活方式改善、手术或部分药物进行治疗，中度/重度纤维化，可使用Resmetirom进行治疗，代偿性肝硬化目前没有好的治疗手段，非代偿性肝硬化只能进行肝移植。七、潜力疗法目前，全球仅有 2款MASH药物已上市，分别为 Resmetirom（美国上市）和 Saroglitazar（印度上市）。与此同时，全球目前共有超过500款MASH药物处于研发阶段，其中有 5款药物已进入3期临床试验，并且这些药物的试验结果表现积极，预计在未来几年内有望获得批准上市。 1. 作用机制目前MASH的在研药物主要聚焦于改善代谢、抗炎和抗纤维化作用。FGF21、THRβ和PPAR在这些机制中发挥直接作用。FGF21和PPAR在全身组织中广泛表达，能够有效改善脂肪代谢、减轻炎症反应和纤维化进程；而THRβ则主要在肝脏中发挥作用，主要通过降脂作用对代谢产生影响。GLP-1主要在肠道和胰腺等部位发挥间接作用，能够调节血糖、抑制食欲、降低体重，并具有一定的肝脏保护作用。 2. MASH F2-F3临床数据除司美格鲁肽和Resmetirom已公开3期临床数据外，其余药物均为2期临床结果。根据2项关键终点结果来看，Tirzepatide 15mg 对于MASH改善效果最好，52周时安慰剂校正后的MASH改善且纤维化不恶化的患者比例为52%，而Resmetirom 100mg 52周比例为20%。而Efruxifermin 50mg抗纤维化效果最好，96周时安慰剂校正后的肝纤维化改善1分且MASH不恶化的患者比例为30%，而Resmetirom 100mg 52周比例为20%。从靶点来看，GLP-1单靶点抗纤维化效果有限，引入GCGR和GIPR后，可以进一步增强，Tirzepatide比Survodutide效果更优。THR-β药物中，VK2809效果远超Resmetirom，部分原因可能是基线差异大，VK2809试验中F2+F3比例75%，Resmetirom中比例为95%。 PPAR药物表现中规中矩，Lanifibranor 1200mg 24周在两项指标中处于中位，但是f2+f3人群占比最佳。FGF21药物抗纤维化效果好，起效快，Pegozafermin在24周时肝纤维化改善1分且MASH不恶化的患者比例为20%，两项数据略好于Efruxifermin，长期数据暂未公布。在MASH缓解且纤维化改善的指标上，Efruxifermin效果优于Resmetirom。在50mg剂量下，在24周和96周时的经安慰剂校正患者比例能维持在28%，而Resmetirom 100mg为11%。一项由Inventiva开展的样本量为95人的调查（包含支付方和医生）显示，99%的受访者认为，理想的药物应同时具备改善MASH和纤维化的能力。这对于Efruxifermin是显著优势。所有药物均对胃肠道有一定影响，其中GLP-1类药物的不良反应发生率较高。以Survodutide 4.8mg为例，恶心发生率为68%，腹泻为56%，呕吐为46%。FGF21类药物的不良反应发生率较为中等，Efruxifermin 28mg的腹泻发生率为40%。THR-β类药物对胃肠道的影响较小，Resmetirom 100mg的腹泻发生率为33.4%。PPAR类药物对胃肠道的影响最轻，Lanifibranor 1200mg的腹泻发生率为12%。 GLP-1类药物抑制食欲，而FGF21类药物则可能增加食欲。在MASH疾病控制过程中，饮食因素起着一定作用，因此FGF21类药物在这一方面可能存在劣势。此外，FGF21类药物在注射部位容易引发不良反应，例如注射部位红斑、瘀伤和皮疹，发生率在10%-20%之间。 PPAR类药物在临床中报道了一些不良反应，包括转氨酶升高、体重增加和水肿，发生率在10%及以下。在GLP-1类药物中，司美格鲁肽（Semaglutide）和Survodutide 的停药率相对较高。具体来说，Survodutide 6mg在48周时的停药率达到了23%。与之相比，Tirzepatide的停药率控制得较好，15mg的剂量组停药率仅为Survodutide 的三分之一。在THR-β类药物中，停药率普遍较低。对于FGF21类药物，Efruxifermin和Pegozafermin在24周时的停药率都接近10%。而PPAR类药物的停药率则相对较低。 3. MASH F4临床数据目前，司美格鲁肽和Efruxifermin已报道MASH F4 2期试验结果。对于F4患者，司美格鲁肽的疗效较差，从两个临床指标来看，效果未见明显改善，甚至低于安慰剂组。相比之下，Efruxifermin在F4患者中仍表现出一定疗效。在肝纤维化改善一级且MASH未恶化的指标中，50mg组的比例为24%，经安慰剂校正后仍为10%。在安全性方面，Efruxifermin的停药率约为10%，各类不良反应的发生率与F2/3患者群体相似。八、未来竞争格局 Resmetirom已于2024年通过加速批准上市，如果F4试验结果为阳性，预计最早在2027年获得FDA完全批准。司美格鲁肽目前已获得72周的数据，预计将在明年提交上市申请，最早可能于2025年获得加速批准，完全批准预计要到2029年。而根据目前的开发进度，Survodutide、Pegozafermin、Efruxifermin和Lanifibranor预计最快可于2027年获得加速批准，完全批准可能需要等到2029年以后。Tirzepatide和VK2809暂时未公布开展MASH 3期临床试验的具体计划。到2027年，预计将有6款药物在MASH领域展开激烈竞争。 Resmetirom的化合物专利2026年到期，NCE市场独占权在2029年。司美格鲁肽化合物专利2026年到期，NP市场独占权2024年已到期。因此除了新药的竞争外，还需要考虑仿制药竞争。九、新靶点的探索今年新披露的MASH治疗靶点中，进展最快的是BI的SIRPα拮抗剂BI-770371，预计将在2024年11月开始针对因MASH导致代偿性肝硬化患者开展静脉注射治疗的安全性、耐受性和药效学的2a期临床试验。