A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD STUDY IN HEALTHY ADULT MALE PARTICIPANTS TO ASSESS THE EXTENT OF EXCRETION, ABSOLUTE BIOAVAILABILITY, FRACTION ABSORBED, AND PHARMACOKINETICS OF [14C]PF-06865571 USING A 14C-MICROTRACER APPROACH

This study is a Phase 1, open-label, non-randomized, 2-period, fixed-sequence, single-dose study of PF-06865571 in healthy male participants to characterize the ADME properties of [14C]PF-06865571 following oral administration; and to evaluate the absolute oral bioavailability (F) and fraction absorbed (Fa) of PF-06865571 following oral administration of unlabeled PF-06865571 and IV administration of [14C]PF-06865571.

开始日期2021-05-11

申办/合作机构

Pfizer Inc.

CTR20210412

/ Completed临床2期

一项在经活检证实的非酒精性脂肪性肝炎（NASH）伴2 期或3 期纤维化的成人受试者中评价 PF-06865571（DGAT2I）单药及其与 PF-05221304（ACCI）联合治疗的疗效和安全性的 II 期、随机、双盲、双模拟、安慰剂对照、剂量范围探索、剂量探索、平行组研究

主要目的：在经活检证实的 NASH 伴肝纤维化的受试者中，评价多个 DGAT2i 剂量单药治疗和 DGAT2i+ACCi 联合治疗对缓解NASH和改善纤维化的作用次要目的：评价多个 DGAT2i 剂量单药治疗和 DGAT2i + ACCi 联合治疗与安慰剂相比，以及 DGAT2i + ACCi 联合治疗与 DGAT2i 单药治疗相比，对肝脂肪含量的影响，符合不同应答者定义的受试者中的作用，及安全性和耐受性第三目的：评价多个 DGAT2i 剂量单药治疗和 DGAT2i+ACCi 联合治疗与安慰剂相比，以及 DGAT2i+ACCi 联合治疗与 DGAT2i 单药治疗相比，在活检终点成分出现恶化的受试者中的作用

开始日期2021-04-06

申办/合作机构

Pfizer Inc.

[+1]

NCT04839393

/ Completed临床1期

A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETIC INTERACTIONS BETWEEN PF-06882961 AND PF-06865571 IN HEALTHY ADULT PARTICIPANTS (PART A) AND OVERWEIGHT ADULTS OR ADULTS WITH OBESITY WHO ARE OTHERWISE HEALTHY (PART B)

This study will be conducted in 2 parts. Part A will investigate the potential effect of PF-06865571 on the pharmacokinetics (PK) of PF-06882961 in healthy adult participants. Part B will evaluate the effect of PF-06882961 on the PK of PF-06865571, as well as the effect of PF-06865571 on the PK of PF-06882961 in overweight adults or adults with obesity who are otherwise healthy.

开始日期2021-04-05

申办/合作机构

Pfizer Inc.

100 项与 Ervogastat 相关的临床结果

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100 项与 Ervogastat 相关的转化医学

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100 项与 Ervogastat 相关的专利（医药）

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项与 Ervogastat 相关的文献（医药）

2025-02-01·CPT: Pharmacometrics & Systems Pharmacology

Exposure–response modeling of liver fat imaging endpoints in non‐alcoholic fatty liver disease populations administered ervogastat alone and co‐administered with clesacostat

Article

作者: Vourvahis, Manoli ; Wojciechowski, Jessica ; Hughes, Jim H. ; Amin, Neeta B.

