VK2809 A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY, SAFETY, AND TOLERABILITY OF VK2809 ADMINISTERED FOR 52 WEEKS FOLLOWED BY A 4-WEEK OFF-DRUG PHASE IN SUBJECTS WITH BIOPSY PROVEN NON-ALCOHOLIC STEATOHEPATITIS WITH FIBROSIS - VOYAGE

开始日期2021-02-16

申办/合作机构

Viking Therapeutics, Inc.

NCT04173065 / Completed临床2期

VK2809 A Phase 2B, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of VK2809 Administered for 52 Weeks Followed by a 4-Week Off-Drug Phase in Subjects With Biopsy Proven Non-Alcoholic Steatohepatitis With Fibrosis

The study includes 52 weeks, double-blind treatment period. Clinic visits will occur at Randomization and every four weeks from Week 4 through Week 52 and through End of Study period. The study includes a post-dosing study visit that will occur 4 weeks after the last dose of study drug. This visit represents the End-of-Study Visit (Week 56 Visit). Three hundred thirty-seven subjects will be enrolled into five treatment arms and there will be an equal distribution of males and females in each treatment arm. Subjects will be stratified by gender, fibrosis stage, and diabetes status.

开始日期2019-11-15

申办/合作机构

Viking Therapeutics, Inc.

NCT02927184 / Completed临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess The Efficacy, Safety, and Tolerability of VK2809 Administered for 12 Weeks Followed by a 4-Week Off-Drug Phase in Patients With Primary Hypercholesterolemia and Non-Alcoholic Fatty Liver Disease

This study will investigate the efficacy, safety, and tolerability of VK2809 in lowering LDL-C and liver fat content in patients with primary hypercholesterolemia and fatty liver disease. The primary efficacy endpoint is percent change from baseline LDL-C at the end of the treatment period (Week 12). Secondary endpoints include effects on liver fat content and other liver and lipid markers, as well as effects on safety and tolerability, and pharmacokinetic (PK) measurements.

开始日期2016-09-28

申办/合作机构

Viking Therapeutics, Inc.

100 项与 MB-07811 相关的临床结果

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100 项与 MB-07811 相关的转化医学

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100 项与 MB-07811 相关的专利（医药）

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项与 MB-07811 相关的文献（医药）

2023-09-01·Journal of pharmaceutical and biomedical analysis

Development and validation for bioanalysis of VK2809, its active metabolite VK2809A and glutathione-conjugated metabolite MB06588 in rat liver using LC-MS/MS

Article

作者: Wang, Jiankun ; Jin, Hao-Wen ; Zhang, Yu ; Zhen, Le ; Xie, Tao ; Jin, Xin ; Xu, Bi-Xin ; Xu, Si-Tao ; Wang, Guangji

VK2809 is a promising drug candidate in Phase II clinical trials for the treatment of non-alcoholic steatohepatitis (NASH). It is a prodrug with a HepDirect strategy, which can achieve selective hepatic metabolic activation, generating an active metabolite VK2809A as a potent and selective agonist for thyroid hormone receptor beta (TRβ), a concomitant reactive metabolite VK2809B, and a glutathione (GSH) conjugate MB06588. Currently, there is no convenient and sensitive bioanalytical method for the simultaneous determination of the above three metabolites. Herein, we established an LC-MS/MS method to separate VK2809 and its metabolites on the XSelect HSS T3 column and quantified them in negative electrospray ionization mode. Subsequently, several factors were investigated such as the use of 60% acetonitrile for homogenization to stabilize the analytes, the addition of 20 mM glutathione for the derivation of VK2809B, and the protein precipitation with methanol containing Sobetirome as the internal standard (IS). The method exhibited good linearity for all compounds (19.4-388.4 nM for VK2809; 27.4-2744.4 nM for VK2809A and 10.6-211.0 nM for MB06588) with great correlation coefficients (r > 0.996). The method validation also demonstrated acceptable precision (RSD < 13.0% for VK2809, RSD < 7.9% for VK2809A, RSD < 14.4% for MB06588) and accuracy (92.7%-103% for VK2809, 91.2%-107.3% for VK2809A, 96%-106.7% for MB06588). The matrix effect, recovery, and stability were also suitable to determine all the analytes. This method is suitable for the bioanalysis of VK2809 and its metabolites and has been successfully applied to the study of intrahepatic exposure in rats. It is expected to be further practiced in drug design, optimization, and metabolism study in the following research.

