Cilofexor tromethamine

“ 点击蓝字 关注我们 邢峻豪 药物化学博士，副研究员。2016年毕业于中国药科大学药物科学研究院，2015年10 月至2016年11月赴美国密西根大学安娜堡分校进行访学。主要研究方向为全新小分子药物的发现及药物合成工艺研究。先后主持国家自然科学基金和江苏省自然科学基金等纵向课题多项，并作为主要成员参与重大新药创制项目1项、国家级及省级科研课题多项。近年来以第一作者或通信作者在Angew Chem Int Ed, ACS Catal, Eur J Med Chem 等学科权威期刊发表论文多篇。此外，完成盐酸替罗非班、阿格列汀、利格列汀及阿哌沙班的工艺研究，授权专利8项，成果转化1项。 凋亡信号调节激酶1抑制剂的研究进展 PPS  柏琛，王小宇，邢峻豪* （中国药科大学理学院，江苏 南京 211198） [摘要] 凋亡信号调节激酶1（ASK1）是细胞丝裂原活化蛋白激酶激酶激酶（MAP3K）家族成员之一，其调控的ASK1-c-Jun氨基末端激酶（JNK）-p38丝裂原活化蛋白激酶（p38）信号通路与多种疾病密切相关。在细胞应激的刺激下ASK1被激活，诱导其下游JNK和p38磷酸化，进而激活下游细胞因子，促进细胞增殖、分化、凋亡及炎症因子的产生，导致机体出现破坏性的炎症反应、细胞 死亡与纤维化。目前，ASK1抑制剂已在如肾脏、肝脏、中枢神经系统和关节等疾病中表现出治疗潜力。综述ASK1抑制剂的研究进展 及其在疾病治疗中的潜在应用，旨在为该类抑制剂的设计与开发提供参考。 细胞凋亡信号调节激酶1（apoptosis signal regulating kinase 1，ASK1）已成为预防p38丝裂原活化蛋白激酶（p38 mitogen activated protein kinases，p38）和c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）介导的细胞死亡和疾病的重要靶点[1-4]。大量研究表明，p38和JNK是细胞应激反应的关键介质，与多种人类疾病密切相关[5-9]。然而p38及JNK等普遍表达的蛋白对细胞存活、维持稳态和调节代谢功能至关重要，因此，完全抑制p38或JNK的活性会导致严重问题[10-12]。此外，p38及JNK抑制剂均表现出严重的肝毒性等副作用，故直接靶向p38或JNK的治疗策略欠佳[13-15]。ASK1与p38和JNK类似，均在多种细胞中普遍表达，但ASK1主要在细胞应激下被激活，受氧化还原信号的严格控制[16]。因此，作为p38和JNK的上游调节因子，ASK1是较理想的可成药靶点，能够在p38和JNK介导的疾病中发挥显著的治疗作用。 1 细胞凋亡信号调节激酶1 ASK1 是人丝裂原活化蛋白激酶激酶激酶（mitogen-activated protein kinase kinase kinases， MAP3K）家族成员之一，可激活人丝裂原活化蛋白激酶激酶4/7（mitogen-activated protein kinase kinase 4/7，MKK4/7）-JNK 通路和人丝裂原活化蛋白激酶激酶3/6（mitogen-activated protein kinase kinase 3/6，MKK3/6）-p38通路，然后磷酸化多种底物以促进炎症和细胞死亡（见图1）[17]。ASK1可响应各种应激源，包括活性氧（reactive oxygen species，ROS）、内质网（endoplasmic reticulum，ER）应激、热、渗透休克、受体介导的炎症信号[如肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）或脂多糖（lipopolysaccharide，LPS）]、钙离子超载和病原体感染等[18-19]。在正常条件下，ASK1通常被含硫醇的抗氧化蛋白结合和抑制，包括硫氧还蛋白（thioredoxin，Trx）、谷氧还蛋白（glutaredoxin，Grx）和过氧化物还原蛋白（peroxiredoxin，Prx）[20]。在细胞应激下，这些抗氧化蛋白发生氧化并与ASK1解离，导致激活环内ASK1同型二聚体，在Thr838位点发生反式自磷酸化。磷酸化的ASK1具有更高的催化活性并磷酸化MKK3、MKK4、MKK6和MKK7，进而磷酸化并激活p38和JNK，这些磷酸化的激酶通过核内转录因子诱导细胞凋亡、炎症和纤维化，从而导致组织损伤[21]。鉴于前述的广泛影响，多项研究表明，异常的ASK1信号与人类疾病密切相关[22-23]。此外，ASK1敲除小鼠在基础条件下未显示任何明显的表型[24]。该证据表明，ASK1抑制剂可能是一种可用于治疗多种疾病的安全且有效的药物，具有较大的临床应用价值。 2 细胞凋亡信号调节激酶1抑制剂与疾病 2.1 非酒精性脂肪肝病 目前已报道的ASK1抑制剂主要应用于非酒精性脂肪性肝炎（non-alcoholic steatohepatitis，NASH）治疗。NASH是非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）最严重的类型，也是慢性肝衰竭的主要诱因[25]。2016年，吉利德科学公司公布了高选择性ASK1抑制剂化合物1的Ⅱ期临床试验结果，确定其对患有Ⅱ期或Ⅲ期肝纤维化NASH患者安全有效[26]。在该项试验中，接受化合物1治疗的受试者肝病进展显著减缓；治疗24周后，在给药剂量18 mg组中，30例NASH患者中有13例纤维化得到逆转，给药剂量6 mg组中，27例中有8例纤维化症状明显缓解。上述研究结果表明，化合物1治疗对NASH患者安全有效。随后，大规模Ⅲ期临床试验评估化合物1用于NASH诱导的代偿性肝硬化治疗，该试验原计划持续240周，但在48周后停止，中止的原因为未达到预期临床终点[27]。然而，评估化合物1、firsocostat（GS-0976，一种ACC抑制剂）、cilofexor（GS-9674，一种非甾体类FXR激动剂）单一及联合用药治疗NASH（NCT02781584）以及NASH引起的桥接性 纤维化或代偿性肝硬化（NCT03449446）等2项Ⅱ期临床试验显示，使用组合疗法进行为期12周的治疗是安全的，并能改善肝脏脂肪变性、肝脏生化指标和纤维化指标，疗效与单一疗法相似。上述研究结果表明，ASK1抑制剂仍具有治疗NASH的潜力[28-29]。 