A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2a Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as Well as in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (NASH)

This is a Phase 2a Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as well as in Combination with TERN-101 in Noncirrhotic Adults with Presumed Non-Alcoholic Steatohepatitis (NASH)

开始日期2022-06-28

申办/合作机构

Terns, Inc.

NCT04328077

/ Completed临床2期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2a Clinical Trial to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Orally Administered TERN-101 Tablets in Adult Patients With Presumed Non-Cirrhotic Non-Alcoholic Steatohepatitis (NASH)

This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics (PK) of TERN-101 in non-cirrhotic NASH patients.

开始日期2020-06-18

申办/合作机构

Terns, Inc.

NL-OMON32962

/ CompletedN/A

A MULTIPLE ASCENDING DOSE PHARMACOLOGY, FOOD EFFECT AND DRUG INTERACTION STUDY OF LY2562175 IN HEALTHY ADULT SUBJECTS - LY2562175 MAD/DDI/FE study

开始日期2009-08-06

申办/合作机构-

100 项与 LY-2562175 相关的临床结果

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100 项与 LY-2562175 相关的转化医学

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100 项与 LY-2562175 相关的专利（医药）

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452

项与 LY-2562175 相关的文献（医药）

2025-03-01·Journal of Biological Chemistry

FXR-ApoC2 pathway activates UCP1-mediated thermogenesis by promoting the browning of white adipose tissues

Article

作者: Kwak, Hyun Jeong ; Kim, Sang Hee ; Park, Ja Yeon ; Um, Jae-Young ; Jung, Se Jin ; Ahn, Kwang Seok ; Song, Gahee ; Park, Woo Yong ; Kim, Beomsu ; Jiao, Wenjun ; Kim, Jin-Hyung

FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.

2025-02-01·FEBS Open Bio

FXR activation reduces the formation of macrophage foam cells and atherosclerotic plaque, possibly by down regulating hepatic lipase in macrophages

Article

作者: Shen, Li Li ; Liu, Jia ; Gu, Qiang

Macrophages are the most important immune cells affecting the formation of atherosclerotic plaque. Nevertheless, the mechanisms that promote formation of foamy macrophages during atherogenesis remain poorly understood. This study explored the effects of Farnesoid X receptor (FXR) and hepatic lipase (HL, encoded by LIPC) on atherogenesis, particularly in foamy macrophage formation. A luciferase reporter assay indicated that FXR could bind to the LIPC promoter and inhibit LIPC transcription. FXR agonist GW4064 decreased HL expression, foam cell formation, and increased the expression of FXR downstream genes and polarization to M2 in ox‐LDL‐induced THP‐1 and U937 foam cells. In addition, GW4064 exerted anti‐atherosclerotic effects in ApoE−/− mice, manifested as decreased serum cholesterol and triglyceride levels, and alleviated atherosclerotic plaque formation. Collectively, FXR exerted anti‐atherosclerotic effects, possibly by negatively regulating HL expression in macrophages.

2025-02-01·European Journal of Pharmacology

Role of 11β-hydroxysteroid dehydrogenase type 1 inhibition in the antiobesity effect of J2H-1702 on adipocytes and a high-fat diet-induced NASH model

Article

作者: Eom, Dae-Woon ; Kang, Hyo Jin ; Ham, Dayeon ; Lee, Dahae ; Lee, Jaemin ; Kang, Ki Sung ; Cho, Jaejin ; Jung, Kiwon ; Lee, Ju Young ; Kim, Jason