2022-09-03·Expert review of endocrinology & metabolism

Thyroid hormones as a disease modifier and therapeutic target in nonalcoholic steatohepatitis

Review

作者: Puengel, Tobias ; Tacke, Frank ; Spranger, Joachim ; Wirth, Eva K.

INTRODUCTION:

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and closely interconnected to the metabolic syndrome. Liver-specific and systemic signaling pathways orchestrating glucose and fatty acid metabolism contribute to intrahepatic accumulation of lipids and inflammatory processes eventually causing disease progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Since a high number of key regulatory genes regarding liver homeostasis are directly mediated via thyroid hormone (TH) signaling, targeting TH receptors (TRs) represent a promising therapeutic potential for the treatment of NAFLD.

AREAS COVERED:

In this review, we elucidate the effects of TH on metabolic regulations in the liver via local availability and actions. We discuss recent advances and the potential impact of thyromimetics in basic research and clinical trials including liver-targeted and TRβ-specific agents for the treatment of NAFLD.

EXPERT OPINION:

Unselective TR targeting can be accompanied by negative side effects due to high TRβ expression in other organs and TRα-mediated effects. Recent advances in drug development and the introduction of liver-targeted thyromimetics selectively activating TRβ such as Resmetirom (MGL-3196) and VK2809 bring new hope of translating the knowledge on local TH effects into effective hepatic lipid-clearing therapies against NASH.

