Vinod S. Hegade

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

BACKGROUND Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. METHODS We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. FINDINGS Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 μM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. INTERPRETATION In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. FUNDING GlaxoSmithKline and National Institute for Health Research.

The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study

Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus.

Novel bile acid therapeutics for the treatment of chronic liver diseases

Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases.

Drug treatment of pruritus in liver diseases

Pruritus (itch) is a common complication of cholestatic liver diseases (CLD). It can be a distressing and debilitating symptom, causing significant impairment in quality of life. Treatment of pruritus in liver diseases can be challenging and requires specific management with early initiation and a step-wise approach using specific drugs. Clinical trials are ongoing with novel agents that demonstrate potential efficacy. Patients with cholestatic pruritus are likely to present to a variety of clinicians who would benefit from medical awareness of available treatment options. In this review, we outline the pharmaceutical agents currently used to treat cholestatic pruritus and provide the evidence base for targeted symptom control of itch in liver diseases. We also highlight recent developments in the pathophysiology of cholestatic pruritus and the emerging novel therapies.

Complications of cholestasis

Cholestasis (impairment of, or reduction in, bile flow) can both predispose to the development of chronic liver disease and result in its own specific symptoms. The severity of cholestatic symptoms (which themselves can often impair quality of life) is typically independent of the severity of the underlying liver disease, the link with cholestasis frequently being missed as a result. The most characteristic symptoms of cholestasis are pruritus and fatigue, the former being the most responsive to treatment. Following exclusion of surgically or endoscopically treatable biliary tree obstruction, the first-line treatment for cholestatic pruritus is colestyramine. Rifampicin and the oral opiate antagonist, naltrexone, are extremely effective second-line treatments. Currently there is no recommended therapy for fatigue. Osteoporosis can complicate cholestatic liver disease, although the risk has in the past been overstated. The highest additional cholestasis-associated risk is seen in male patients, in patients taking corticosteroid treatment and in the most severely cholestatic patients. Patients should undergo formal bone mineral density screening and bisphosphonate treatment is highly effective.

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

Bile acids (BAs) have gained mainstream attention since the discovery of their key role as signalling molecules in health and disease. The apical sodium-dependent transporter (ASBT) protein located in the terminal ileum plays an important physiological role in the enterohepatic circulation of BAs and therefore essential for the BA homeostasis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the 2 most common cholestatic liver diseases are characterised by altered BA flow and BA composition, which contribute to disease progression and symptom (pruritus) development. Therefore, changing the circulating BA pool in patients with PBC and PSC may have therapeutic implications. To this end, pharmacological inhibition of ASBT is fast emerging as an interesting target. In this review, we discuss the recent evidence for potential therapeutic use of ASBT inhibitors to treat PBC and PSC patients.

A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis

Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients’ quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC.

What Comes after Ursodeoxycholic Acid in Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second-line therapy in PBC and has been recently licensed by the Food and Drug Administration and European Medicines Agency for use in patients showing an inadequate response to UDCA or who are unable to tolerate it. Although evidence for biochemical improvement by OCA is compelling, there is, as yet, no evidence that OCA improves hard clinical outcomes or quality of life. In addition, OCA may not be suitable for PBC patients with pruritus as it can worsen the symptom. Other novel agents currently in clinical development may have better side-effect profile. Fibrates have the potential but currently lack high quality evidence to support their routine clinical use in PBC. Symptom management of PBC is challenging and ASBT inhibitors and rituximab are being evaluated for pruritus and fatigue, respectively.

Itch and liver: management in primary care

Pruritus can be defined as ‘an unpleasant sensation that causes the need to scratch.’1 Although it is most commonly seen in skin diseases it can occur as a consequence of systemic conditions and the possibility of the presence of such conditions should be considered in any patient presenting with pruritus in the absence of rash. Pruritus can be a feature of renal failure, haematological diseases (including lymphoma, leukaemia, and myeloproliferative disorders),2 and of liver diseases in which there is an element of cholestasis (impaired bile secretion). Pruritus in liver diseases can often be a debilitating symptom causing significant impairment in quality of life. Not all patients with liver disease develop pruritus and its prevalence varies depending on the underlying cause of liver disease. It is more common in conditions characterised by bile duct inflammatory destruction than in those characterised by hepatocellular injury.3 For example, the prevalence of pruritus is high in autoimmune liver diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and biliary obstructive diseases secondary to benign (stones/strictures) or malignant diseases (for example, carcinoma of head of pancreas). It can also be seen in patients with chronic viral hepatitis (mainly hepatitis C) and drug-induced liver injury (DILI). In comparison, pruritus is relatively uncommon in alcohol-induced liver diseases (ALD) and non-alcoholic fatty liver disease (NAFLD). Patients with pruritus often seek treatment from their GPs but studies have shown there is lack of awareness among clinicians in relation to pruritus associated with liver diseases.4 GPs are able to initiate treatments recommended by the guidelines so they and their patients would benefit from a knowledge of the condition and the …

A Phase 2 Randomised Crossover Trial of Ileal Bile Acid Transporter Inhibitor GSK2330672 in Patients with Primary Biliary Cholangitis and Symptoms of Pruritus

♦ Denotes AASLD Presidential Poster of Distinction 1 A multi-center study to define sarcopenia in patients with end-stage liver disease: From the Fitness, Life Enhancement, and Exercise in Liver Transplantation (FLEXIT) Consortium Elizabeth J. Carey1, Jennifer C. Lai2, Connie W. Wang2, Srinivasan Dasarathy3, Iryna Lobach2, Aldo J. Montano-Loza4, Michael A. Dunn5; 1Mayo Clinic Arizona, Phoenix, AZ; 2University of California San Francisco, San Francisco, CA; 3Cleveland Clinic, Cleveland, OH; 4University of Alberta, Alberta, AB, Canada; 5University of Pittsburgh, Pittsburgh, PA