[Translation] A randomized, double-blind, parallel-group, multicenter study to evaluate the efficacy, safety, and tolerability of oral tropifexor (LJN452) and licogliflozin (LIK066) combination therapy versus monotherapy versus placebo in adult subjects with nonalcoholic steatohepatitis (NASH) and fibrosis (ELIVATE)

本研究的目的为根据NASH临床研究网络（CRN）组织学评分，在伴肝纤维化（2期或3期）的NASH受试者中比较tropifexor和licogliflozin联合治疗、各单药治疗与安慰剂组治疗的疗效、安全性和耐受性。

[Translation]

The aim of this study was to compare the efficacy, safety, and tolerability of tropifexor plus licogliflozin, each agent alone, and placebo in subjects with NASH and fibrosis (stage 2 or 3) according to the NASH Clinical Research Network (CRN) histology score.

Start Date21 Jul 2021

Sponsor / Collaborator

Aptuit (Verona) Srl

[+3]

NCT04147195 / TerminatedPhase 2

NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype

This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.

Start Date04 Jun 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT04408937 / CompletedPhase 1

A Randomized, Investigator and Subject Blinded, Multicenter, Parallel-arm Study to Determine the Safety and Tolerability of Tropifexor.

The purpose of this study is to determine whether dosing tropifexor is safe and tolerable.

Start Date29 May 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Tropifexor

100 Translational Medicine associated with Tropifexor

100 Patents (Medical) associated with Tropifexor

Literatures (Medical) associated with Tropifexor

01 Mar 2024·European journal of pharmacology

Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the glutamine metabolism and urea cycles in cholestatic livers

Article

Author: Cai, Wei ; Lu, Ying ; Du, Jun ; Xiao, Yongtao ; Peng, Shicheng ; Wang, Weipeng

Hyperammonemia refers to elevated levels of ammonia in the blood, which is an important pathological feature of liver cirrhosis and hepatic failure. Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia significantly elevated in patients with biliary atresia (BA) and was positively correlated with liver injury. Targeted metabolomics and immunblotting showed glutamine metabolism and urea cycles were impaired in BA patients. Next, we observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries in liver and brain with improving the glutamine metabolism and urea cycles. Within the liver, TXR enhances glutamine metabolism and urea cycles by up-regulation of key regulatory enzymes, including glutamine synthetase (GS), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers.

01 Oct 2023·Hepatology (Baltimore, Md.)

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study

Article

Author: Gadano, Adrian C ; Kochuparampil, Jossy ; Rodriguez-Araujo, Gerardo ; Martic, Miljen ; Sanyal, Arun J ; Lucas, Kathryn J ; Sarin, Shiv K ; Pedrosa, Marcos C ; Lazas, Donald ; Loomba, Rohit ; Naoumov, Nikolai V ; Schattenberg, Jörn M ; Brass, Clifford ; Anstee, Quentin M ; Yilmaz, Yusuf ; Stringer, Rowan ; Rinella, Mary ; Noureddin, Mazen ; Francque, Sven ; Charlton, Michael ; Goh, George B B ; Mena, Edward ; Ratziu, Vlad ; Abdelmalek, Manal F ; Chen, Li ; Chng, Elaine

Background and Aims::

With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies.

Approach and Results::

Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: −21%, TXR140; −16%, TXR140 + CVC; −13%, TXR90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR140, −2.5 kg; TXR140 + CVC, −1.7 kg; TXR90 + CVC, −1.0 kg; and CVC, −0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC, and TXR90 + CVC groups, respectively.

Conclusions::

The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

01 Oct 2023·Hepatobiliary surgery and nutrition

Tropifexor, a selective non-acid farnesoid X receptor agonist, improved nonalcoholic steatohepatitis in a phase 2 trial, but several issues remain to be resolved.