2020-08-01·Thyroid : official journal of the American Thyroid Association1区 · 医学

Thyroid Hormone Analogues: An Update

1区 · 医学

Review

作者: Zucchi, Riccardo

The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

147

项与 MB-07811 相关的新闻（医药）

2024-06-14

·药渡Daily

【药渡药闻报告-创新药篇】-2024年第22期/总第143期

全球药物批准/研发动态 01 全球新药批准情况根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）全球（不含中国）共有3个新药获批上市。其中，NDA批准1个，新适应症批准1个，新剂型批准1个。与上个统计周期相比，本次减少4个批准新药。 6月6日，Scilex宣布FDA已批准Gloperba®商业化生产的sNDA。Gloperba®是抗痛风药物秋水仙碱的唯一液体口服版本，用于预防成人痛风发作。预防的标准剂量低于0.6毫克，每天一次或两次。在接受低于0.6mg剂量治疗的患者中，150毫升瓶装的Gloperba®预计将持续30天以上，为患者提供额外的价值。2024年6月10日起，Scilex将在所有主要批发商和药店储存Gloperba®。 6月7日，FDA批准葛兰素史克的Arexvy扩大年龄适应症，这是第一种用于50-59岁高危成年人的呼吸道合胞病毒（RSV）疫苗。监管申请得到了III期试验的积极结果的支持（NCT05590403），评估葛兰素史克RSV疫苗在50-59岁成年人中的免疫反应和安全性，包括因某些基础疾病而患RSV-LRTD风险增加的人群。GSK还提交了监管文件，将其RSV疫苗的使用范围扩大到欧洲、日本和其他地区风险较高的50-59岁成年人，监管申请正在审查中。全球（不含中国）新药批准情况（部分） 02 全球新药申报进展根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）全球（不含中国）共有5个新药申报上市。其中，NDA申报进展4个，BLA申报进展1个。与上次统计周期相比，本次减少7个NDA/BLA申报。 6月1日，基石药业宣布CHMP推荐批准舒格利单抗联合化疗用于转移性非小细胞肺癌（NSCLC）患者的一线治疗的积极意见。舒格利单抗是最接近人体的IgG4单抗药物，有望成为全球首个在欧洲上市、不论PD-L1表达水平、且同时覆盖一线鳞状和非鳞状NSCLC的PD-L1单抗。 NDA/BLA申报根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）全球（不含中国）共有3个药物获监管机构特殊资格认定。其中，化学药1个，细胞疗法2个。与上次统计周期相比，本次减少8个获监管机构特殊资格认定的药物。 6月4日，Be Bio宣布FDA已授予BE-101孤儿药资格。BE-101是一种B细胞药物（BCM），正在开发用于治疗B型血友病，旨在将人类FIX基因插入原代人类B细胞中，允许表达用于治疗B型血友病的活性FIX。在降低与当前FIX替代方案相关的给药频率的同时维持治疗性FIX活性水平的潜力将解决与当前疗法相关的相当大的输注负担，并可能显着降低年化出血率和FIX使用。Be Bio预计将在2024年下半年启动一项I/II期研究BeCoMe-9，评估BE-101在重度或中度重度B型血友病患者中的疗效。 6月5日，Adicet Bio宣布，FDA已授予ADI-001快速通道资格，用于治疗复发/难治性III级或IV级狼疮性肾炎，这突显了对此慢性疾病新疗法的迫切需求。ADI-001在非霍奇金淋巴瘤中的临床数据显示CD19+ B细胞耗竭，这与自体α-β CAR T在几种自身免疫性疾病的学术临床研究中的数据相一致。特殊资格认定情况 03 全球新药研发进展根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）全球（不含中国）新药临床研发状态更新共计107条，涉及肿瘤、血液和淋巴疾病、遗传代谢病、精神疾病、神经疾病以及皮肤病等共计14个领域。其中，肿瘤临床进展更新居各领域之首，为52条：肿瘤领域涉及化学药25条，生物药23条，细胞疗法2条，疫苗2条。 