在化合物1的基础上，江苏豪森药业集团有限公司发现了一系列新型ASK1抑制剂，可用于治疗NASH[30]。其中，通过环化法获得的化合物2和消旋化合物3对ASK1表现出相同的体外生化抑制活性，其IC50均为3.9 nmol · L-1；然而它们的药代动力学参数在小鼠中显示出显著差异。化合物3是在化合物2的结构基础上将甲基引入异吲哚啉酮环中获得，但表现出更好的药代动力学性质。该结果表明，当脂溶性基团（如甲基）被引入ASK1抑制剂 的结构中时，化合物在体内的代谢一般会减慢，其生物半衰期也会相应延长。在高脂饲料和CCl4诱导的NASH小鼠的体内实验表明，化合物2具有比化合物1更好的疗效，提示通过环化策略开发新型ASK1抑制剂是可行的。 此外，江苏豪森和广东东阳光分别用适当的连 接子环化化合物1的环丙基和三氮唑基团，获得另一类新型ASK1抑制剂[31-32]。该研究首先制备了化合物4 ~ 6以分析其环大小对活性的影响，体外活性实验结果显示，这些化合物均在低纳摩尔水平下对ASK1表现出抑制活性，表明该位置环的大小对ASK1蛋白的抑制活性具有良好的耐受性。随后，该研究引入含有杂原子的官能团进入新环，结果表明，除三氮唑吡嗪骨架化合物8的抑制活性（IC50 = 47.8 nmol · L-1）大幅下降以外，氧杂环产物7和砜杂环产物9对ASK1的抑制活性基本保持不变，IC50 均低于10 nmol · L-1。然后，该研究向化合物 4 的吡咯环引入了不同性质的取代基以进行详细的构效关系研究，得到了化合物10 ~ 13，并发现除 化合物13以外，该类化合物均显示出较高的抑制活性，但这些脂溶性基团反而促进了其在体内的代谢，半衰期均比化合物4短。为了探究该类抑制剂与ASK1蛋白的作用机制，将化合物4和ASK1蛋白进行分子对接，结果显示，化合物4的羰基与 ASK1 的铰链区氨基酸残基Val757产生关键性的氢键作用，而三氮唑伸入疏水口袋和Lys709形成氢键，吡咯环在疏水口袋边缘（见图2）。该研究结果表明，虽然环的大小不会影响对ASK1的抑制活性，但当环上含有NH等极性较大的基团时，可能会影响三氮唑伸入疏水口袋而使抑制活性降低。在对高脂饲料和CCl4诱导的NASH小鼠的体内实验表明，该类化合物均可显著降低小鼠的谷丙转氨酶和谷草转氨酶水平，且效果优于化合物1。综上可见，通过环化策略开发新型ASK1抑制剂具有可行性，且引入不同大小及性质的环能够在保留较高ASK1抑制活性的同时，改善药物分子的药代动力学性质。 2.2 慢性肾脏疾病 在慢性肾脏疾病（chronic kidney disease，CKD）患者中，ASK1-JNK-p38信号通路被激活，驱动肾小管上皮细胞、足细胞和系膜细胞的凋亡，引起肾脏炎症和纤维化[33]。目前已有大量研究表明，抑制ASK1活性能够通过减少细胞死亡、炎症和纤维化来维持肾功能[34]。为了开发出新型ASK1抑制剂，吉利德科学公司使用竞争性时间分辨荧光共振能量转移免疫测定法针对ASK1激酶结构域筛选了含约100 000种化合物的化合物库，筛选出的先导化合物吡啶酰胺衍生物14具有中等抑制活性（IC50 = 2.2 μmol · L-1）[35]。对化合物14与ASK1的结合模式分析表明，三氮唑N-甲基取代基周围有一个疏水口袋，可以填充更大的基团，而在吡啶环上引入亲水性芳香基团可以改善其理化性质。通过组合这些优选元素发现，化合物15具有较高的活性。随后，研究人员进一步优化了氢键受体的性质以提高选择性，在对该位置的芳基、杂芳基和杂环取代基进行广泛筛选后发现，将吡啶环替换为咪唑不仅保持了抑制活性，而且还提高了溶解度。随后，引入4-环丙基咪唑合成了化合物16，其生物活性比化合物14提高了750倍以上。分子对接结果显示，化合物16与Val757和Lys709形成关键性的氢键，三氮唑的N-环丙基填充了Ser821、Asp822、Leu810和Asn808等氨基酸残基形成的口袋，咪唑环延伸到铰链区，并与Tyr814形成氢键。体内外实验研究表明，化合物16是一种有效的选择性ASK1小分子抑制剂，在啮齿动物中口服有效且耐受性良好。另外，多个急性和慢性肾脏疾病的体内模型研究表明，ASK1是肾纤维化、细胞凋亡和炎症的关键介质；接受化合物16预防性或治疗性给药的啮齿动物，其肾小管间质纤维化和凋亡、肾小球硬化和蛋白尿等症状明显减缓，且肾功能得到改善。 基于吉利德科学公司的研究，广东东阳光公司开发了一系列酰胺类新型ASK1抑制剂（化合物17 ~ 23），用于慢性肾脏疾病的治疗[36]。值得注意的是，该研究所涉及化合物的酰胺结构位置与化合物16等其他抑制剂的结构位置不同，其中氨基和羰基的位置发生了交换，但仍保留了较高的抑制活性，化合物17的IC50为2.43 nmol · L-1，与化合物16的活性基本相同。提示，这可能是因为化合物16吡啶环上氮原子能够与酰胺键形成分子内氢键使整体构象趋近于平面，将化合物16的氨基和羰基互换位置并将苯环替换为吡啶环后，分子内的氢键得以保留因而不影响其抑制活性。化合物16和化合物17与ASK1的分子对接结果（见图3）也证明了这一点，并且其作用模式均与化合物1相似。将环丙基替换为异丙基得到的化合物18活性有显著提高，但将溶剂区吡啶氮原子更换位置后，活性会下降。另外，当溶剂区吡啶环上引入N-吗啉基、甲氧基、甲硫基等亲水性取代基时活性显著高于引入亲脂性的氟原子。体内实验结果表明，该系列化合物在口服给药后大鼠体内血药浓度及暴露量水平较高，清除率较低，口服生物利用度较好，在肝和肾中的浓度较高，具有良好的药代动力学性质；将其应用于单侧输尿管梗阻的肾纤维化大鼠模型中，可以显著降低肾纤维化水平。 2.3 神经退行性疾病 阿尔茨海默病（Alzheimer , s disease，AD）和帕金森综合征（Parkinson , s disease，PD）等神经退行性疾病发病率逐年提升，严重威胁人类健康。目前的研究表明，在氧化应激的条件下，神经毒性氧化物能够显著且持续地使ASK1磷酸化，激活ASK1-JNK-p38信号通路，造成神经元细胞死亡，引起相应疾病的发生[37]。因此，通过调节ASK1的 活性治疗人类神经系统疾病具有巨大的潜在价值。为了开发强效、高选择性和高脑渗透性的ASK1抑制剂，Felix研究小组采用基于结构的药物设计策略（structure-based drug design，SBDD），通过检测被人ASK1-V5全长质粒转染的高表达ASK1 的HEK-293T细胞系中的磷酸化水平，发现化合物24具有中等ASK1磷酸化抑制活性（细胞IC50 = 138 nmol · L-1），并且药物在大鼠脑间质液与血液中的游离药物浓度比Kp, uu达0.38，具有较好的中枢渗透性[38]。