A Double-Blind, Multicenter, Placebo-Controlled, Randomized, Parallel, Multiple-Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Pegbelfermin in Healthy Overweight and Obese Chinese and Korean Participants

The purpose of this study is to evaluate the safety, tolerability, and drug level of Pegbelfermin in healthy overweight and obese Chinese and Korean participants.

开始日期2021-06-21

申办/合作机构

Bristol Myers Squibb Co.

NCT04634149 / Completed临床1期

An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of BMS-986036 in Participants With Normal Hepatic Function and Participants With Moderate and Severe Hepatic Impairment

The purpose of this study is to investigate the effect of impaired liver function on the drug levels, safety, and tolerability of BMS-986036 in participants with moderate and severe liver impairment. Results from this study will be used to determine whether dose adjustment is required for patients with decreased liver function.

开始日期2020-11-23

申办/合作机构

Bristol Myers Squibb Co.

NCT04493567 / Completed临床1期

An Open-label, Randomized, Two-period Cross-over Study to Investigate the Relative Bioavailability of BMS-986036 in Healthy, Overweight, and Obese Participants Following Subcutaneous Administration Via Auto-injector Versus Pre-filled Syringe

The purpose of this study is to develop an auto-injector (AI) device for the BMS-986036 subcutaneous formulation that can be self-administered conveniently by participants.

开始日期2020-07-29

申办/合作机构

Bristol Myers Squibb Co.

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2024-01-01·Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study

Article

作者: Harrison, Stephen A ; Lawitz, Eric J ; Goodman, Zachary D ; Jacobson, Ira M ; Neuschwander-Tetri, Brent A ; Shevell, Diane E ; Yamaguchi, Masayuki ; Abdelmalek, Manal F ; Tirucherai, Giridhar S ; Akahane, Takemi ; Charles, Edgar D ; Halegoua-DeMarzio, Dina ; Imajo, Kento ; Du, Shuyan ; Boone, Bradly ; Gunn, Nadege ; Sanyal, Arun J ; Nakajima, Atsushi ; Loomba, Rohit ; Chatterjee, Arkendu

BACKGROUND & AIMS:

Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis.

METHODS:

FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation.

RESULTS:

Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P = .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites).

CONCLUSIONS:

FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

2024-01-01·Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study

Article

作者: Abdelmalek, Manal F ; Loomba, Rohit ; Lawitz, Eric J ; Goodman, Zachary D ; Harrison, Stephen A ; Gunn, Nadege ; Neuschwander-Tetri, Brent A ; Yamaguchi, Masayuki ; Shevell, Diane E ; Ravendhran, Natarajan ; Akahane, Takemi ; Tirucherai, Giridhar S ; Charles, Edgar D ; Imajo, Kento ; Boone, Bradly ; Du, Shuyan ; Sanyal, Arun J ; Nakajima, Atsushi ; Chatterjee, Arkendu

BACKGROUND & AIMS:

Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis.

METHODS:

The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study. Patients with biopsy-confirmed NASH and stage 3 fibrosis (N = 197) received weekly subcutaneous pegbelfermin (10, 20, or 40 mg) or placebo injections for 48 weeks. The week 24 primary endpoint was a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = 0.05). Secondary/exploratory endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation.

RESULTS:

At week 24, the primary endpoint was met by 14% (placebo) vs 24%-31% (pegbelfermin arms); statistical significance was not reached due to lack of pegbelfermin dose response (P = .134). At weeks 24 and 48, more patients who received pegbelfermin had ≥30% relative reductions in hepatic fat fraction (magnetic resonance imaging-proton density fat fraction) vs placebo, although no differences reached statistical significance. In the pegbelfermin arms, improvements in liver fibrosis (magnetic resonance elastography and N-terminal type III collagen propeptide) and liver injury/inflammation (alanine aminotransferase, aspartate aminotransferase) were observed vs placebo. Adverse events occurred at similar frequencies across arms. No treatment-related serious adverse events were observed.

CONCLUSIONS:

The FALCON 1 study did not meet its primary endpoint; a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening assessed via biopsy. Pegbelfermin was generally well tolerated during 48 weeks of treatment.

2023-06-27·World journal of hepatology

Treatment of liver fibrosis: Past, current, and future.

Review

作者: Yang, Ming ; Zhang, Chun-Ye ; Liu, Shuai

Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty liver disease. It is commonly associated with liver injury, inflammation, and cell death. Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins. Activated hepatic stellate cells contribute to the major population of myofibroblasts. Many treatments for liver fibrosis have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment (e.g., simtuzumab), drug (e.g., pegbelfermin and natural herbs), genetic regulation (e.g., non-coding RNAs), and transplantation of stem cells (e.g., hematopoietic stem cells). However, none of these treatments has been approved by Food and Drug Administration. The treatment efficacy can be evaluated by histological staining methods, imaging methods, and serum biomarkers, as well as fibrosis scoring systems, such as fibrosis-4 index, aspartate aminotransferase to platelet ratio, and non-alcoholic fatty liver disease fibrosis score. Furthermore, the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis. To avoid the life-threatening stage of liver fibrosis, anti-fibrotic treatments, especially for combined behavior prevention, biological treatment, drugs or herb medicines, and dietary regulation are needed. This review summarizes the past studies and current and future treatments for liver fibrosis.

