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)

Start Date28 Jun 2022

Sponsor / Collaborator

Terns, Inc.

NCT04328077

/ CompletedPhase 2

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.

Start Date18 Jun 2020

Sponsor / Collaborator

Terns, Inc.

NL-OMON32962

/ CompletedNot Applicable

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

Start Date06 Aug 2009

Sponsor / Collaborator-

100 Clinical Results associated with LY-2562175

100 Translational Medicine associated with LY-2562175

100 Patents (Medical) associated with LY-2562175

456

Literatures (Medical) associated with LY-2562175

01 May 2025·PHYTOMEDICINE

Liang-Ge-San attenuates virus-induced acute lung injury by targeting FXR-mediated ACE2 downregulation to modulate the formation of the cytokine storm

Article

Author: Yu, Linzhong ; Tan, Weifu ; Li, Wei ; He, Jiayang ; Yang, Guangli ; Yang, Liling ; Liu, Junshan ; Yu, Jingtao ; Zhou, Xiangjun ; Ma, Qinhai ; Fang, Xiaochuan ; Lu, Zibin

BACKGROUND:

Traditional Chinese medicine has been recognized for its significant role in treating acute lung injury (ALI) due to its distinct therapeutic advantages. Liang-Ge-San (LGS), a formulation from the ancient "Taiping Huimin Hejiju Fang", is believed to possess beneficial effects for treating ALI. However, LGS's precise mechanisms and efficacy in addressing viral ALI remain inadequately explored.

PURPOSE:

To evaluate LGS's therapeutic effects and underlying mechanisms in treating viral-induced ALI.

METHODS:

The protective effects of LGS were examined in a Polyinosinic-polycytidylic acid [Poly(I:C)]-induced ALI model using real-time quantitative PCR, enzyme-linked immunosorbent assay, and histopathological analysis. A bioinformatics approach combined with network pharmacology was utilized to ascertain the key targets of LGS in viral pneumonia. The pharmacodynamic mechanisms of LGS in viral ALI were further validated through immunofluorescence, overexpression, short hairpin RNA, chromatin immunoprecipitation, and target agonist assays.

RESULTS:

LGS administration resulted in a reduction of IL-1β, IL-6, and TNF-α levels, along with a decrease in macrophage infiltration, pulmonary damage, and pneumonedema following the Poly(I:C) challenge. Bioinformatics and network pharmacology analyses suggested that Farnesyl X receptor (FXR) and angiotensin converting enzyme 2 (ACE2) are potential therapeutic targets for LGS in viral pneumonia. Further experiments revealed that LGS suppressed the expression of FXR, ACE2, and NF-κB-p65 in Poly(I:C)-infected cells. Notably, overexpression of FXR counteracted the repressive effects of LGS, while ACE2 expression remained unchanged in FXR-knockdown RAW264.7 cells upon treatment with Poly(I:C) or LGS. Additionally, LGS inhibited the interaction between FXR and ACE2 transcriptional promoters. In vivo, LGS attenuated the Poly(I:C)-induced upregulation of FXR, ACE2, IL-1β, IL-6, and TNF-α in ALI zebrafish and mice models, effects that could be reversed by chenodeoxycholic acid (CDCA), an FXR agonist. Moreover, LGS markedly alleviated weight loss, improved survival rates, reduced lung index, diminished viral load, and inhibited lung pathological changes in H1N1-PR8-induced ALI mice. IL-1β, IL-6, TNF-α, INF-γ, FXR, ACE2, small heterodimer partner, and NF-κB-p65 levels were markedly reduced by LGS, with these effects being reversed by CDCA.

CONCLUSION:

This investigation provides the first evidence that FXR/ACE2 signaling is pivotal in acute respiratory viral infections, while LGS demonstrates antiviral activity against viral-induced ALI. LGS inhibits ACE2 expression induced by viral infection via FXR inhibition and modulates the cytokine storm, thus alleviating viral ALI. These findings suggest that LGS may be a promising treatment strategy for treating viral ALI.