为了提高活性及选择性，研究人员首先将化合物24中的异丙基位置引入三氟甲基，旨在靶向极性氨基酸残基Asp807、Asn808和Ser821，得到化合物25。研究结果显示，化合物25具有更好的药效及药代动力学性质，但选择性并没有较大改善；通过分子对接分析（见图4）表明，手性三氟甲基更偏向溶剂区而远离疏水口袋，无法与极性氨基酸形成额外的作用。随后，研究人员将化合物25的溶剂区替换为极性表面积（polar surface area， PSA）更小的甲氧基吡啶基，并且让杂原子处于合适的位置与酰胺的NH形成分子内氢键，因为更小的PSA有利于提高化合物的脑渗透性，分子内的氢键有利于降低分子的极性并使分子构象趋近于平面而保持较高活性。该研究结果显示，化合物26活性（细胞IC50 = 25 nmol · L-1）、脑渗透性（Kp, uu = 0.46）等理化性质均较佳。此外，虽然化合物26激酶选择性仍低于化合物1，但在0.1 μmol · L-1下，其仅对468种激酶中的9种结合率超过90%。体内实验结果表明，化合物26通过抑制ASK1活性，可减少Tg4510转基因AD小鼠模型中异常升高的IL-1β、趋化因子KC/GRO及单核细胞趋化蛋白-1（monocyte chemoattractant protein-1，MCP-1）等脑细胞因子以达到治疗疾病的效果。上述实验结果显示，用中枢神经系统渗透性ASK1抑制剂是治疗神经退行性疾病的潜在方案，可通过对溶剂结合区的结构修饰提升ASK1抑制剂的选择性及脑渗透性。 2.4 自身免疫引起的炎症性疾病 当机体受到热、渗透压、病原体感染等外界刺激时，ASK1-JNK-p38信号通路被激活，释放出白介素-6（interleukin-6，IL-6）、TNF-α 和 IL-1β 等促炎细胞因子，诱导细胞程序性死亡以清除体内多余或受损的细胞[39]。然而当免疫功能紊乱时，ASK1被持续激活，释放出的炎症因子对机体造成持久性损伤。因此，选择性抑制ASK1的活性有望治疗自身免疫引起的炎症性疾病[40-41]。Swinnen等[42]采用基于靶点的高通量筛选（high throughput screening，HTS）开发了三唑并吡啶类小分子ASK1抑制剂（化合物27 ~ 30），其先导化合物27显示出对ASK1 中等抑制活性，其IC50为3 000 nmol · L-1。分子对接结果（见图5）显示，化合物27的羰基与Val757形成氢键。为了提高其药效和药代动力学性质，研究人员合成了182种三唑并吡啶类衍生物。分子对接和活性测试结果表明，三唑并吡啶环伸入疏水口袋，因此，在7位碳原子上引入亲脂性的三氟甲基有助于活性的提高；在5位碳原子上引入单取代的含氮基团可以与疏水口袋边缘的Leu686形成额外的氢键作用从而大幅度提高活性及选择性，且氮原子上取代基为柔性基团时活性要优于刚性基团，刚性环越大活性越低；将苯环替换为吡啶环后，不仅可以使吡啶环氮原子与Tyr814形成额外的氢键作用，同时分子构象产生了较大的变化，三唑并吡啶环的1位氮原子及酰胺键的NH与Val757形成氢键网络从而大幅度提升活性。药代动力学和药效学研究表明，化合物28不仅具有较高的ASK1抑制活性（IC50 = 93 nmol · L-1）和优异的选择性，其代谢稳定性强、 细胞膜渗透性高且血浆蛋白结合率适宜。同时，体内实验表明，化合物28可以改善由自身免疫紊乱引起的变态反应性脑脊髓炎（experimental allergic encephalomyelitis，EAE）和自身免疫性视神经炎（autoimmune optic neuropathy，AON），并可能有助于治疗包括多发性硬化症（multiple sclerosis， MS）在内的自身免疫引起的神经性炎症。 陈亚东课题组采用SBDD策略，开发了1H-吲唑衍生物作为有效的ASK1抑制剂[43]。为了使1H吲唑骨架靶向ASK1，研究人员向先导化合物31（IC50 = 532 nmol · L-1）引入化合物1的异丙基和4环丙基咪唑片段，合成了化合物32，其IC50达到 62.2 nmol · L-1。随后，研究人员进行了构效关系研究，合成了20多种衍生物，筛选出了候选化合物33，其在体外显示出优异的ASK1激酶抑制活性（IC50 = 29.9 nmol · L-1）。分子对接结果（见图6）表明，该类化合物与化合物1的作用模式类似，但化合物33 是通过1H-吲唑环的2位氮原子与Val757形成氢键，并且1位NH与Glu755形成额外的氢键作用，这为ASK1抑制剂的开发提供了新的思路。研究人员采用AP1-HEK293细胞系进行了机制及细胞活性验证，该细胞系含有一个萤火虫荧光素酶基因，当细胞受到佛波酯（phorbol-12-myristate-13-acetate，PMA）刺激时，ASK1-JNK信号通路被激活而使荧光素酶基因表达增加，使用ASK1抑制剂可抑制 ASK1 活性进而使其表达降低，化合物33对该细胞系中的ASK1具有良好的抑制作用。在TNF-α诱导的HT-29 肠上皮细胞模型中，化合物33对细胞的保护作用与化合物1相当，且在高达25 μmol · L-1的浓度下对正常的HT-29细胞无明显的细胞毒性。通过蛋白质印迹分析表明，化合物33能够通过抑制TNF-α诱导的HT-29细胞中ASK1-JNK-p38信号通路的磷酸化调控细胞凋亡相关蛋白的表达水平，可能是一种治疗免疫性肠炎（inflammatory bowel disease，IBD）的潜在化合物。 3 结语与展望 ASK1是一种广泛表达且进化上保守的诱导细胞死亡、纤维化和炎症的关键介质，抑制ASK1的活性有望为肾脏、肝脏、中枢神经系统、炎症等多系统疾病提供新的治疗策略。目前已开发出多种具有良好药效和高选择性的ASK1抑制剂。这些 ASK1 抑制剂大多数为小分子，且具有出色的药代动力学性质。然而，目前大多数ASK1抑制剂是基于化合物1作为先导化合物通过环化策略或生物电子等排原理开发的类似物，母核结构类型较为单一且作用机制类似。此外，目前报道的抑制剂构效关系研究尚不够深入，多数化合物的激酶选择性仍不够理想，ASK1在靶标特异性、配体结合力方面的结构基础仍需进一步探索。 