AbstractNon‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non‐invasive measures such as magnetic resonance imaging proton density fat fraction (MRI‐PDFF) and FibroScan® controlled attenuation parameter (CAP™) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure–response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic/pharmacodynamic (PK/PD) modeling of both liver fat measurements simultaneously. Population pharmacokinetic and exposure–response models using individual predictions of average concentrations were used to describe ervogastat/clesacostat PKPD. Due to both liver fat endpoints being continuous‐bounded outcomes on different scales, a dynamic transform‐both‐sides approach was used to link a common latent factor representing liver fat to each endpoint. Simultaneous modeling of both MRI‐PDFF and CAP™ was successful with both measurements being adequately described by the model. The clinical trial simulation was able to adequately predict the results of a recent Phase 2 study, where subjects given ervogastat/clesacostat 300/10 mg BID for 6 weeks had a LS means and model‐predicted median (95% confidence intervals) percent change from baseline MRI‐PDFF of −45.8% and −45.6% (−61.6% to −31.8%), respectively. Simultaneous modeling of both MRI‐PDFF and CAP™ was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies.

2024-10-01·International Journal of Biological Macromolecules

Combined structure-based virtual screening and machine learning approach for the identification of potential dual inhibitors of ACC and DGAT2

Article

作者: Wu, Lixing ; Tong, Huangjin ; Deng, Liangying ; Ding, Feng ; Liu, Yanfeng ; Zhang, Shuran ; Mi, Nana

Acetyl-coenzyme A carboxylase (ACC) and diacylglycerol acyltransferase 2 (DGAT2) are recognized as potential therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Inhibitors targeting ACC and DGAT2 have exhibited the capacity to reduce hepatic fat in individuals afflicted with NAFLD. However, there are no reports of dual inhibitors targeting ACC and DGAT2 for the treatment of NAFLD. Here, we aimed to identify potential dual inhibitors of ACC and DGAT2 using an integrated in silico approach. Machine learning-based virtual screening of commercial molecule databases yielded 395,729 hits, which were subsequently subjected to molecular docking aimed at both the ACC and DGAT2 binding sites. Based on the docking scores, nine compounds exhibited robust interactions with critical residues of both ACC and DGAT2, displaying favorable drug-like features. Molecular dynamics simulations (MDs) unveiled the substantial impact of these compounds on the conformational dynamics of the proteins. Furthermore, binding free energy assessments highlighted the notable binding affinities of specific compounds (V003-8107, G340-0503, Y200-1700, E999-1199, V003-6429, V025-4981, V006-1474, V025-0499, and V021-8916) to ACC and DGAT2. The compounds proposed in this study, identified using a multifaceted computational strategy, warrant experimental validation as potential dual inhibitors of ACC and DGAT2, with implications for the future development of novel drugs targeting NAFLD.

2024-02-01·Clinical and Translational Science

Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants

Article

作者: Sawant‐Basak, Aarti ; Mendes da Costa, Laure ; Gosset, James R. ; Mancuso, Jessica ; Esler, William P. ; Calle, Roberto A. ; Tripathy, Sakambari ; Bergman, Arthur J.

AbstractCo‐administration of clesacostat (acetyl‐CoA carboxylase inhibitor, PF‐05221304) and ervogastat (diacylglycerol O‐acyltransferase inhibitor, PF‐06865571) in laboratory models improved non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH) end points and mitigated clesacostat‐induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion‐transporting polypeptide‐mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time‐dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer‐term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non‐randomized, open‐label, fixed‐sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1–7) and co‐administered with ervogastat 300 mg b.i.d. (Days 8–14). Mean systemic clesacostat exposures, when co‐administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration–time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1–7) and co‐administered with clesacostat 15 mg b.i.d. (Days 8–14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co‐administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co‐administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.