Obesity due to excessive body fat accumulation remains a global problem. Patients with obesity have high cortisol levels, and its dysregulation is caused by increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) levels. The effects and mechanism of J2H-1702, an 11β-HSD1 inhibitor, on nonalcoholic steatohepatitis (NASH) were explored. This study compared the antiadipogenic effects of J2H-1702, elafibranor (PPARα/δ agonist), and BVT14225 (selective 11β-HSD1 inhibitor) using mouse 3T3-L1 pre-adipocytes. J2H-1702, elafibranor, and BVT14225 inhibited adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells by downregulating phospho-extracellular signal-regulated kinase, extracellular signal-regulated kinase, phospho-c-Jun-N-terminal Kinase, c-Jun-N-terminal Kinase, phospho-P38 (P-P38), P38, CCAAT/enhancer-binding proteins alpha and β, peroxisome proliferator-activated receptor γ, and glucocorticoid receptor. Additionally, J2H-1702, elafibranor, and BVT14225 treatments effectively inhibited 11β-HSD1 activity, as revealed by cortisol concentrations, and inhibited cortisone-induced adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells. These effects were associated with 11β-HSD1 protein inhibition. Furthermore, J2H-1702 and BVT14225 increased the expression of Akt and phosphoinositide 3-kinase involved in insulin resistance in 3T3L-1 adipocytes. In the LX-2 human hepatic stellate cell line, the relative expression of N-cadherin, 11β-HSD1, collagen1α (COLA1), α-actin of smooth muscle (α-SMA) genes in LX-2 activated with TGF-β increased significantly, and after treatment with J2H-1702, it was significantly reduced. The expression of E-cadherin is decreased in TGF-β-treated LX-2 cells and increased after treatment with J2H-1702. We tested the potential of J2H-1702 as a therapeutic agent for NASH using a high-fat diet-induced NASH model, with obeticholic acid, an FXR agonist, and elafibranor as reference drugs. All drugs significantly decreased the elevated triglyceride levels in the livers of high-fat, high-carbohydrate (HFHC-fed mice. The results may add to the benefits of targeting 11β-HSD1 inhibitors with antiadipogenic activity in developing a therapeutic agent for obesity treatment.

148

项与 LY-2562175 相关的新闻（医药）

2025-02-26

·FierceBiotech

Eli Lilly buys Organovo\'s FXR program for $10M, sending biotech\'s stock skyrocketing 244%

Organovo\'s stock skyrocketed 244%—welcome news for the company as it faces Nasdaq delisting.\n Eli Lilly has acquired Organovo’s lead asset, a clinical FXR agonist designed to treat inflammatory bowel disease (IBD), in a deal worth up to $50 million in biobucks. Organovo’s stock skyrocketed 244% Tuesday on the news. The deal sees Lilly pay out $9 million upfront plus another $1 million after 15 months to the San Diego biotech, according to Securities and Exchange Commission (SEC) documents filed Feb. 25.Lilly is also offering Organovo the chance to bank potential milestone payments up to $50 million, according to the SEC filing.In exchange, the Big Pharma has acquired all commercial and intellectual property rights to Organovo’s FXR program. This includes lead candidate FXR314, an oral investigational med that the biotech was assessing in a phase 2/3 IBD trial and touted as phase 2-ready in liver fibrosis.The asset also has potential applications in metabolic diseases and oncology, according to the biotech. FXRs, short for farnesoid X receptors, are nuclear receptors mainly expressed in the liver and intestine. FXR agonists are synthetic compounds thought to hold potential across several gastrointestinal (GI) diseases. However, the drug class has faced several setbacks, namely for Intercept Pharmaceuticals. The company was testing its own FXR agonist for metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by liver inflammation and damage tied to a buildup of fat in the liver.The FDA rejected Intercept’s drug, dubbed Ocaliva or obeticholic acid, for patients with MASH after raising concerns over the drug’s modest efficacy and range of safety problems. That 2023 rejection was the second time the federal agency denied approval for Intercept’s drug in the indication.While Intercept abandoned its MASH plans, the company had secured accelerated approval for Ocaliva in primary biliary cholangitis back in 2016. Last fall, however, the FDA denied Intercept\'s ask for a full nod in the rare liver disease. Earlier, 13 outside experts had voted against the full approval, saying Ocaliva’s clinical benefit wasn’t adequately proven. As for Organovo, FXR314 was developed after being tested in 3D human tissues designed to mimic aspects of human tissue composition, function and disease. “This is a significant milestone for our efforts to advance medicines for IBD using insights from our proprietary 3D human tissue models,” Organovo CEO Keith Murphy said in a press release. “We are excited to deliver FXR314 and our FXR program to Lilly for phase 2 and further development.”The biotech’s stock skyrocketed 244% since the news was announced, although from a low base: rising from just 36 cents at market close on Feb. 24 to $1.27 per share at market close on Feb. 25.This is welcome news, as the biotech had faced the prospect of delisting for the last several months since it was unable to maintain the Nasdaq’s minimum of $1 per share. The company initially had until Jan. 16 to regain compliance but has requested a hearing to delay delisting or suspension.