除了采用SBDD及HTS开发新型ASK1抑制剂以外，已有分子胶、蛋白水解靶向嵌合体等多种异双功能分子被报道能够用于调控蛋白激酶活性，并且在细胞层面表现出显著的活性和较高的选择性，这些策略的应用将进一步拓展基于ASK1开发新药分子的研究思路。 参考文献： [1] Matsuzawa A. 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DOI: 10.1016/ j.ejmech.2021.113482. 美编排版：陈鑫茹 感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 2 期。 《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。 《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。 《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。 联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn； 邮箱：yxjz@163.com； 电话：025-83271227。 欢迎投稿、订阅！ 往期推荐 “兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航 我知道你在看哟

The MASH treatment landscape is evolving rapidly, driven by a diverse array of therapeutic classes, each with unique mechanisms and potential impacts. The forecast period reveals significant shifts and emerging trends that will shape future market dynamics. LAS VEGAS, Jan. 30, 2025 /PRNewswire/ -- DelveInsight's Metabolic Dysfunction-Associated Steatohepatitis Market Insights report includes a comprehensive understanding of current treatment practices, MASH emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan]. Key Takeaways from the Metabolic Dysfunction-Associated Steatohepatitis Market Report According to DelveInsight's analysis, the market size for MASH was found to be USD 2.1 billion in the 7MM in 2023. In 2023, there were an estimated 42 million prevalent cases of MASH in the 7MM. Out of these, a total of ~15 million cases were diagnosed, and this number is projected to increase by the end of 2034 in the 7MM. Leading MASH companies such as Inventiva Pharma, Novo Nordisk A/S, Cirius Therapeutics, Akero Therapeutics, 89bio, Boehringer Ingelheim, Zealand Pharma, Galectin Therapeutics, Lipocine, Viking Therapeutics, Eli Lilly and Company, Boston Pharmaceuticals, Pfizer, HighTide Biopharma, CytoDyn, Merck & Co., Hanmi Pharmaceutical, Hepagene (Shanghai), Hepion Pharmaceuticals, Enyo Pharmaceuticals, Gilead Sciences, Poxel SA, Zydus Therapeutics, Sagimet Biosciences, Ionis Pharmaceuticals, Corcept Therapeutics, and others are developing novel MASH drugs that can be available in the MASH market in the coming years. The promising MASH therapies in the pipeline include Lanifibranor (IVA337), Semaglutide, Azemiglitazone (MSDC-0602K), Efruxifermin (EFX), BIO89-100 (Pegozafermin), Survodutide (BI 456906), GR-MD-02 (Belapectin), LPCN1144, VK2809, Tirzepatide, BOS-580, Ervogastat (PF-06865571) + Clesacostat (PF-05221304), HTD1801, Leronlimab (PRO 140), Efinopegdutide, HPG1860, Rencofilstat (CRV431), EYP001 (Vonafexor), Semaglutide/Cilofexor/Firsocostat, PXL065, Saroglitazar Magnesium, Denifanstat (TVB-2640), ION224, Miricorilant (CORT118335), and