A Randomized, Double-blind, Parallel-group, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Oral Tropifexor (LJN452) & Licogliflozin (LIK066) Combination Therapy and Each Monotherapy, Compared With Placebo for Treatment of Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis.(ELIVATE)

Randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor & licogliflozin combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

开始日期2019-12-30

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT03320941

/ Completed临床2期

A Randomized, Double-blind, Dose-finding Study to Evaluate the Change in Weight After 12 Weeks Treatment With 4 Doses of LIK066 Compared to Placebo in Japanese Patients With Obesity Disease

The purpose of the study is to evaluate the efficacy, tolerability and safety of LIK066 to support dose selection for Phase 3 development in Japanese adults with obesity disease.

开始日期2017-12-07

申办/合作机构

Novartis Pharmaceuticals Canada, Inc.

NCT03205150

/ Completed临床2期

A 12-week Randomized, Patient and Investigator Blinded, Placebo-controlled, Parallel Group Study to Investigate the Efficacy of LIK066 in Obese Patients With Non-alcoholic Steatohepatitis (NASH)

The purpose of this study was to assess the effects of LIK066 on a variety of metabolic and inflammation biomarkers in patients with non-alcoholic steatohepatitis (NASH)

开始日期2017-10-04

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 Licogliflozin 相关的临床结果

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100 项与 Licogliflozin 相关的转化医学

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100 项与 Licogliflozin 相关的专利（医药）

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项与 Licogliflozin 相关的文献（医药）

2025-04-09·Journal of the American Chemical Society

Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug

Article

作者: Ranson, Neil A. ; Willis, Leon F. ; Brinkworth, Alice ; Xu, Yong ; Zhuravleva, Anastasia ; Radford, Sheena E. ; Foster, Richard ; Chakraborty, Pijush ; Wilkinson, Martin ; Taylor, Alexander I. P.

Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.

2025-02-01·CLINICAL THERAPEUTICS

Recent Advances in Individualized Clinical Strategies for Polycystic Ovary Syndrome: Evidence From Clinical Trials and Emerging Pharmacotherapies

Review

作者: Moka, Murali Krishna ; George, Melvin ; Sriram, Damal Kandadai

PURPOSE:

Clinical trials are advancing the treatment of polycystic ovary syndrome (PCOS), an endocrine disorder affecting 8-13% of women. Lifestyle interventions, including nutritional plans, physical activity, and stress management, can improve reproductive hormones and metabolic health. Novel pharmacotherapies targeting hormonal, metabolic, and reproductive abnormalities are being explored for individualized treatment. Combination therapies and lifestyle interventions like acupuncture, high-intensity interval training, and vitamin D3 supplementation are also being explored.

METHODS:

We conducted a narrative review by searching English-language studies across electronic databases such as PubMed, Science direct, and Google Scholar for articles related to the topics of PCOS and novel drug therapies such as metformin, LIK-066, elagolix, saxenda, exenatide, clomiphene, letrozole, and other diagnostic interventions. Our review excluded preclinical studies and articles not in english.

FINDINGS:

In addition to pharmacological treatments, lifestyle interventions such as Tung's acupuncture, high-intensity interval training (HIIT), and vitamin D3 supplementation have proven effective in managing symptoms of PCOS and enhancing overall health outcomes. These interventions offer a complementary approach to traditional medical therapies, emphasizing the importance of integrating lifestyle modifications into the treatment plan for women with PCOS.

IMPLICATIONS:

This comprehensive approach underscores the importance of tailored treatments in optimizing clinical outcomes and quality of life for women with PCOS. The aim of this review is to highlight recent advancements in the treatment of PCOS through clinical trials and emerging pharmacotherapies, emphasizing the need for individualized and multifaceted treatment approaches.

2024-09-21·EXPERT OPINION ON PHARMACOTHERAPY

A systematic review on effect of sodium-glucose cotransporter-2 inhibitors on the metabolic and endocrinological profile of patients with polycystic ovarian syndrome

Review

作者: Parveen, Rizwana ; Roy, Madhura ; Majid, Haya ; Khan, Parvej ; Saxena, Rajesh ; Nidhi ; Pathak, Mani

BACKGROUND:

Polycystic ovarian syndrome (PCOS) has been a common metabolic and endocrinal disorder, prevalent amongst women belonging to the reproductive age group. The aim of this systematic review was to assess the safety and efficacy profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, and Licogliflozin) for the treatment of women suffering from PCOS.