项与 Ervogastat 相关的新闻（医药）

2024-04-22

·药智网

MASH爆发在即，十余款新药有望上市

40余年里，全球无数知名药企扎堆MASH（原NASH，非酒精性脂肪性肝炎）领域而不得，数十款MASH疗法折戟，一度让领域内的新药研发陷入低谷。2019年2月11日，吉利德宣布其NASH药物ASK1抑制剂selonsertib在第一个Ⅲ期临床（STELLAR-4）错过主要终点。次年，全球最先进的MASH候选药物之一的elafibranor也同样未能走出临床Ⅲ期。2019年6月25日，诺华（Novartis）与合作伙伴Conatus Pharmaceuticals联合宣布，emricasan治疗非酒精性脂肪性肝炎（NASH）的Ⅱb期研究ENCORE-LF未能达到主要终点。之后，诺华更是在2023年将管线缩减了10%，其中就有ADTP02、FIA586、tropifexor等4款MASH候选药物。2022年，辉瑞开发的danuglipron(PF-06882961)+PF-06865571用于伴有肝纤维化的非酒精性脂肪性肝炎（MASH)1期临床试验遭遇停止，不再作为NASH的潜在治疗药物被推进。而在此之前，辉瑞还有PF-06835919、PF-05221304、PF-06427878等多款MASH新药被终止。另一方面，对于行业内谁能率先在MASH领域撞线也倍感期待，毕竟从历史上看，似乎任何一款“首批新药”的诞生，都将意味着一大波“风口”的到来。2024年3月，Madrigal宣布其THR-β抑制剂Resmetirom获美国FDA加速批准上市，成为首款获FDA批准上市的MASH新药。尘埃落地的同时，也让MASH如愿站上了“热搜”，曾经那些寂寂无闻的在研管线们则顺势成为了众多资本市场争相追捧的宠儿。更有人直言，MASH就没有不火的可能，Resmetirom的获批仅仅只是提前了这个进程。三大因素奠定MASH爆火前提所谓MASH，其实是非酒精性脂肪肝炎（NASH）的更新命名，是随着科学水平进步之后，对该疾病与代谢紊乱之间的联系更清晰了解之后的结果。而之所以，MASH能被资本与药企寄予厚望，则主要源于其三大方面的优势。首先，是极为庞大的患者群体。据最新文献资料显示，肥胖与糖尿病与MASH的发展密切相关，前者更是被定义为导致MASH的主要风险因素之一，不仅增加MASH的风险，还会加剧已有MASH的病情，使得治疗更加困难。而在全球肥胖人群数量倍增的当下，MASH的患者群体也是水涨船高，2023年AASLD（美国肝病学会年会）数据显示，MASH全球患病率已从过去预估的3%-5%增长至5.27%左右，部分区域甚至超过了6%。而FDA则估计，仅美国大约就有600万-800万人患有MASH，全球肝脏研究所预计，全球有超过3.5亿人受MASH影响。而就是这么庞大的患者群体之下，其药品市场空间自然也是惊人，据弗若斯特沙利文预计，2025年全球MASH市场规模将达107亿美元，2023年有望突破322亿美元。更关键的是，该领域在Resmetirom上市之前甚至都基本处于空白情况。其次，是迫切的临床需求。从疾病进展上，MASH的最初阶段通常只表现为单纯的脂肪肝，其本身并不会引起较为严重的肝损伤，且基本不会出现明显的身体症状，并且在生活水平提升的当今，极其容易被忽视，但其却为更严重的肝病提供了基础。随着肥胖等因素的持续影响下，脂肪肝则可能发展为MASH，造成肝脏中的炎症和肝细胞损伤，伴随肝功能的轻微下降，之后持续的炎症与损伤则就形成了MASH的重要阶段成果，即肝脏纤维化，并伴严重肝功能下降，进展为肝硬化、肝衰竭与肝癌。