others. In March 2024, Madrigal Pharmaceuticals' groundbreaking product, REZDIFFRA (resmetirom), a once-daily, oral THR-ß agonist, received accelerated endorsement from the US FDA based on results from the Phase III MAESTRO-NASH trial. This approval marks a significant stride in the medical landscape, as REZDIFFRA becomes the inaugural and sole FDA-sanctioned therapy for adults afflicted with non-cirrhotic MASH, accompanied by moderate to advanced liver scarring (fibrosis) corresponding to stages F2–F3 fibrosis. Discover which therapies are expected to grab the major MASH market share @ Metabolic Dysfunction-Associated Steatohepatitis Market Report Metabolic Dysfunction-Associated Steatohepatitis Overview Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that stems from metabolic dysfunction, often linked to obesity, diabetes, and other conditions of metabolic syndrome. MASH is characterized by the accumulation of fat in liver cells, accompanied by inflammation and liver cell injury, which can progress to fibrosis, cirrhosis, or even liver cancer. The primary drivers of MASH include insulin resistance, obesity, type 2 diabetes, and dyslipidemia. Genetic predisposition and a sedentary lifestyle also play significant roles. Environmental factors, such as a poor diet high in sugars and fats, exacerbate the condition. MASH is often asymptomatic in its early stages. When symptoms occur, they can include fatigue, vague abdominal discomfort, or pain in the upper right quadrant. In advanced stages, signs of liver dysfunction such as jaundice, swelling of the abdomen or legs, and confusion may arise. Diagnosis involves a combination of clinical history, physical examination, and diagnostic tests. Blood tests measuring liver enzymes (ALT, AST) often indicate liver inflammation. Imaging techniques like ultrasound, MRI, or FibroScan can identify liver fat and fibrosis. In some cases, a liver biopsy is required to confirm the diagnosis and assess disease severity. Metabolic Dysfunction-Associated Steatohepatitis Epidemiology Segmentation The MASH epidemiology section provides insights into the historical and current MASH patient pool and forecasted trends for the 7MM. It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders. The MASH market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Prevalent Cases of MASH Diagnosed Prevalent Cases of MASH Gender-specific Diagnosed Prevalent Cases of MASH Severity-specific Diagnosed Prevalent Cases of MASH Metabolic Dysfunction-Associated Steatohepatitis Treatment Market The approval of REZDIFFRA (resmetirom) in March 2024 represents a pivotal achievement in medical innovation, transforming the treatment landscape for MASH disease. This groundbreaking