6月2日，迪哲医药公布了I类新型肺癌靶向药舒沃哲®针对经治EGFR exon20ins NSCLC的首个全球多中心注册临床研究“悟空1B”最新数据，并在ASCO年会以口头报告形式首次亮相。舒沃哲®是一款针对多种EGFR突变亚型的高选择性EGFR靶向药物，研究达到主要终点，舒沃哲®高效低毒，再现全球同类最佳潜力。同日，信达生物在ASCO年会上公布了IBI343治疗晚期胰腺导管腺癌或胆道癌的临床I期数据。截至2024年1月15日，在25例至少接受过1次基线后肿瘤评估的受试者中，7例达到部分缓解 (PR)，其中5例为PDAC患者，2例为BTC患者，ORR为28.0%，DCR为80.0%。安全性方面，80.0%受试者发生治疗相关不良事件，未发生与治疗相关的死亡事件。全球新药研发进展详情（部分） 04 全球医药交易事件本次统计周期（2024.06.01-06.07）全球（含中国）医药交易时间共计52起，涉及药物权益转让、公司并购等多起交易事件。全球医药交易时间汇总表（部分）国内药物批准/研发动态 01 国内新药批准情况根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）国内共有1个新药获NMPA批准上市。其中，新适应症批准1个。与上次统计周期相比，本次减少1个NMPA批准新药。 6月3日，艾尔建美学旗下保妥适®暂时性改善成人显著或非常显著的咬肌突出（肥大）适应症获NMPA批准。III期临床试验研究结果表明：保妥适®单次治疗可有效改善咬肌突出（肥大）严重程度，使下面部形态改善长达6-9个月，且在长达540天的III期临床研究中对疗效及安全性进行了充分观察。中国新药批准情况（部分） 02 国内新药临床默示许可进展根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）国内共有16个新药获临床默示许可，涉及22个受理号。其中，化学药10个，治疗用生物制品5个，预防性生物用品1个。与上个统计周期相比，本次减少5个临床默示许可获批受理号。本周国内新药临床默示许可进展（部分） 03 国内新药申报进展根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）国内共有7个新药申报上市，涉及11个受理号。其中，化药3个，治疗用生物制品4个。与上个统计周期相比，本次增加7个新药申报上市受理号。国内新药申报上市情况（部分）根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）国内共有27个新药申报临床，涉及51个受理号。其中，化学药14个，治疗用生物制品10个，预防用生物制品3个。与上个统计周期相比，本次减少2个临床申报受理号。国内新药临床申报情况（部分）根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）无国内药物获NMPA特殊资格认定。 04 国内新药研发进展根据药渡数据统计分析，本次统计周期（2024.06.01-06.07）国内新药临床研发状态更新共计18条，涉及肿瘤、血液和淋巴疾病共计2个领域。其中，化学药6个，生物药11个，细胞疗法1个。 6月2日，亚盛医药宣布，公司已在第60届ASCO年会上，以壁报展示形式公布了公司原创1类新药、FAK/ALK/ROS1三联酪氨酸激酶抑制剂（TKI）APG-2449在非小细胞肺癌（NSCLC）患者中的最新数据。APG-2449在未经TKI治疗或2代ALK TKI耐药的NSCLC患者中都显示了初步疗效，对脑转移病灶亦有初步抑制作用；此外，生物标志物研究结果显示，在对2代ALK TKI耐药的NSCLC患者中，APG-2449的治疗效果与基线肿瘤组织中的pFAK表达水平和PBMC中pFAK下降程度相关。 6月7日，齐鲁制药公布其有3项临床研究结果入选ASCO大会壁报展示，研究涉及的新药包括靶向PD-L1/4-1BB的双特异性抗体QLF31907，靶向PD-1/CTLA-4的组合抗体艾帕洛利托沃瑞利单抗（艾托组合抗体），以及靶向PD-1的艾帕洛利单抗。研究领域分别涉及晚期实体瘤和淋巴瘤、鼻咽癌、以及DNA错配修复缺陷（dMMR）或高度微卫星不稳定（MSI-H）的实体瘤。国内新药研发进展情况 05 国内新药研发领域政策法规动态关于公开征求《儿童临床试验药物警戒技术指导原则（征求意见稿）》意见的通知随着我国鼓励和推进儿童用药的研发创新，儿童药物临床试验逐渐增多。