其可能的作用机制是，SIRPα拮抗剂通过抑制肝细胞中的CD47，增强肝巨噬细胞对坏死性凋亡肝细胞的摄取，从而降低肝星状细胞的活化，抑制肝纤维化的进展。十、未来用药逻辑 MAFLD和MASH的常见合并症包括肥胖（51%～80%）、糖尿病（23%～44%）、高脂血症（70%～72%）等，因此GLP-1类药物可以作为基础治疗方案。在轻度阶段，可以通过改善生活方式并联合使用GLP-1类药物进行治疗；当仅出现NAS评分增加时，可通过GLP-1类药物改善脂质代谢和炎症反应；若伴随纤维化进展，可结合GLP-1类药物和FGF21类药物来改善纤维化。在中度至重度阶段，可将GLP-1类药物与FGF21、THR-β及PPAR类药物联合使用，以实现更全面的治疗效果。结语 MASH（代谢相关脂肪性肝病）作为全球普遍存在的疾病，影响着约1.5%的人群，疾病负担超过万亿美元，市场潜力巨大。经过数十年的研发，虽然许多药物未能成功，但首个MASH治疗药物Resmetirom的获批标志着这一领域从“无药可治”迈向“有药可治”。随着研发的不断推进，针对降脂、抗炎和抗纤维化的药物，如GLP-1多靶点药物和FGF21药物，已显示出显著疗效。预计在未来3-5年内，将有6款新药竞相上市，这些药物不仅要面对彼此的竞争，还将面临Resmetirom和司美格鲁肽仿制药的激烈竞争。因此，差异化竞争仍需通过新靶点的探索加以推动，尽管新靶点的开发仍在路上，药企依然充满信心。随着药物选择的逐步丰富，未来的治疗方式大概率将以联合治疗为主，覆盖MASH的全阶段患者群体，为患者带来更多的治疗希望。参考资料 1.Novo Nordisk、Madrigalpharma、Akero网站 2.https://my.clevelandclinic.org/health/diseases/22988-nonalcoholic-steatohepatitis 3.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77(4):p 1335-1347, April 2023. Current status and future trends of the global burden of MASLD. Trends in Endocrinology & Metabolism, Volume 35, Issue 8, 697 - 707 4.非酒精性脂肪性肝病诊断——病理的重要性. 临床肝胆病杂志, 2023, 39(3): 491-497. 5.非酒精性脂肪性肝病诊断方法研究进展. 生命科学, 2023 6.Expert Panel Review to Compare FDA and EMA Guidance on Drug Development and Endpoints in Nonalcoholic Steatohepatitis. Gastroenterology, 162(3), 680–688. 7.MASH-Webinar-January-2021 8.FDA、NMPA、EMA指导原则 9.Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. The Lancet Gastroenterology & Hepatology, Volume 8, Issue 6, 511 - 522 10.A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021;384:1113-1124 11.Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med 2023;389:998-1008 12.A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 2024;391:311-319 13.A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med 2021;385:1547-1558 14.Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis. N Engl J Med 2024;391:299-310 药事纵横征稿启事

临床3期临床结果申请上市

2024-11-18

·医药魔方

国产MASH新药谁能率先突围？

提到MASH（Metabolic Associated Steatohepatitis，代谢相关脂肪性肝炎），业内人士对其第一印象就是“研发黑洞”、“研发重灾区”，这主要源于MASH病因和病理学机制复杂，新药开发难度极大，导致历年来堆积的研发失败案例不一而足，而直到今年3月，才有一款真正意义上治疗MASH的创新药（Resmetirom）获得FDA批准上市。但作为最常见的肝病，MASH有着十分庞大的患者群体和临床治疗需求，这也推动其成为全球高度关注的代谢类疾病领域，吸引着各大制药企业重金投入。近年来，国内药企在这一领域的创新也热潮涌动，不少企业投入大量资源，以期攻克这一世界级难题，微芯生物便是其中之一。 “18周快速起效，64mg组肝脏脂肪含量下降39.5%，超过65%的患者肝脂肪含量下降超过30%”，微芯生物旗下一款潜在首创最优产品凭借亮眼的临床数据从一众竞争对手中脱颖而出。该研究成果成功入选了2024美国肝病研究学会（AASLD 2024）年会口头报告，站上国际化舞台向全球肝病学界展示来自中国的创新力量，引发了行业对西格列他钠MASH治疗潜力的关注。 MASH：隐形杀手 MASH，早前被称为NASH（Nonalcoholic Steatohepatitis，非酒精性脂肪性肝炎），是一种以肝脏脂肪过度积累和炎症为特征的代谢性疾病，可能导致肝脏纤维化、肝衰竭乃至肝癌，被认为是全球健康领域中亟待解决的“隐形杀手”。