$Eli Lilly buys Organovo\'s FXR program for $10M, sending biotech\'s stock skyrocketing 244%$

上市批准加速审批

2025-02-26

·Pharmaceutical Technology

Eli Lilly pays $10m upfront for Organovo’s FXR agonist

IBD is a group of inflammatory conditions of the colon and small intestine. Credit: Elena Vafina via Getty Images. Eli Lilly (Lilly) has agreed to make a $10m upfront payment for full worldwide rights to San Diego-based Organovo Holdings’ farnesoid X receptor (FXR) agonist programme, aimed at treating inflammatory bowel disease (IBD). Under the deal, Lilly will pay $10m upfront and up to $50m in milestones, as per a Securities and Exchange Commission (SEC) filing, for rights to the programme that includes a Phase II asset trialled for ulcerative colitis (UC) and metabolic dysfunction-associated steatohepatitis (MASH). Following the 25 February announcement, Organovo’s shares surged, closing 243% higher that day. The company’s lead asset, dubbed FXR314, is central to the agreement. FXR314 acts on the FXR, a nuclear hormone receptor that plays a key role in carbohydrate and lipid metabolism, insulin sensitivity regulation, and liver regeneration during injury. Organovo presented Phase II trial (NCT04773964) data for FXR314 in MASH in November 2024. Results showed a statistically significant reduction in liver fat content compared to placebo, with the highest dose achieving a 22.8% mean reduction compared to 6.1% in the placebo group. A greater proportion of patients receiving FXR314 also achieved more than a 30% reduction in liver fat. Additionally, the drug demonstrated a favourable safety profile. At the time of the MASH data release last year, Organovo expressed enthusiasm about continuing FXR314’s development in MASH. However, in its announcement with Lilly, the company only mentions its focus on IBD. A Phase II trial in IBD is planned, with initiation expected in Q4 2025. Organovo has previously said it sees potential for FXR314 in metabolic liver disease and oncology. These findings are surprising because FXR agonism as a therapeutic approach for MASH has faced significant hurdles. Intercept Therapeutics’ efforts with FXR agonist Ocaliva (obeticholic acid) ended in disappointment when the US Food and Drug Administration (FDA) rejected the drug for MASH in 2023, forcing the company to cut a third of its workforce. A second FDA rejection last year – this time for primary biliary cholangitis (PBC) – further solidified the challenges of FXR-targeting drugs in liver disease. Alternative mechanisms of action have since gained traction in MASH treatment. Madrigal Pharmaceuticals’s Rezdiffra (resmetirom), a small molecule THRB agonist, was the first drug approved by the FDA for the illness in March 2024. In addition, Eli Lilly announced earlier this month that it is paying $630m for South Korea-based biotech OliX Pharmaceuticals’ antisense RNAi oligonucleotide OLX75016 to treat MASH.

临床结果临床2期上市批准寡核苷酸临床1期

2025-02-25

·Endpoints

Lilly pays $10M upfront for Organovo’s FXR agonist program

Eli Lilly is buying Organovo’s farnesoid X receptor (FXR) agonist program, which includes a drug in Phase 2 development for ulcerative colitis and metabolic dysfunction-associated steatohepatitis (MASH), the biotech said Tuesday . The drugmaker will pay $9 million upfront plus $1 million in 15 months and up to $50 million in milestones, according to an SEC filing . Lilly is obtaining all worldwide rights to the program. Organovo’s share price $ONVO nearly tripled in early trading on Tuesday. The deal is remarkable because Intercept Pharmaceuticals’ attempts to pursue this mechanism in MASH ended in grave disappointment. The FDA rejected the company’s treatment, called Ocaliva, for the fatty liver disease — which used to be called NASH — in 2020 . A subsequent Phase 3 trial failed too . Since then, FXR agonism has been superseded as a MASH approach by other mechanisms like thyroid hormone receptor beta agonism (used by Madrigal’s approved Rezdiffra and Viking Therapeutics’ experimental VK2809, among others) and FGF21 agonism (used by assets which include Akero’s efruxifermin and 89bio’s pegozafermin). That said, it’s not clear that Lilly intends to pursue Organovo’s asset, called FXR314, in MASH. The only indication mentioned in Organovo’s statement is inflammatory bowel disease, and Lilly has not commented. However, Organovo has trialed the drug in the disorder. The company presented Phase 2 data in November that showed statistically significant reductions versus placebo in liver fat, a commonly used biomarker in early MASH trials. According to its website , it was actively seeking a partner for this indication.