儿童的体格、生理及心理发育是一个动态发展的过程，药物进入体内后的吸收、分布、代谢和排泄，以及对药物的反应与成人之间可能存在显著差异，从而决定了儿童受试者在临床试验中可能面临不同于成人的其他安全风险。为更好地保护儿童受试者，指导科学、规范、可推广的儿童临床试验的药物警戒工作模式，药品审评中心起草了《儿童临床试验药物警戒技术指导原则（征求意见稿）》。 06 国内新药研发领域热点新闻金斯瑞没那么脆弱距离金斯瑞遭遇精准狙击已经过去了几天时间，虽然其股价仍未恢复元气，市场在担忧的情绪中仍是一片看空之声。但这类事情早有先例，华为的事迹相信都耳熟能详，包括近期被针对的“药明系”，都清楚地阐明一个道理：只要打不死，终将更强大。精准狙击 5月底，美国众议院中国委员会官网显示，该委员会两名成员致函美国联邦调查局（FBI）局长和美国国家情报总监。信中写道：金斯瑞为美国政府实体和企业提供定制基因合成的生产等服务，人们担忧美国公司的知识产权或面临潜在风险，以及金斯瑞与美国政企合作或有助于提高中国的生物技术能力。更多资讯，请阅读原文冷静过后，要如何看待艾力斯的未来最近一个多月来的艾力斯可谓是经历了大起大落。先是在4月26日公布了2023年年报以及2024年一季报，跨越式的业绩增长迅速吸引了资本市场的目光，当日股价实现“20cm”涨停，此后三日连续创下历史新高，四日时间股价从46.84元/股最高涨至68.47元/股。然而，随着热度消散，艾力斯的股价也重回理性，从巅峰一路阴跌至56元/股左右，最近几日才趋于稳定。冷静过后，重新回看艾力斯，仅凭一款产品能否担得起260多亿的市值，下一步又将怎么走？更多资讯，请阅读原文 98款在研产品，中药、生物药、化学药，天士力可以“全都要”吗？一直以来，中药企业都被认为是重营销轻研发。2023年，A股73家中药上市企业研发费用合计102.1亿元，平均研发费用率仅为4.8%；同期销售费用合计873.7亿元，是研发费用的8倍多。然而，作为中药企业龙头，天士力近年来一直走在中药创新的前列。年研发费用从2021年的5.8亿元增长至2023年的9.2亿元，研发费用率10.57%，远超中药行业平均水平。高额研发投入，让天士力拥有了98款在研产品，中药、生物药、化学药“三管齐下”，产品涵盖心脑血管、消化代谢、肿瘤三大疾病领域。广撒网之下，天士力真的可以“全都要”吗？更多资讯，请阅读原文当Viking达到IIb期主要、次要终点，NASH将迎新药？ 6月4日，Viking Therapeutics公布了其口服的新型肝脏选择性甲状腺受体β亚型（TRβ）激动剂VK2809的IIb期VOYAGE研究的52周组织学数据的阳性结果。 VK2809 VK2809是一种口服的TRβ激动剂，对肝组织和β受体亚型具有选择性，在一系列脂质疾病中表现出良好的治疗潜力。 TRβ是在肝细胞中高度表达的甲状腺激素受体，被激活后可以促进甲状腺激素生成，同时……更多资讯，请阅读原文全球唯二P53 Y220C激活剂，加科思即将启动中国临床研究根据CDE，日前加科思的JAB-30355片已经获得临床试验默认许可。这是一种口服生物可利用的小分子激活剂，用于治疗携带TP53 Y220C突变的晚期实体瘤。作为一种关键的肿瘤抑制因子，P53精确地调控细胞活动，包括细胞周期停滞、细胞凋亡、衰老和DNA修复。与此同时，P53还是人类癌症中最常见的单一变异基因，约50%的侵袭性肿瘤都存在TP53基因突变。其中，TP53 Y220C是一种热点（hot-spot）功能丧失突变，发生在1%的实体肿瘤中。更多资讯，请阅读原文当BMS“不得不”暂停核药的III期研究患者招募放射性药物正在成为肿瘤学领域的热门议题，然而供应问题却成为困扰该领域研究开展的关键性问题。根据Fierce报道，BMS的子公司RazyeBio确认，因同位素锕短缺，已暂停ACTION-1第3阶段研究中的新患者招募。先前，BMS以约250%溢价、总计41亿美元收购核药公司RayzeBio，以获得RYZ101。 RYZ101 RYZ101是一种首创、高效α发射放射性药物，用于治疗生长抑素受体（SSTR）2+实体肿瘤……更多资讯，请阅读原文咨询、合作请联系作者小D有话说为方便读者阅读及保存，我们将周报原文整理成了PDF版本，如需获取全文，可点击最上方蓝字，在药渡Daily公众号后台回复“0614创新药周报”，即可下载。