Communications

Author: Nakajima, Atsushi ; Kobayashi, Takashi ; Yoneda, Masato ; Iwaki, Michihiro ; Otani, Tomohiro ; Nogami, Asako ; Wada, Naohiro

News (Medical) associated with Tropifexor

26 Jun 2023

·www.prnewswire.com

Ascletis Announces Poster Presentation of Phase II Study of ASC42 FXR Agonist for Functional Cure of Chronic Hepatitis B at EASL CONGRESS 2023

HANGZHOU and SHAOXING, China, June 25, 2023 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX:1672, "Ascletis") today announces the poster presentation of ASC42, a novel farnesoid X receptor (FXR) agonist, in combination with PEGylated interferon (PEG-IFN) and entecavir (ETV) in chronic hepatitis B (CHB) patients with 12-week treatment at European Association for the Study of the Liver (EASL) CONGRESS 2023. The summary of the abstract is shown as below: Title: A phase 2 study of ASC42, a novel farnesoid X receptor (FXR) agonist, in combination with PEGylated interferon (PEG-IFN) and entecavir (ETV) in chronic hepatitis B patients with 12-week treatment Presenter: Jinzi J. Wu, Ph.D. Principal Investigator: Prof. Jinlin Hou, Nanfang Hospital of Southern Medical University Poster Number: SAT-201 Category: Viral Hepatitis B and D Study Design: This Phase 2 trial (NCT05107778) was a multi-center, randomized, single-blind, placebo-controlled study conducted in China. Forty-three HBeAg negative, hepatitis B virus (HBV) DNA Results: In total, 122, 119, and 107 adverse events (AEs) were reported in 10 mg ASC42, 15 mg ASC42 and PBO cohorts, respectively, and most AEs (94.3%) were mild (grade 1) or moderate (grade 2) in severity. One subject in 15 mg ASC42 cohort experienced a grade 3 serious AE (SAE) of liver function injury with a final outcome of recovered. Pruritus is the most common AE, and study drug-related pruritus was reported in 1 (6.7%), 7 (50%) and 0 (0%) subjects in 10 mg ASC42, 15 mg ASC42 and PBO cohorts, respectively. Pruritus rate of 10 mg ASC42 (6.7%) is lower than other FXR agonists in non-alcoholic steatohepatitis (NASH) patients. Conclusion: In CHB patients, 12-week treatment of 10 mg ASC42 in combination of PEG-IFN-α-2a and ETV was safe and well-tolerated and showed minimum and mild pruritus (6.7%). Previous study indicated that in healthy subjects, 14-day treatment of ASC42 alone demonstrated 471%~1,780% increase of fibroblast growth factor 19 (FGF19) and 53%~91% decrease of 7α-hydroxy-4-cholesten-3-one (C4) at a dose range of 5 mg~15 mg. Data suggest that at the therapeutic dose of 10 mg, the novel FXR agonist ASC42 is differentiated from other FXR agonists in terms of pruritus. [1]. Data on file [2]. Younossi Z.M., Ratziu V., Loomba R., et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial [J]. The Lancet, 2019, 394(10215): 2184-96.DOI: 10.1016/s0140-6736(19)33041-7 [3]. Lau G.K., Piratvisuth T., Luo K.X., et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B [J]. N Engl J Med, 2005, 352(26): 2682-95.DOI: 10.1056/NEJMoa043470 [4]. Loomba R., Noureddin M., Kowdley K.V., et al. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH [J]. Hepatology, 2021, 73(2): 625-43.DOI: 10.1002/hep.31622 [5]. Anstee Q.M., Lucas K.J., Francque S., et al. Tropifexor plus cenicriviroc combination versus monotherapy in non-alcoholic steatohepatitis: Results from the Phase 2b TANDEM study [J]. Hepatology, 2023.DOI: 10.1097/hep.0000000000000439 About EASL EASL, the European Association for the Study of the Liver, founded in 1966, is a medical association dedicated to pursuing excellence in liver research, to the clinical practice of liver disorders, and to providing education to all those interested in hepatology. As of 2022, EASL serves 4,900 members from 112 countries. About Ascletis Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to manufacturing and commercialization. Led by a management team with deep expertise and a proven track record, Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has three marketed products, i.e. ritonavir tablets, GANOVO® and ASCLEVIR®, and 23 drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (HBV functional cure), ASC10 and ASC11(oral small molecules for COVID-19 treatment), ASC40 (recurrent glioblastoma), ASC42 (PBC, primary biliary cholangitis), and ASC40 (acne). For more information, please visit . SOURCE Ascletis Pharma Inc.

