Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study

Hegade, Vinod S.; Kendrick, Stuart; Dobbins, Robert L.; Miller, Sam; Thompson, Douglas; Richards, Duncan; Storey, James R.; Dukes, George E.; Corrigan, Margaret; Elferink, Ronald P.J. Oude; Beuers, Ulrich; Hirschfield, Gideon M.; Jones, David

doi:10.1016/s0140-6736(17)30319-7

Cited by 171 publications

(147 citation statements)

References 38 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…Itch severity was assessed using a 0‐10 numerical rating scale (NRS), PBC‐40 itch domain score and 5‐D itch scale . The trial protocol is available online and we have recently published the safety and efficacy data of GSK2330672 in PBC patients with pruritus …”

Section: Methodsmentioning

confidence: 99%

“…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%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although NTCP expression and activity are already reduced during cholestasis, we show here that the residual activity can effectively be targeted by myrcludex B administration. This is comparable to the situation for ASBT inhibition, as this bile acid transporter is also downregulated during cholestasis, and further pharmacological inhibition still ameliorates cholangitis in mice and reduces pruritus severity in PBC patients . One of the main differences between effects of ASBT and NTCP inhibition is the induction of diarrhea.…”

Section: Discussionmentioning

confidence: 98%

“…So far ursodeoxycholic acid (UDCA), either alone or in combination with obeticholic acid (OCA) for primary biliary cholangitis (PBC), is the only clinically approved treatment for chronic cholestatic liver disease . Recently, pharmacological interruption of the enterohepatic transport of bile salts has been suggested as a means to attenuate cholestatic liver injury by reducing bile salt load on hepatocytes Indeed, apical sodium dependent bile salt transporter (ASBT) inhibitors reduce liver injury and fibrosis in Abcb4 deficient mice, a model of progressive familial intrahepatic cholestasis type 3 (progressive familial intrahepatic cholestasis [PFIC] 3) and sclerosing cholangitis, and displayed a beneficial safety profile and reduced pruritus in PBC patients in a phase II trial . The effect of disruption of the enterohepatic circulation at the level of the basolateral membrane of the hepatocyte has not been tested as an anti‐cholestatic treatment strategy.…”

mentioning

confidence: 99%

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Slijepćević¹,

Abbing²,

Fuchs

et al. 2018

Hepatology

Self Cite

View full text Add to dashboard Cite

Accumulation of bile salts (BSs) during cholestasis leads to hepatic and biliary injury, driving inflammatory and fibrotic processes. The Na+‐Taurocholate Cotransporting Polypeptide (NTCP) is the major hepatic uptake transporter of BSs, and can be specifically inhibited by myrcludex B. We hypothesized that inhibition of NTCP dampens cholestatic liver injury. Acute cholestasis was induced in mice by a 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) diet or by bile duct ligation (BDL). Chronic cholestasis was investigated in Atp8b1‐G308V and Abcb4/Mdr2 deficient mice. Mice were injected daily with myrcludex B or vehicle. Myrcludex B reduced plasma alkaline phosphatase (ALP) levels in DDC‐fed, Atp8b1‐G308V and BDL mice by 39%, 27% and 48% respectively. Expression of genes involved in fibrosis, proliferation and inflammation was reduced by myrcludex B treatment in DDC‐fed and Atp8b1‐G308V mice. NTCP‐inhibition increased plasma BS levels from 604±277 to 1746±719 μm in DDC‐fed mice, 432±280 to 762±288 μm in Atp8b1‐G308V mice and from 522±130 to 3625±378 μm in BDL mice. NTCP‐inhibition strongly aggravated weight loss in BDL mice, but not in other cholestatic models studied. NTCP‐inhibition reduced biliary BS output in DDC‐fed and Atp8b1‐G308V mice by ∼50% while phospholipid (PL) output was maintained, resulting in a higher PL/BS ratio. Conversely, liver injury in Abcb4 deficient mice, lacking biliary phospholipid output, was aggravated after myrcludex B treatment. Conclusion: NTCP‐inhibition by myrcludex B has hepatoprotective effects, by reducing BS load in hepatocytes and increasing the biliary PL/BS ratio. High micromolar plasma BS levels after NTCP‐inhibition were well tolerated. NTCP‐inhibition may be beneficial in selected forms of cholestasis. (Hepatology 2018).

show abstract

“…An alternative and much simpler approach is to block the bile acid transporter (IBAT inhibition) located in the terminal ileum. Oral administration of compound GSK2330672 at dosage of 90 mg twice a day for 14 days was shown to be both effective and well tolerated in a very recently published phase 2a double-blind crossover trial of 22 patients with PBC and symptoms of pruritus [11]. Major reduction in three different itch scores was demonstrated and associated with significant reduction in circulating total and conjugated bile acids and enhanced fecal excretion.…”

mentioning

confidence: 98%

Extracorporeal devices for treatment of refractory pruritus in cholestatic liver disease

Williams

2017

Hepatol Int

View full text Add to dashboard Cite

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study

Abstract: GlaxoSmithKline and National Institute for Health Research.

Cited by 171 publications

References 38 publications

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

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

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Extracorporeal devices for treatment of refractory pruritus in cholestatic liver disease

Contact Info

Product

Resources

About