项与培贝夫明(Ambrx, Inc.) 相关的新闻（医药）

2024-01-02

·行舟Drug

非酒精性脂肪肝炎治疗药物临床研发进展

点击上方的行舟Drug ▲ 添加关注非酒精性脂肪肝炎治疗药物临床研发进展来源《药学学报》2023年作者刘彩红, 侯少聪, 李平平中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室; 中国医学科学院代谢紊乱和肿瘤发生相关机制和靶点发现研究重点实验室摘要非酒精性脂肪肝炎(nonalcoholic steatohepatitis, NASH)正在成为全球范围内的慢性肝病, 与肥胖、高血压和糖尿病等代谢风险因素密切相关。其发病机制复杂, 涉及肝脏糖脂代谢紊乱、胆汁酸毒性、氧化应激、炎症、纤维化、肠道菌群失调和易感基因变异之间的相互作用。NASH治疗药物研发进展十分缓慢, 本文重点综述前景较好的几类NASH治疗药物临床研发进展及其作用机制, 如靶向肠肝轴类药物、改善代谢类药物、抗炎及抗纤维化类药物等, 旨在为NASH的新药研发提供最新参考。关键词非酒精性脂肪肝炎; 糖脂代谢; 肠−肝轴; 抗炎; 抗纤维化_正文_非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)是世界范围内的慢性肝病, 占世界人口的25%, 中国人口发病率约20%~29%[1]。NAFLD包括非酒精性脂肪肝(nonalcoholic fatty liver, NAFL)和非酒精性脂肪肝炎(nonalcoholic steatohepatitis, NASH), 前者病症较轻, 而后者炎症反应进一步加重, 除了肝细胞脂肪变性外, 还表现为肝细胞损伤(气球样变)、炎症和纤维化。其中, 25%的NAFL患者可进展为NASH, 35%~50%的NASH患者进一步发展为肝癌, 最终需要肝移植[2]。然而, 尚未有FDA正式批准用于治疗NASH的药物, 在研药物在临床试验中存在瘙痒、肝损伤和心血管疾病风险等不良反应, 寻找高效安全的NASH治疗药物迫在眉睫。目前, 针对NASH治疗的药物研发聚焦于以下4类(图1): ①靶向肠−肝轴类药物靶点, 包括调节胆汁酸肝肠循环和信号转导、改善肠道菌群的组成等; ②改善代谢类药物靶点, 包括改善胰岛素敏感性、抑制脂质从头合成的关键酶或促进脂肪酸在线粒体中的氧化等; ③抗炎类药物靶点, 包括抑制炎症细胞招募或者阻断炎症信号传导、减少氧化应激和内质网应激、抑制肝细胞凋亡等; ④抗纤维化类药物靶点, 包括靶向肝星形细胞、减少肝脏胶原分布、增强纤维分解等[3]。第1类和第2类以改善糖脂代谢为主的治疗策略目前研究较多, 并且大多受到各种核受体的调控[4]。NASH的治疗目标是延缓、阻止、逆转疾病的进展, 改善临床结局, 包括降低肝硬化及其并发症的发生, 降低肝移植的需求, 提高存活率, 改善生活质量等。在药物研发过程中, 临床治疗终点的准确选择对于NASH药物疗效的评价意义重大, 是否能够反映临床结局、预测临床获益是终点选择的基本原则。下面将对已经进入临床试验阶段的NASH治疗药物研发进展及相关临床设计进行综述。1NASH治疗药物临床主要评价方法和终点NASH新药研发的有效性评价终点包括临床结局终点和肝组织学替代终点, 以及血清生化检查、影像学检查等其他探索性终点[5]。临床结局终点主要是全因死亡率和肝脏相关死亡率, 然而, NASH进展为肝硬化的过程是缓慢的[6], 若以全因死亡率和肝脏相关死亡率降低作为主要研究终点, 可能需要对早期NASH患者随访长达10~15年, 这无法践行于新药研发和审批中。因此, 我国指导原则、FDA和欧盟药监系统都选择肝组织病理学作为替代终点, 包括脂肪性肝炎和纤维化的改善[7]。对于非肝硬化NASH研究, Ⅱb期的药物临床试验(探索性临床试验阶段)建议使用的组织学替代终点为: NASH改善, 纤维化不恶化(NAS评分降低≥2分, 其中至少1分是小叶炎症或气球样变); 或纤维化改善≥1级, NASH不恶化; Ⅲ期临床试验(确证性临床试验阶段)可接受的组织学替代终点为: NASH消退(气球样变消失, 小叶内炎症灶的减少或消失), 纤维化不恶化; 和/或纤维化改善≥1级, NASH不恶化。对于代偿期NASH相关肝硬化的临床试验, 仍建议以临床结局改善为终点评价, 但组织学的改善也是Ⅱ/Ⅲ期临床试验重要治疗终点之一, 即肝纤维化改善≥1级, NASH不恶化[8, 9]。此外, 我国、美国等食品药品监督管理机构允许在临床试验早期概念验证阶段及药物研发后期使用无创生物标志物作为探索性终点及次要终点。无创生物标志物中, 与评价糖脂代谢相关的有体重、体质量指数、腰臀比、空腹血糖、糖化血红蛋白、胰岛素抵抗如胰岛素抵抗的稳态模型评估(homeostatic model assessment of insulin resistance, HOMA-IR)、血脂等; 与肝脏炎症/损伤相关的有丙氨酸氨基转移酶(alanine aminotransferase, ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase, AST)、细胞角蛋白18(cytokeratin18, CK18)片段等; 与评价肝纤维化相关的有肝纤维化测试、增强型肝纤维化(enhanced liver fibrosis, ELF)测试、NAFLD纤维化评分(NAFLD fibrosis score, NFS)、III型前胶原N端前肽(procollagen type III N-terminal propeptide, Pro-C3)、纤维化-4指数(fibrosis-4 index, FIB-4)、AST与血小板计数(platelet count, PLT)比值指数(AST/PLT ratio index, APRI)等。总之, 对于非肝硬化NASH临床评价, 早期概念验证阶段可采用无创指标作为探索性终点; 在后期探索和确证性临床试验阶段, 主要采用肝组织学替代终点, 同时需要长期随访以评估这些组织学替代终点是否与临床结局终点一致。对于合并肝硬化的NASH新药研发, 应结合临床结局、组织学及无创指标共同作为疗效终点。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。2靶向肠−肝轴类药物靶点2.1 法尼醇X受体(farnesoid X receptor, FXR)激动剂FXR是核受体超家族的成员之一[10], 在肝脏和小肠中高度表达, 其天然配体为胆汁酸(bile acid, BA)。FXR在调节胆汁酸合成、吸收、转运、肝肠循环及与脂质吸收和合成相关的过程中发挥关键作用[11]。基于FXR靶点的NASH治疗药物的研发很早就已经开始, 这一类药物目前进展最快。此类在研药物均为FXR激动剂, 可通过肠道和肝脏两方面的作用改善糖脂代谢。在肝脏, FXR激活后可与其下游小异源二聚体伙伴(small heterodimer partner, Shp)、肝细胞核因子4(hepatocyte nuclear factor 4, Hnf4)等基因相互作用, 抑制肝脏胆汁酸合成酶如细胞色素P450家族7亚家族A成员1(cytochrome P450 family 7subfamily A member1, Cyp7a1)等基因的表达, 减少胆汁酸的合成[12]; 并且降低脂肪酸和甘油三酯(triglyceride, TG)合成通路中硬脂酰辅酶a去饱和酶1(stearoyl-CoA desaturase1, Scd1)、二酰基甘油酰转移酶2(diacylgycerol acyltransferase, Dgat2)和Lipin1的表达, 从而减少单不饱和脂肪酸甘油三酯的含量。在肠道, FXR激活后可上调靶基因成纤维细胞生长因子15/19(fibroblast growth factor15/19, Fgf15/FGF19)的表达, FGF15/19可分泌入血, 经血液到达肝脏后同样可抑制胆汁酸的合成, 从而减少肠道脂质吸收[13, 14]。FXR激动剂可分为两类, 一类是具有胆汁酸结构的化合物, 如Intercept Pharmaceuticals研发的奥贝胆酸(obeticholic acid, OCA); 一类是不具有胆汁酸结构的非固醇类化合物, 如Tropifexor、Cilofexor、TERN-101、EDP-305和MET-409等[15]。OCA在结构上与天然胆汁酸有相似之处, 但引入了一个乙基基团, 使其比天然胆汁酸具有更强的FXR激动效果。2016年5月, 美国FDA有条件加速批准其用于治疗原发性胆汁性胆管炎, 这鼓励了许多企业跟随Intercept的脚步进行FXR靶点的研究。OCA在临床前研究中可显著减少胆汁酸总量及疏水性胆汁酸的含量, 从而显著减少肠道TG及胆固醇的吸收[16]。OCA是全球第一个进入III期临床的NASH治疗药物, 而其上市历程却并不顺利。