Clinical ResultPhase 2Phase 3

24 Feb 2023

·www.fiercebiotech.com

Novartis punts Pliant-partnered NASH prospect amid pipeline prioritization pivot

Walking away from PLN-1474 continues Novartis’ retreat from nonalcoholic steatohepatitis. Novartis is nixing a nonalcoholic steatohepatitis (NASH) candidate amid a narrowing of its therapeutic focus, walking away from a Pliant Therapeutics program it paid $50 million for back in 2019. Over the past 10 months, Novartis has formed a new organizational structure focused on five core therapeutic segments: cardiovascular, hematology, solid tumors, immunology and neuroscience. While the Swiss drugmaker may pursue other therapeutic areas opportunistically, most of its R&D dollars will go into its core areas. NASH, once the subject of a big push by Novartis, is no longer a neat fit for its focus. Pliant has paid the price for Novartis’ pipeline rethink. Late Thursday, the biotech revealed Novartis has decided to terminate its agreement “as part of its new strategy focusing on a limited number of therapeutic areas.” The agreement covered PLN-1474, a small molecule selective inhibitor of integrin αvß1. Novartis paid $50 million upfront, and made an investment in Pliant, to secure rights to the then-preclinical prospect and candidates against up to three additional integrin research targets. Last year, Novartis paid another $4 million to license compounds associated with an integrin research target. Walking away from PLN-1474 continues Novartis’ retreat from NASH. The Big Pharma licensed LLF580, an FGF21 stimulator, to Boston Pharmaceuticals in 2020, as well as dropping its FXR agonist tropifexor from the pipeline last year. The phase 1 candidate FIA586 is now the last Novartis NASH asset standing. But, with Pliant saying Novartis plans to “divest clinical NASH assets,” that prospect could also be on the way out. Novartis’ nixing of PLN-1474 comes weeks after CEO Vas Narasimhan, M.D., said he was “streamlining the pipeline” and told analysts to expect to see the company “exiting additional assets as we really try to prune out non-core areas.” The pruning is intended to allow Novartis to put all its “scientific firepower and ingenuity towards building out a deep set of pipeline assets” in its five core areas, Narasimhan said. Pliant exits the deal having received $79 million from Novartis but without pocketing most of the $416 million in milestones covered by the deal. The biotech has added PLN-1474 back into its wholly owned pipeline—describing it as phase 2 ready—and expects to post phase 2 data on bexotegrast, its lead drug, in idiopathic pulmonary fibrosis and primary sclerosing cholangitis this year.

