Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism. Patients with HFI develop acute abdominal pain, nausea, vomiting, hypoglycemia and proximal tubular dysfunction upon consumption of a fructose containing food product. In rare cases, (prolonged) fructose consumption can even lead to liver and kidney failure. Patients with HFI are therefore treated with a lifelong fructose-restricted diet. Animal studies have shown that the clinical manifestations of HFI are abrogated upon inhibition of ketohexokinase (KHK), the enzyme that catalyses the first step in fructose metabolism.
Recently, PF-06835919, a KHK inhibitor (KHKi), was developed as a new treatment for non-alcoholic fatty liver disease. The compound was well tolerated in several phase II clinical trials.
It is hypothesized that PF-06835919 is also effective in patients with HFI.

开始日期2023-06-15

申办/合作机构

Maastricht UMC+

[+1]

NCT05463575 / Completed临床2期IIT

Metabolic Effects of Ketohexokinase Inhibition on Individuals With Non-alcoholic Fatty Liver Disease

Fructose is a big contributor to the development of non-alcoholic fatty liver disease (NAFLD). Inhibiting ketohexokinase (KHK), the enzyme catalyzing the first committed step in fructose metabolism, is thought to reduced intrahepatic lipid (IHL) content. Pharmacological inhibition of KHK resulted in a decrease in IHL content in NAFLD patients, but additional health effects are still unknown. In this study the investigators aim to look at additional health effects following KHK inhibition (KHKi).

开始日期2022-10-01

申办/合作机构

Maastricht UMC+

[+1]

NCT04427917 / Completed临床1期

A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-06835919 IN HEALTHY ADULT JAPANESE PARTICIPANTS

This is a Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of multiple oral doses of PF-06835919 in healthy adult Japanese participants.
A total of approximately 8 healthy participants will be enrolled in this study. Participants will be randomized to 2 groups to receive PF-06835919 or placebo treatment with a randomization ratio of 3:1.

开始日期2020-11-24

申办/合作机构

Pfizer Inc.

100 项与 PF-06835919 相关的临床结果

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100 项与 PF-06835919 相关的转化医学

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100 项与 PF-06835919 相关的专利（医药）

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项与 PF-06835919 相关的文献（医药）

2024-01-01·Clinical and translational science

Study of the ketohexokinase inhibitor PF‐06835919 as a clinical cytochrome P450 3A inducer: Integrated use of oral midazolam and liquid biopsy

Article

作者: Bergman, Arthur ; Fahmy, Alia ; Lin, Jian ; Tess, David ; Qiu, Ruolun ; Rodrigues, David ; Newman, Lauren ; Fonseca, Kari ; Rowland, Andrew ; Vourvahis, Manoli ; Useckaite, Zivile

Abstract:

PF‐06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration‐time curve [AUC] ratio [AUCR] = 0.23–0.79). Therefore, a drug–drug interaction study was conducted to evaluate the effect of multiple doses of PF‐06835919 (300 mg once daily × 10 days; N = 10 healthy participants) on the pharmacokinetics of a single oral midazolam 7.5 mg dose. The adjusted geometric means for midazolam AUC and its maximal plasma concentration were similar following co‐administration with PF‐06835919 (vs. midazolam administration alone), with ratios of the adjusted geometric means (90% confidence interval [CI]) of 97.6% (90% CI: 79.9%–119%) and 98.9% (90% CI: 76.4%–128%), respectively, suggesting there was minimal effect of PF‐06835919 on midazolam pharmacokinetics. Lack of CYP3A4 induction was confirmed after the preparation of subject plasma‐derived small extracellular vesicles (sEVs) and conducting proteomic and activity (midazolam 1′‐hydroxylase) analysis. Consistent with the midazolam AUCR observed, the CYP3A4 protein expression fold‐induction (geometric mean, 90% CI) was low in liver (0.9, 90% CI: 0.7–1.2) and non‐liver (0.9, 90% CI: 0.7‐1.2) sEVs (predicted AUCR = 1.0, 90% CI: 0.9–1.2). Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9–1.3) and non‐liver (0.9, 90% CI: 0.5‐1.5) sEVs was evident (predicted AUCR = 0.9, 90% CI: 0.6‐1.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma‐derived sEVs to assess a drug candidate as inducer.