根据最新的流行病学研究，全球成人MAFLD（代谢相关脂肪性肝病）患病率高达32.4%，也就是说，全球平均每3个人中就有1人罹患MAFLD，这其中，有15%~25%的MAFLD患者会进展为MASH，预计到2030年，全球MASH患病人数将达到数亿级别[1]。而由于大部分患者在疾病早期并不会感受到明显的症状，且缺乏理想的早期诊断工具，MASH的发病率和患病率可能远被低估。当前，临床主要以生活方式干预为主，用以缓解MASH恶化，但对于疾病进展严重的患者，这种方式的治疗效果有限，因而患者迫切需要能够有效逆转肝纤维化或减缓病程的创新药物。然而，由于病因、病理学机制尚未研究清晰，且该类疾病异质性强，动物模型无法很好的模拟人类的疾病特征，诊断检测也非常困难，导致MAFLD、MASH新药研发的进展十分缓慢[2-3]。迄今为止，绝大部分在研创新药物都在后期临床试验出现疗效不佳，甚至就此折戟。截至目前，仅有一款由Madrigal Pharmaceuticals开发的甲状腺激素受体β（THR-β）激动剂Resmetirom（商品名：Rezdiffra）于今年3月获FDA加速批准上市，也是FDA批准的首个MASH创新药。而在中国，尚无相关产品获批进入市场。不过，以Resmetirom为起点，MASH领域正逐步揭开谜题，迎来曙光。2023年6月，AASLD正式宣布将NAFLD（非酒精性脂肪肝）、NASH更名为MASLD、MASH。此番术语变更真正落地，不仅体现了业内对该病因、病理机制的更深入理解，凸显出代谢功能障碍与疾病的关系，新的MASH诊断标准将重点放在代谢指标上，如肥胖、2型糖尿病和其他代谢综合症特征上，有助于识别更广泛的受影响人群，也标志着以THR-β、GLP-1、FGF、PPAR等MASH热门靶点的市场竞赛迈向更加精准、个性化临床研究新征程。要知道，在过去几年创新药发展浪潮中，肿瘤领域能够得以急速发展，除了巨大的患者群体驱动，清晰明确、量化可行的临床诊疗路径和治疗目标也是不可或缺的推动力，而MASH无疑也有了更明确的研究方向。 PPAR全激动剂：三重守护，直击核心病因 MASH病程涉及脂肪堆积、氧化应激、肝细胞损伤和慢性炎症反应等多重病理因素。根据这一特征，目前MASH新药开发主要集中在以下三大机制，一是代谢调节通路：如GLP-1受体激动剂，旨在调节体内脂肪代谢与体重；二是炎症抑制通路：如FXR激动剂，降低肝脏炎症反应；三是抗纤维化通路：如抗CCL2/5拮抗剂，通过干预纤维化关键通路，减缓肝脏纤维化进展[4]。不过，针对复杂类疾病，单一靶点的药物往往无法全面改善病情，而多靶点药物则可以同时覆盖多条通路，从而提高整体治疗效果。因此，现阶段进入中后期临床试验的候选药物大都具备多靶点优势。 PPAR（过氧化物酶体增殖物激活受体）全激动剂西格列他钠就是其中之一，因其能够作用于核受体，调节多种基因表达，并影响多种类型的疾病过程，成为热门研发方向之一，备受全球关注。 PPAR家族是调控脂质代谢、炎症和纤维化的重要受体，包括PPARα、PPARγ和PPARδ三种亚型。PPARα激动通过调节脂肪酸氧化，降低肝脏脂质堆积；PPARγ激动则在抑制炎症的同时调节糖脂代谢，降低胰岛素抵抗；PPARδ激动能够改善肝脏细胞的能量代谢，并减少炎症反应[5]。因此，作为PPAR全激动剂，西格列他钠能够同时且适度激活这三种亚型，具备三重防护，即降脂肪、改善纤维化以及降炎症，在机制上有多重优势。西格列他钠潜在作用机理图研究显示，MASH核心病因包括代谢紊乱、胰岛素抵抗和慢性炎症，这些因素共同驱动了肝脏脂肪沉积、肝细胞损伤和纤维化的发展。这其中，胰岛素抵抗是MASH发展的初步驱动因素，不仅会引发高血糖，还会导致高脂血症、超重/肥胖、脂肪肝、动脉粥样硬化性心血管疾病（ASCVD）等，为之后的肝脏病变埋下了安全隐患[6]。因此，若能直接改善胰岛素抵抗，从源头扭转这一病变，或许能够降低疾病进展危害。西格列他钠则有望实现这一治疗目标，独特的作用机制使其能够有选择性地改变一系列与胰岛素敏感性相关的基因表达，直击MASH核心病因，提高患者胰岛素敏感性、调节血糖，并改善并发的脂质代谢紊乱，降低心血管并发症的发生及其危害程度。西格列他钠：潜在首创最优率先突围西格列他钠机制上的优势在临床研究中也得以充分体现，其用于治疗NASH/MASH的II期临床研究（CGZ203试验）取得了令人振奋的积极结果。数据显示，西格列他钠不仅能显著降低肝脏脂肪含量，改善炎症和纤维化，还表现出良好的安全性，展现出“首创最优”的潜力。在该项研究中，临床诊断为MASH的患者按2:2:1随机分配至西格列他钠48mg（n=42），64mg（n=41），或安慰剂组（n=21），每天服药一次，进行为期18周的治疗。对于MASH患者而言，肝脏中过度堆积的脂肪和炎症是其疾病进展的重要特征之一，患者肝脏脂肪含量越高，发生肝纤维化的风险就越大。西格列他钠十分突出的特点就是显著的肝脏脂肪含量降低。从结果来看，治疗18周后，无论是患者的肝脏脂肪含量，还是肝脏脂肪含量下降超过30%的患者比例，西格列他钠组较基线都有明显的改善，且呈现高度剂量依赖性。 MRI-PDFF检测结果显示，西格列他钠48mg患者肝脏脂肪含量相比基线下降了28.1%，随着剂量的加大，64mg组下降幅度更大，达到了39.5%（安慰剂组下降3.2%）；肝脂肪含量下降比例超过30%的患者比例也有着同样的剂量依赖趋势，48mg组有40.5%的患者达到这一比例，64mg组则高达65.9%（安慰剂组为14.3%）。这一组数据也预示着，若在安全可控情况下增大剂量，西格列他钠有望达到更好的治疗效果。此外，经西格列他钠治疗后，与慢性炎症及肝脏损伤紧密相关的血浆生化标志物，诸如CK-18、肝转氨酶及胆红素等，均呈现出显著下降的趋势。尤为值得注意的是，高剂量组患者的谷丙转氨酶（ALT）水平相较于基线下降了50%以上，且超过70%的患者ALT水平成功恢复到正常范围内。肝脏纤维化改善程度也是评价药物疗效的核心指标，而肝硬度是评估肝纤维化严重程度的重要生物标志物。