METHODS:

A literature search in PubMed, Science Direct, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted for randomized clinical trials of SGLT-2 inhibitors in PCOS patients by applying predetermined inclusion and exclusion criteria. The articles in English language were included.

RESULTS:

Four randomized controlled trials including 146 subjects were included in the review. The clinical studies indicated a significant decrease in the levels of total testosterone, free androgen index, total body fat, homeostasis model assessment-estimated insulin resistance (HOMA-IR), body mass index (BMI), dehydroepiandrosterone sulfate (DHEAS) and fasting plasma glucose (FPG). However, no significant difference was reported in levels of sex hormone-binding globulin (SHBG). Overall, there was improvement in metabolic and endocrine profiles, suggesting a potentially beneficial impact of SGLT2 inhibitors in the management of PCOS.

CONCLUSION:

There is a requirement for large extensive clinical trials to demonstrate the efficacy of SGLT-2 inhibitors in PCOS patients.

项与 Licogliflozin 相关的新闻（医药）

2023-05-30

·研发客

心衰新药4年等来FDA上市绿灯 |第一现场

// 被赛诺菲放弃的索格列净，成为FDA批准的首款SGLT1/2双靶点抑制剂，在心衰方面的疗效全面超越SGLT2单靶点抑制剂。一向对慢性病用药临床研究数据要求苛刻的FDA，最近却对一款新药格外开恩。上周五Lexicon Pharmaceuticals宣布，其产品索格列净（sotagliflozin）获FDA上市批准，用于降低成人患者因风险因素导致发生心血管事件死亡、心力衰竭而住院或接受急救的风险。索格列净递交的两项研究SOLOIST和SCORED，试验对象都仅限于2型糖尿病患者。出人意料的是，FDA最终却未限定使用者是否患糖尿病，也未限定左心室射血分数（LVEF）。指标全面超越单靶点同类产品此次FDA将索格列净适应症范围扩大至研究以外人群，猜测一方面是基于同类产品的研究经验，更重要的应该还在于其展示出SGLT1/2双重抑制剂对比于SGLT2单靶点抑制剂的疗效优势。近年，SGLT2抑制剂作为降糖药开发的同时，意外被发现对心力衰竭有预防和治疗作用，成为新药研发领域的一项重要突破。自2020年以来，已有多款SGLT2抑制剂心衰适应症获FDA批准，如恩格列净、达格列净等，适应症覆盖也逐渐从射血分数降低扩大到射血分数保留的心衰。FDA对心衰药物的要求是“三好学生”，获批产品必须在三个主要指标上体现出治疗获益，包括总MACEs事件风险率、总心血管死亡事件风险率、总心衰住院风险率。而在上述三项指标上，索格列净的表现均对比安慰剂组有显著差异，同时数据较已上市的“列净”类产品，也有较大改善（见下表）。来源|上海研健整理除此以外，索格列净最明显的进步之处，体现在降低中风和心梗事件发生风险上。从数据看，目前已上市的SGLT2抑制剂并不能在该指标上让患者获益，而索格列净降低两项事件的发生率均超过30%。