而在上述整个疾病发展过程中，缺乏有效的药物治疗方案就是其最大的难题，疾病多数阶段的治疗都依赖于饮食控制、增加体育活动等生活方式的调整，以及疾病进展之后的对症、延缓疾病进展的治疗。因此，临床上对于MASH由症状治疗转向病因治疗的需求尤其迫切，也奠定了创新药强大的想象空间。最后，是强烈的支付意愿。虽然，患者群体与临床需求确实是决定一个领域市场天花板的基础，但在众多疾病中有着与MASH相同的患者群体与临床需求情况绝不是少数，导致MASH爆火的主要原因或许也并不仅仅是上述两者。MASH能脱颖而出还有一个重要因素，即其背后强大的“支付意愿”，要知道无论细胞疗法、基因疗法还是其他，领域内药物成功商业化的最核心步骤一定在于“购买”，只有当大多数患者在“买与不买”之间选择前者时，药品才有成功的希望。而通常情况下，决定患者对药品的支付意愿主要有三大因素：疾病后果、现有治疗情况、药品疗效。且不提现有治疗情况与药品疗效，其主要与药品本身有关，更具宏观的疾病后果则更具预判性，理论上疾病后果可分为生死问题与生活质量两类，前者相对能接受较高的治疗费用，支付意愿更强，而后者则需根据患者支付能力因人而异。这就是为何肿瘤新药一直以来都是新药研发领域的重点方向，而自身免疫性疾病却被大多数人称为“穷病”的原因。当然，万事并非绝对，肥胖就并不适用上述规律，其疾病后果虽不会关乎生死，但其致病因素却决定了该群体的支付能力更强（肥胖患者的经济水平普遍较高，可以将肥胖想象成富贵病），其支付意愿反而更强。而对于MASH而言，原则上其既满足了生死攸关，也满足了肥胖的患病基础条件，其支付能力想不高都难。大戏将近Resmetirom绝非MASH的唯一不同于传统的治疗方式，MASH对新药的核心治疗需求不仅有脂肪的代谢、更需要减少炎症反应甚至逆转纤维化，从而显著改善患者肝功能，而Resmetirom的上市，想必也绝非MASH新药的终点。据药智数据显示，截至目前全球有超过300种新药将适应症放在了MASH之上，其中不乏众多在逆转肝脏纤维化方面效果明显的新药。并且随着更多关于GLP-1在减少肝脏脂肪积累、降低炎症水平以及改善肝纤维化的潜力被证实，MASH市场竞争想必还将更加激烈。从药理学机制上，目前MASH管线中大致上可以分为以下几大类别：FXR （法尼醇 X 受体）激动剂FGF21 （成纤维细胞生长因子21）受体激动剂FGF19 类似物PPAR（过氧化物酶体增殖物活化受体）调节剂甲状腺激素β受体激动剂GLP-1受体激动剂表1 部分MASH领域在研管线药学机制产品名称分类靶点研发企业适应症最高阶段更新时间FGF21受体激动剂efruxifermin多肽FGF21安进公司Akero Therapeutics临床Ⅲ期12/6/23BIO89-100（Pegozafermin）生物药FGF21;FGFR89bio Inc临床Ⅱ期3/13/24AP-025生物药FGF21安源医药科技（上海）有限公司临床Ⅱ期10/9/23HEC-88473生物药FGF21;GLP-1R东莞市东阳光生物药研发有限公司临床Ⅱ期11/20/23FGF19类似物aldafermin生物药CYP7A1;FGF19NGM Biopharmaceuticals Inc临床Ⅱ期11/10/21PPAR（过氧化物酶体增殖物活化受体）调节剂lanifibranor化学药PPAR-alpha;PPAR-delta;PPAR-gammaInventiva临床Ⅲ期11/7/23pemafibrate化学药PPAR-alphaKowa Co Ltd临床Ⅲ期11/2/23elafibranor化学药PPAR-alpha;PPAR-deltaGenfit