Fibroscan检测发现，西格列他钠对肝脏硬度值具有剂量和时间依赖性的降低，西格列他钠高剂量组患者接受18周治疗后LSM值（肝脏硬度值）降幅达2 Kpa，表明这部分患者肝脏纤维化或炎症状况已有一定程度改善。在本次针对MASH的临床试验中，西格列他钠展现出与糖尿病临床使用中一致的安全性，无新增安全信号，未见显著的PPAR激动剂相关副作用，高剂量组甚至出现了轻微体重下降，且仅1例低剂量组患者发生轻微水肿。这一低副作用特性为长期使用铺平了道路，进一步验证了西格列他钠在MASH适应症的应用潜力。尤红教授在美国肝病研究学会年会（AASLD 2024）介绍CGZ203研究时表示：“西格列他钠在短短18周内，改善了肝脏脂肪蓄积、慢性炎症、肝脏纤维化等多种病理特征，同时具有良好的安全性。我们即将启动III期临床研究，以进一步探索西格列他钠在长期MASH治疗中对于患者肝纤维化的影响。” 通常情况下，同时作用于多个靶点的低选择性药物能够带来全面的治疗效果，但广泛的作用机制也易导致安全有效剂量范围窄，从而增加用药安全管理难度。作为能够调控三种亚型的PPAR全激动剂，西格列他钠的安全性能备受关注。我们或可先从2型糖尿病适应症中找到答案。MASH并不是西格列他钠开发的第一个适应症。早在2021年10月，西格列他钠就获得国家药监局批准上市，单药用于配合饮食控制和运动，改善成人2型糖尿病患者的血糖控制，目前该适应症已进入医保。就在今年7月，西格列他钠还获批扩大适应症，联合二甲双胍用于治疗2型糖尿病。这不仅是对西格列他钠降糖疗效的认可，无疑也体现了临床对其安全性的肯定。而整整3年的临床应用，西格列他钠也积累了丰富的安全性数据，抵住了市场的考验，为后续MASH临床应用提供了良好的保障。拥有30余年肝病临床和科研经验的尤红教授十分看好西格列他钠临床应用前景，她指出： “在国内，MASH诊疗面临众多挑战，特别是缺乏有效的治疗方案。西格列他钠作为一种新型药物，II期研究疗效和安全性方面数据表现积极，不仅能综合改善肝脏脂肪蓄积、慢性炎症、肝脏纤维化等多种病理特征，同时具备良好的安全耐受性，也进一步证实了PPAR全激动剂的多靶点治疗策略的有效性和安全性。我们期待它在III期临床试验中加以验证。“ 众所周知，针对MASH这种需要长期治疗管理的慢病，小分子药物为患者带来的便利性、依从性等价值是不可言喻的，西格列他钠每日一次的口服给药模式无疑更具优势，大大减轻患者的用药负担。更值得关注的是，在海外MASH成功的临床靶点中，泛PPAR是口服小分子疗效的最佳靶点。而在优异的疗效数据托举下，西格列他钠未来的发展似乎也更具想象空间了。总结 2024年是MASH治疗领域实现里程碑式进展的一年——全球首款治疗药物Resmetirom获批上市。这对于患者意义重大，意味着他们将获取更加专业有效的治疗，提升生存质量。于后来者而言，Resmetirom无疑树立了MASH研发新典范，引领着行业的发展方向。当然，MASH赛道的故事还远未结束，譬如西格列他钠这般具备潜在首创最优实力的选手已经开始书写新的篇章，彰显出可喜的治疗潜力。未来，相信在更多扎实数据的支撑下，西格列他钠还会为MASH疾病治疗带来更多惊喜。 - 上下滑动查看参考资料 - [1]The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis - The Lancet Gastroenterology & Hepatology [2]Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm [3]From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights [4]Potential therapeutic strategies for MASH: from preclinical to clinical development | Life Metabolism | Oxford Academic [5]https://academic.oup.com/lifemeta/article/3/5/loae029/7708552 [6]https://www.verywellhealth.com/non-alcoholic-steatohepatitis-nash-5196357 Copyright © 2024 PHARMCUBE. 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上市批准加速审批

2024-11-08

·GlobeNewswire-Health Care

Akero Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Update

— First patients dosed in Phase 3 SYNCHRONY Outcomes study of lead candidate efruxifermin (EFX) in patients with compensated cirrhosis (F4) due to MASH — — Phase 3 SYNCHRONY Real-World and Histology studies on track to report results for their respective primary endpoints in 2026 and the first half of 2027 — — Phase 2b SYMMETRY study week 96 results expected to readout in February 2025 — SOUTH SAN FRANCISCO, Calif., Nov. 08, 2024 (GLOBE NEWSWIRE) -- Akero