上市批准孤儿药临床3期疫苗申请上市

2024-06-10

·空之客

【药海听涛】GLP-1也不是万能的：2024年欧肝会NASH药物数据更新

好像自从GLP-1成为医药界顶流以来，但凡被它“临幸”过的领域就要寸草不生，其中NASH就是很多人说是下一个“被GLP-1打没了的市场”。恰逢今年的EASL，几个重要的NASH在研管线都首次公布了病理数据，我们可以横向比较一下，在这个领域GLP-1是否还是万能的？ 1 THR-β 在Madrigal的Resmetirom带头大哥，成为首个获批的NASH治疗药物后，THR-β自然而然成为这个适应症绝对的显学，而继续光大门楣的任务就落到新贵Viking身上。本次会议Viking公布了VK-2809的2b期临床VOYAGE研究的52周病理结果，在每日一次10mg/5mg/2.5mg/1mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为75.0%/63.0%/65.4%/71.4%/29.3%、最高剂量组相比安慰剂组高45.7%，纤维化改善且NASH不恶化的患者比例为56.8%/51.9%/44.2%/57.1%/34.1%，最高剂量组相比安慰剂高22.7%。安全性方面也相对可接受，虽然不良反应发生率偏高，但最高剂量组因不良反应而停药的比例不到10%、且与安慰剂组相差不大。 https://ir.vikingtherapeutics.com/2024-06-04-Viking-Therapeutics-Announces-Positive-52-Week-Histologic-Data-from-Phase-2b-VOYAGE-Study-of-VK2809-in-Patients-with-Biopsy-Confirmed-Non-Alcoholic-Steatohepatitis-NASH 与之相比，本门大师兄Resmetirom就有点黯然失色了，最高剂量组在两个终点的安慰剂修正比例分别为20.2%和11.7%，都远低于VK-2809。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2028395 VK-2809这次的临床数据其实可以说是超预期的，不仅显著优于同靶点已获批的Resmetirom，而且从两个终点的绝对值来看也处于整个NASH在研药物的领先位置。不过蹊跷之处在于逆天的安慰剂效应（两个终点安慰剂组响应率为29%和34%），导致相对来看有效性没有那么惊艳，而且剂量依赖性也不明显，可能都成为数据发布后股价大跌的一些解释。 2 GLP-1 在GLP-1的封神之路上，NASH应该是除减重以外最大的适应症机会之一，Semaglutide已经一马当先（尽管结果也不算很理想，见后文），紧随其后的是两个双靶点Tirzepatide和Survodutide。本次会议Eli Lilly公布了Tirzepatide的2期临床SYNERGY-NASH研究的52周病理结果，在每周一次15mg/10mg/5mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为73.3%/62.8%/51.8%/13.2%、最高剂量组相比安慰剂组高60.1%，纤维化改善且NASH不恶化的患者比例为51.0%/51.3%/54.9%/29.7%、最高剂量组相比安慰剂高21.3%。虽然安全性尚未具体披露，但入组190例患者到最后只有157例完成治疗接受肝穿，脱落率还是有点偏高了。 https://events-distribution.easl.eu/from.storage?image=mIoM6rsplpmkPbT9D4cRMhCdB962jqqPLI0ekg3BGloLb0klBbYoN9dNVhvU-7Oz0 本次会议BI也公布了Survodutide的2期临床48周病理结果，在每周一次6.0mg/4.8mg/2.4mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为43%/62%/47%/14%、最优剂量组相比安慰剂组高48%，纤维化改善且NASH不恶化的患者比例为32.4%/36.1%/34.2%/17.6%、最优剂量组相比安慰剂高18.5%。安全性就有点堪忧，不仅不良反应发生率高达93-97%，而且因不良反应而停药的比例也在16-23%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2401755 与新一代的这两个双靶点GLP-1相比，Semaglutide此前公布的数据同样也都是明显处于下风，最高剂量组在两个终点的安慰剂修正比例分别为42%和10%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2028395 从GLP-1这几个药物的NASH临床结果中，可以读出一些共性的问题：1）首先看起来GLP-1药物对于纤维化的改善不太在行，相对而言在NASH缓解上表现要好不少；2）其次GLP-1药物有效性的剂量依赖程度很低，三个药物都出现了随着剂量升高而效果增加不明显、甚至倒挂的情况，可能说明其作用机制与想象中存在较大差异；3）这三个临床，在NASH缓解且纤维化不恶化终点的安慰剂效应都控制到比较低（13-17%），但在另一边纤维化改善且NASH不恶化终点的安慰剂组都响应率偏高（S药和T药分别33%和30%），这对于统计学显著性与否产生了很关键的作用。 3 FGF-21 Akero在今年三月公布了Efruxifermin的2b期临床HARMONY试验的96周病理结果，在每日一次50mg/28mg和安慰剂组中，纤维化改善且NASH不恶化的患者比例为75%/46%/24%、最高剂量组相比安慰剂高达51%，NASH缓解且纤维化不恶化的患者比例为57%/62%/24%、最高剂量组相比安慰剂组高达33%。安全性方面略有点尴尬，SAE和因不良反应而停药的比例都超过10%。 https://ir.akerotx.com/static-files/c76e5581-39ab-4d46-a6c7-b5893f7a2210 另一家企业89Bio在今年五月公布了Pegozafermin的2b期临床ENLIVEN试验的24周病理结果（又在本次会议公布了48周非病理结果），在每两周一次44mg、每周一次30mg/15mg和安慰剂组中，纤维化改善且NASH不恶化的患者比例为27%/26%/22%/7%、最高剂量组相比安慰剂高20%，NASH缓解且纤维化不恶化的患者比例为26%/23%/37%/2%、最高剂量组相比安慰剂组高24%。安全性方面则相当优秀，特别是每两周一次的剂量组，不良反应发生率67%、停药比例仅2%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2304286 FGF-21的有效性在两个终点之间相对均衡，而Efruxifermin很明显更加突出，其改善纤维化能力是目前的全场最佳；然而除了同样存在剂量依赖性不足的问题外，Efruxifermin最大的蹊跷在于24周和96周在NASH终点的倒挂，以及安全性的隐忧。 4 横向对比在纤维化改善且NASH不恶化终点上，Efruxifermin处在一骑绝尘的位置（哪怕是结合96周和24周的数据），VK-2809和Tirzepatide看绝对值本来也有希望、但在奇高的安慰剂效应抵消之下显得较为平庸，另有Denifanstat也值得关注，至少目前这几个后来者都优于已获批的Resmetirom。在NASH缓解且纤维化不恶化终点上，GLP-1们就比较优秀，VK-2809也很能打，Efruxifermin则呈现吊诡的“长短倒挂”，同样地也都优于Resmetirom。综上所述，NASH目前仍处于群雄逐鹿的蛮荒状态，既没有因为首个获批的药物而定鼎大局，也没有看出会被GLP-1扫穴犁庭之势，这几家正在推进的三期临床都还有充分的竞争机会。往期NASH药物相关文章：【药海听涛】最后的烛火能否燃到黎明：NASH领域再现希望【药海听涛】弦歌不辍还是功败垂成：NASH药物近期主要进展【药海听涛】Madrigal鼙鼓动地来，惊破NASH羽衣曲【药海听涛】以往不谏，来者可追：NASH研发方向的新旧交替

