DOCSLIB.ORG

Highlights in Primary Biliary Cholangitis from the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Highlights in Primary Biliary Cholangitis from the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, And February 2021 Volume 17, Issue 2, Supplement 3 A SPECIAL MEETING REVIEW EDITION Highlights in Primary Biliary Cholangitis From the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, and the AASLD 2020 Liver Meeting Digital Experience Special Reporting on: • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis From the POISE Trial Grouped Biochemically by Risk of Disease Progression • Long-Term Efficacy and Safety of Obeticholic Acid in Primary Biliary Cholangitis: Responder Analysis of More Than 5 Years of Treatment in the POISE Trial • ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis— A Phase 3, International, Randomized, Placebo-Controlled Study • Real-World Effectiveness of Obeticholic Acid in Patients With Primary Biliary Cholangitis • Results of a Phase 2, Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Saroglitazar Magnesium in Patients With Primary Biliary Cholangitis (EPICS) • Primary Biliary Cholangitis: Patient Characteristics and the Health Care Economic Burden in the United States • Bezafibrate Add-On Therapy Improves Liver Transplantation–Free Survival in Patients With Primary Biliary Cholangitis: A Japanese Nationwide Cohort Study • GLIMMER Trial—A Randomized, Double-Blind, Placebo-Controlled Study of Linerixibat, an Inhibitor of the Ileal Bile Acid Transporter, in the Treatment of Cholestatic Pruritus in Primary Biliary Cholangitis PLUS Meeting Abstract Summaries With Expert Commentary by: Kris V. Kowdley, MD Director, Liver Institute Northwest Clinical Professor, Elson S. Floyd College of Medicine Washington State University Seattle, Washington ON THE WEB: gastroenterologyandhepatology.net Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE SPECIAL MEETING REVIEW EDITION HIGHLIGHTS IN PRIMARY BILIARY CHOLANGITIS Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial rimary biliary cholangitis (PBC) imately 40% of patients do not benefit ated OCA in patients with PBC. In is a chronic autoimmune disease from this approach.6,7 the 12-month double-blind phase, of the liver that damages the Obeticholic acid (OCA) is a mod- patients were randomized to 1 of 3 Pbile ducts, resulting in cholestasis and ified bile acid farnesoid X receptor arms: placebo with or without UDCA fibrosis if left untreated.1,2 Patients agonist that was first approved by the (73 patients), 5 mg of OCA with are also at higher risk for hepato- US Food and Drug Administration allowed adjustment to 10 mg with cellular carcinoma, osteoporosis, (FDA) in May 2016 for use in con- or without UDCA (70 patients), and osteopenia. The disease is rare junction with UDCA.2 OCA acts on or 10 mg of OCA with or without and mainly diagnosed in women in several steps in bile acid homeostasis, UDCA (73 patients). Key inclusion their 40s. Importantly, the incidence ultimately improving the clearance of criteria included a diagnosis of PBC; appears to be steadily increasing in bile acid from the body and decreasing alkaline phosphatase (ALP) of at least the United States, Europe, and Asia.3-5 the amount being made. It also reduces 1.67 times the upper limit of normal Urso deoxycholic acid (UDCA), the inflammation and cholestasis in the (ULN) or total bilirubin greater than standard first-line treatment, alters liver.8 In addition, OCA is antifibrotic. the ULN to less than 2 times the ULN; the course of the disease, but approx- The phase 3 POISE trial evalu- and inadequate response to UDCA or 100 90 80 Year 1 Year 5 Year 6 70 60 50 40 Responders (%) 30 20 10 0 n= 15 11 4 170 114 48 97 60 21 88 65 31 99 63 19 86 62 33 Male Female Age at Age at Age at Age at Study Entry Study Entry Diagnosis Diagnosis ≤55 yrs >55 yrs ≤47.5 yrs >47.5 yrs Figure 1. POISE primary endpoint (ALP <1.67 × ULN, total bilirubin ≤ ULN, and ALP reduction ≥15%) from OCA baseline by demographic subgroup. For patients who received placebo in the double-blind phase, OCA baseline was the last assessment prior to the first OCA dose in OLE. For patients who received OCA in the double-blind phase, OCA baseline was the mean of all available evaluations prior to double-blind treatment. ALP, alkaline phosphatase; OCA, obeticholic acid; OLE, open-label extension; ULN, upper limit of normal. Adapted from Bowlus CL et al. ACG abstract 58. Presented at the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting; October 23-28, 2020.10 2 Gastroenterology & Hepatology Volume 17, Issue 2, Supplement 3 February 2021 HIGHLIGHTS IN