在REGENERATE临床Ⅲ期研究中, 治疗18个月时, OCA高剂量组中23%的患者实现了纤维化改善≥1级且NASH不恶化, 而安慰剂组仅有12%患者达到这一指标(P=0.0002)[14], 治疗效果很好。但OCA容易引发严重的瘙痒症状, 并可导致低密度脂蛋白胆固醇(low-density lipoprotein, LDL-C)升高和高密度脂蛋白胆固醇(high-density lipoprotein, HDL-C)降低, 较高剂量OCA还可导致晚期肝病患者肝功能恶化, 这极大限制了临床应用。2020年6月, FDA认为OCA的治疗收益并未超过潜在风险, 拒绝批准其用于治疗NASH引起的肝纤维化。2023年6月, FDA再次拒绝了OCA用于治疗NASH引起的肝硬化前纤维化的新药申请, 提出需要完成长期随访的临床数据, 以证明其安全性和有效性, Intercept的挫折再次验证了NASH新药研发赛道的残酷性。由于怀疑OCA的不良反应是具有胆汁酸结构导致的, 目前在研的其他数款FXR激动剂均与OCA结构不同, 不具有类固醇类结构, 希望能在保持疗效的前提下降低不良反应[15]。拓臻生物(Terns Pharmaceuticals)的TERN-101是一种强效的非胆汁酸FXR激动剂, Ⅱa期临床数据显示TERN-101治疗可显著降低ALT、校正T1(cT1)弛豫时间和磁共振成像−质子密度脂肪分数(MRI-PDFF), 对LDL-C影响比较轻微, 但是也会导致瘙痒和HDL-C降低, 治疗相关不良事件为轻度/中度[17, 18], FDA已授予TERN-101治疗NASH适应症的快速通道资格认定。EDP-305也曾获得过FDA的快速通道资格认定, 不过EDP-305并未展现出比OCA更好的疗效, 也会导致瘙痒等不良反应, Enanta公司提前终止了72周的ARGON-2研究, 转而寻求联合治疗方案[19]。Metacrine公司的MET-409在疗效及不良反应方面也并未展现出显著优势, 目前已经停止相关项目的研发[20]。Gilead Sciences研发的Cilofexor显著减少NASH患者的肝脏脂肪变性、肝脏生化指标和血清胆汁酸水平, 而未改变肝纤维化评分[21]; Bayer研发的Tropifexor也未显著改善NASH或纤维化组织学变化[22], Cilofexor及Tropifexor作为单药治疗NASH的希望不大, 临床试验重点转向联合治疗。肠道FXR激活后可在回肠末端刺激肠道产生FGF19, FGF19能够抑制脂肪生成和糖异生, 增强脂肪酸氧化和糖原合成, 调节胆汁酸合成和脂质稳态。FGF19类似物NGM282(Aldafermin)由NIDDK和NGM生物制药公司合作开发, 可显著降低肝脏脂肪含量并改善肝功能, 但其Ⅱb期临床未能达到主要临床终点, 后续开发已被终止[23]。由于FXR的重要生物学功能, 基于FXR靶点的NASH治疗药物的研发很早就已经开始, 这一类药物目前进展最快, 但产生的瘙痒等不良反应又限制其在临床上的应用, 备受期待的FXR激动剂OCA的上市申请再次遭受FDA拒绝, 而结构优化后的其他数款FXR激动剂也并未产生更好的疗效及更低的不良反应, 临床试验重点转向联合治疗。研究人员正在努力改进这些药物并找到更好的治疗方案, 以满足患者的需求。2.2 胰高血糖素样肽1受体(glucagon-like peptide1receptor, GLP-1R)激动剂GLP-1主要由回肠和结肠中的L细胞分泌, 通过与胰岛、肠道、大脑等组织的GLP-1R结合, 触发一系列生理反应, 涉及胰岛素分泌、胃排空延迟、食欲抑制、糖代谢改善等, GLP-1R是糖尿病领域的成熟靶点。GLP-1R在肝脏中的表达量相对较低, 不过越来越多的数据表明, GLP-1R激动剂可以通过多种途径改善NASH患者的肝脏组织学特征[24], 主要机制是减轻体重、降低糖化血红蛋白及脂毒性、改善胰岛素敏感性、抑制肝脏脂肪变性和炎症[25]。目前多个GLP-1R激动剂已进入NASH临床试验研究[26]。司美格鲁肽(Semaglutide)是Novo Nordisk公司研发的长效GLP-1R激动剂, 用于治疗成年2型糖尿病及肥胖, 因其优秀的降糖减重效果备受关注。2020年10月30日, FDA授予其治疗NASH的突破性疗法资格。在治疗NASH和代偿性肝硬化患者中, Semaglutide能够改善肝酶、肝脂肪变性、体重、糖尿病和血脂指标, 但并未显著改善纤维化[27]。Novo Nordisk公司已在中国启动Semaglutide用于非肝硬化性NASH的III期国际多中心临床试验。值得一提的是, Semaglutide与FXR激动剂Cilofexor及乙酰辅酶A羧化酶(acetyl-CoA carboxylase, ACC)抑制剂Firsocostat联用的Ⅱ期试验达到了主要终点, 疗效及安全性良好[28]。利拉鲁肽(Liraglutide)能够改善NASH患者的肝脏组织学, 在接受Liraglutide治疗的患者中, 39%的患者在48周内达到NASH缓解, 而接受安慰剂治疗的患者达到了9%。然而, 经减重调整后, 组织学反应与安慰剂组无显著差异, 提示Liraglutide的益处可能与减重有关[29]。新一代的双靶点和多靶点疗法在靶向GLP-1R之外, 还靶向胰高血糖素受体(glucagon receptor, GCGR)及葡萄糖依赖性胰岛素多肽受体(glucose-dependent insulinotropic peptide receptor, GIP)介导的信号通路。2023年6月, Merck公司公布了其GLP-1R/GCGR双重激动剂Efinopegdutide治疗NAFLD的Ⅱa期临床试验结果, 相较于GLP-1R激动剂, Efinopegdutide具有较长的血浆半衰期, 降低患者肝脏脂肪水平的效果更为显著。Eli Lilly公司的Tirzepatide是一种GLP-1R/GIPR双重激动剂, 在一项事后分析中, 与服用安慰剂的患者相比, 服用Tirzepatide26周的患者与NASH相关的ALT和Pro-C3等生物标志物显著降低[30]。此外, 2023年6月, 第83届美国糖尿病学会公布了Eli Lilly公司的GLP-1R/GCGR/GIPR三重激动剂Retatrutide在肥胖和NAFLD治疗中的Ⅱ期临床试验数据, 与安慰剂相比, 所有剂量的Retatrutide治疗均显著减少肝脏脂肪水平及NASH相关生物标志物(K-18和Pro-C3)。总体而言, GLP-1R激动剂在NASH早期治疗中显示出一定的潜力, 在改善脂肪代谢及胰岛素敏感性、减轻体重方面作用显著, 并且作为降糖减重的成熟靶点, 其用药安全性展现出一定优势。肥胖和2型糖尿病患者出现脂肪性肝炎、肝纤维化、肝硬化和肝癌的风险较高, 高危人群的早期诊断尤为重要, GLP-1R激动剂可用于此类患者的早期个体化治疗, 患者同时需要改变生活方式, 调整饮食结构, 增加体育锻炼。3改善代谢类药物靶点3.1 甲状腺激素受体(thyroid hormone receptors, THR)激动剂THR包括THRα和THRβ, 虽然这两种异构体在大多数组织中都有表达, 但THRβ是在肝脏表达的主要形式, 而THRα在心脏和骨骼中高表达[31]。基于两者在不同组织的分布, 制药业一直在努力开发具有THRβ选择性的化合物, 用于治疗代谢疾病, 同时避免对心脏及骨骼的不良反应。THRβ能够结合甲状腺激素T3或T4, 形成一个激活的复合物, 然后通过结合到DNA上的甲状腺激素响应元件(thyroid hormone response element, TRE)来调控能量代谢、脂质代谢等相关基因的表达。THRβ激动剂可以提高线粒体功能, 促进脂肪酸氧化和能量代谢, 从而减少肝脏脂质堆积; 调控胆汁酸及胆固醇代谢, 减轻肝脏负担; 抑制肝内炎症和氧化应激, 减少免疫细胞浸润, 降低纤维化相关蛋白的合成[32]。因此, THRβ激动剂具备调控多种肝脏代谢通路来治疗NASH的潜力。Resmetirom是Madrigal Pharmaceuticals研发的一款潜在“first-in-class”THRβ口服选择性激动剂, 能够被肝脏特异性摄取, 两项Ⅱ期临床试验结果均显示, Resmetirom可显著降低NASH患者的肝脏脂肪相对含量[33, 34]。2022年12月19日, Madrigal Pharmaceuticals宣布, Resmetirom治疗NASH的Ⅲ期临床试验MAESTRO-NASH达到主要终点(纤维化改善≥1级且NASH不恶化)和关键次要终点(LDL-C及NASH生物标志物显著降低), 安全且耐受性良好。2023年4月, FDA授予Resmetirom治疗伴肝纤维化的NASH成人患者的突破性疗法认定; 2023年9月, FDA接受Resmetirom的新药申请(NDA)并纳入优先审评, 用于治疗伴有肝纤维化的NASH成人患者。