2023-10-12·Journal of medicinal chemistry1区 · 医学

Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease.

1区 · 医学

Article

作者: Li, Yunfei ; Lin, Xiaoyan ; Huo, Shuhua ; Li, Jiao ; Hu, Tao ; Zhu, Guodong ; Zhang, Zhen

Excessive fructose absorption and its subsequent metabolisms are implicated in nonalcoholic fatty liver disease, obesity, and insulin resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved in fructose metabolism via the conversion of fructose to fructose-1-phosphate. KHK inhibition might be a potential approach for the treatment of metabolic disorders. Herein, a series of novel KHK inhibitors were designed, synthesized, and evaluated. Among them, compound 14 exhibited more potent activity than PF-06835919 based on the rat KHK inhibition assay in vivo, and higher drug distribution concentration in the liver. Its good absorption, distribution, metabolism, and excretion and pharmacokinetic properties make it a promising clinical candidate.

2022-09-01·Drug metabolism and disposition: the biological fate of chemicals

Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, a First-In-Class Ketohexokinase Inhibitor for Metabolic Disorders and Nonalcoholic Fatty Liver Disease

Article

作者: Mathialagan, Sumathy ; Di, Li ; Litchfield, John E ; Tess, David A ; Fonseca, Kari R ; Bessire, Andrew J ; Cerny, Matthew A ; Tseng, Elaine ; Rodrigues, A David ; Kalgutkar, Amit S ; Riccardi, Keith ; Varma, Manthena V S ; Weng, Yan ; Bi, Yi-An

Excess dietary fructose consumption promotes metabolic dysfunction thereby increasing the risk of obesity, type 2 diabetes, non-alcoholic steatohepatitis (NASH), and related comorbidities. PF-06835919, a first-in-class ketohexokinase (KHK) inhibitor, showed reversal of such metabolic disorders in preclinical models and clinical studies, and is under clinical development for the potential treatment of NASH. In this study, we evaluated the transport and metabolic pathways of PF-06835919 disposition and assessed pharmacokinetics in preclinical models. PF-06835919 showed active uptake in cultured primary human hepatocytes, and substrate activity to organic anion transporter (OAT)2 and organic anion transporting-polypeptide (OATP)1B1 in transfected cells. "SLC-phenotyping" studies in human hepatocytes suggested contribution of passive uptake, OAT2- and OATP1B-mediated transport to the overall uptake to be about 15%, 60% and 25%, respectively. PF-06835919 showed low intrinsic metabolic clearance in vitro, and was found to be metabolized via both oxidative pathways (58%) and acyl glucuronidation (42%) by CYP3A, CYP2C8, CYP2C9 and UGT2B7. Following intravenous dosing, PF-06835919 showed low clearance (0.4-1.3 mL/min/kg) and volume of distribution (0.17-0.38 L/kg) in rat, dog and monkey. Human oral pharmacokinetics are predicted within 20% error when considering transporter-enzyme interplay in a PBPK model. Finally, unbound liver-to-plasma ratio (Kp_uu) measured in vitro using rat, NHP and human hepatocytes was found to be approximately 4, 25 and 10, respectively. Similarly, liver Kp_uu in rat and monkey following intravenous dosing of PF-06835919 was found to be 2.5 and 15, respectively, and notably higher than the muscle and brain Kp_uu, consistent with the active uptake mechanisms observed in vitro. Significance Statement This work characterizes the transport/metabolic pathways in the hepatic disposition of PF-06835919, a first-in-class KHK inhibitor for the treatment of metabolic disorders and NASH. Phenotyping studies using transfected systems, human hepatocytes and liver microsomes signifies the role of OAT2 and OATP1B1 in the hepatic uptake and multiple enzymes in the metabolism of PF-06835919. Data presented suggest hepatic transporter-enzyme interplay in determining its systemic concentrations and potential enrichment in liver, a target site for KHK inhibition.