PRIMARY BILIARY CHOLANGITIS inability to tolerate it.9 The primary age at study entry (≤55 years vs >55 long-term OCA treatment is associated POISE endpoint was ALP of less than years), age when diagnosed with PBC with durable improvements or stabili- 1.67 times the ULN, a reduction of at (≤47.5 years vs >47.5 years), and sex zation in markers of disease severity in least 15% in ALP from baseline, and (male vs female). PBC patients, regardless of age or sex. normal total bilirubin (≤ ULN) at 12 A total of 193 of the 198 patients months. who completed the double-blind phase References 1. Hirschfield GM, Beuers U, Corpechot C, et al; Euro- The primary endpoint was met by of the study enrolled in the open-label pean Association for the Study of the Liver. EASL Clin- 46% of patients in the 5-mg to 10-mg extension. Of these, 116 completed 5 ical Practice Guidelines: the diagnosis and management OCA arm and by 47% of patients years of OCA treatment, including 52 of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172. in the 10-mg OCA arm, compared who received OCA in the double-blind 2. Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam with 10% of patients in the placebo phase and thus received a total of 6 years KK. Clinical updates in primary biliary cholangitis: arm. In addition, PBC patients who of OCA treatment. Figure 1 shows the trends, epidemiology, diagnostics, and new therapeutic approaches. J Clin Transl Hepatol. 2020;8(1):49-60. received OCA for 12 months experi- POISE primary endpoint from OCA 3. Lu M, Li J, Haller IV, et al. Factors associated with enced significantly decreased levels of baseline by demographic subgroup prevalence and treatment of primary biliary cholangi- ALP, alanine aminotransferase (ALT), for years 1, 5, and 6. Total bilirubin tis in United States health systems. Clin Gastroenterol Hepatol. 2018;16(8):1333-1341.e6. aspartate aminotransferase (AST), and remained stabilized and the improve- 4. Kim KA, Ki M, Choi HY, Kim BH, Jang ES, Jeong gamma-glutamyl transferase (GGT), ments in ALP were maintained across SH. Population-based epidemiology of primary biliary compared with those on placebo, as all subgroups after 6 years of treatment cirrhosis in South Korea. Aliment Pharmacol Ther. 9 2016;43(1):154-162. well as stabilization of total bilirubin. with OCA. Likewise, all of the sub- 5. Lleo A, Jepsen P, Morenghi E, et al. Evolving trends Following the 12-month dou- groups sustained the improvements in in female to male incidence and male mortality of pri- ble-blind phase of the POISE trial, both ALT and GGT that they achieved mary biliary cholangitis. Sci Rep. 2016;6:25906. 6. Younossi ZM, Bernstein D, Shiffman ML, et al. patients were eligible to enter an during the early phase of the study. In Diagnosis and management of primary biliary cholan- open-label extension. All patients were general, both ALT and AST were higher gitis. Am J Gastroenterol. 2019;114(1):48-63. treated with OCA 5 mg for 3 months, in the 2 younger-age subgroups. The 7. Bahar R, Wong KA, Liu CH, Bowlus CL. Update on new drugs and those in development for the treatment after which the dose could be titrated most common side effect was mild to of primary biliary cholangitis. Gastroenterol Hepatol (N based on tolerability. moderate pruritus, which occurred at Y). 2018;14(3):154-163. At the American College of Gas- similar rates in all demographic sub- 8. Santiago P, Scheinberg AR, Levy C. Cholestatic liver diseases: new targets, new therapies. Therap Adv Gastro- troenterology 2020 Virtual Annual groups. enterol. 2018;11:1756284818787400. Scientific Meeting, Dr Christopher L. OCA led to sustained improve- 9. Nevens F, Andreone P, Mazzella G, et al; POISE Bowlus presented results from an analy- ments in ALP, ALT, AST, and GGT as Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. sis of the long-term efficacy and safety well as stabilization of total bilirubin 2016;375(7):631-643. of OCA in demographic subgroups of through 5 years across demographic 10. Bowlus CL, Trauner M, Nevens F, et al. Long-term patients who had been treated for 5 or subgroups. Adverse events were con- efficacy and safety of obeticholic acid in patients with 10 primary biliary cholangitis: a demographic subgroup more years in the POISE trial. This sistent with OCA’s established safety analysis of 5-year results from the POISE trial [ACG analysis pooled double-blind placebo profile, and there were no new safety abstract 58]. Presented at the American College of Gas- and double-blind OCA patients, and observations during long-term treat- troenterology 2020 Virtual Annual Scientific Meeting; October 23-28, 2020.