此外, 还有很多在研的用于治疗NASH的THRβ激动剂药物, 如Metabasis/Viking的VK2809、歌礼制药(Ascletis)的ASC41和拓臻生物的TERN-501等。VK2809[35]是一款肝脏靶向性前体药物, 在肝脏被特有的CYP3A4酶切断后释放活性化合物, 其IIa期临床试验结果显示出很好的降脂能力, 目前已进入Ⅱb期研究。ASC41也是一款肝脏靶向性前体药物, 与Resmetirom相比, ASC41与THRβ受体结合亲和力更强, 在I期临床试验中取得良好数据, 不过其在美国的一项II期临床试验处于撤回状态, 陷入了Viking的诉讼风波。TERN-501在DUET IIa期研究中能有效减少患者肝脏脂肪含量并达到了主要和次要研究终点。THRβ选择性激动剂通过调控脂肪代谢、胰岛素敏感性、炎症和纤维化等多种作用机制发挥作用, 在临床试验中获得了积极结果, 同时THRβ选择性激动剂在肝脏部位被特异性摄取, 对骨骼或心脏参数无影响, 不良反应风险较低, 此类药物有可能在NASH治疗中率先获得突破。在一些情况下, 特别是当NASH与THR功能失调相关时, THRβ选择性激动剂可用于个性化治疗。3.2 过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor, PPAR)激动剂PPAR是调节糖脂代谢、炎症和纤维化的一组核受体, 其亚型包括α、β(或δ)和γ。PPARα主要在肝脏表达, 调控成纤维细胞生长因子21(fibroblast growth factor21, FGF21)分泌、脂肪酸β氧化、脂肪酸吸收、脂蛋白酯酶活性及极低密度脂蛋白(very low-density lipoprotein, VLDL)输出等一系列过程[36]; PPARβ主要表达于骨骼肌、脂肪组织等, 调控脂肪酸氧化、促进胰岛素敏感性; PPARγ在脂肪组织中高表达, 主要调节机体免疫、胰岛素抵抗及脂肪细胞分化[37]。IVA337(Lanifibranor)是Inventiva公司开发的一种泛PPAR激动剂, 在一定剂量范围内能激活3种PPAR受体亚型, 协同改善胰岛素抵抗及脂质代谢。Ⅱb期临床试验结果显示, Lanifibranor显著降低了脂肪变性及纤维化评分, NASH改善且纤维化无恶化[38], FDA也因此授予Lanifibranor治疗NASH的“突破性疗法”称号, 其Ⅲ期临床试验正在多个国家和地区开展。中国生物制药附属公司正大天晴与Inventiva签署协议, 允许在中国研发、制造和商业化Lanifibranor。2023年7月, 正大天晴就Lanifibranor向国家药监局CDE递交申请并获同意拟纳入突破性治疗药物程序, 国际多中心III期临床试验即将在中国启动入组, Lanifibranor是中国第一个进入临床Ⅲ期的NASH口服药物。深圳微芯生物的西格列他钠(chiglitazar sodium)也是一种泛PPAR激动剂, 获NMPA批准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, 展现出治疗NASH的潜力, 其Ⅱ期试验正在进行。此外, Genfit研发的PPARα/β双效激动剂ElafibranorⅢ期临床试验效果不佳, 没有达到NASH缓解且纤维化不恶化的治疗目标而被中止。Zydus Cadila研发的PPARα/γ受体激动剂Saroglitazar于2020年3月被印度药品管理局批准用于治疗NASH, 但该适应证尚未通过美国FDA的审批。PPAR的3种亚型具有相似的生物学功能, 也有各自的特点。单一受体激动剂对NASH治疗无显著作用, 而PPAR泛激动剂以一种均衡有效的方式靶向所有3种PPAR亚型, 显示出良好的治疗效果。因此, PPAR泛激动剂是未来靶向PPAR治疗NASH的研发方向之一。而NASH患者的具体病情和病史可能有很大差异, 其最佳治疗策略可能是综合性的, 包括药物联合治疗、生活方式干预和可能的手术干预。3.3 FGF21类似物FGF21是肝脏分泌的肝脏因子, 这类因子由肝脏分泌, 分泌后既反过来作用于自身, 也可以作用于全身其他组织。FGF21表达受到PPAR调控, 主要通过其受体FGFR1发挥功能。FGF21是调节葡萄糖和脂质代谢、胰岛素敏感性、能量稳态的基本代谢信使, 也可通过抑制c-JNK和NF-κB信号通路发挥抗炎作用[39]。内源性FGF21的半衰期极短, 治疗药物一般是通过化学修饰或基因工程改造获得的半衰期更长的类似物。Akero公司的FGF21衍生物AKR-001(Efruxifermin)研发进展较快且潜力较大, 目前FDA已授予其用于NASH治疗的快速通道资格。Efruxifermin是基于人体免疫球蛋白G1的Fc片段与FGF21融合的长效FGF21类似物, 比天然FGF21的半衰期更长, 受体亲和力更强[40]。2022年9月13日, Akero公司宣布Efruxifermin在Ⅱb期HARMONY研究中获得了积极数据, 28和50mg剂量的Efruxifermin在短短24周内均达到了改善肝脏纤维化的主要终点及多个次要终点, 且Efruxifermin耐受性良好, 最常见的不良事件是1级或2级胃肠道事件, 研发者对Efruxifermin寄予厚望。然而, 2023年10月, Akero公布Efruxifermin治疗代偿性肝硬化NASH患者的IIb期研究中期分析结果未达预期, 第36周时, 试验观察到了肝纤维化改善的主要终点趋势, 但不具有统计学意义, 不过在肝损伤和纤维化非侵入性标志物、血糖控制和脂蛋白方面观察到统计学意义上的改善, 未来将进一步观察96周的长期数据。此外, BMS-986036(Pegbelfermin)是聚乙二醇化的FGF21类似物[41], 但其Ⅱb期临床试验(FALCON1和FALCON2)结果不如人意, Bristol Myers Squibb已经停止了对Pegbelfermin的开发[42]。FGF21类似物作为治疗NASH的新型药物, 具有调节代谢、抗炎和改善病理损伤等优点, 能够显著缓解肝纤维化, 其组织学改善效果是目前公布数据的NASH药物中最为显著的, 并且其治疗作用不仅局限于肝脏, 还可能对全身脂质代谢产生积极影响, 这对NASH患者尤为重要。不过FGF21类似物治疗代偿性肝硬化NASH患者的效果暂未达到预期, 多数以注射形式给药, 并且产生胃肠道相关不良反应, 仍需要进一步研究来评估其长期疗效、安全性和给药方案的优化, 以及与其他治疗方法的组合应用。3.4 靶向肝脏脂质生成通路肝脏TG的来源主要有从头合成(de novo lipogenesis, DNL)和3-磷酸甘油(glyceraldehyde3-phosphate, G3P)途径, DNL的底物是乙酰辅酶A, 碳水化合物和脂肪酸代谢均可产生乙酰辅酶A, SCD1、脂肪酸合成酶(fatty acid synthetase, FASN)、ACC、DGAT2是DNL过程中的关键酶, 其表达受到核受体PPAR、FXR等的调控[43, 44], 直接抑制DNL关键酶以减少肝脏内TG堆积是治疗和预防NASH的重要策略之一。3.4.1 SCD1抑制剂SCD1是将饱和脂肪酸(如硬脂酸和棕榈酸)转化为单不饱和脂肪酸(如油酸和亚油酸)的限速酶[45], Aramchol是Galmed自主研发的一款口服新型脂肪酸胆酸偶联物[46], 通过抑制肝细胞和肝星形细胞中SCD1的表达发挥作用: 在肝细胞中, 抑制SCD1能够减少单不饱和脂肪酸的合成, 促进胆固醇逆向转运, 减少肝脏脂质堆积, 增加GSH/GSSG比率, 减少肝脏氧化应激; 在肝星形细胞中, 抑制SCD1会导致PPARγ的特异性上调, 从而阻止胶原蛋白的产生。Aramchol治疗NASH的Ⅱb期研究结果显示, Aramchol可有效降低肝脏脂肪浸润, 并具有良好的安全性和耐受性[47]。2023年1月4日, Galmed宣布Aramchol用于治疗NASH的Ⅲ期ARMOR研究开放标签部分达到主要终点。数据显示, 在经过48周治疗后, Aramchol显著改善NASH患者的肝纤维化程度, 显著降低多项肝损伤、肝硬化与纤维化生物标志物的水平。3.4.2 FASN抑制剂FASN是位于SCD1上游的脂肪酸合成酶。歌礼药业FASN抑制剂TVB-2640(ASC40)可抑制肝内DNL, 并直接抑制炎症和纤维化通路。Ⅱa期临床试验结果显示, ASC40可以剂量依赖的方式显著改善NASH患者的糖脂代谢、炎症和纤维化[48]。2021年3月23日, 歌礼药业发布新闻稿称, ASC40获得美国FDA快速通道资格, 用于NASH适应症。3.4.3 ACC抑制剂ACC是位于FASN上游的脂肪酸合成酶[49], ACC有2个亚型, ACC1位于细胞质, ACC2位于线粒体, 前者催化产生的丙二酰辅酶A用于DNL, 后者产物则可抑制脂肪酸氧化限速酶CPT1的活性。