SA临床Ⅲ期（停止）12/7/23甲状腺激素β受体激动剂resmetirom化学药THRBMadrigal Pharmaceuticals Inc;罗氏制药临床Ⅲ期3/14/24TERN-501化学药THRB上海拓臻生物科技有限公司临床Ⅱ期-ASC41化学药THRB歌礼制药有限公司;甘莱制药有限公司临床Ⅱ期7/7/22HSK-31679化学药THRB海思科医药集团股份有限公司临床Ⅱ期12/5/23FXR（法尼醇 X 受体）激动剂obeticholic acid化学药NR1H4Intercept Pharmaceuticals Inc临床Ⅲ期（拒绝上市）2023.6.2211/2/23CS-0159化学药NR1H4Van Andel Institute;中国科学院上海药物研究所;凯思凯迪（上海）医药科技有限公司临床Ⅱ期9/21/23TERN-101化学药NR1H4上海拓臻生物科技有限公司;礼来制药临床Ⅱ期6/8/22HEC96719化学药NR1H4广东东阳光药业股份有限公司临床Ⅱ期5/25/22数据来源：药智数据其中，在各药学机制之下，有不少品种临床研究进度较靠前，被誉为MASH强有力的候选药物，更根据这些MASH候选药物的II 期试验公布数据中的“纤维化改善”主要临床终点与Resmetirom进行对比，可以发现不少有趣的地方。图片来源：蓝精灵壹号GLP-1难以颠覆MASH市场？从上图中可以发现，对于MASH患者最期望的“纤维化改善”终点指标上看，被寄予厚望的诺和诺德司美格鲁肽似乎并不及大多数MASH潜力疗法，是所有项目中纤维化改善程度最低疗法（非头对头数据，不同的入组标准和不同设计之间存在明显差异，仅作为参考）。这一点上，与之前多数人期待GLP-1能颠覆MASH药物的预期有所不及，或许GLP-1在MASH的治疗效果仍主要体现在其调节血糖水平、体重管理和代谢改善之后的综合作用，更多表现为减少肝脏脂肪积累、降低炎症水平，当然这也需要后续真正意义上头对头试验数据来进一步说明。不过，不可否认的是，GLP-1的爆火以及后续多款产品的上市，很大程度或将降低整体MASH的市场天花板，毕竟突出的减肥效果，一定程度还会导致肥胖患者的数量规模下降，继而直接影响MASH的治疗顺位，拉低预期。Resmetirom并非最佳？而从上图中，除了GLP-1与多数MASH潜在疗法在“纤维化改善”终点指标上对比外，随着Resmetirom以后，其与众多MASH潜在疗法在这项临床终点上的对比，或许更受人关注。数据上看，很明显Resmetirom的纤维化改善效果并非最佳，至少efruxifermin、pemafibrate、lanifibranor、Pegozafermin与ION-224的数据比之均有不同程度的超越，尤其是efruxifermin。Efruxifermin是基于人体免疫球蛋白G1的Fc片段与成纤维细胞生长因子21（FGF21）融合多肽的长效FGF21类似物，能够模拟内源性FGF21在其与β-Klotho和3种FGF受体（FGFR1c、FGFR2c、FGFR3c）之一的共受体复合物上的平衡效价。其最初由安进研发，后于2018年被Akero引进，是目前MASH潜在疗法中最受关注的管线之一，其最新的临床数据显示，主要终点方面（纤维化改善），有效性上 50mg剂量组有76%的患者在肝纤维化不恶化的情况下获得了MASH缓解（即：MASH缓解且肝纤维化未进展比例最高达76%）；次要终点方面，Efruxifermin在肝损伤标志物、软组织纤维化与纤维发生的血清生物标志物水平明显下降。