Load more

Recommended publications
  • Advances in Hepatology
    ADVANCES IN HEPATOLOGY Current Developments in the Treatment of Hepatitis and Hepatobiliary Disease Hepatology Section Editor: Eugene R. Schiff, MD Novel Therapies for Cholestatic Liver Disease Cynthia Levy, MD Professor of Medicine Arthur Hertz Chair in Liver Diseases Associate Director, Schiff Center for Liver Diseases Division of Hepatology University of Miami Miller School of Medicine Miami, Florida G&H Currently, how is cholestatic liver G&H What are the limitations of the therapies disease in adults typically treated? currently being used? CL Cholestatic liver disease in adults mainly consists of CL Up to 40% of patients with PBC may not respond to primary biliary cholangitis (PBC) and primary sclerosing UDCA therapy, meaning that they will not have signifi- cholangitis (PSC). For PBC, the traditional first-line treat- cant biochemical improvement in alkaline phosphatase, ment is ursodeoxycholic acid (UDCA), starting at a dose which will remain elevated above 1.5 or 2 times the upper of 13 to 15 mg/kg/day. In May 2016, obeticholic acid limit of normal. In addition, in the PBC clinical trials for (Ocaliva, Intercept Pharmaceuticals) was approved by the obeticholic acid, only half of the patients met the primary US Food and Drug Administration (FDA) for second- endpoint. Furthermore, as previously mentioned, there is line treatment of PBC patients who either do not respond no FDA-approved treatment for PSC. Therefore, there are to UDCA therapy or who are intolerant of it. Dosing for unmet needs for PBC and PSC treatment, which have led noncirrhotic or well-compensated cirrhotic patients is 5 to a plethora of ongoing clinical trials exploring drugs of mg daily, which can be increased to 10 mg daily after 3 various mechanisms of action.
    [Show full text]
  • A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)
    ( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61P1/16 (2006.01) A61P3/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/192 (2006.01) C07C 321/28 (2006.01) Declarations under Rule 4.17: (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/IB2020/000808 earlier application (Rule 4.17(iii)) (22) International Filing Date: Published: 25 September 2020 (25.09.2020) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/906,288 26 September 2019 (26.09.2019) US (71) Applicant: ABIONYX PHARMA SA [FR/FR] ; 33-43 Av¬ enue Georges Pompidou, Batiment D, 31130 Bahna (FR). (72) Inventor: DASSEUX, Jean-Louis, Henri; 7 Allees Charles Malpel, Bat. B, 31300 Toulouse (FR). (74) Agent: HOFFMANN EITLE PATENT- UND RECHTSANWALTE PARTMBB, ASSOCIATION NO. 151; Arabellastrasse 30, 81925 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
    [Show full text]
  • The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
    International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.
    [Show full text]
  • Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D
    | PRACTICE GUIDANCE HEPATOLOGY, VOL. 0, NO. 0, 2018 Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D. Lindor, Christopher L. Bowlus, James Boyer, Cynthia Levy, and Marlyn Mayo Intended for use by health care providers, this guid- Preamble ance identifies preferred approaches to the diagnostic This American Association for the Study of and therapeutic aspects of care for patients with PBC. Liver Diseases (AASLD) 2018 Practice Guidance As with clinical practice guidelines, it provides gen- on Primary Biliary Cholangitis (PBC) is an update eral guidance to optimize the care of the majority of of the PBC guidelines published in 2009. The 2018 patients and should not replace clinical judgment for updated guidance on PBC includes updates on etiol- a unique patient. ogy and diagnosis, role of imaging, clinical manifesta- The major changes from the last guideline to this tions, and treatment of PBC since 2009. The AASLD guidance include information about obeticholic acid 2018 PBC Guidance provides a data-supported (OCA) and the adaptation of the guidance format. approach to screening, diagnosis, and clinical man- agement of patients with PBC. It differs from more recent AASLD practice guidelines, which are sup- Etiology of Primary Biliary ported by systematic reviews and a multidisciplinary panel of experts that rates the quality (level) of the Cholangitis evidence and the strength of each recommendation Primary Biliary Cholangitis (PBC) is considered using the Grading of Recommendations Assessment, an autoimmune disease because of its hallmark sero- Development, and Evaluation system. In contrast, this logic signature, antimitochondrial antibody (AMA), (1-4) guidance was developed by consensus of an expert and specific bile duct pathology.