赛诺菲没有坚持到最后SGLT1/2双靶点抑制剂的设计理念，是利用双通道同时减少消化道对葡萄糖的吸收，以及肾小管对葡萄糖的重吸收。以此进一步减少糖尿病患者的葡萄糖吸收量，并为伴有肾损伤的人群提供更优治疗选择。赛诺菲曾对上述产品在糖尿病领域的开发寄予厚望。2015年11月，Lexicon和赛诺菲签订合作开发协议，获得索格列净全球开发和商业化权利。该合作首付款3亿美元，此外还有14亿美元的里程碑付款及一定比例的销售分成。赛诺菲当时做出这样的决定，并不能说是赌徒心态，毕竟SGLT2单靶点抑制剂已诞生多款重磅炸弹。谁料后来SGLT1/2双靶点抑制剂在糖尿病适应症上的开发会如此坎坷。索格列净的首个适应症上市申请就遭FDA当头一棒。在与赛诺菲达成合作后，索格列净完成了数项与1型糖尿病治疗有关的研究，并于2019年4月获欧盟批准，用于接受最佳胰岛素疗法但血糖控制仍不达标的1型糖尿病成人患者。然而，FDA却因担心可能导致糖尿病酮症酸中毒（DKA）风险而拒绝了索格列净的上市申请。事实上，SGLT2单靶点抑制剂未获批1型糖尿病适应症，也主要因为这一原因，索格列净未能将其克服。而索格列净在2型糖尿病上开展的几项临床研究，结果也是喜忧参半。在最能说明SGLT1/2双靶点抑制剂优势的肾损伤患者研究中，索格列净相比于选择性SGLT2抑制剂，在伴有轻、中度肾损伤的糖尿病患者（损伤程度小于DKD3a）中显示出不错的降糖效果，但未能给伴有更严重肾损伤（DKD3b及以上）的2型糖尿病患者带来额外的临床收益。这成为压垮赛诺菲信心的最后一根稻草。2019年赛诺菲宣布与Lexicon终止索格列净项目合作，为此还向Lexicon支付了2.6亿美元的分手费。而Lexicon也因缺少支持，无法继续推进已经启动的多项3期临床研究，其中包括SOLOIST和SCORED两项大型临床研究，只得在2021年使用中期分析结果向FDA递交心衰适应症上市申请。面对索格列净时隔4年获批心衰适应症的消息，不知赛诺菲此时会作何感想？根据GlobalData的预测，到2028年仅全球8个主要市场（美国、法国、德国、意大利、西班牙、英国、日本和中国），心衰药物市场年复合增长率达19.5%，预计2028年市场规模将达221亿美元。国内有同类产品在研除了已获批上市的索格列净，全球还有两款SGLT1/2双靶点抑制剂进入临床研究阶段，分别是诺华的LIK066以及上海研健的YG1699。其中上海研健的YG1699是国内唯一进入临床研究的SGLT1/2双靶点抑制剂。该公司提到，2022年YG1699已获FDA首肯，可直接在美国启动心衰适应症的2期临床研究。研健公司研发负责人李成海说：“YG1699与索格列净（同期所获得的数据）相比具有多重优势，它在安全窗、人体PK暴露量及生物活性等方面都远好于索格列净。对于业内普遍关注的索格列净酮症酸中毒（DKA）问题，YG1699在已经完成的T1DM治疗2期临床研究中，在人为增加DKA风险因素的条件下，未观察到有受试者出现该不良反应。并且该研究结果同时显示，YG1699的疗效显著好于头对头比较的达格列净。”（具体数据见下图）图中：纵坐标是餐后血糖，横坐标是时间。深灰色线是对照组，绿线是达格列净10mg，橘色和红色分别是YG1699的10mg和25mg。图中显示：未用药和使用达格列净的两组，在90分钟内血糖是上升的。90分钟开始，达格列净起效开始降糖。而YG1699的10mg和25mg均在吃药后立刻起效，并保持血糖平稳。试验证明：YG1699在降糖和控制餐后血糖平稳方面优于达格列净。根据研健提供的资料，YG1699具有更高的人体PK暴露量（见下表），在25mg用药剂量时，血药浓度即可达到索格列净400mg剂量时的4倍。来源|上海研健整理还值得一提的是，研健现任首席医学官（CMO）Pablo Lapuerta，之前就曾在Lexicon公司任全球执行副总裁兼CMO，主导了索格列净产品的多项临床开发。索格列净在心衰领域的获批，增加了国内SGLT1/2双靶点抑制剂研发者的信心。但接下来公司着手启动全球大规模3期临床研发，还需要投入大量的资金和人力支持。未来SGLT1/2双靶点抑制剂还能在哪些适应症上崭露头角，包括YG1699未来的临床研究进展，这些都值得期待。编辑 | 姚嘉yao.jia@PharmaDJ.com总第1892期访问研发客网站可浏览更多文章www.PharmaDJ.com