therapy addresses the root causes of MASH, offering renewed hope to patients grappling with this challenging condition. Clinical trials have shown impressive results, with REZDIFFRA effectively reducing symptoms like inflammation and fibrosis, enhancing liver function, and improving patients' quality of life. By providing healthcare professionals with a robust treatment option, this approval addresses a critical unmet need and has the potential to significantly alleviate the complications linked to advanced liver disease. The prevalence of MASLD is strongly linked to type 2 diabetes mellitus and obesity, particularly in individuals with a higher body mass index. However, MASLD occurrence is reduced in T2DM patients receiving treatments such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, GLP-1 receptor agonists, and insulin. Vitamin E, with its antioxidant properties, is regarded as a first-line pharmacological option for managing MASH, especially when dietary and lifestyle interventions are insufficient. Antifibrotic agents can help prevent the progression of liver fibrosis and MASLD into fibrotic MASH. The role of pioglitazone, an anti-diabetic medication, in improving MASH histology in T2DM patients is well-documented, but concerns remain regarding potential side effects like weight gain, fluid retention, cancer risk, and bone fractures. Additional therapeutic targets for MASLD and MASH include G protein-coupled receptors (GPCRs), estrogen-related receptor alpha (ERRα), bone morphogenetic proteins (BMPs), and KLFs. Bariatric surgery, or weight loss surgery, is the most effective intervention for treating obesity and diabetes, as it reduces food absorption while influencing gut hormone secretion and metabolic function. To know more about MASH treatment guidelines, visit @ Metabolic Dysfunction-Associated Steatohepatitis Management Metabolic Dysfunction-Associated Steatohepatitis Pipeline Therapies and Key Companies Lanifibranor (IVA337): Inventiva Pharma Semaglutide: Novo Nordisk A/S Azemiglitazone (MSDC-0602K): Cirius Therapeutics Efruxifermin (EFX): Akero Therapeutics BIO89-100 (Pegozafermin): 89bio Survodutide (BI 456906): Boehringer Ingelheim/Zealand Pharma GR-MD-02 (Belapectin): Galectin Therapeutics LPCN1144: Lipocine VK2809: Viking Therapeutics Tirzepatide: Eli Lilly and Company BOS-580: Boston Pharmaceuticals Ervogastat (PF-06865571) + Clesacostat (PF-05221304): Pfizer HTD1801: HighTide Biopharma Leronlimab (PRO 140): CytoDyn Efinopegdutide: Merck & Co./Hanmi Pharmaceutical HPG1860: Hepagene (Shanghai) Rencofilstat (CRV431): Hepion Pharmaceuticals EYP001 (Vonafexor): Enyo Pharmaceuticals Semaglutide/ Cilofexor/ Firsocostat: Gilead Sciences PXL065: Poxel