    [Show full text]
  • Lessons from Liver-Specific PPAR-Null Mice
    International Journal of Molecular Sciences Review PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice Yaping Wang 1, Takero Nakajima 1, Frank J. Gonzalez 2 and Naoki Tanaka 1,3,* 1 Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; [email protected] (Y.W.); [email protected] (T.N.) 2 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] 3 Research Center for Social Systems, Shinshu University, Matsumoto, Nagano 390-8621, Japan * Correspondence: [email protected]; Tel.: +81-263-37-2851 Received: 21 February 2020; Accepted: 9 March 2020; Published: 17 March 2020 Abstract: Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver. Keywords: PPAR; NAFLD; NASH; insulin resistance; liver fibrosis 1. Introduction Administration of Wy-14643, nafenopin, and fibrate drugs to rodents results in hepatic peroxisome proliferation. These agents are thus designated as peroxisome proliferators (PPs) [1]. To explain a mechanism of rapid and drastic changes following PP administration, the involvement of transcription factors was assumed and the first peroxisome proliferator-activated receptor (PPAR, later defined as PPARα (NR1C1)) was identified in 1990 [2].
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
    cells Review Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease Anne Fougerat 1,*, Alexandra Montagner 1,2,3, Nicolas Loiseau 1 , Hervé Guillou 1 and Walter Wahli 1,4,5,* 1 Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; [email protected] (A.M.); [email protected] (N.L.); [email protected] (H.G.) 2 Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France 3 Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France 4 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore 5 Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland * Correspondence: [email protected] (A.F.); [email protected] (W.W.); Tel.: +33-582066376 (A.F.); +41-79-6016832 (W.W.) Received: 29 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD.
    [Show full text]
  • Ppardelta Mediates the Effect of Dietary Fat in Promoting Colorectal Cancer Metastasis
    Author Manuscript Published OnlineFirst on June 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0384 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PPAR mediates the effect of dietary fat in promoting colorectal cancer metastasis Dingzhi Wang1#, Lingchen Fu2#, Jie Wei1#, Ying Xiong1, and Raymond N. DuBois1, 3* 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425 2Laboratory for Inflammation and Cancer, Biodesign Institute of Arizona State University, Tempe, AZ 85287 3Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259 Running Title: PPAR, high-fat diets, and metastatic colorectal cancer Keywords: PPAR, dietary fat, Nanog, cancer stem cells, metastasis Additional Information Financial support: DW, LF, and RND (NIH R01 DK047297 to R.N. DuBois, NCI R01 CA184820 to R.N. DuBois, NCI P01 CA077839 to R.N. DuBois), JW (NIH R01 DK047297 to R.N. DuBois, NCI R01 CA184820 to R.N. DuBois), YX (NIH R01 DK047297 to R.N. DuBois) *Correspondence to: Raymond N. DuBois, MD. Ph.D. 601 Clinical Science Building 96 Jonathan Lucas Street, Suite 601, Charleston, SC 29425 Tel: 843-792-2842 and Fax: 843-792-2967 E-mail: [email protected] Conflict of interest disclosure statement: All authors have no any conflict interests # Equal contribution to the manuscript Word: 4814, Figures: 6, Tables: 1 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0384 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Exploration and Development of PPAR Modulators in Health and Disease: an Update of Clinical Evidence
    International Journal of Molecular Sciences Review Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence Hong Sheng Cheng 1,* , Wei Ren Tan 2, Zun Siong Low 2, Charlie Marvalim 1, Justin Yin Hao Lee 2 and Nguan Soon Tan 1,2,* 1 School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore; [email protected] 2 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; [email protected] (W.R.T.); [email protected] (Z.S.L.); [email protected] (J.Y.H.L.) * Correspondence: [email protected] (H.S.C.); [email protected] (N.S.T.); Tel.: +65-6904-1294 (H.S.C.); +65-6904-1295 (N.S.T.) Received: 30 September 2019; Accepted: 10 October 2019; Published: 11 October 2019 Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner.