静待花开国内MASH的有生力量当然，面对MASH领域市场确定性强、临床需求明确、支付意愿明确的优势，国内药企绝不可能放任其从手中流走，据悉，国内市场已经有超过80家药企在MASH领域上有所布局，并且这个数字还有望在今后几年继续增长。现阶段，国内MASH疗法主要分布在临床前中期，除部分GLP-1疗法外，暂无任何新药进入临床III期间以及之后，其中临床II期疗法有16种、临床I期疗法21种，临床前与临床申请阶段疗法则多达67种。其中，国内研发进度相对靠前的MASH疗法中，安源医药的AP-025、君圣泰生物的HTD1801、东阳光的HEC-88473、海思科的HSK-31679等创新疗法MASH的适应症临床近一年有所更新，也是国内较受关注的品种之一。表2 部分MASH国内在研管线产品名称分类靶点研发企业适应症最高阶段适应症更新时间AP-025生物药FGF21安源医药科技（上海）有限公司全球：临床Ⅱ期8/11/23中国：临床Ⅱ期HTD1801化学药Bile acid深圳君圣泰生物技术有限公司全球：临床Ⅱ期12/21/23中国：临床Ⅱ期HEC-88473生物药>未分类FGF21;GLP-1R东莞市东阳光生物药研发有限公司全球：临床Ⅱ期8/17/23中国：临床Ⅱ期HSK-31679化学药THRB海思科医药集团股份有限公司全球：临床Ⅱ期11/9/23中国：临床Ⅱ期VSA-006生物药>核酸类>小干扰RNA（siRNA）HSD17B13维亚臻生物技术（上海）有限公司全球：临床Ⅱ期12/22/23中国：临床Ⅱ期ASC41化学药THRB歌礼制药有限公司;甘莱制药有限公司全球：临床Ⅱ期6/21/22中国：临床Ⅱ期CS-0159化学药NR1H4Van Andel Institute;中国科学院上海药物研究所;凯思凯迪（上海）医药科技有限公司全球：临床Ⅱ期12/30/22中国：临床申请ZSP1601化学药PDE上海药明康德新药开发有限公司;广东众生药业股份有限公司全球：临床Ⅱ期12/30/22中国：临床Ⅱ期RAY-1225生物药>多肽GIP;GLP-1广东众生睿创生物科技有限公司全球：临床Ⅱ期8/12/22西格列他钠 Chiglitazar Sodium化学药PPAR-alpha;PPAR-delta;PPAR-gamma成都微芯药业有限公司全球：临床Ⅱ期12/7/21中国：临床Ⅱ期HPG1860化学药NR1H4雅创医药技术（上海）有限公司全球：临床Ⅱ期11/18/21中国：临床Ⅰ期HEC96719化学药NR1H4广东东阳光药业股份有限公司全球：临床Ⅱ期7/27/21中国：临床Ⅱ期TERN-101化学药NR1H4上海拓臻生物科技有限公司;礼来制药全球：临床Ⅱ期3/13/20TERN-501化学药THRB上海拓臻生物科技有限公司全球：临床Ⅱ期-图片来源：药智数据小结很明显，随着MASH的全球患病率突破5%，全球患病人数激增至3.5亿人，临床上对新机制MASH药物的需求还在继续加大，最终导致MASH的市场想象空间也在水涨船高。而困扰了全球制药企业的MASH难题，随着Resmetirom的上市也迎来了新的出路，犹如一针强心剂。紧随之后，全球领域还有如efruxifermin、pemafibrate、lanifibranor等众多创新疗法破茧在即，国内众多biotech抓紧追赶。大胆预测，或许未来十年都将是MASH集中爆发的时间段，领域也将迎来真正意义上的快速发展期，而国内药企或许也将借此良机，与全球制药企业站在统一舞台，值得期待。来源 | 博药（药智网获取授权转载）撰稿 | 弎责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