Therapeutics, Inc. (Nasdaq: AKRO), a clinical-stage company developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including metabolic dysfunction-associated steatohepatitis (MASH), today reported third quarter financial results for the period ending September 30, 2024 and provided business updates. "The third quarter of 2024 marked an important milestone for EFX with the first patient dosed in the Phase 3 SYNCHRONY Outcomes study," said Andrew Cheng, president and CEO. "With this advancement, all three of our Phase 3 studies are actively enrolling — furthering our assessment of the safety and efficacy of EFX and moving us closer to delivering a differentiated treatment option, if approved, to patients living with MASH." Phase 3 SYNCHRONY Program Akero's Phase 3 SYNCHRONY program is comprised of three ongoing, randomized, placebo-controlled trials evaluating the safety and tolerability of EFX to support marketing applications for both pre-cirrhotic MASH (F2-F3) and compensated cirrhosis (F4) due to MASH. The SYNCHRONY program builds on two biopsy-based Phase 2b studies in corresponding patient populations, with a combined total of 300 patients treated for up to 96 weeks.SYNCHRONY Outcomes (F4, compensated) SYNCHRONY Outcomes is a two-cohort study evaluating EFX in the treatment of patients with compensated cirrhosis (F4) due to MASH. Patients were first dosed in the study in the third quarter of 2024 and are receiving weekly injections of either EFX 50mg or placebo.The primary histology endpoint, for Cohort 1 only, is the proportion of patients experiencing ≥ 1-stage improvement in fibrosis and no worsening of steatohepatitis after 96 weeks of treatment.The primary outcomes endpoint is measured as the time from randomization to first occurrence of any of the protocol-specified clinical events across all patients enrolled in Cohort 1 and Cohort 2. SYNCHRONY Histology (F2-F3) SYNCHRONY Histology is a two-cohort study evaluating EFX in the treatment of patients with pre-cirrhotic MASH, fibrosis stage 2 or 3 (F2-F3). Patients are receiving weekly injections of EFX 28mg, EFX 50mg, or placebo.The primary histology endpoint (Cohort 1 only), to support an application for accelerated approval, is the proportion of patients experiencing ≥ 1-stage fibrosis improvement AND resolution of MASH after 52 weeks of treatment.All patients in Cohort 1 and Cohort 2 will be evaluated for long-term clinical outcomes for up to 240 weeks of treatment.Results for the 52-week primary histology endpoint