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors
    PPAR Peroxisome proliferator-activated receptors PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. www.MedChemExpress.com 1 PPAR Inhibitors, Agonists, Antagonists, Activators & Modulators 13-Oxo-9E,11E-octadecadienoic acid 15-Deoxy-Δ-12,14-prostaglandin J2 Cat. No.: HY-N5097 (15d-PGJ2; 15-Deoxy-Δ12,14-PGJ2) Cat. No.: HY-108568 13-Oxo-9E,11E-octadecadienoic acid, an isomer of 15-Deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) is a 9-oxo-ODA, is a potent PPARα activator derived cyclopentenone prostaglandin and a metabolite of from tomato juice. 13-Oxo-9E,11E-octadecadienoic PGD2. 15-Deoxy-Δ-12,14-prostaglandin J2 is a acid decreases plasma and hepatic triglyceride in selective PPARγ (EC50 of 2 µM) and a covalent obese diabetic mice. PPARδ agonist. Purity: >98% Purity: ≥96.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 1 mg, 5 mg 4-O-Methyl honokiol 5-Aminosalicylic Acid Cat. No.: HY-U00450 (Mesalamine; 5-ASA; Mesalazine) Cat. No.: HY-15027 4-O-Methyl honokiol is a natural neolignan 5-Aminosalicylic acid (Mesalamine) acts as a isolated from Magnolia officinalis, acts as a specific PPARγ agonist and also inhibits PPARγ agonist, and inhibtis NF-κB activity, used p21-activated kinase 1 (PAK1) and NF-κB.
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors
    PPAR Peroxisome proliferator-activated receptors PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. www.MedChemExpress.com 1 PPAR Inhibitors & Modulators 4-O-Methyl honokiol 5-Aminosalicylic Acid Cat. No.: HY-U00450 (Mesalamine; 5-ASA; Mesalazine) Cat. No.: HY-15027 Bioactivity: 4-O-Methyl honokiol is a natural neolignan isolated from Bioactivity: 5-Aminosalicylic acid acts as a specific PPARγ agonist and Magnolia officinalis, acts as a PPARγ agonist, and inhibtis also inhibits p21-activated kinase 1 ( PAK1) and NF-κB. NF-κB activity, used for cancer and inflammation research. Purity: >98% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: Launched Size: 5 mg, 10 mg, 25 mg Size: 10mM x 1mL in DMSO, 10 g Adelmidrol Aleglitazar Cat. No.: HY-B1026 (R1439; RO0728804) Cat. No.: HY-14728 Bioactivity: Adelmidrol exerts important anti-inflammatory effects that are Bioactivity: Aleglitazar(R1439; RO-0728804) is a new dual PPAR-α/γ agonist partly dependent on PPARγ. Adelmidrol reduces NF-κB with IC50 of 2.8 nM/4.6 nM. translocation, and COX-2 expression.
    [Show full text]
  • Seladelpar (MBX-8025), a Selective PPAR-Δ Agonist, in Patients with Primary Biliary Cholangitis with an Inadequate Response To
    Jones DEJ, Boudes P, Swain M, Bowlus C, Galambos M, Bacon B, Doerffel Y, Gitlin N, Gordon S, Odin J, Sheridan D, Wörns M-A, Clark V, Corless L, Hartmann H, Jonas ME, Kremer A, Mells G, Buggisch P, Freilich B, Levy C, Vierling J, Bernstein D, Hartleb M, Janczewska E, Rochling F, Shah H, Shiffman M, Smith J, Choi Y-J, Steinberg A, Varga M, Chera H, Martin R, McWherter C, Hirschfield G. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterology and Hepatology 2017, 2(10), 716-726. Copyright: © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license DOI link to article: https://doi.org/10.1016/S2468-1253(17)30246-7 Date deposited: 07/09/2017 Embargo release date: 14 February 2018 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence Newcastle University ePrints - eprint.ncl.ac.uk PPAR-δ agonism in PBC A double-blind, randomized, placebo-controlled phase 2 proof of concept study of seladelpar (MBX- 8025), a selective PPAR- δ agonist, in patients with Primary Biliary Cholangitis with an inadequate response to ursodeoxycholic acid Running title: PPAR-δ agonism in PBC Professor Jones David, M.D., Ph.D.1*, Boudes Pol F, M.D.2*ǂ, Professor Swain Mark G, M.D.3, Professor 4 5 6 Bowlus Christopher L, M.D. , Galambos Michael R, M.D.
    [Show full text]
  • The Role of Lipid Sensing Nuclear Receptors (Ppars and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD
    G C A T T A C G G C A T genes Review The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD Emmanuel D. Dixon , Alexander D. Nardo , Thierry Claudel and Michael Trauner * Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (E.D.D.); [email protected] (A.D.N.); [email protected] (T.C.) * Correspondence: [email protected]; Tel.: +43-140-4004-7410; Fax: +43-14-0400-4735 Abstract: Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them Citation: Dixon, E.D.; Nardo, A.D.; therapeutically.
    [Show full text]