项与 PF-06835919 相关的新闻（医药）

2024-12-05

·奇点网

《自然》：揭秘果糖促癌真相！科学家发现，有些癌细胞根本不吃果糖，是肝脏帮忙化糖为脂，帮助癌细胞增殖丨科学大发现

*仅供医学专业人士阅读参考这几年，糖类的风评可以说是一个急转直下。特别是果糖，我记得以前还有人夸过果糖热量低、升糖慢，可现在随手在我们后台一搜索，跳出来的简直没一个好消息，果糖促癌特别瞩目。果糖促癌看似并不新鲜，卡路里嘛，癌细胞肯定喜欢。不过今天发表在《自然》杂志上的一项研究却给了我们一些新认知——癌细胞，其实根本就不“吃”果糖！那么到底是谁在当中间商？圣路易斯华盛顿大学科研团队在《自然》杂志发文，研究者们发现，虽然果糖能够促进模式动物中多种癌症的进展，但癌细胞本身并不直接利用果糖。在这一过程中，首先由肝脏将果糖代谢为脂质，这些脂质通过血液循环送达癌细胞，再被癌细胞利用成为后续繁殖壮大的养分。虽说肝脏本来就管果糖代谢这一摊子吧，但被癌细胞利用到，属实好心办坏事儿了呀。论文题图果糖带来的健康问题，还真是一个现代社会独有的问题。其实果糖在各种蔬菜、水果、乳制品、谷物中都天然存在，但在高果糖糖浆出现之后，人类的果糖摄入增加了十几倍。随便拿起一样带包装的食品，很难不看见糖浆的身影。我顺手拿了同事的沙拉油醋汁↓ 超量摄入果糖带来了肥胖、代谢乃至癌症等一系列问题。越来越多的证据表明，膳食中的果糖会促进多种癌症的进展。研究者测试了BrafV600E黑色素瘤、E0771乳腺癌、CaSki宫颈癌、TC-1肺癌，在小鼠中，都观察到20%高果糖糖浆水（HFCS）显著促进了肿瘤的生长。果糖促进了小鼠肿瘤生长但是当研究者直接在体外实验中给癌细胞喂果糖，却发现癌细胞并不会因此长得更快更强。事实上，癌细胞根本就不表达果糖代谢需要的两种酶，酮己糖激酶c（KHK-C）和醛缩酶b，对果糖是一个有心无力的状态。为了寻找果糖的去向，研究者们调头回去分析小鼠血液中相关代谢物的变化。代谢组学结果显示，血液中多种脂类的水平升高，主要是甘油三酯和溶血磷脂酰胆碱（LPC）。尤其是LPC，水平增加了7倍有余。癌细胞可以将LPC转化代谢为磷脂酰胆碱，这是细胞膜的关键组成部分。直接给小鼠喂养LPC，也能促进肿瘤生长。将果糖转变为癌细胞物资的，则是拥有KHK-C、平时就在代谢果糖的肝细胞。当研究者使用PF06835919抑制KHK活性，果糖促癌的效果就不见了。抑制KHK可以抵消果糖促癌效果研究者猜测，近年来50岁以下人群中癌症的高发与果糖消费激增脱不开关系，他们正与多方科学家合作，尝试寻找背后的联系。研究者提示道，无论如何，对已经患癌的人来说，注意果糖摄入量是有必要的。但很可悲的是，想要在生活中不接触果糖，实在是不容易。不过我想或许也不用那么担心，毕竟从果糖代谢路径来说，先是小肠后是肝，适量摄入还是可以的。参考资料： [1]Fowle-Grider, R., Rowles, J.L., Shen, I. et al. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer. Nature (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-08258-3 本文作者丨代丝雨