are expected in the first half of 2027. SYNCHRONY Real-World (F1-F4) SYNCHRONY Real-World is enrolling patients with MASH or metabolic dysfunction-associated steatotic liver disease (MASLD) to receive weekly injections of EFX 50mg or placebo. The primary endpoint of safety and tolerability will be assessed after 52 weeks of treatment.Results from the SYNCHRONY Real-World study are expected in 2026. Phase 2b SYMMETRY Study The ongoing Phase 2b SYMMETRY study is evaluating the efficacy and safety of EFX in patients with compensated cirrhosis (F4) due to MASH, who were treated with EFX 28mg, EFX 50mg or placebo for up to 96 weeks.All planned end-of-treatment biopsies have been collected. Consistent with the protocol, enrolled patients continue in the study through follow-up assessments 30 days after completion of treatment with EFX or placebo.Week 96 results are on track to be reported in February 2025. Third Quarter 2024 Financial Results Akero's cash, cash equivalents and short and long-term marketable securities as of September 30, 2024, were $787.1 million.Akero believes that its current cash, cash equivalents, and short- and long-term marketable securities will be sufficient to fund its Phase 3 SYNCHRONY Histology and Real-World studies through readout of their respective primary endpoints and Akero's current operating plan into the second half of 2027.Research and development expenses for the three-month period ended September 30, 2024 were $72.2 million, compared to $38.6 million for the comparable period in 2023. These increases were attributable to higher expenses associated with the ongoing SYMMETRY study, the ongoing Phase 3 SYNCHRONY Histology and Real-World studies, initiation of the Phase 3 SYNCHRONY Outcomes study, and manufacture of clinical supplies for Phase 3 and potential marketing applications, as well as higher expenses for personnel.General and administrative expenses for the three-month period ended September 30, 2024 were $9.5 million, compared to $8.0 million for the comparable period in 2023. These increases are attributable to higher expenses for personnel, professional services and other costs associated with operating as a public company.Total operating expenses were $81.7 million for the three-month period ended September 30, 2024, compared to $46.6 million for the comparable period in 2023. About Efruxifermin Efruxifermin (EFX), Akero's lead product candidate for MASH, is a differentiated Fc-FGF21 fusion protein that has been engineered to mimic the balanced