01 May 2025·JHEP Reports

A novel in vitro system for simultaneous infections with hepatitis B, C, D and E viruses

Article

Author: Diaz, Olivier ; Meuleman, Philip ; Wedemeyer, Heiner ; Michelet, Maud ; Salvetti, Anna ; Durantel, David ; Verrier, Eloi R ; Passot, Guillaume ; Verhoye, Lieven ; Doceul, Virginie ; Pons, Caroline ; De Meyer, Amse ; Fouillé, Roxanne ; Rivoire, Michel ; Pavio, Nicole ; Steinmann, Eike ; Lucifora, Julie ; Darteil, Raphaël ; Barnault, Romain

Background & Aims:

The liver, and more precisely hepatocytes, can be infected by several hepatotropic viruses, including HBV, HDV, HCV and HEV, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on their interplay as well as on the potential cross-reactivity of antivirals in multi-infection cases. The aim of our study was to set up such a model.

Methods:

HuH7.5-NTCP cells were cultured with 2% DMSO (dimethyl sulfoxide) for 1 week to allow partial differentiation into hepatocytes (dHuH7.5-NTCP) before infection with the different viruses and treatment with known antiviral molecules.

Results:

We observed increased expression of liver specific transcripts and production of ApoB containing VLDL in dHuH7.5-NTCP cells and replication of HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. We recapitulated the known antiviral effect of sofosbuvir on HCV and HEV (>90% reduction in the levels of intracellular viral RNAs, p <0.0005) and of IFN-α on HCV, HEV and HDV (80% reduction in the levels of intracellular viral RNAs, p <0.0005). Besides its already described antiviral effect on HBV and HDV, we observed that GW4064, a farnesoid X receptor (FXR) agonist, also strongly inhibited HEV replication (85 to 95% reduction in the levels of intracellular HEV RNAs, p <0.0005). Using HEV-infected HuHep mice, we confirmed the antiviral effect of vonafexor, an FXR agonist, that is currently being tested clinically against HBV/HDV.

Conclusions:

We set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening and highlighted FXR ligands as potential broad-acting antivirals.

Impact and implications:

Hepatitis virus infections caused by HBV, HCV, HDV, and HEV represent a global health threat. Treatment options remain limited, notably due to the lack of knowledge about molecular virus-host interactions. Moreover, the interplay between these four viruses in the context of co-infections remains unknown. In this study, we report the first in vitro system that allows for mono and multi-infections with these four viruses and characterize the broad antiviral activity of farnesoid X receptor agonists, paving the way for the development of new strategies for viral cure.

01 Apr 2025·Immunity Inflammation and Disease

Farnesoid X Receptor Regulated Sepsis‐Induced Abnormal Bile Acid Metabolism via the Fibroblast Growth Factor 15/Fibroblast Growth Factor Receptor 4 Pathway

Article

Author: Tang, Jianguo ; Huang, Liou ; Cui, Yuhui ; Xu, Dan ; Zhou, Ziyang ; Chen, Hui

Abstract:

Objective:

The study aims to investigate the mechanism of Farnesoid X receptor (FXR) activation in sepsis‐induced abnormal bile acid metabolism and the metabolism status of each bile acid type.

Methods:

The sepsis mouse model was developed via lipopolysaccharide intraperitoneal injection and confirmed via hematoxylin and eosin (H&E) staining. FXR agonist activated the FXR/fibroblast growth factor (FGF)15/FGFR pathway via quantitative real‐time polymerase chain reaction and Western blot. Consequently, metabolomics and bioinformatics analysis were conducted to identify the alterations in each kind of bile acid content following FXR agonist/inhibitor intervention.

Results:

The H&E staining indicated that FXR activation alleviates the liver injury of the sepsis mouse model. The increased FGF15 and FXFR expression levels and decreased CYP7A1 demonstrated FXR/FGF15/FGFR pathway activation following FXR agonist treatment. Furthermore, total bile acid, interleukin (IL)‐6, and tumor necrosis factor‐α concentrations were downregulated after FXR activation, whereas IL‐10 concentration was upregulated, indicating the alleviated effect of FXR agonist in sepsis. Consequently, metabolomics and bioinformatics analysis determined that T‐a‐MCA were downregulated in both FXR agonist and inhibitor groups, whereas six bile acid types were altered in the control group.

Conclusion:

FXR activation was crucial in alleviating sepsis‐induced hepatic injury and cholestasis through the FGF15/FGFR signaling pathway, and FXR may act as a potential preventive and intervention target of sepsis.