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

2024-03-14

·Firstwordpharma

Madrigal's Rezdiffra clinches first FDA approval for MASH

After years of clinical failures and FDA rejections in the liver disease space, Madrigal Pharmaceuticals has finally taken gold in the race for the first approval in metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH). Specifically, the FDA granted Rezdiffra (resmetirom) accelerated approval to treat adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis consistent with stages F2 to F3 fibrosis, in conjunction with diet and exercise. A biopsy is not required for diagnosis.The THR-β selective agonist will be available to US patients starting April, after months of building excitement. In a 70-physician FirstWord poll conducted last month, 30% of respondents said they were very enthusiastic about prescribing the drug (see: Physician Views Results: Potential new NASH drug gets positive assessment from US docs).This greenlight will most likely open the MASH floodgates. Despite the difficulty designing drugs for the heterogeneous liver disease, which has a variety of etiologies and paths of progression, a series of promising candidates across multiple mechanisms have lined up behind Rezdiffra, such as FGF21 analogues and GLP-1 agonists. For more on the development landscape, see Spotlight On: MASH pipeline holds promise of multiple mechanisms for disease management.Rezdiffra’s approval comes, in part, because it was able to demonstrate efficacy without the safety concerns that sunk Intercept Pharmaceuticals’ obeticholic acid. Treatment defining dataRezdiffra, a once-daily, oral candidate secured FDA approval on Thursday thanks to 52-week data from the pivotal MAESTRO-NASH study, which met the co-primary endpoints of MASH resolution with no worsening of fibrosis, and at least a one-stage reduction in fibrosis with no worsening of non-alcoholic fatty liver disease (NAFLD) activity score. According to results, 25.9% of patients who received the 80mg dose, and 29.9% in the 100mg arm, achieved MASH resolution endpoint, compared with 9.7% for placebo. For fibrosis improvement, the rates were 24.2% and 25.9% for the low- and high-dose arms, respectively, versus 14.2% for placebo.Most of the reported side effects were mild-to-moderate, with a roughly 11-13% serious adverse event rate across each of the three cohorts. There was no incidence of drug-induced liver injury, increases in bone fractures or adverse events linked to thyroid hormone effects outside the liver such as heart rate changes.Rezdiffra’s label reflects the clinical safety results. The drug does not carry a boxed warning, and its label notes that the most common side effects are diarrhoea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.First success of many failuresMadrigal’s journey to FDA approval comes after the failures of several other drug developers to show both safety and efficacy of their MASH programmes, most notably that of obethicholic acid from Intercept.The biotech received its first complete response letter for the candidate in 2020, which said that the predicted benefit of obethicholic acid "does not sufficiently outweigh the potential risks.” Three years later, FDA again rejected the treatment, saying that approval would require, at a minimum, the successful completion of a long-term outcomes Phase III trial.Large pharmas have also seen their fair share of setbacks in the disease. Last year, Novartis ended a partnership with Pliant Therapeutics to develop the latter's integrin αVβ1 inhibitor PLN-1474 for MASH.Pfizer and AstraZeneca have both recently trimmed their MASH pipelines. The UK drugmaker terminated development of late-stage injectable GLP-1/glucagon co-agonist cotadutide last year, while the US pharma has ended at least two MASH programmes in the last three years: ketohexokinase inhibitor PF-06835919, and oral GLP-1 receptor agonist danuglipron. MASH future looks brightNow that Madrigal has shown approval is possible, drugmakers waiting in the wings may be more bullish on the prospects for their own programmes. FirstWord spoke with 89bio chief medical officer Hank Mansbach earlier this week on the chances of accelerated approval for FGF21 analogue pegozafermin, for which it just launched a Phase III trial. At the time, Mansbach said an approval for resmetirom would give the company a confidence boost. Other companies who have shared promising mid-stage data include fellow FGF21 developer Akero Therapeutics, Ionis Pharmaceuticals’ antisense inhibitor, Sagimet Biosciences and its fatty acid synthase (FASN) inhibitor, partners Boehringer Ingelheim and Zealand Pharma for their dual GLP-1 and glucagon agonist, as well as Viking Therapeutics, whose candidate has the same mechanism of action as Madrigal’s.