临床3期临床2期加速审批

2024-03-13

·BioSpace

Ionis’ Antisense Molecule Hits Primary Endpoint in Phase II MASH Trial

Pictured: 3D illustration of a damaged liver/iStoc The biotech announced Wednesday that patients on ION224 had histologic improvement in the liver disease without worsening of fibrosis. Ionis’ mid-stage win comes as the FDA is set to decide whether to approve rival Madrigal’s resmetirom by Thursday. Pictured: Illustration depicting a damaged liver/iStock, Mohammed Haneefa Nizamudeen A Phase II clinical trial of Ionis Pharmaceuticals ’ metabolic dysfunction-associated steatohepatitis drug candidate has hit its primary endpoint, the company said Wednesday. Investigators randomized 160 people with metabolic dysfunction-associated steatohepatitis (MASH), the liver disease formerly known as nonalcoholic steatohepatitis, to receive placebo or one of three doses of ION224 subcutaneously once a month. Ionis designed the ligand-conjugated antisense medicine to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. After 51 weeks, the proportion of patients who had MASH histologic improvement without worsening of fibrosis was significantly higher in the top two dose cohorts than in the placebo group. The significant differences caused the trial to meet its primary endpoint. Ionis shared the p values for the successful 90-mg and 120-mg doses—0.015 and less than 0.001, respectively—but is yet to provide a closer look at the primary endpoint data. Subgroup analyses found patients with both F2 and F3 fibrosis, the middle scores on a four-point scarring severity scale, improved after taking ION224. The biotech published some secondary endpoint data. ION224 beat placebo on an endpoint that looked at MASH resolution without worsening of fibrosis, as measured by biopsy. At the highest dose, 44% of patients had a 50% or greater relative reduction in liver steatosis, as measured by imaging, while 3% of people on placebo experienced such an improvement. Ionis also saw a trend favoring ION224 for a liver scarring endpoint. In the high-dose arm, 32% of people had at least a one stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of their peers in the placebo cohort. The FDA asks sponsors to show a one stage improvement in fibrosis with no worsening of MASH or the resolution of MASH with no worsening of fibrosis in Phase III clinical trials. The first wave of MASH assets failed to clear that bar but recent studies have fared better, with Madrigal Pharmaceuticals hitting both the endpoints in Phase III. The FDA is set to decide whether to approve Madrigal’s resmetirom by Thursday. The success of resmetirom, a THR-β agonist, in clinical trials is part of a series of events that suggest Ionis will face competition if it delivers its own pivotal study victory and brings ION224 to market. Companies are working on MASH molecules against a range of targets, from Boehringer Ingelheim ’s glucagon/GLP-1 receptor dual agonist survodutide to Akero Therapeutics ’ FGF21 analog efruxifermin. Other companies are interested in Ionis’ MASH target, DGAT2. Pfizer axed one DGAT2 inhibitor after Phase I but still has another candidate, PF-06865571, in mid-stage development. Data from the Phase II clinical trial are imminent, according to ClinicalTrials.gov . Other companies including Sinew Pharma and Viking Therapeutics are working on DGAT1 inhibitors. Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn .

临床2期临床3期临床1期临床结果

2024-03-13

·BioSpace

Ionis’ Antisense Molecule Hits Primary Endpoint in Phase II MASH Trial

Pictured: Illustration depicting a damaged liver/iStock, Mohammed Haneefa Nizamudeen A Phase II clinical trial of Ionis Pharmaceuticals’ metabolic dysfunction-associated steatohepatitis drug candidate has hit its primary endpoint, the company said Wednesday. Investigators randomized 160 people with metabolic dysfunction-associated steatohepatitis (MASH), the liver disease formerly known as nonalcoholic steatohepatitis, to receive placebo or one of three doses of ION224 subcutaneously once a month. Ionis designed the ligand-conjugated antisense medicine to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. After 51 weeks, the proportion of patients who had MASH histologic improvement without worsening of fibrosis was significantly higher in the top two dose cohorts than in the placebo group. The significant differences caused the trial to meet its primary endpoint. Ionis shared the p values for the successful 90-mg and 120-mg doses—0.015 and less than 0.001, respectively—but is yet to provide a closer look at the primary endpoint data. Subgroup analyses found patients with both F2 and F3 fibrosis, the middle scores on a four-point scarring severity scale, improved after taking ION224. The biotech published some secondary endpoint data. ION224 beat placebo on an endpoint that looked at MASH resolution without worsening of fibrosis, as measured by biopsy. At the highest dose, 44% of patients had a 50% or greater relative reduction in liver steatosis, as measured by imaging, while 3% of people on placebo experienced such an improvement. Ionis also saw a trend favoring ION224 for a liver scarring endpoint. In the high-dose arm, 32% of people had at least a one stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of their peers in the placebo cohort. The FDA asks sponsors to show a one stage improvement in fibrosis with no worsening of MASH or the resolution of MASH with no worsening of fibrosis in Phase III clinical trials. The first wave of MASH assets failed to clear that bar but recent studies have fared better, with Madrigal Pharmaceuticals hitting both the endpoints in Phase III. The FDA is set to decide whether to approve Madrigal’s resmetirom by Thursday. The success of resmetirom, a THR-β agonist, in clinical trials is part of a series of events that suggest Ionis will face competition if it delivers its own pivotal study victory and brings ION224 to market. Companies are working on MASH molecules against a range of targets, from Boehringer Ingelheim’s glucagon/GLP-1 receptor dual agonist survodutide to Akero Therapeutics’ FGF21 analog efruxifermin. Other companies are interested in Ionis’ MASH target, DGAT2. Pfizer axed one DGAT2 inhibitor after Phase I but still has another candidate, PF-06865571, in mid-stage development. Data from the Phase II clinical trial are imminent, according to ClinicalTrials.gov. Other companies including Sinew Pharma and Viking Therapeutics are working on DGAT1 inhibitors. Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.