SA Saroglitazar Magnesium: Zydus Therapeutics Denifanstat (TVB-2640): Sagimet Biosciences ION224: Ionis Pharmaceuticals Miricorilant (CORT118335): Corcept Therapeutics Discover more about MASH drugs in development @ Metabolic Dysfunction-Associated Steatohepatitis Clinical Trials Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics The MASH market dynamics are expected to change in the coming years. Growing research activities and multiple clinical trials for MASH, driven by the rapid surge in its prevalence due to rising obesity and type 2 diabetes rates, highlight an active drug development pipeline and an expanding market size. The large pool of patients and lucrative growth opportunities present attractive prospects for key players, further supported by ongoing preclinical studies aimed at advancing imaging techniques for MASH diagnosis, potentially eliminating the need for invasive biopsy-based histopathological confirmation. Furthermore, potential therapies are being investigated for the treatment of MASH, and it is safe to predict that the treatment space will significantly impact the MASH market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the MASH market in the 7MM. However, several factors may impede the growth of the MASH market. Lack of awareness and negligence in the early stages of MASH by physicians often lead to disease progression, culminating in irreversible damage where liver transplantation becomes the only viable option. Diagnosing advanced MASH typically requires procedures like liver biopsy, which are costly, invasive, and risky. Regulatory challenges also pose hurdles, as the FDA mandates achieving one MASH endpoint for approval, while the EMA's draft guidance requires efficacy in both endpoints, potentially delaying first-mover approvals in major European markets. Additionally, access to expensive MASH treatments may be limited in certain regions, further hindering patient adoption. Moreover, MASH treatment poses a significant economic burden and disrupts patients' overall well-being and QOL. Furthermore, MASH market growth may be offset by failures and discontinuation of emerging therapies, unaffordable pricing, market access and reimbursement issues, and a shortage of healthcare specialists. In addition, the undiagnosed, unreported cases and the unawareness about the disease may also impact MASH market growth. Scope of the Metabolic Dysfunction-Associated Steatohepatitis Market Report Therapeutic Assessment: Metabolic Dysfunction-Associated Steatohepatitis current marketed and emerging therapies Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics: Key Market Forecast Assumptions of Emerging Metabolic Dysfunction-Associated Steatohepatitis