引进/卖出医药出海

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

2022-12-02

·药智网

NASH市场战况激烈！最新研发进度一览，谁将“登顶”？

我国脂肪肝患者约1.5亿，且在不断增加，NASH（非酒精性脂肪性肝炎）是脂肪肝中比较严重的类型。据悉，有1.1亿轻度脂肪肝患者，可以通过饮食及锻炼好转，但是上千万中度重度NASH患者不能通过该方法恢复。且NASH需要终生用药，市场规模大。预测在2030年内，NASH将超过乙肝，成为威胁人类健康的又一杀手。预计国际NASH的市场规模，在2025年能达到350-400亿美元。不过，好消息是Madrigal公司最近披露，旨在治疗NASH的新药Resmetirom首个全球III期临床研究积极的试验数据，给NASH患者带来新希望的同时，也预示着NASH领域的新药开发即将迎来新一轮“黄金期”。6家药企布局一览雅创医药：FXR激动剂HPG-1860雅创医药的HPG-1860，国内研发进度最快的FXR激动剂之一。具有高度选择性的非胆汁酸结构的FXR激动剂。FXR通过调控胆汁酸合成相关的基因表达，成为胆汁酸稳态的关键控制器。研究表明NASH疾病进展中FXR的表达下调，且FXR在炎症调节中的作用已被广泛关注并研究。HPG1860在临床前研究和早期临床试验中表现出卓越的FXR靶向激活特性和良好的安全性。不过，由于FXR激活剂主要改变脂肪代谢途径，有增加血脂的副作用，因此心血管疾病患者不宜使用，即使能成功上市后市场受限。歌礼制药：FXR激动剂ASC40歌礼制药发布公告称，其研发的FXR激动剂ASC42用于治疗原发性胆汁性胆管炎(PBC)的一项药物－药物相互作用(DDI)研究临床试验申请，已获得FDA批准，该研究将为后续在中国、美国和欧盟开展ASC42 III期临床试验提供更多支持。不过，FXR激动剂在不同临床试验中，均出现剂量依赖的皮肤瘙痒和血脂异常，这些是FXR激活后的靶效应。目前，面临的主要挑战是优化FXR激动剂的结构并确定最佳剂量，在减轻不良反应的同时，保持确定性的肝组织学改善和临床疗效，这是一个有待解决的两难选择。广东众生药业：ZSP1601该企业在NASH领域布局了6个产品，分别是ZSP1601、ZSP0678、ZSYM008及RCYM001、RAY001以RAY002布局了覆盖肝脂肪，炎症，纤维化等不同作用靶点，并且有联合用药潜力的产品管线。其中，ZSP1601已完成Ib/IIa期临床试验，试验获得了积极结果，达到了主要终点，支持ZSP1601片继续开展IIb期临床试验，在国内研发进展位于第一梯队。深圳君圣泰：HTD1801其研发的新药全球同步开发，且已有2个品种进入到临床II期，并获得美国FDA的快速审评通道资格认定2项和孤儿药认定1项。拓臻生物：FXR激动剂TERN101主要针对NASH、肝纤维化、肝细胞癌等慢性肝脏疾病的全新疗法，去年成功登陆纳斯达克。TERN-101正是来自于礼来的授权许可。与其他FXR激动剂相比，TERN-101具有更好的组织特异性，在肝脏分布高，最大限度减少肠道通路的激活，从而减少瘙痒和不良脂质变化等副作用，提高了药物的耐受性。另外，还有SSAO抑制剂TERN-201、THR-β激动剂TERN-501、以及一款GLP-1R激动剂。韩国LG-Chem VAP-1抑制剂LR20056LG化学从国内药捷安康获得授权的LR20056，是一种新型、强效、选择性和不可逆的半衰期敏感胺氧化酶（SSAO，又称血管粘附蛋白-1（VAP-1））抑制剂，拟作为非酒精性脂肪性肝炎（NASH）的口服治疗药物，正在美国进行临床I期实验。图1 NASH研发十大药企布局图片来源：pharmacodia global数据库NASH药物研发策略目前，NASH靶向药物治疗策略主要可以分为四大类：第一类，靶向改善胰岛素敏感性的代谢靶点，抑制参与新脂肪生成的不同酶，或改善线粒体对脂肪酸的利用；第二类，靶向炎症或细胞损伤靶点，抑制炎症细胞的招募或阻断炎症信号传导，减少氧化和/或内质网压力，或抑制肝细胞凋亡；第三类，调节胆汁酸肠道肝脏循环和信号，或改变肠道微生物群的肝肠轴靶标；最后一类，直接针对肝星状细胞的抗纤维化目标，减少肝脏中胶原蛋白的沉积，减少肝纤维化。表1总结了具有代表性的五款药物。图2 NASH及纤维化通过临床II期以上的药物图片来源：《自然》综述doi.org/10.1038/s41574-021-00507-z图3临床实验中的NASH代表药物及靶点一览图片来源：Nature Reviews Gastroenterology&Hepatology,18(6),373-392.靶向胆汁酸受体研究发现，胆汁酸作为信号分子与受体结合，在ＮＡＦＬＤ／ＮＡＳＨ发生、进展和消退中起关键作用。２０１５年ＦＬＩＮＴ试验中期结果“奥贝胆酸（ＯＣＡ）通过激活法尼醇Ｘ受体（ＦＸＲ）可以降低ＮＡＳＨ患者的ＮＡＦＬＤ活动性评分（ＮＡＳ）及纤维化“程度”引起业界关注。FXR激动剂奥贝胆酸，虽然已在临床III期研究中达到FDA设定的临床终点。但其是否能够被批准上市，尚有很大的不确定性。更重要的问题是：是否值得继续开发更好的FXR小分子激动剂？答案似乎是肯定的，但摆脱骚痒这样的副作用，也可能只是研究者的一厢情愿。加上其它可能的肝毒性，这就限制药物能使用的剂量，其总体疗效就很有限。最近发布了两个FXR激动剂，EDP-305和MET409的临床II期数据，但瘙痒仍然是很大的问题。2019年9月25日，Enanta Pharmaceuticals发布了另一个FXR激动剂，EDP-305的临床2a研究（ARGON-1）数据。该研究测试了两个剂量（1mg和2.5mg）的EDP-305，高剂量组的肝酶水平下降了28单位/升，而安慰剂组下降了15单位/升。结果刚刚超过有统计学意义的阈值，与OCA临床测试中减少28单位/升的指标一致。接受高剂量EDP-305的患者肝脂肪（MRI-PDFF）在统计学上显著减少。45%受试者是MRI-PDF应答者，即取得≥30%的脂肪减少。EDP-305也表现出强大的靶标参与度，如C4的减少以及FGF-19和ALP的增加；也观察到了GGT的强力降低。总体而言，EDP-305总体上是安全的，大多数与治疗相关的不良事件（TEAEs）是轻度至中度。最常见的（≥5%）包括瘙痒（pruritus），胃肠道（GI）相关症状（恶心，呕吐，腹泻），头痛和头晕。迄今为止，在所有研究中，在400多个接受EDP-305的受试者中，都观察到了一致的安全性特征。至于EDP-305在这个为期12周的临床2a研究中的耐受性，则不令人乐观：在2.5mg剂量组中，大约51%的受试者存在瘙痒，而在1mg手臂中，低于10%的受试者出现瘙痒；大多数瘙痒是轻度或中度。因瘙痒导致的停药率分别为1.8%（1 mg剂量组）和20.8%（2.5 mg剂量组）。在2.5mg剂量组中，所有停药都是由于中度瘙痒。2020年8月27日，位于美国加州圣地亚哥的Metacrine，Inc.，发布了为期12周的随机，安慰剂控制的MET409临床1b研究最终的积极结果，MET409是该公司的非胆汁酸FXR激动剂，用于治疗NASH。靶向PPARs过氧化物酶体增殖物激活受体(PPAR)，是核激素受体超家族的配体依赖性转录因子，包括PPARα、PPARγ和PPARβ/δ三种亚型。其中，PPAR-α的激活可降低甘油三酯水平并参与能量稳态的调节，而PPAR-β/δ的激活增强了脂肪酸代谢。PPARγ激动剂吡格列酮可在改善胰岛素抵抗基础上促进脂肪重新分布，减轻肝脂肪变性、炎症和肝纤维化。PPARα和PPARγ激动剂saroglitazar于2020年3月在印度获批上市，用于治疗非肝硬化NASH，是全球首个获批用于NASH治疗的药物，其既可减少肝内脂肪含量，降低肝酶水平，又可通过调节糖脂代谢降低心血管疾病危险因素，适用于合并他汀类药物不能控制的糖尿病和高脂血症的NASH患者。近期，印度研究报告，saroglitazar(4mg/d)治疗9个月可降低NAFLD患者的血清总胆固醇和肝酶水平，改善肝脏硬度。临床研究显示，PPARα和PPARδ双重激动剂elafibranor和泛PPAR激动剂lanifibranor等均可降低NAFLD患者的血脂水平和改善肝脏组织病理学。但这个靶点最近也是困难重重：苏州泽璟暂停“ZG0588非酒精性脂肪性肝炎适应症临床前研究、临床研究及药学研究”项目的原因中就强调：PPAR激动剂在治疗NASH的临床研究中疗效低于预期，如2020年5月，Genfit公司宣布其PPAR激动剂elafibranor治疗非酒精性脂肪肝（NASH）的III期临床研究未能达到预先设定的主要终点。靶向肝脏特异性甲状腺受体（THRs）甲状腺激素调节肝脏甘油三酯和胆固醇代谢的很多过程，甲状腺受体的两种亚型THRα和THRβ在大多数组织中都有表达，其中THRβ是在肝脏中表达的主要形式，选择性更高。Resmetirom是目前在NASH适应症上研发进展最快的THRβ激动剂，今年1月底，上文提到的Madrigal Pharmaceuticals宣布药物在III期研究中达到了主要终点和关键的次要终点，患者肝脏脂肪和致动脉粥样硬化的脂质实现了“显著的、临床相关的”减少，且安全性良好。图4 Resmetirom优化合成路径图片来源：J.Med.Chem.2014,57,3912-3923国内公司自主研发的产品中，进展最快的是拓臻生物的TERN-501。今年3月已经在美国启动了单药以及与FXR激动剂TERN-101联合用药的II期临床。靶向GLP-1受体胰高血糖素样肽-1（GLP-1）受体激动剂，属于肠促胰岛素类似物，已被广泛用于2型糖尿病的治疗。越来越多的证据发现，这类药物可改善NASH患者的肝脏脂肪含量。司美格鲁肽用于320名NASH患者的II期多中心研究结果显示，在所有剂量组中均达到NASH消退和肝纤维化未恶化的主要终点。另外，GIP和GLP-1受体双重激动剂替尔泊肽的II期研究证实了药物使得NASH患者的ALT、K-18和Pro-C3标志物降低。国内的先为达生物专注于研发慢性代谢性疾病的创新药物，有多款GLP-1受体激动剂产品在进行NASH适应症的研究。去年底，该公司将一款临床前长效GIP受体激动剂项目的全球开发和商业化权益授权给赛诺菲。靶向ACCGS-0976(firsocostat)是一款肝乙酰辅酶A羧化酶(ACC)直接抑制剂，吉利德引自Nimus。