141

News (Medical) associated with LY-2562175

26 Feb 2025

·www.fiercebiotech.com

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.

Drug ApprovalAccelerated Approval

26 Feb 2025

·www.pharmaceutical-technology.com

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.

Clinical ResultPhase 2Drug ApprovalOligonucleotidePhase 1

25 Feb 2025

·endpts.com

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.

Phase 2Phase 3Clinical ResultClinical Trial Failure

100 Deals associated with LY-2562175

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10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	United States	Terns, Inc.	18 Jun 2020
Cholangitis	Phase 1	United States	Terns Pharmaceuticals, Inc.	17 Jul 2019
Dyslipidemias	Preclinical	United States	Eli Lilly & Co.	24 Dec 2015

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05415722 (DUET, CTgov)	Phase 2	Nonalcoholic Steatohepatitis	162	TERN-501 (Arm 1: TERN-501 1 mg)	secxhlpwof(vcgbktifvj) = tawqszatdn birlcspace (zkydoueteb, 5.186) View more	-	12 Mar 2025
NCT05415722 (DUET, CTgov)	Phase 2	Nonalcoholic Steatohepatitis	162	TERN-501 (Arm 2: TERN-501 3 mg)	secxhlpwof(vcgbktifvj) = znzcecfntz birlcspace (zkydoueteb, 5.740) View more	-	12 Mar 2025
NCT04328077 (LIFT, EASL2022)	Phase 2	Nonalcoholic Steatohepatitis	100	TERN-101 15 mg	zyjchlywvy(mrelcucwow) = Pruritus AEs (including pruritic rash) were reported in 11 of 74 (14.8%) patients receiving TERN-101 and none receiving placebo. Onset of pruritus ranged from Day 2 to Day 73. Pruritus resolved with ongoing TERN-101 treatment for 8 of 11 patients. All events were mild or moderate (Grade 1 – 2), with incidence overall balanced across TERN-101 groups. Grade 2 pruritus occurred in two 10 mg patients (generalized pruritus) and one 15 mg patient (pruritus localized to bilateral forearms). No patient discontinued TERN-101 due to pruritus. fhpinxdeci (sfwiilrmzl )	Positive	25 Jun 2022
NCT04328077 (LIFT, CTgov)	Phase 2	Nonalcoholic Steatohepatitis	101	Placebo	xtzdbebxeg = wlnohuhoup gxxdnipdbe (tqzlhqmlno, brqqcolmfs - dehbnqsewo) View more	-	14 Jun 2022
NCT04328077 (LIFT, NASH_TAG2022)	Phase 2	Nonalcoholic Steatohepatitis MRI-PDFF	100	TERN-101 5 mg	xskmulbgol(acymjyfbwl) = qqryrenmad fpebrcdpfp (pirdeapvwa ) View more	Positive	06 Jan 2022
NCT04328077 (LIFT, NASH_TAG2022)	Phase 2	Nonalcoholic Steatohepatitis MRI-PDFF	100	TERN-101 10 mg	xskmulbgol(acymjyfbwl) = qqpbdkszni fpebrcdpfp (pirdeapvwa ) View more	Positive	06 Jan 2022
MET642 (NASH_TAG2021)	Phase 1	7Î±-hydroxy-4-cholesten-3-one (C4)	-	MET642	obvmvlkffs(oorzphyqvm) = There were no serious adverse events, and all adverse events were mild-moderate in severity. MET642 did not increase serum low-density lipoprotein cholesterol (LDL-C) or cause generalized pruritus lnhgywdxnx (bsqkmccqdu ) View more	Positive	12 Mar 2021
NASH_TAG2021	Phase 2	Nonalcoholic Steatohepatitis 7-alpha-hydroxy-4-cholesten-3-one \| FXR pathway genes	-	TERN-101 (10 mg/kg)	eyukugskde(ubgcnxzicw) = iquggyofli xfljutivid (bqosyjhiki, p<0.01) View more	Positive	12 Mar 2021
NASH_TAG2021	Phase 2		-	OCA (30 mg/kg)	eyukugskde(ubgcnxzicw) = eztuuyqpxv xfljutivid (bqosyjhiki, p<0.05) View more	Positive	12 Mar 2021

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