Phase 1Phase 2License out/inPROTACs

24 Feb 2023

·www.biospace.com

Novartis Culls Pliant-Partnered NASH Program in Pipeline Sweep

Courtesy of Harold Cunningham/Getty Images Novartis is trimming the fat in 2023. The Swiss pharma announced yet another program cut, this time for nonalcoholic steatohepatitis (NASH). After inking a collaboration in 2019, Novartis exercised its option to scoop up Pliant Therapeutics’ small molecule αvß1 inhibitor for NASH after a completed Phase I study. But now it is returning the program to Pliant, cutting its losses on the $79 million it has already paid to its now ex-partner, according to an SEC filing dated Feb. 17. In the filing, Novartis pointed to its “new strategy focusing on a limited number of therapeutic areas” as its reason for dropping the program. While Novartis might be done with PLN-1474, Pliant isn’t. The company is evaluating options for the program, “including another partnership... for this Phase II ready asset,” Chris Keenan, VP of corporate communications, Pliant told BioSpace. With an excellent safety and PK profile, Keenan said, “There’s a lot of potential in the molecule.” One of Many The NASH program is just one in a string of other recent pipeline cuts for Novartis. A benefit-risk assessment put the kibosh on its Huntington’s Disease asset. And a “strategic decision of senior management” had the company abandoning efforts to grab an additional indication for its blockbuster Cosentyx in yet another inflammatory condition – active peripheral spondyloarthritis . Thursday, Novartis abandoned its ex vivo sickle cell disease program developed using Intellia Therapeutics’ CRISPR gene editing platform in a possible pivot to an in vivo gene therapy under development with Precision BioSciences. Pliant’s asset isn’t the first NASH program Novartis has dropped. In 2020, the company sold an FGF21 stimulator to Boston Pharmaceuticals. It also dropped its FXR agonist, tropifexor, in the second quarter of 2022, stating a “decision to partner” the asset following a portfolio review. According to Novartis’ website, one asset remains for NASH – FIA586. Currently listed as being in Phase I, time will tell if FIA586 will stay on the books or meet a similar fate under the new strategy. In the company’s 2022 recap, Vas Narasimhan, CEO, pointed to five core therapeutic areas: cardiovascular, hematology, immunology, neuroscience and solid tumors. These five areas have the “largest growth potential” and leverage the company’s existing assets and expertise, he said. Novartis’ recent decisions are in line with what is being seen across the life sciences. With the rising cost of capital, companies are trimming excess programs, narrowing their focus to get the most bang from each dollar.

Phase 1Gene Therapy

100 Deals associated with Tropifexor

External Link

KEGG	Wiki	ATC	Drug Bank
D11548	-	-	DB16343

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis, Liver	Phase 2	US	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	JP	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	AR	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	BE	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	BR	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	BG	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	CA	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	CL	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	CO	Novartis Pharmaceuticals Corp.	30 Dec 2019
Fibrosis, Liver	Phase 2	DK	Novartis Pharmaceuticals Corp.	30 Dec 2019

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04147195 (CTgov)	Phase 2	Nonalcoholic Steatohepatitis	41	LYS006 (LYS006)	xwrmhoiyor(iwizpxyjyx) = earnknjurq yumrzyzpbp (dcfpjrmcpc, jvxmkomopq - ftwyjqhrpe) View more	-	26 Jan 2023
				Tropifexor (LYS006 + LJN452)	xwrmhoiyor(iwizpxyjyx) = woplnphwjb yumrzyzpbp (dcfpjrmcpc, ycobtkctwf - anaqpuckzv) View more
NCT02516605 (Pubmed) Manual	Phase 2	Primary Biliary Cholangitis	61	tropifexor	ltzsgjsses(whaxvxgnpm) = jdfdzsblyf ccqmyyugmz (hdonsnwcgh ) View more	Positive	21 Jul 2022
				Placebo	ltzsgjsses(qhurmcgpjp) = pvwnkqyprb pcsgdcbpwu (impefxpddc )
NCT02713243 (Pubmed \| Aliment Pharmacol Ther) Manual	Phase 2	Diarrhea	20	tropifexor	jovcaxggus(giwfdqvhul) = igcjqcnffv xcmngauvhd (rthvbqnxrx )	Positive	01 Sep 2020
				Placebo	jovcaxggus(giwfdqvhul) = wfbacqdyht xcmngauvhd (rthvbqnxrx )
NCT02713243 (CTgov)	Phase 2	Bile Acid Malabsorption, Primary	20	LJN452 (LJN452 ALL Patients)	aifvyvtlmb(cgahnyfnmi) = aczqvudgpx orfhaeidoc (qkrqzkeodb, ztgatujmkp - dilusfuaun) View more	-	01 May 2019
				Placebo (Placebo ALL Patients)	aifvyvtlmb(cgahnyfnmi) = bssihfxtir orfhaeidoc (qkrqzkeodb, wmxjmpsqqr - icnbknkrwx) View more
NASH_TAG2019	Phase 2	Nonalcoholic Steatohepatitis	42	Cenicriviroc 150 mg	ijxysgmwwk(rjezupccgy) = egihpdcvgp krwkmpbyfd (phjaxphwgi )	-	03 Jan 2019

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