临床2期ASH会议临床结果细胞疗法

2024-06-07

·BioSpace

MASH Clash Between Lilly and Boehringer-Zealand Takes Center Stage at EASL24

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace You would be forgiven if, with all the cancer news from ASCO24 in Chicago this week, you missed the hepatology data dump at the 2024 Congress of the European Association for the Study of the Liver in Milan, Italy. However, there’s a battle brewing between Eli Lilly and the partnered companies Boehringer Ingelheim and Zealand Pharma in metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). The drugs being tested in MASH belong to the now-blockbuster class of therapies known as glucagon-like peptide-1 receptor agonists (GLP-1s). Lilly’s tirzepatide is already approved for type 2 diabetes (marketed as Mounjaro) and weight loss (marketed as Zepbound), spaces it shares with Novo Nordisk’s semaglutide products Ozempic and Wegovy—a duopoly that has led to skyrocketing revenue for both companies, which continue to seek additional indications. Meanwhile, Boehringer and Zealand are looking to leap into the space with its own GLP-1 agonist, survodutide, which is under investigation for obesity and other indications. What was interesting this week at EASL24 was the GLP-1 clash between Lilly and Boehringer/Zealand in the MASH space, with both sides providing readouts on their latest Phase II data and each declaring victory. MASH is a potentially deadly fatty liver disease that affects more than 115 million people globally and is expected to increase to 357 million by 2030. In March, the FDA approved Madrigal Pharmaceuticals’ Rezdiffra, a liver-directed thyroid hormone receptor (THR)-β agonist, as the first-ever treatment for the disease. On Wednesday, Lilly’s Phase II data was presented at the European Association for the Study of the Liver (EASL24), showing that 54.9% of MASH patients treated with a 5-mg dose of tirzepatide saw at least a one-stage improvement in fibrosis. In the study of MASH patients with F2 and F3 fibrosis, tirzepatide treatment was found to be more effective than placebo in achieving MASH resolution without worsening of fibrosis. Just two days later, following a data leak snafu at EASL24 on Thursday, Boehringer and Zealand announced that survodutide demonstrated “breakthrough improvement” in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. The companies said the new data also revealed up to 52.3% of adults with fibrosis stages F1, F2 and F3 had improvement in fibrosis without worsening of MASH. Survodutide, which is licensed to Boehringer from Zealand, is moving into a Phase III study. While GLP-1 drugs may have beneficial effects on MASH by improving insulin sensitivity, reducing liver fat accumulation and reversing fibrosis, Jefferies analysts said in a note to investors this week that they “don’t think GLP-1s will eliminate the market opportunity” for Madrigal in MASH. Likewise, Evercore ISI analysts opined, “there is room for different treatment options for patients with different needs, including daily oral pills and injectable products.” Evercore estimated a potential U.S. market opportunity for Madrigal’s Rezdiffra of $4 billion, while Jefferies’ estimate was considerably lower, pegging peak U.S. sales for Rezdiffra at $2.3 billion. Of course, there are a host of other promising MASH candidates, including Akero Therapeutics. Also at EASL24 this week, Viking Therapeutics announced its candidate VK2809—a thyroid hormone beta receptor agonist—significantly improved secondary histologic endpoints at 52 weeks with no worsening of fibrosis, as assessed by hepatic biopsy. And tomorrow, 89bio will be presenting Phase IIb data for pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21. Meanwhile, new data from Altimmune and a preclinical poster presentation from Aligos Therapeutics also hint at promise in the treatment of MASH. Still, MASH is a complex and confounding disease that has caused many once-promising programs to be discontinued. However, with a projected $25.7 billion total market by 2032 in the U.S., France, Germany, Italy, Spain, the U.K. and Japan, competitors will continue to be in hot pursuit of Madrigal, which has set the standard. Let the clash of the MASH titans begin! Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