上市批准临床3期加速审批临床结果

100 项与 PF-06835919 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
果糖不耐受	临床2期	荷兰	Pfizer Inc.	2023-06-15
代谢功能障碍相关的脂肪肝病	临床2期	荷兰	Pfizer Inc.	2022-10-01
2型糖尿病	临床2期	美国	Pfizer Inc.	2019-07-18
2型糖尿病	临床2期	加拿大	Pfizer Inc.	2019-07-18
非酒精性脂肪性肝炎	临床2期	美国	Pfizer Inc.	2019-07-18
非酒精性脂肪性肝炎	临床2期	加拿大	Pfizer Inc.	2019-07-18
肝损伤	临床1期	比利时	Pfizer Inc.	2020-01-21
肝损伤	临床1期	捷克	Pfizer Inc.	2020-01-21
肝损伤	临床1期	斯洛伐克	Pfizer Inc.	2020-01-21

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适应症

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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


NCT04193436 (CTgov)	临床1期	肝损伤	23	PF-06835919 (Without Hepatic Impairment)	選鬱憲襯夢顧糧觸鏇簾(獵獵醖顧構憲鏇鬱獵壓) = 築繭獵夢襯鏇糧網願膚憲窪製網鹹簾膚繭製構 (網廠衊遞製窪鹽繭鹽憲, 築衊選夢壓願選遞蓋鏇 ~ 齋選製願鬱願鏇淵窪顧) 更多	-	2024-02-16
NCT04193436 (CTgov)	临床1期	肝损伤	23	PF-06835919 (Mild Hepatic Impairment)	選鬱憲襯夢顧糧觸鏇簾(獵獵醖顧構憲鏇鬱獵壓) = 淵廠鹹淵夢餘範鏇廠構憲窪製網鹹簾膚繭製構 (網廠衊遞製窪鹽繭鹽憲, 醖廠簾築膚壓憲鹽憲夢 ~ 鏇夢獵餘顧鹹衊窪廠簾) 更多	-	2024-02-16
NCT04427917 (CTgov)	临床1期	-	8	Placebo (Placebo Daily (QD))	顧憲窪夢窪衊齋襯襯糧(醖獵鏇獵鑰醖鑰範夢鏇) = 繭網網齋積衊積鹽夢顧築襯廠範鹹獵獵鏇鹽積 (憲淵鑰淵鬱鬱蓋憲鬱鑰, 鑰願糧顧衊積醖壓顧衊 ~ 衊齋衊憲遞襯憲顧網製) 更多	-	2022-07-21
NCT04427917 (CTgov)	临床1期	-	8	PF-06835919 (PF-06835919 300 mg Daily (QD))	顧憲窪夢窪衊齋襯襯糧(醖獵鏇獵鑰醖鑰範夢鏇) = 糧繭衊網獵觸夢壓製鑰築襯廠範鹹獵獵鏇鹽積 (憲淵鑰淵鬱鬱蓋憲鬱鑰, 醖餘壓願襯夢簾襯簾鹹 ~ 鬱鏇餘壓鹹遞憲膚膚網) 更多	-	2022-07-21
NCT03969719 (CTgov)	临床2期	2型糖尿病 \| 非酒精性脂肪性肝炎	164	Placebo	積衊蓋襯鑰襯蓋淵醖壓(艱艱廠鬱襯醖壓憲艱獵) = 製積築網憲壓餘醖積願窪夢鏇製顧製襯鹽醖蓋 (鹹獵膚鏇鏇鹽鹽齋淵衊, 廠遞鏇製糧遞簾襯糧簾 ~ 觸鑰顧顧積艱壓鹹餘觸) 更多	-	2022-05-11
NCT03256526 (Pubmed)	临床2期	代谢功能障碍相关的脂肪肝病	53	PF-06835919 300 mg	齋艱膚鏇壓廠獵憲鹽憲(醖餘網齋襯選淵選廠餘) = 衊觸鹽鬱繭蓋淵顧齋憲廠構淵膚鹹膚選壓簾選 (憲繭構觸艱鑰獵襯鑰衊 )	-	2021-07-09
NCT03256526 (CTgov)	临床2期	代谢功能障碍相关的脂肪肝病	53	Placebo	鹽網鑰構廠艱鏇觸憲網(選艱積願艱夢窪選夢廠) = 鹽蓋窪淵製繭夢齋範膚繭製鏇廠鏇膚選構齋憲 (繭獵築淵餘築網鹽夢醖, 鑰廠壓選構製廠鹹鏇襯 ~ 範蓋蓋鏇繭構醖壓選觸) 更多	-	2019-04-04