另一在研的此类药物是辉瑞公司的ACC1/2双重抑制剂PF-05221304（clesacostat）。这两个药物均在包括中国在内的多个国家开展治疗NASH的II期研究，初步研究显示了积极结果，但都发现甘油三酯升高这一主要的不良事件。联合用药探索NASH发病机制复杂，单一药物的临床研究有些未能显示出显著的组织学改善，且高剂量应用时会出现耐受性问题。因此，目前也有不少联合用药的研究正在开展，以提高疗效，减轻潜在的耐受性问题，并提高依从性。吉利德开展了非甾体FXR激动剂cilofexor(GS-9674)和ACC抑制剂firsocostat(GS-0976)联用的II期研究。早期研究显示，联合用药可以降低患者的肝脂肪，但是对于有严重肝纤维化（F3-F4期）的患者，未达到改善纤维化的主要终点。不过，研究达到了多项次要终点，包括NAS积分的改善。吉利德于去年下半年和诺和诺德合作，启动了诺和诺德GLP-1受体激动剂semaglutide与cilofexor和firsocostat固定剂量复方三药联合的IIb研究。此外，辉瑞和诺华也在包括中国在内的多个国家开展了两药联合治疗NASH的II期研究。辉瑞的组合为ACC抑制剂PF-05221304联合DGAT2抑制剂PF-06865571（ervogastat），诺华为FXR激动剂tropifexor联合SGLT1/2抑制剂LIK066（licogliflozin）。不过，鉴于诺华已经终止了两项tropifexor的研究，该联合研究也面临终止风险。小结对于新药开发来说，虽然NASH市场巨大，但也是一个深不见底的黑洞：已有多款药物研发失败，且这个名单还在不断增加中，很多药物都是在进入晚期临床研究后宣告失败。道阻且长，行则将至；行而不辍，未来可期！期待国内外创新药企，在NASH领域的快速崛起。参考资料：1、自然子刊综述：Therapeutic pipeline in nonalcoholic steatohepatitishttps://www.nature.com/articles/s41575-020-00408-y2、Madrigal公司resmetirom介绍 https://www.madrigalpharma.com/our-programs/resmetirom/Targeting progression of liver damage in NASH(astrazeneca.com)3、NASH在研新药分析 http://www.phirda.com/artilce_28446.html?cId=14、非酒精性脂肪性肝病的药物治疗进展http://www.lcgdbzz.org/cn/article/doi/10.3969/j.issn.1001-5256.2022.07.033?viewType=HTML5歌礼医药NASH管线 https://www.gannexpharma.com/portal/list/index/id/9.html声明：如需转载，请务必注明文章作者和来源。如涉及作品内容、版权和其它问题，请您留言，我们将在第一时间删除。责任编辑 | 八角转载开白 | 马老师 18323856316（同微信）药智网原创作品 | 尽情分享朋友圈 | 转载请联系授权— Tips —如果您有医药行业相关的线索或对医药政策、研发创新、资本市场、行业发展有深度观察欢迎投稿给我们马老师 18323856316（同微信）邮箱：maxuelian@yaozh.com 阅读原文，是昨天最受欢迎的文章哦