因此, 当将两个亚型同时敲除后, 虽然可降低DNL从而减少肝脏脂肪含量, 但同时激活了G3P途径, 增加了肝脏对血液里游离脂肪酸的摄取, 进而通过G3P途径合成TG, 通过VLDL分泌到肝外, 从而导致血脂升高; 同时虽然缺少ACC2产物对CPT1的抑制, 脂肪酸氧化增加, 但是由于DNL的抑制, 导致PPARα的配体大幅减少, 因此脂肪酸氧化增加的幅度并不足以抵消G3P途径带来的脂质的绝对增加。因此, 针对肝脏脂质合成通路的药物研发应综合考虑DNL和G3P两个途径的作用, 和TG合成最后一步关键酶DGAT2抑制剂联用能解决ACC抑制剂的不良反应。针对ACC下游脂肪酸合酶FASN也存在着类似的问题, 其产物也是PPARα的配体, 因此FASN在肝脏的敲除可能会因为脂肪酸氧化被抑制而增加肝脏脂质水平, 但抑制下游的SCD1则不会有此问题[50, 51]。目前, 处于临床阶段的ACC抑制剂有Firsocostat和PF-05221304(Clesacostat)。如前所述, Firsocostat与Cilofexor及Semaglutide联用的疗效及安全性较好。Clesacostat能有效抑制肝脏ACC以降低NASH患者肝脏DNL, 但其单药临床试验结果疗效不佳, 并且会导致高脂血症[52]。Pfizer已停止Clesacostat作为单药治疗的相关试验, 在此之前, Pfizer研发的DGAT2抑制剂Ervogastat也从NASH管线中移除, 重点转向Ervogastat和Clesacostat联合治疗[53]。Ervogastat/Clesacostat组合疗法的非临床试验结果和Ⅱa期临床试验(NCT03248882、NCT03776175)结果积极, 使其获得治疗NASH合并肝纤维化的快速通道资格。3.4.4 DGAT2抑制剂DGAT2是催化TG合成最后一步的关键酶[54]。PF-06865571(Ervogastat)是Pfizer研发的治疗NASH的DGAT2抑制剂。DGAT2抑制剂能阻止脂肪酸储存为TG, 从而抵消ACC抑制剂导致的高脂血症[51], 如前所述, Ervogastat和ACC抑制剂Clesacostat联合治疗具有良好的安全性和耐受性。总之, 干预脂质合成通路来治疗NASH仍然具有前景, SCD1抑制剂具有良好的安全性和耐受性, ACC抑制剂及FASN抑制剂会产生高脂血症的不良反应, 临床上在针对此类靶点进行药物开发时须考虑周全, 进行联合给药或采取其他方法以消减其不良反应带来的不利影响, 同时需要充分考虑个体差异、不良反应和药物相互作用等因素。3.5 钠-葡萄糖协同转运蛋白(sodium-dependent glucose transporters, SGLT) 1/2抑制剂SGLT1和SGLT2都是上皮葡萄糖转运的重要介质, 在肾脏葡萄糖的重吸收中起重要作用, 是治疗糖尿病的主要靶标[55]。SGLT-2抑制剂卡格列净(Canagliflozin)可降低78%的脂肪含量, 有效改善炎症。T2DM合并NAFLD患者(n= 57)经SGLT-2抑制剂达格列净(Dapagliflozin)(每天5mg)治疗24 周后, 血清ALT、AST均有明显改善[56], 展示出治疗NASH的潜力, 不过此类药物目前尚未展开大规模的临床试验。4靶向炎症通路的药物靶点NASH发生时, 肝脏脂质堆积会引起肝细胞损伤, 激活免疫细胞释放炎症因子, 炎症进一步加剧细胞凋亡及坏死, 促进胶原生成及细胞外基质沉积, 从而导致肝脏纤维化或瘢痕形成, 肝脏炎症和纤维化会导致门静脉高压, 进而显著增加产生危及生命的食管静脉曲张风险。半乳糖凝集素-3(galectin-3, Gal-3)是一种β半乳糖苷结合蛋白, 介导细胞间的黏附, 参与炎症细胞的迁移和活化, 促进细胞外基质积累及组织纤维化过程[57]。Belapectin是Galectin公司研制的一种Gal-3抑制剂, 能够预防NASH肝硬化食管静脉曲张的发生[58]。NAVIGATE临床Ⅱb/Ⅲ期试验结果显示, Belapectin在NASH引起的肝硬化患者中疗效与安全性良好。趋化因子受体2/5(CC-chemokine receptor2/5, CCR2/5)的异常激活可导致单核细胞和巨噬细胞向炎症组织募集, 并激活肝星形细胞, 导致纤维化[59]。Cenicriviroc是一种口服的CCR2/5双重抑制剂, 但其Ⅲ期临床试验结果未达到主要终点, 临床试验被迫终止[60]。Caspase是一类细胞内半胱氨酸蛋白酶, 通过活化IL-1β、IL-18和IL-33等促炎因子, 调控凋亡和炎症[61]。Emricasan是一种全caspase抑制剂, 但其IIb期临床试验结果显示, 未达到治疗NASH的主要终点[62, 63]。5抗纤维化类药物靶点细胞凋亡信号调节激酶1(apoptosis signal regulated kinase1, ASK1)可激活TNFα的下游p38/JNK通路, 导致细胞凋亡和纤维化[64]。Selonsertib是一款ASK1抑制剂, 但两项评估Selonsertib治疗NASH导致的晚期纤维化患者的安全性和有效性的III期试验均未达到主要终点, 该项目已终止[65]。赖氨酰氧化酶样2(lysyloxidase-like2, LOXL2)通过催化胶原的交联促进纤维生成。Simtuzumab是一种靶向LOXL2的单克隆抗体, 两项评估Simtuzumab治疗NASH导致的晚期纤维化患者的IIb期试验, 由于缺乏预期的疗效而提前终止[66]。靶向脂质代谢的药物通常适用于NASH早期阶段, 减少肝脏内的脂肪积累, 从而延缓或阻止NASH向纤维化的进展; 而靶向炎症及纤维化的药物更适用于进展到晚期的NASH, 伴随着明显的肝纤维化或肝硬化, 这些药物旨在减轻或逆转肝脏中的疤痕组织, 治疗晚期NASH通常更具挑战性, 因为肝脏已经受到了严重的结构和功能损害, 可能需要更复杂的治疗方法。因此, NASH的早期干预非常重要, 在疾病的早期阶段采取适当的措施可有效预防严重肝病的发展。6小结与展望NASH的药物研发面临着临床诊断困难、动物模型数据难以转化为临床结果、发病机制复杂等困难。肝活检仍然是临床确诊NASH的金标准, 但存在有创和取样随机性等缺陷, 非侵入性诊断技术的开发对评估药物疗效将会更加直观全面。目前尚无NASH动物模型能够完全模拟人类NASH病理特征, 需要建立基于不同病因的NASH动物模型以全面模拟人类NASH的发生发展, 同时研究并使用其他创新性临床前模型, 如人源化的肝脏NASH类器官和肝脏芯片。NASH病因复杂、多样, 肝脏功能异常的同时合并全身代谢紊乱, 单药治疗存在一定缺陷, 目前多种药物的联合治疗方案已投入Ⅱ期临床试验, 与单一用药相比或许会有突破性的进展, 多靶点药物开发也是NASH领域的研究热点方向。NASH是一类异质性很强的疾病, 而目前大多数NASH临床试验的受试者招募采用的是“非精准化”方案, 这也增加了新药研发的难度, 因此, 在开展临床试验时应该对患者进行更精细的分类, 从而实现更精准、个性化的治疗, 最终提高新药研发成功率。综上所述, FXR激动剂OCA及THRβ激动剂Resmetirom是目前治疗NASH前景较好的药物, 其他进展较快的药物还包括FGF21衍生物Efruxifermin、PPAR激动剂Lanifibranor、SCD1抑制剂Aramchol及GLP-1受体激动剂Semaglutide等(表1)[15, 28-30, 33-35, 38, 40, 46, 47, 58, 67]。以上潜力较大的药物均靶向肝脏脂质代谢, 而针对炎症和纤维化靶点(CCR、Caspase、ASK1、LOXL2)进行开发的药物都宣告失败, 这可能是由于从脂毒性到细胞损伤、炎症和纤维化的信号通路复杂交错, 而靶标所处的病理生理学通路越下游, 其改善疾病发展的难度就越高。由此看来, 改善脂质代谢紊乱和胰岛素抵抗仍然是目前治疗NASH较好的策略。同时, NASH的发生发展与肝外组织如肠道和脂肪组织等关系密切, 肠道是人体重要的营养物质吸收器官, 在脂质代谢中有着重要作用, 也可通过肠道菌群、FGF19及神经酰胺等方式影响肝脏生理和代谢, FXR激动剂和THRβ激动剂取得较好临床试验结果的原因可能也与其能够直接(FXR激动剂)或者间接(二者都可调节胆汁酸代谢)影响肠道功能, 同时作用于肝脏和肠道有关。而FGF21是由肝脏分泌的因子, 也可同时作用于肝脏和脂肪组织, 从而显著改善NASH相关病理表现。因此, 未来靶向肠道组织, 或者同时靶向肝脏、肠道组织及脂肪组织等的药物研发也可能是极具潜力的方向之一。作者贡献刘彩红负责文献调研及文章撰写; 侯少聪负责思路指导及文章修改; 李平平负责主题制定及文章审阅参考文献详见《药学学报》2023年文章信息源于公众号凡默谷，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新欢迎订阅+医药大数据|行业动态|政策解读