临床2期临床3期临床结果临床失败

100 项与 LY-2562175 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16045

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非酒精性脂肪性肝炎	临床2期	美国	Terns, Inc.	2020-06-18
胆管炎	临床2期	美国	Terns Pharmaceuticals, Inc.	2019-07-17
血脂障碍	临床2期	美国	Eli Lilly & Co.	2015-12-24

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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


NCT05415722 (DUET, CTgov)	临床2期	非酒精性脂肪性肝炎	162	TERN-501 (Arm 1: TERN-501 1 mg)	觸夢夢繭鬱膚憲夢選鹹(鬱衊觸襯壓齋願積餘衊) = 鹽選襯壓簾廠顧鹹願鑰鏇壓遞廠選襯襯膚膚艱 (鬱淵網構網鬱齋鏇顧繭, 築範鹽壓簾壓網鏇壓願 ~ 簾鹽艱選鏇顧鏇壓觸蓋) 更多	-	2025-03-12
				TERN-501 (Arm 2: TERN-501 3 mg)	觸夢夢繭鬱膚憲夢選鹹(鬱衊觸襯壓齋願積餘衊) = 壓繭觸築艱衊鑰蓋繭簾鏇壓遞廠選襯襯膚膚艱 (鬱淵網構網鬱齋鏇顧繭, 積繭廠艱鬱淵壓夢鏇艱 ~ 選觸廠鏇廠鏇鏇鹽餘餘) 更多
NCT05415722 (DUET, GlobeNewswire) 人工标引	临床2期	非酒精性脂肪性肝炎	-	TERN-501	(膚蓋選夢艱積鹹衊襯鏇) = 鹹簾鏇構衊餘齋鑰餘鏇願衊遞夢壓齋觸壓衊憲 (鏇壓鏇膚鏇齋鹽壓艱觸 )	积极	2023-11-13
				TERN-501	(膚蓋選夢艱積鹹衊襯鏇) = 鏇積繭憲鏇選製繭憲鏇願衊遞夢壓齋觸壓衊憲 (鏇壓鏇膚鏇齋鹽壓艱觸 )
NCT04328077 (LIFT, CTgov)	临床2期	非酒精性脂肪性肝炎	101	Placebo	鬱積顧簾製觸艱醖鏇觸(鬱願壓網壓鹽壓齋鏇艱) = 簾鹽糧製鑰構壓蓋衊鹹憲遞鬱艱糧選襯積獵獵 (膚鏇憲簾簾窪簾糧簾願, 衊艱艱憲鬱獵淵夢構鏇 ~ 鹹鹽選範夢網鏇齋製積) 更多	-	2022-06-14
NASH_TAG2021	临床2期	非酒精性脂肪性肝炎 7-alpha-hydroxy-4-cholesten-3-one \| FXR pathway genes	-	TERN-101 (10 mg/kg)	積鏇築夢鑰獵膚壓鬱願(蓋顧襯壓齋膚壓鬱鹹觸) = 窪網鹹鏇蓋遞鏇襯壓鑰顧鏇簾製範壓網鏇顧襯 (齋積範選鏇廠簾齋遞鹹, p<0.01) 更多	积极	2021-03-12
				OCA (30 mg/kg)	積鏇築夢鑰獵膚壓鬱願(蓋顧襯壓齋膚壓鬱鹹觸) = 繭衊廠網繭醖積齋選鹹顧鏇簾製範壓網鏇顧襯 (齋積範選鏇廠簾齋遞鹹, p<0.05) 更多