快速通道孤儿药ASH会议临床2期

100 项与 Licogliflozin 相关的药物交易

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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
肝纤维化	临床2期	美国	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	日本	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	阿根廷	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	比利时	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	巴西	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	保加利亚	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	加拿大	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	智利	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	哥伦比亚	Novartis Pharmaceuticals Corp.	2019-12-30
肝纤维化	临床2期	丹麦	Novartis Pharmaceuticals Corp.	2019-12-30

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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


NCT03205150 (Pubmed \| Nat Med)	临床2期	非酒精性脂肪性肝炎	107	Licogliflozin 30mg	夢淵膚繭繭鹹鹹構窪膚(顧獵襯簾顧膚顧襯膚選) = Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. 艱襯鹹鹹餘蓋網廠構觸 (範窪糧繭製壓淵蓋糧鑰 )	积极	2022-06-20
				Licogliflozin 150mg
NCT03152591 (Pubmed) 人工标引	临床2期	多囊卵巢综合征	-	licogliflozin	夢衊簾積膚衊壓顧膚憲(糧衊鹹鬱糧築製鏇鏇齋) = Concentration of FT did not change 襯鹹範鹽鏇顧蓋獵鹹淵 (鹽鹹簾夢衊獵繭繭鬱淵 )	积极	2021-11-01
				Placebo
NCT03131479 (Pubmed) 人工标引	临床2期	慢性肾病	53	Licogliflozin	鹹簾簾網願淵鑰醖構構(壓壓獵範鑰醖艱觸鹹憲) = increased in all pts but not in severe (6.2 [-0.71, 13.18] g) CKD 糧壓糧膚鑰餘蓋簾鹽製 (膚餘簾壓築艱窪遞繭衊 ) 更多	积极	2021-05-01
				Placebo
NCT03320941 (Pubmed \| Diabetes Obes Metab)	临床2期	肥胖	126	Licogliflozin 2.5 mg qd	顧蓋獵繭築蓋衊膚襯淵(鑰願製醖醖繭衊簾醖簾) = 窪積醖積觸構鬱憲觸窪蓋齋觸蓋憲鑰齋願壓鑰 (餘衊鹹製選鹽憲窪廠齋, -2.92, ~ 0.21)	-	2020-07-01
				Licogliflozin 10 mg qd	顧蓋獵繭築蓋衊膚襯淵(鑰願製醖醖繭衊簾醖簾) = 製製願蓋夢襯醖願獵顧蓋齋觸蓋憲鑰齋願壓鑰 (餘衊鹹製選鹽憲窪廠齋, -4.15, ~ 1.7)
NCT03100058 (Pubmed \| Obesity (Silver Spring)) 人工标引	临床2期	超重 \| 肥胖	-	Licogliflozin	夢艱艱衊積壓獵餘膚網(簾簾淵顧顧膚夢淵醖蓋) = 糧鑰衊構顧範艱鏇壓膚簾簾繭壓鬱醖齋製廠齋 (艱憲膚淵網夢觸築願膚 )	积极	2020-05-01
				Placebo	-
NCT03320941 (CTgov)	临床2期	肥胖	126	Placebo	鹹窪壓鏇醖餘蓋夢襯鏇 = 積選衊獵齋獵膚積鏇鹹顧網積襯築膚顧襯顧夢 (願顧簾鬱齋憲壓餘膚艱, 範顧淵鏇襯醖夢願醖鹽 ~ 繭簾網遞襯網願製醖鹹) 更多	-	2019-10-02
NCT03152552 (CTgov)	临床2期	2型糖尿病 \| 心脏衰竭 \| 慢性心力衰竭	125	LIK066 (LIK066 2.5mg)	齋襯廠選鑰艱鬱鏇憲齋(膚壓膚艱顧鑰觸淵獵壓) = 鹽齋構觸鹽繭網窪壓夢鏇窪夢構膚繭鬱繭淵壓 (憲壓醖夢淵憲糧淵鹽鏇, 醖糧觸窪鹽憲糧繭繭簾 ~ 願壓積顧獵鬱夢襯製築) 更多	-	2019-08-28
				LIK066 (LIK066 10mg)	齋襯廠選鑰艱鬱鏇憲齋(膚壓膚艱顧鑰觸淵獵壓) = 選觸遞獵衊夢齋窪構蓋鏇窪夢構膚繭鬱繭淵壓 (憲壓醖夢淵憲糧淵鹽鏇, 網壓願範衊顧衊範窪壓 ~ 廠鑰獵蓋鏇夢窪顧製衊) 更多
NCT03152591 (PCOS, CTgov)	临床2期	多囊卵巢综合征 \| 肥胖	29	LIK066 (LIK066)	觸壓蓋繭蓋艱壓製獵鹹(鑰繭願鏇獵繭鏇鬱築構) = 壓願衊鬱膚憲願艱餘膚網簾鬱壓簾醖鹽繭夢觸 (醖繭憲鏇壓築醖壓遞網, 糧獵遞醖鹽觸憲願鏇廠 ~ 壓觸鏇憲餘繭蓋鏇遞壓) 更多	-	2019-05-09
				Placebo (Placebo)	觸壓蓋繭蓋艱壓製獵鹹(鑰繭願鏇獵繭鏇鬱築構) = 鬱壓願構鑰獵築獵艱選網簾鬱壓簾醖鹽繭夢觸 (醖繭憲鏇壓築醖壓遞網, 壓範憲範願餘鹹簾夢網 ~ 網鹹網醖選製鹹壓網壓) 更多
NCT03131479 (CTgov)	临床2期	肾功能不全	53	LIK066 (Normal)	膚蓋獵繭憲淵獵製範衊(壓窪鑰築壓簾糧選糧鑰) = 網願廠糧鹹鹽膚蓋遞簾範構齋製醖製願觸積鹽 (襯壓鏇蓋襯鬱齋鑰構觸, 21.93) 更多	-	2019-02-06
				LIK066 (Mild)	膚蓋獵繭憲淵獵製範衊(壓窪鑰築壓簾糧選糧鑰) = 築製鬱鹽艱夢艱鬱襯鏇範構齋製醖製願觸積鹽 (襯壓鏇蓋襯鬱齋鑰構觸, 13.79) 更多