Drugs and Market Outlook Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's views, Analyst's views, Metabolic Dysfunction-Associated Steatohepatitis Market Access and Reimbursement Download the report to understand which factors are driving MASH market trends @ Metabolic Dysfunction-Associated Steatohepatitis Market Trends Table of Contents Related Reports Non-Alcoholic Steatohepatitis Epidemiology Forecast Non-Alcoholic Steatohepatitis Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted NASH epidemiology in the 7MM, i.e., the United States, EU4 (Germany, France, Italy, Spain), the United Kingdom, and Japan. Nonalcoholic Steatohepatitis Pipeline Nonalcoholic Steatohepatitis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key nonalcoholic steatohepatitis companies, including Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Inventiva, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, 89bio, Inc., Eccogene, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, Arrowhead Pharma, LG Chem, Redx Pharma, Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Chemomab Therapeutics, NuSirt Biopharma, HK inno. N, Aligos Therapeutics, Altimmune, Inc., Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Merck Sharp & Dohme LLC, Cascade Pharmaceuticals, Hepion Pharmaceuticals, Chipscreen Biosciences, Boston Pharmaceuticals, Bristol-Myers Squibb, Sunshine Lake Pharma, GSK plc., Future Medicine, Gilead Sciences, ENYO Pharma, Histogen, among others. Non-Alcoholic Fatty Liver Disease Market Non-Alcoholic Fatty Liver Disease Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key NAFLD companies, including MediciNova, Eli Lilly and Company, AstraZeneca, Inventiva Pharma, Oasis Pharmaceuticals, LLC, Madrigal Pharmaceuticals, Inc., BioMarin Pharmaceutical, GlaxoSmithKline, Zydus Therapeutics Inc., Akero Therapeutics, Inc, Pfizer, Boehringer Ingelheim, Neuraly, Inc., Merck Sharp & Dohme LLC, Rivus Pharmaceuticals, Inc., Hepion Pharmaceuticals, Inc. , among others. Non-Alcoholic Fatty Liver Disease Pipeline Non-Alcoholic Fatty Liver Disease Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key NAFLD companies, including BeiGene, Inventiva Pharma, Cirius Therapeutics, Madrigal Pharma, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Dr. Falk Pharma GmbH, Sagimet Biosciences, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Afimmune, Poxel SA, AngioLab, Pfizer, Oramed Pharmaceuticals, Can Fite Biopharma, MediciNova, Metacrine, Inc., Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma, Chemomab Therapeutics, NuSirt Biopharma, HK inno.N, Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Enanta Pharmaceuticals, Cascade Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED