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Nonsteroidal FXR Ligands: Current Status and Clinical Applications

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Bile Acids and Their Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 256))

Abstract

FXR agonists have demonstrated very promising clinical results in the treatment of liver disorders such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH). NASH, in particular, is one of the last uncharted white territories in the pharma landscape, and there is a huge medical need and a large potential pharmaceutical market for a NASH pharmacotherapy. Clinical efficacy superior to most other treatment options was shown by FXR agonists such as obeticholic acid (OCA) as they improved various metabolic features including liver steatosis as well as liver inflammation and fibrosis. But OCA’s clinical success comes with some major liabilities such as pruritus, high-density lipoprotein cholesterol (HDLc) lowering, low-density lipoprotein cholesterol (LDLc) increase, and a potential for drug-induced liver toxicity. Some of these effects can be attributed to on-target effects exerted by FXR, but with others it is not clear whether it is FXR- or OCA-related. Therefore a quest for novel, proprietary FXR agonists is ongoing with the aim to increase FXR potency and selectivity over other proteins and to overcome at least some of the OCA-associated clinical side effects through an improved pharmacology. In this chapter we will discuss the historical and ongoing efforts in the identification and development of nonsteroidal, which largely means non-bile acid-type, FXR agonists for clinical use.

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Notes

  1. 1.

    FDA Drug Safety Communication. https://www.fda.gov/Drugs/DrugSafety/ucm594941.htm.

  2. 2.

    FDA Adverse Event Reporting System (FAERS) Public Dashboard. https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e8068-f564c31baa25/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis.

  3. 3.

    FDA Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment-Guidance for Industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf.

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  1. Phenex Pharmaceuticals AG, Drug Discovery Research, Heidelberg, Germany

    Christian Gege, Eva Hambruch, Nina Hambruch, Olaf Kinzel & Claus Kremoser

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  1. Christian Gege
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  2. Eva Hambruch
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  3. Nina Hambruch
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  4. Olaf Kinzel
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  5. Claus Kremoser
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Correspondence to Claus Kremoser .

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  1. University of Perugia, School of Medicine, Perugia, Italy

    Stefano Fiorucci

  2. S.C. Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy

    Eleonora Distrutti

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Gege, C., Hambruch, E., Hambruch, N., Kinzel, O., Kremoser, C. (2019). Nonsteroidal FXR Ligands: Current Status and Clinical Applications. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_232

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