biological activity profile of native FGF21, an endogenous hormone that alleviates cellular stress and regulates metabolism throughout the body. EFX appears to reduce liver fat and inflammation, reverse fibrosis, increase insulin sensitivity and improve lipid metabolism. This holistic approach offers the potential to address the complex, multi-system disease state of MASH, including improvements in lipoprotein risk factors linked to cardiovascular disease — the leading cause of death in MASH patients. EFX is designed to offer convenient once-weekly dosing and has been generally well tolerated in clinical trials to date. About MASH MASH is a serious form of MASLD that is estimated to affect more than 17 million Americans. MASH is characterized by an excessive accumulation of fat in the liver that causes stress and injury to liver cells, leading to inflammation and fibrosis, which can progress to cirrhosis, liver failure, cancer and eventually death. MASH is the fastest growing cause of liver transplants and liver cancer in the US and Europe. About Akero Therapeutics Akero Therapeutics is a clinical-stage company developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including MASH. Akero's lead product candidate, EFX, is currently being evaluated in three ongoing Phase 3 clinical trials in patients with pre-cirrhotic MASH (F2-F3) or compensated cirrhosis (F4) due to MASH: SYNCHRONY Histology, SYNCHRONY Real-World, and SYNCHRONY Outcomes. The SYNCHRONY program builds on the results of two Phase 2b clinical trials, the completed HARMONY study in patients with pre-cirrhotic MASH (F2-F3) and the ongoing SYMMETRY study in patients with compensated cirrhosis (F4) due to MASH, in which more than 300 patients have been treated for up to 96 weeks. Akero is headquartered in South San Francisco. Visit us at akerotx.com and follow us on LinkedIn and X for more information. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, statements regarding Akero's business plans and objectives, including future plans or expectations for EFX; expectations regarding the SYNCHRONY Phase 3 program, including the anticipated timing to report Phase 3 study results and the program's clinical trial design; the timing to report results of the ongoing Phase 2b SYMMETRY Study; the therapeutic effects of EFX as well as the dosing, safety and tolerability of EFX; and Akero's growth as a company and expectations regarding its uses of capital, expenses, and financial results, including the expected cash runway. Any