临床结果临床2期临床3期上市批准

100 项与 MB-07811 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
纤维化	临床2期	美国	Viking Therapeutics, Inc.	2019-11-15
纤维化	临床2期	比利时	Viking Therapeutics, Inc.	2019-11-15
纤维化	临床2期	法国	Viking Therapeutics, Inc.	2019-11-15
纤维化	临床2期	墨西哥	Viking Therapeutics, Inc.	2019-11-15
纤维化	临床2期	波多黎各	Viking Therapeutics, Inc.	2019-11-15
非酒精性脂肪性肝炎	临床2期	美国	Viking Therapeutics, Inc.	2019-11-15
非酒精性脂肪性肝炎	临床2期	比利时	Viking Therapeutics, Inc.	2019-11-15
非酒精性脂肪性肝炎	临床2期	法国	Viking Therapeutics, Inc.	2019-11-15
非酒精性脂肪性肝炎	临床2期	墨西哥	Viking Therapeutics, Inc.	2019-11-15
非酒精性脂肪性肝炎	临床2期	波多黎各	Viking Therapeutics, Inc.	2019-11-15

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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


NCT04173065 (VOYAGE, PRNewswire) 人工标引	临床2期	非酒精性脂肪性肝炎	-	VK2809 (1 mg QD)	鹽夢餘鬱糧衊網憲選鹹(鏇範夢襯繭積築構餘鹽) = 醖艱醖鬱積夢衊築餘製築築糧鹹範鑰蓋糧窪鏇 (艱鹹壓艱鑰醖醖選齋壓 ) 更多	积极	2024-06-04
				VK2809 (2.5 mg QD)	鹽夢餘鬱糧衊網憲選鹹(鏇範夢襯繭積築構餘鹽) = 廠遞糧醖夢夢鹹顧鹽鑰築築糧鹹範鑰蓋糧窪鏇 (艱鹹壓艱鑰醖醖選齋壓 ) 更多
EASL2020	临床2期	代谢功能障碍相关的脂肪肝病	-	VK2809 5 mg QD	艱範選鹽鹽衊艱鏇鹹鹹(獵願構壓鑰廠蓋築築糧) = VK2809 was well-tolerated in this study; no serious adverse events were reported in any cohort 淵夢齋獵獵蓋鬱憲遞獵 (夢鏇餘衊齋衊鬱鏇淵衊 )	积极	2020-08-27
				VK2809 10 mg QOD
EASL2019	临床2期	代谢功能障碍相关的脂肪肝病	-	VK2809 5 mg QD	觸膚鹽繭醖鏇糧簾鹽觸(顧繭鏇鬱遞糧壓衊膚夢) = 鑰膚蓋選繭選築齋醖壓繭製築鬱網壓窪夢襯簾 (淵壓獵積積衊齋窪襯淵 ) 更多	-	2019-04-11
				VK2809 10 mg QOD	觸膚鹽繭醖鏇糧簾鹽觸(顧繭鏇鬱遞糧壓衊膚夢) = 鹽鹹願艱壓鏇蓋齋鏇蓋繭製築鬱網壓窪夢襯簾 (淵壓獵積積衊齋窪襯淵 ) 更多