ASH会议快速通道

2023-11-19

·药时代

百亿美金蓝海市场，NASH药物进展如何？

全球有很多NASH患者，如美国约有1500-3000万NASH患者，中国约有5000万，但是目前美国和中国都没有一款NASH药物获批上市，大量的临床治疗需求仍未得到满足。据Frost & Sullivan数据分析，预计2025年NASH市场将达107亿美元，2030年达到322亿美元，百亿美元市场亟待瓜分。NASH药物由于巨大的市场前景而备受关注，很多国内外药企纷纷加入布局，如Madrigal、礼来、诺和诺德、默沙东、歌礼制药、拓臻生物、海思科和雅创医药等。临床上有很不同类型在研的NASH药物，根据靶点主要可以分为以下几类：FXR（Farnesoid X受体）激动剂、THR-β（甲状腺激素受体β亚型）激动剂、GLP-1R激动剂、FGF19（成纤维细胞生长因子19）和FGRF21（成纤维细胞生长因子21）类似物和FASN（脂肪酸合成酶）抑制剂等。NASH的形成及药物类型非酒精性脂肪性肝病（NAFLD）包括一系列肝脏表现，从肝脂肪变性开始，并可能发展为非酒精性脂肪性肝炎（NASH）、肝硬化甚至肝细胞癌（图1）[1]。图1. NAFLD进展从市场前景来看，NASH拥有庞大的患者基础，但大量的临床治疗需求仍未得到满足。流行病学数据显示，美国约有1500-3000万NASH患者，而中国约有5000万。据Frost & Sullivan分析数据，全球NAFLD/NASH药物市场已从2016年的17亿美元增至2020年的19亿美元，CAGR为 3.2%。预计未来会呈现快速增长趋势，2025年将达107亿美元，并于2030年达322亿美元，CAGR分别为41.8%和24.6%。2020年3月，印度制药企业Zydus Cadila研发的PPARα/PPARγ的双重激动剂Saroglitazar获得了印度药品管理局批准，用于非肝硬化性NASH的治疗，成为全球首个获批用于NASH治疗的药物，不过Saroglitazar的市场表现不佳。FDA或NMPA都没有批准过治疗NASH的药物，但是临床上有很多不同类型的NASH药物在研，从代谢和抗纤维化等方面来治疗NASH，包括FXR激动剂、THR-β激动剂、GLP-1R激动剂、FGF19和FGRF21类似物和FASN抑制剂等（图2）[2]。图2. 治疗NASH不同的药物类型 FXR激动剂FXR是核受体（NR）超家族的成员，被鉴定为胆汁酸（BA）结合转录因子，FXR激动剂通过纠正中间代谢和脂质积累的异常、抑制代谢应激诱导的p53激活、抑制纤维化的进展和减少炎症，具有治疗肝脏疾病的治疗潜力。FXR激动剂用于治疗NASH的开发命运多舛，此前有在临床2期终止试验的cilofexor（GS-9674）、LMB763和EDP-305等，今年奥贝胆酸（Obeticholic acid）在6月份因疗效不佳且副作用明显而被FDA拒绝批准其上市申请。但是，临床上还有很多在研的用于治疗NASH的FXR激动剂，如HTD1801、TERN-101、ASC42和HEC-96719等（图3）。图3. 部分在研治疗NASH的FXR激动剂HTD1801是由君圣泰医药独立自主研发针对代谢及消化系统疾病的原创口服小分子新药。今年的EASD会议上，北京大学人民医院内分泌科主任、北京大学糖尿病中心主任纪立农教授报道了HTD1801用于改善T2DM患者的血糖控制的最新2期研究结果：HTD1801能够在有效降糖的同时改善肝功能相关指标，且安全性和耐受性良好，提示其对于T2DM合并NAFLD患者的治疗潜力。ASC42是由歌礼制药自主研发的新型高效选择性非甾类FXR激动剂，用于治疗NASH和慢性乙型肝炎（CHB）。ASC42于2020年10月获得FDA批准在NASH患者中开展临床试验，随后12月份被FDA授予治疗NASH快速通道资格，目前处于临床2期。 THR-β激动剂THR-β在肝脏中高度表达，THR-β激动剂被证实在人体中具有降低低密度脂蛋白（LDL）、甘油三酯（TG）和肝脏脂肪变性的活性。与此同时，THR-β还可以通过促进脂肪酸的分解和刺激线粒体的生物发生来减少脂肪毒性并改善肝功能，进而减少肝脏脂肪。因此，THR-β激动剂具备调控多种肝脏代谢通路来治疗NASH的潜力。临床在研的用于治疗NASH的THR-β激动剂药物有Madrigal Pharmaceuticals的Resmetirom、歌礼制药的ASC41、拓臻生物的TERN-501、海思科的HSK31679和Viking的VK2809等（图4）。图4. 部分在研治疗NASH的THR-β激动剂Resmetirom是由Madrigal Pharmaceuticals研发的每日一次的口服THR-β选择性激动剂，旨在针对肝脏NASH的关键潜在原因。9月13日，Madrigal宣布FDA已接受Resmetirom用于治疗患有肝纤维化的成年NASH患者的新药申请（NDA）审查。FDA 已授予优先审查，处方药使用者费用法案日期（PDUFA）是2024 年 3 月 14 日[3]。11月10日，Madrigal Pharmaceuticals公布了来自3期MAESTRO-NASH试验的新数据，证明了Resmetirom对肝脏健康非侵入性措施的广泛治疗效果，主要肝活检终点和降低低密度脂蛋白胆固醇的关键次要终点均达到。MAESTRO-NASH是一项随机、双盲、安慰剂对照的3期系列肝活检试验评估Resmetirom在活检证实的NASH成人中的疗效和安全性（NCT03900429）[4]。在MAESTRO-NASH中，Resmetirom治疗帮助肝活检诊断为严重纤维化（F2/F3）的NASH患者实现肝酶、磁共振成像-质子密度脂肪分数（MRI-PDFF）、磁共振弹性成像（MRE）、FibroScan 振动控制瞬时弹性成像（VCTE）、FibroScan 控制衰减参数（CAP）和增强的肝纤维化（ELF）测试的改善（图5）[5]。Resmetirom还降低了低密度脂蛋白胆固醇和其他与心脏病相关的脂质的水平。图5. MAESTRO-NASH结果绝大多数（>70%）接受Resmetirom 100 mg治疗的患者具有≥30%的MRI-PDFF反应。MRI-PDFF降低≥30%与NASH消退（96%的患者）和纤维化改善（88%的患者）密切相关。该组MRI-PDFF的中位降低总体为 52%[4]。 GLP-1R激动剂GLP-1类药物因其显著的降糖减重效果而备受关注，随着研究的深入，人们发现GLP-1类药物也能治疗NASH。临床上有很多GLP-1R激动剂或GLP-1R/GIPR双重激动剂用于治疗NASH，其中司美格鲁肽进展最快，处于临床3期（图6）。图6. 部分在研的GLP-1R类用于治疗NASH的药物诺和诺德的司美格鲁肽是目前进展最快的治疗NASH的GLP-1类药物，此前一项在治疗NASH的2期临床结果显示司美格鲁肽0.1 mg、0.2 mg和0.4 mg治疗组分别有47.3%、46.8%和66.7%患者的NASH症状得到消除（图7）[6]。图7. 司美格鲁肽治疗NASH的2期结果 FGF19和FGF21类似物据报道，成纤维细胞生长因子（FGF）家族的几个成员（即FGF1、FGF19和FGF21）为对NAFLD有益的代谢激素。这些 FGF受核受体的转录控制，如即FXR调节FGF19，而 PPARγ和α分别调节 FGF1和21。FGF19是一种在肠道中产生的激素，调节胆汁酸的产生和能量代谢。重组FGF19的药物给药在改善T2D和NAFLD/NASH等代谢紊乱方面显示出显著的临床前疗效。FGF21是FGF家族的另一个成员，通过与跨膜蛋白βKlotho（KLB）复合的FGF受体（FGFRs）结合发挥其生物学作用，导致各种典型信号通路的激活，如丝裂原活化蛋白激酶（MAPK）和PI3K-PKB/AKT[7]。然而天然FGF在患者中有几个缺点，包括不良反应和半衰期短，因此人们开发它们的类似物，希望改善药代动力学和药效学特征，如图8所示。图8. 部分临床在研的FGF19和FGF21类似物Aldafermin（NGM282）是由NGM Bio研发的人类激素FGF19的工程变体，每日注射一次用于治疗非酒精性脂肪性肝炎（NASH）。今年5月份，NGM 公布了NGM282的一项为期48周的2b期ALPINE 4 的顶线研究数据，该研究招募了160名因 NASH（肝纤维化 4 期或 F4）引起的代偿性肝硬化患者，评估了1 mg和3 mg剂量的NGM282与安慰剂相比的疗效、安全性和耐受性。该研究达到了其主要终点，与接受安慰剂的患者相比，接受3 mg NGM282治疗的患者从基线到第 48 周的增强型肝纤维化（ELF）评分在统计学上显着降低。NGM282已在800多名患者和健康志愿者中给药，涉及多种肝脏和代谢疾病，包括400多名NASH患者，并且在迄今为止的临床试验中普遍耐受性良好[8]。其它类型的NASH药物除了上述治疗NASH药物类型，还有很多不同机制的NASH药物，如FASN抑制剂和PPAR激动剂等（图9）。图9. 部分在研的其它类型NASH药物FASN是肝脏脂质合成的关键酶，肝脏过量的脂质沉积是基于脂质合成增多、分解减少、转运增多，因此抑制FASN可以用于治疗NASH。今年EASL大会上，美国O'Farrell在口头报告中介绍了FASN抑制剂denifanstat治疗活检证实NASH的多中心、随机、双盲、安慰剂对照2b期试验FASCINATE-2研究的26周中期分析结果：使用50 mg/d denifanstat可以显著抑制NASH患者FASN的功能和显著改善NASH患者的肝脏损伤[9]。小结NASH市场前景巨大，全球的患者逐年增加，迫切需要新机制NASH药物来满足临床需求。目前全球尚无FDA或NMPA批准治疗NASH的药物，但是临床上有很不同类型在研的NASH药物，此前，FXR激动剂进展最快的奥贝胆酸折戟而归，不过THR-β激动剂Resmetirom的上市申请获FDA受理且纳入优先审评，近期，Resmetirom的一项MAESTRO-NASH显示超过70%患者NASH关键指标改善，该突破性疗法有望明年获批。临床上还有很多在研的NASH药物，未来十年或将获批十余款NASH药物。ReferencesThierry Huby and Emmanuel L. Gautier, Immune cell-mediated features of non-alcoholic steatohepatitis, Nat Rev Immunol. 2022 Jul;22(7):429-443.Stephen A. Harrison , Alina M. Allen, Julie Dubourg, Mazen Noureddin & Naim Alkhouri, Challenges and opportunities in NASH drug development, Nature Medicine | Volume 29 | March 2023 | 562–573https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priorityhttps://ir.madrigalpharma.com/node/15071/pdfhttps://ir.madrigalpharma.com/static-files/e8a35f47-f841-49d4-9c21-781f41177609https://investor.novonordisk.com/q2-2023-presentation/?page=303Cristy R.C. Verzijl, Ivo P. Van De Peppel, Dicky Struik and Johan W. Jonker, Pegbelfermin (BMS-986036): an investigational PEGylated fibroblast growth factor21 analogue for the treatment of nonalcoholic steatohepatitis, EXPERT OPINION ON INVESTIGATIONAL DRUGS2020, VOL. 29, NO. 2, 125–133https://www.ngmbio.com/pipeline/O’Farrell M, Grimmer K, Zetter A, et al. Multicenter, randomized, double-blind, placebo-controlled trial of Fatty Acid Synthase (FASN) inhibitor, denifanstat, versus placebo in the treatment of biopsy-proven NASH: A 26-week interim analysis of the FASCINATE-2 Phase 2B trial. Journal of Hepatology 2023 vol. 78(S1) | S1–S99. EASL 2023. Abstract OS-061.封面图来源：123rf药时代BD-092项目 | 高活性，低风险THRβ靶向NASH新药寻求合作药时代BD-053项目 | 与奥贝胆酸同靶点临床II期NASH口服小分子寻求合作药时代BD-034项目 | KHK靶向安全、有效BIC潜质口服小分子 NASH I期项目药时代BD-033项目 | FXR靶向安全有效潜在BIC小分子 NASH I期项目药时代BD项目 | 具有独特MOA且安全、有效的美国IIb期NASH项目寻求中国权益转让药时代BD项目 | 潜在更优THR-β激动剂，目标适应症：NASH和血脂异常。寻找全球或中国权益合作伙伴点击在看共济新药研发浪潮

