Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Hegade, Vinod S.; Jones, David; Hirschfield, Gideon M.

doi:10.1159/000450988

Cited by 24 publications

(18 citation statements)

References 49 publications

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“…ASBT inhibitors decrease absorption of bile acids, hindering intra‐ileal activation of FXR and subsequently preventing the FXR induced downstream inhibition of CYP7A1. Also, by blocking ASBT, the overall size of the BA pool decreases causing less of a buildup and decreased toxicity in the bile canaliculi . The 2 ASBT inhibitors currently being studied are maralixibat and GSK2330672.…”

Section: Treatment Of Pruritusmentioning

confidence: 99%

Novel and emerging therapies for cholestatic liver diseases

Goldstein

Levy

2018

Liver International

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While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

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Section: Treatment Of Pruritusmentioning

confidence: 99%

Novel and emerging therapies for cholestatic liver diseases

Goldstein

Levy

2018

Liver International

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“…The treatment of pruritus in PBC is challenging because of the limited efficacy and poor tolerability of currently available drugs and lack of effective new therapies. Ileal bile acid transporter (IBAT) inhibitor agents are emerging as potential novel therapy for pruritus in PBC . Recently, we investigated GSK2330672, a novel, selective human IBAT inhibitor in a phase 2a, randomised controlled trial (RCT) and showed that PBC patients with pruritus receiving 2 weeks of oral treatment with GSK2330672 had significant improvement in their pruritus compared to placebo …”

Section: Introductionmentioning

confidence: 99%

“…Ileal bile acid transporter (IBAT) inhibitor agents are emerging as potential novel therapy for pruritus in PBC. [7][8][9][10] Recently, we investigated GSK2330672, a novel, selective human IBAT inhibitor in a phase 2a, randomised controlled trial (RCT) and showed that PBC patients with pruritus receiving 2 weeks of oral treatment with GSK2330672 had significant improvement in their pruritus compared to placebo. 11 Over the years, metabonomics has been applied to study the metabolic signatures in a variety of liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus

Hegade

Pechlivanis

McDonald

et al. 2019

Liver International

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Background and Aims Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. Methods We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2 weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC‐MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. Results In PBC patients with pruritus, serum levels of total and glyco‐conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro‐ and glyco‐conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro‐ and glyco‐ conjugated BAs and increased faecal levels of CA (P = 0.048) and CDCA (P = 0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P = 0.033) and Clostridia (P = 0.04) and decreased Bacteroidetes (P = 0.033) and Bacteroidia (P = 0.04). Conclusions Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition.

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“…As mentioned, FXR exerts some of its effects through down-regulation of ASBT, reducing the enterohepatic circulation of bile acids and reducing the bile acid pool. Inhibition of ASBT is associated with improved liver histology in animal models of cholestatic liver disease and was hypothesized to bring therapeutic benefit in PSC [110][111][112]. An open-label phase II trial of an ASBT inhibitor (LUM001, maralixibat) has been completed with 27 PSC patients, and preliminary results available at clinicaltrials.gov indicate that no clinically relevant change in liver biochemistries was observed ( Table 2).…”

Section: Asbt Inhibitorsmentioning

confidence: 99%