临床2期临床3期临床1期临床结果

100 项与 Ervogastat 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
非酒精性脂肪性肝炎	临床2期	中国台湾	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	波多黎各	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	波兰	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	韩国	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	加拿大	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	中国	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	日本	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	印度	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	美国	Pfizer Inc.	2020-06-15
非酒精性脂肪性肝炎	临床2期	保加利亚	Pfizer Inc.	2020-06-15

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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


NCT04321031 (MIRNA, CTgov)	临床2期	非酒精性脂肪性肝炎 \| 纤维化	256	Placebo	選構齋壓網艱糧觸積鹽(觸醖齋製窪夢醖淵夢鑰) = 艱築網廠鹹遞襯餘構顧網廠繭憲鏇襯構觸窪觸 (範繭壓繭網餘餘艱醖壓, 衊糧遞獵壓淵餘製簾蓋 ~ 憲選繭鬱鹽遞淵壓壓齋) 更多	-	2025-03-21
NCT04866225 (CTgov)	临床1期	-	6	[14C]PF-06865571 ([14C]PF-06865571 300 mg Oral)	夢齋廠糧憲繭鏇淵窪鹹(積鬱齋襯膚夢淵構選觸) = 選艱艱選鏇壓選構餘齋膚鹹淵構顧積顧簾衊繭 (構蓋繭衊網襯觸餘廠鹽, 夢壓積淵艱鹽製窪鹽觸 ~ 選範願淵選蓋願繭遞壓) 更多	-	2024-07-31
NCT04866225 (CTgov)	临床1期	-	6	[14C]PF-06865571+PF-06865571 (PF-06865571 300 mg Oral & [14C]PF-06865571 100 μg IV)	夢齋廠糧憲繭鏇淵窪鹹(積鬱齋襯膚夢淵構選觸) = 鏇製壓醖網選顧壓顧壓膚鹹淵構顧積顧簾衊繭 (構蓋繭衊網襯觸餘廠鹽, 獵觸餘鏇糧蓋糧衊選觸 ~ 網餘窪齋窪鏇製蓋鹽願) 更多	-	2024-07-31
NCT04399538 (CTgov)	临床2期	非酒精性脂肪性肝炎	75	Placebo	糧願積網範壓齋鑰廠膚(鹽觸遞餘憲鬱壓築糧糧) = 鏇築膚襯範網齋艱艱顧糧齋艱顧簾窪積憲繭構 (衊範壓繭網築願鬱願顧, 顧糧選選製窪鹹願鑰獵 ~ 顧顧襯膚選網獵膚衊觸) 更多	-	2023-04-13
NCT03776175 (CTgov)	临床2期	代谢功能障碍相关的脂肪肝病	99	Placebo	簾鏇夢鏇壓齋網夢獵製(糧壓簾鏇範顧築鬱繭壓) = 憲遞窪鹽製憲積製繭獵顧膚鹹餘憲範膚衊觸鑰 (淵鹽蓋獵糧艱鏇糧壓廠, 餘鏇積構鑰窪簾衊顧觸 ~ 繭襯選積憲觸遞襯願醖) 更多	-	2020-09-23
NCT03513588 (CTgov)	临床1期	非酒精性脂肪性肝炎	48	Placebo	構鏇膚築淵鏇膚鏇簾鹽(鏇鑰鹹遞廠淵襯膚廠餘) = 蓋窪積獵蓋糧積襯壓獵積簾顧鑰願糧膚廠積構 (膚蓋鏇積窪構壓顧簾鏇, 觸製製鬱壓範網築壓鹽 ~ 壓餘窪積鬱網淵齋壓網) 更多	-	2020-03-13