ASH会议临床2期快速通道

2022-12-12

·PRNewswire

Propulsion of Nonalcoholic Steatohepatitis Pipeline as Novel and Extensive 150+ Therapies Likely to Enter in the Treatment Domain | DelveInsight

The prevalence of nonalcoholic steatohepatitis has been rising since the past few years, which prompts the growing demand for treatment options. The increasing prevalence of Nonalcoholic Steatohepatitis and the growing research and development activities drive the market. The Companies developing the potential therapies in the last stage of development include Madrigal Pharmaceuticals, Inventiva, Boehringer Ingelheim, and several others. LAS VEGAS, Dec. 12, 2022 /PRNewswire/ -- DelveInsight's ' Nonalcoholic Steatohepatitis Pipeline Insight – 2022 ' report provides comprehensive global coverage of available, marketed, and pipeline nonalcoholic steatohepatitis therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the nonalcoholic steatohepatitis pipeline domain. Key Takeaways from the Nonalcoholic Steatohepatitis Pipeline Report DelveInsight's nonalcoholic steatohepatitis pipeline report depicts a robust space with 130+ active players working to develop 150+ pipeline therapies for nonalcoholic steatohepatitis treatment. Key nonalcoholic steatohepatitis companies such as Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, 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, 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, and others are evaluating nonalcoholic steatohepatitis drugs to improve the treatment landscape. Promising nonalcoholic steatohepatitis pipeline therapies in various stages of development include TERN-101, SNP-610, LJN452 (tropifexor + licogliflozin), PXL065, ALS-L1023, PF-06865571 + PF-05221304, PF-06835919, PF-06865571, ORMD-0801, Norucholic acid, NNC0194-0499, MN-001, MK-3655, MET642, MET409, LPCN 1144, LIK066, Leronlimab, ALN-HSD, MT-3995, CM101, Leu-Mit-Sil (NS-0200), IN-A010, Efruxifermin (EFX), Efinopegdutide, EDP-305, JKB-122, CS0159 (Linafexor), CRV431, Chiglitazar sodium, BOS-580, BMS-986263, HEC96719, GSK4532990, FM101, Firsocostat, EPY001a, Emricasan, BMS-986036, BIO89-100, BI 456906, BFKB8488A, AXA1125, ASC 41, GS-9674 (Cilofexor), ZSP1601, and others. In November 2022, Sagimet Biosciences announced positive interim data from its Phase IIb clinical trial (FASCINATE-2) with denifanstat, a fatty acid synthase (FASN) inhibitor, in non-alcoholic steatohepatitis patients. Data showed statistically significant improvements across key markers of NASH, reinforcing results observed in earlier studies, including statistically significant reductions in markers of liver fat, inflammation, and fibrosis. There were no treatment-related serious adverse events, with the majority of adverse events mild to moderate in nature (Grade 1 and 2). Additional interim data are expected in early 2023. In November 2022, Inventiva announced that the United States Patent and Trademark Office granted a patent (U.S. Patent No. 11,504,380) that protects the use of lanifibranor for the treatment of cirrhotic patients at risk of progressing from compensated stage to decompensated stage. This patent will expire on November 8, 2039. This patent further expands the intellectual property protection of lanifibranor in the United States for use in patients with cirrhotic NASH. In October 2022, Galectin Therapeutics, Inc. reported the positive outcome of its second data and safety monitoring board (DSMB) meeting for NAVIGATE, its seamless, adaptive, phase IIb/III study of belapectin in patients with liver cirrhosis caused by non-alcoholic steatohepatitis (NASH). The objective of this second independent DSMB was further to review the emerging tolerance and safety profiles of belapectin. Based on its deliberation, the DSMB concluded that NAVIGATE could continue as designed, without modifications. In September 2022, Inventiva and Chia Tai-Tianqing Pharmaceutical Group entered into a licensing and collaboration agreement to develop and commercialize lanifibranor, if approved, for the treatment of nonalcoholic steatohepatitis and potentially other metabolic diseases in mainland China, Hong Kong, Macau, and Taiwan. In June 2022, Poxel SA announced that the U.S. Patent and Trademark Office (PTO) has issued to Poxel US Patent No. 11319313, which represents a new patent for PXL065, a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone which is being investigated in Phase II stage of clinical trial evaluation for the treatment of Nonalcoholic steatohepatitis (NASH). In May 2022, Pfizer Inc. announced the U.S. Food and Drug Administration (FDA) had granted Fast Track designation to Pfizer's investigational combination therapy for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis: ervogastat (PF-06865571, a diacylglycerol O-acyltransferase 2 inhibitor, or DGAT2i) and clesacostat (PF-05221304, an acetyl-CoA carboxylase inhibitor, or ACCi). In May 2022, Hepion Pharmaceuticals, Inc. announced that it has entered into a clinical collaboration with HepQuant, a Denver-based, privately held company with novel, proprietary investigational technology for evaluating liver function and health in patients with chronic liver diseases. Hepion will incorporate the HepQuant 'SHUNT' test into a dedicated Phase IIb clinical trial in presumed NASH F3 subjects. In February 2022, the US Food and Drug Administration (FDA) granted a Fast-Track Designation to Axcella Therapeutics' AXA1125 to treat non-alcoholic steatohepatitis (NASH) with liver fibrosis. In January 2022, LISCure Biosciences announced that it had executed a research collaboration agreement with Mayo Clinic for new drug development for rare liver diseases. LISCure Biosciences Inc. has executed a research collaboration agreement with US based-Mayo Clinic for new drug development for rare liver diseases. Request a sample and discover the nash drugs in development 2022 @ Nonalcoholic Steatohepatitis Pipeline 2022 Report The nonalcoholic steatohepatitis pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage nonalcoholic steatohepatitis drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the nonalcoholic steatohepatitis clinical trial landscape. Nonalcoholic Steatohepatitis Overview Nonalcoholic steatohepatitis (NASH) is a type of liver inflammation and damage caused by fat buildup. It is one of several conditions known as nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease is classified into two types: isolated fatty liver, in which only fat accumulates, and nonalcoholic steatohepatitis, in which fat, inflammation, and liver cell damage occur. NASH does not usually cause symptoms. Most people with NASH feel fine and are unaware that they have it. As NASH progresses and liver damage worsens, a patient may experience fatigue, weight loss, general weakness, and acne in the upper right part of the belly. Screening for nonalcoholic fatty liver disease in the general population is not advised. It is usually considered after discovering unexplained liver enzyme levels, or imaging reveals hepatic steatosis. A patient's medical history, a physical exam, and tests for nonalcoholic steatohepatitis are used by doctors. Want to discover how the Nash treatment pipeline will look like? Request for sample @ NASH Drug Pipeline 2022 A snapshot of the Nonalcoholic Steatohepatitis Pipeline Drugs mentioned in the report: Want to know how nash dash the pipeline race is for new agents? Download the sample page @ NASH Clinical Trials Nonalcoholic Steatohepatitis Therapeutics Assessment The nonalcoholic steatohepatitis pipeline report proffers an integral view of nonalcoholic steatohepatitis emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Nonalcoholic Steatohepatitis Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Intravenous, Parenteral, Oral, Subcutaneous Therapeutics Assessment By Molecule Type: Antibody, Biologic, Cell therapy, Peptide, Protein, Small molecule Therapeutics Assessment By Mechanism of Action: Adiponutrin inhibitor, Diacylglycerol O acyltransferase inhibitor, Adiponutrin modulator, RNA interference, Glucagon like peptide 1 receptor agonist, Ornithine decarboxylase stimulant, Farnesoid X-activated receptor agonist, Thyroid hormone receptor beta agonist, Mitochondrial membrane transport protein modulator, Thyroid hormone receptor beta agonists, Peroxisome proliferator-activated receptor alpha agonist Key Nonalcoholic Steatohepatitis Companies:Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, 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, 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, and others. Key Nonalcoholic Steatohepatitis Pipeline Therapies: TERN-101, SNP-610, LJN452(tropifexor + licogliflozin), PXL065, ALS-L1023, PF-06865571 + PF-05221304, PF-06835919, PF-06865571, ORMD-0801, Norucholic acid, NNC0194-0499, MN-001, MK-3655, MET642, MET409, LPCN 1144, LIK066, Leronlimab, ALN-HSD, MT-3995, CM101, Leu-Mit-Sil (NS-0200), IN-A010, Efruxifermin (EFX), Efinopegdutide, EDP-305, JKB-122, CS0159 (Linafexor), CRV431, Chiglitazar sodium, BOS-580, BMS-986263, HEC96719, GSK4532990, FM101, Firsocostat, EPY001a, Emricasan, BMS-986036, BIO89-100, BI 456906, BFKB8488A, AXA1125, ASC 41, GS-9674 (Cilofexor), ZSP1601, and others. Dive deep into rich insights for nonalcoholic steatohepatitis research; visit @ NASH Treatment Pipeline Table of Contents For further information on the most promising nash drugs, reach out @ NASH Medication Pipeline Related Reports Nonalcoholic Steatohepatitis Epidemiology Nonalcoholic Steatohepatitis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted nonalcoholic steatohepatitis epidemiology in the 7MM. Nonalcoholic Steatohepatitis Market Nonalcoholic Steatohepatitis Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key nonalcoholic steatohepatitis companies, including Boehringer Ingelheim, Oramed Pharmaceuticals, ENYO Pharma, Terns Pharmaceuticals, Cirius Therapeutics, among others. Non-Alcoholic Fatty Liver Disease Market Non-Alcoholic Fatty Liver Disease Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key non-alcoholic fatty liver disease companies including AstraZeneca, Novartis, Pfizer, Roche, among others. Non-Alcoholic Fatty Liver Disease Pipeline Non-Alcoholic Fatty Liver Disease Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key advanced non-alcoholic fatty liver disease companies, including AstraZeneca, Novartis, Pfizer, Roche, among others. Non-Alcoholic Fatty Liver Disease Epidemiology Non-Alcoholic Fatty Liver Disease Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted non-alcoholic fatty liver disease epidemiology in the 7MM. Other Trending Reports Alcohol Use Disorder Market | Liver Cancer Market | Alcoholic Hepatitis - Market | Acute Liver Failure - Market | Liver Angiosarcoma - Market | Liver Cirrhosis - Market | Chronic Liver Disease - Market | Advanced Liver Cancer - Market | Acute On Chronic Liver Failure (ACLF) Market Related Healthcare Services Healthcare Business Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. Connect with us at LinkedIn Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research LLP