forward-looking statements in this press release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost, and timing of Akero's product candidate development activities and planned clinical trials; Akero's ability to execute on its strategy; positive results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies; regulatory developments in the United States and foreign countries; Akero's ability to fund operations; as well as those risks and uncertainties set forth more fully under the caption "Risk Factors" in Akero's most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as filed with the Securities and Exchange Commission (SEC) as well as discussions of potential risks, uncertainties and other important factors in Akero's other filings and reports with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Akero undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Investor Contact:Christina Tartaglia212.362.1200IR@akerotx.com Media Contact:Peg Rusconi617.910.6217peg.rusconi@deerfieldgroup.com Akero Therapeutics, Inc. Condensed Consolidated Balance Sheets (Unaudited) (In thousands) September 30, 2024 December 31, 2023 Assets Cash, cash equivalents and short-term marketable securities $717,247 $550,010 Other current assets 29,641 9,952 Non-current assets 70,659 20,309 Total assets $817,547 $580,271 Liabilities and Stockholders' Equity Current liabilities $43,291 $19,128 Non-current liabilities 35,931 25,837 Stockholders' equity 738,325 535,306 Total liabilities and stockholders' equity $817,547 $580,271 Akero Therapeutics, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(Unaudited)(In thousands, except share and per share amounts) Three Months Ended September30, Nine Months Ended September30, 2024 2023 2024 2023Operating expenses: Research and development $72,232 $38,634 $178,204 $88,406 General and administrative 9,471 7,981 29,194 22,591 Total operating expenses 81,703 46,615 207,398 110,997 Loss from operations (81,703) (46,615) (207,398) (110,997)Interest expense (1,246) (888) (3,468) (2,202)Interest and other income, net 10,244 7,844 28,830 16,626 Net loss $(72,705) $(39,659) $(182,036) $(96,573)Comprehensive loss $(70,341) $(39,914) $(180,203) $(97,116)Net loss per common share, basic and diluted $(1.05) $(0.71) $(2.76) $(1.87)Weighted-average number of shares used in computing net loss per common share, basic and diluted 69,442,136 55,613,120 65,982,798 51,506,766

临床2期财报临床3期临床结果加速审批

100 项与 MASH(Repair) 相关的药物交易

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