临床2期引进/卖出快速通道

100 项与培贝夫明(Ambrx, Inc.) 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11512	-	-	DB15365

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肝纤维化	临床2期	美国	Bristol Myers Squibb Co.	2018-06-12
肝纤维化	临床2期	日本	Bristol Myers Squibb Co.	2018-06-12
肝硬化	临床2期	美国	Bristol Myers Squibb Co.	2018-06-12
肝硬化	临床2期	日本	Bristol Myers Squibb Co.	2018-06-12
非酒精性脂肪性肝炎	临床2期	美国	Bristol Myers Squibb Co.	2015-05-08
肥胖	临床2期	美国	Bristol Myers Squibb Co.	2014-04-15
肥胖	临床2期	加拿大	Bristol Myers Squibb Co.	2014-04-15
2型糖尿病	临床2期	美国	Bristol Myers Squibb Co.	2014-03-17

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03486912 (FALCON 2, CTgov)	临床2期	肝纤维化 \| 非酒精性脂肪性肝炎 \| 肝硬化	155	Placebo	選膚築夢獵窪膚鬱觸醖(遞蓋顧夢窪遞夢繭醖簾) = 觸齋鬱範窪鏇淵鏇夢獵簾醖憲蓋簾餘積鏇醖鏇 (願遞衊衊壓淵積繭醖鹽, 構窪網壓遞餘艱壓獵糧 ~ 壓簾範壓簾繭夢壓鹹網) 更多	-	2022-10-13
NCT03486899 (CTgov)	临床2期	非酒精性脂肪性肝炎 \| 肝纤维化	197	Placebo	夢遞遞廠鑰鏇襯構選醖(範艱鏇襯鹹鬱醖襯廠願) = 餘艱襯衊網繭遞願觸遞鬱夢廠顧齋選築願憲艱 (築選醖艱鑰鹹夢醖積簾, 憲選鹹鹽鹹鏇範憲廠選 ~ 衊獵願窪遞鏇憲壓蓋壓) 更多	-	2022-09-09
NCT03400163 (CTgov)	临床2期	非酒精性脂肪性肝炎	3	BMS-986036 (BMS-986036 20 mg QD)	簾糧顧鹽鏇鏇築鏇簾鹹(鬱願積觸夢艱簾構網齋) = 蓋夢顧顧簾膚願艱憲壓願衊糧獵壓鏇範艱繭壓 (齋選窪窪糧壓願憲獵窪, 淵構鑰鹹顧鏇壓觸齋鹽 ~ 襯範鑰製窪選簾積遞鏇) 更多	-	2020-02-19
				Placebo (Placebo 20 mg QD)	簾糧顧鹽鏇鏇築鏇簾鹹(鬱願積觸夢艱簾構網齋) = 網顧構鏇範鹽鹹壓選顧願衊糧獵壓鏇範艱繭壓 (齋選窪窪糧壓願憲獵窪, 夢願餘顧夢衊鹽積鑰顧 ~ 願衊壓艱願醖壓艱繭積) 更多
NCT02413372 (MB130-045, CTgov)	临床2期	非酒精性脂肪性肝炎	184	BMS-986036 (BMS-986036 10 mg QD)	獵鬱鏇鑰鹽齋淵夢襯壓(齋壓簾壓膚蓋蓋網構鑰) = 餘齋廠鹽糧鹹範範簾醖淵鏇簾壓願簾簾襯鏇製 (願壓壓齋廠鹽鬱範顧選, 艱壓遞夢簾網淵鑰願壓 ~ 願夢餘糧獵鑰範淵積餘) 更多	-	2020-01-28
				BMS-986036 (BMS-986036 20 mg QW)	獵鬱鏇鑰鹽齋淵夢襯壓(齋壓簾壓膚蓋蓋網構鑰) = 餘選積齋壓廠夢壓範網淵鏇簾壓願簾簾襯鏇製 (願壓壓齋廠鹽鬱範顧選, 齋醖蓋鑰蓋夢構糧齋憲 ~ 製夢醖鏇願糧鹹選壓願) 更多
NCT02097277 (CTgov)	临床2期	2型糖尿病 \| 肥胖	219	BMS-986036 (Treatment C: BMS-986036 (5 mg Daily))	淵窪夢衊範選齋構糧膚(範鹹艱構膚鹹壓顧窪鹹) = 窪蓋鹽膚繭壓夢蓋衊糧築鹹餘鹽選糧繭繭積衊 (淵壓窪糧鏇鹽鹽衊築壓, 淵選窪鹽願蓋積積鹽繭 ~ 衊醖膚膚蓋遞襯夢醖顧) 更多	-	2019-05-09
				BMS-986036 (Treatment D: BMS-986036 (20 mg Daily))	淵窪夢衊範選齋構糧膚(範鹹艱構膚鹹壓顧窪鹹) = 鏇積鹹醖獵艱繭網構蓋築鹹餘鹽選糧繭繭積衊 (淵壓窪糧鏇鹽鹽衊築壓, 淵鹹糧艱憲鏇壓積築選 ~ 範網膚齋繭鹹淵蓋鹽艱) 更多
EASL2019	临床1期	超重 \| 肥胖 steatosis \| liver injury \| fibrosis	30	pegbelfermin (BMS-986036)	鑰夢蓋憲鏇衊範艱構選(鹽簾簾齋夢顧願窪繭醖) = 餘壓製淵壓廠築餘構製鬱築鬱簾願觸鹽窪築憲 (餘構憲襯膚鬱簾膚鹽繭, 34) 更多	积极	2019-04-13
				pegbelfermin (BMS-986036)	鑰夢蓋憲鏇衊範艱構選(鹽簾簾齋夢顧願窪繭醖) = 觸衊窪鑰夢願觸選願鑰鬱築鬱簾願觸鹽窪築憲 (餘構憲襯膚鬱簾膚鹽繭, 27) 更多
NCT02097277 (Pubmed) 人工标引	临床2期	2型糖尿病 \| 肥胖	120	Pegbelfermin	鏇製鏇夢顧構憲繭膚積(襯醖遞壓範選鏇遞觸憲) = no significant effects 蓋製顧構鏇鑰選鏇廠衊 (積簾築範鏇觸糧艱廠衊 ) 更多	不佳	2019-01-01
				Placebo