Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study
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.
Introduction
Primary biliary cholangitis (previously called primary biliary cirrhosis)1 is a chronic autoimmune liver disease characterised by progressive cholestasis. Pruritus (itch) is a frequent and troublesome symptom, seen in 60–70% of patients at some point during the disease process.2, 3, 4 The pathogenesis of cholestatic pruritus is complex and several putative pruritogens have been proposed.5 The use of ursodeoxycholic acid (UDCA), the standard of care in primary biliary cholangitis, has improved outcomes in primary biliary cholangitis but has not been shown to improve pruritus.6
The bile acid sequestrant cholestyramine is often given to treat pruritus, but its effectiveness in practice is limited. Despite its modest evidence base, and poor tolerability profile, it is the only US Food and drug Administration (FDA)-approved therapy for cholestatic pruritus and is recommended by both the American and European practice guidelines as the first-line agent.7, 8 Colesevelam is a better tolerated bile acid sequestrant, but was not efficacious in the only randomised controlled trial reported so far.9 Other drug therapies (rifampicin, naltrexone, and sertraline), although recommended by the scientific guidelines,7, 8 are not actually licensed for treating cholestatic pruritus. Moreover, they have the disadvantage of needing regular monitoring due to risk of liver injury and other limiting adverse effects. This is particularly an issue with rifampicin, the most widely used second-line therapy, which has well reported hepatotoxicity.10 In clinical practice, response rates less than 50% are common for most of the guideline recommended drugs11 and despite their step-wise use, many patients report refractory itch, which can only be treated by invasive (usually temporary) treatments such as nasobiliary drainage12 or liver transplantation (the only definitive cure). Therefore, effective anti-pruritic drug therapy is an unmet clinical need in primary biliary cholangitis and other cholestatic liver diseases.13
Research in context
Evidence before this study:
Chronic pruritus is a common symptom associated with cholestatic liver diseases and, along with fatigue, accounts for the greatest burden of symptoms in patients with primary biliary cholangitis. Up to 70% of patients develop pruritus at some point during the course of their disease and many patients describe persistent or severe pruritus which can be debilitating. This form of pruritus goes beyond cutaneous irritation, with secondary effects through sleep deprivation, daytime somnolence, fatigue, depression, and even on occasions, suicidal ideation. Overall, patients with primary biliary cholangitis and pruritus have a poor quality of life reflecting the limitations of current approaches to treatment. We searched PubMed for clinical studies published in English between Jan 1,1950, and Sept 1, 2016, with terms “PBC”, “cholestasis”, “pruritus”, or “itch” and “bile acids”, “bile salts”, “IBAT”, or “ASBT”. Ursodeoxycholic acid, the standard of care for primary biliary cholangitis, has no substantial effect on pruritus and obeticholic acid, a second-line therapy, can actually worsen it. The four classes of available, guideline recommended drugs for pruritus include bile acid sequestrants (cholestyramine), pregnane X receptor agonists (rifampicin), opioid antagonists (naltrexone), and selective serotonin reuptake inhibitors (sertraline). However, the strength of evidence for these drugs is poor to moderate with only rifampicin and naltrexone ever studied in methodologically robust randomised controlled trials. Furthermore, rifampicin is associated with a risk of liver injury necessitating regular monitoring of liver enzymes, and naltrexone is associated with unpleasant symptoms of the opioid withdrawal syndrome. Cholestyramine remains the only licensed treatment but is poorly tolerated by many patients due to its unpleasant taste and texture, resulting in poor therapy adherence. Another bile acid sequestrant colesevelam has better tolerability but the only randomised controlled trial so far did not show that it was more effective than placebo in treating pruritus in primary biliary cholangitis.
Added value of this study
This study is a first-in-class, randomised, placebo-controlled trial of an ileal bile acid transporter (IBAT) inhibitor to treat pruritus in patients with primary biliary cholangitis. Using three different complementary patient-reported outcome measurements, GSK2330672 showed greater effects than placebo in reducing itch intensity, as well as night-time sleep interference and daytime fatigue. GSK2330672 significantly decreased serum activity of autotaxin, which forms lysophosphatidic acid, a novel proposed pruritogen in cholestasis shedding further light on the potential mechanisms for cholestatic pruritus and the actions of the drug. In addition to improving symptoms of primary biliary cholangitis, this study has shown that pharmacological inhibition of IBAT can be used as a therapeutic strategy to decrease the circulating bile acid pool in cholestatic patients. GSK2330672 decreased serum conjugated bile acids and resulted in ∼50% decrease in total bile acid concentrations.
Implication of all the available evidence
Because of the great burden of pruritus in patients and the limitations of treatment options, there is a real unmet need for effective anti-pruritic therapies in primary biliary cholangitis. IBAT inhibitors are a novel class of drugs that have shown therapeutic potential in cholestasis. The results of our early phase randomised controlled trial in conjunction with previous experimental evidence and healthy volunteer trials provide support to further investigate anti-pruritic effect of IBAT inhibitor drugs in larger and longer-term studies of patients with primary biliary cholangitis.
The paucity of effective anti-pruritic therapies in primary biliary cholangitis is probably compounded by the fact that the key emerging second-line disease modifying agent, obeticholic acid, which has been licensed by the FDA and European Medicines Agency, is associated with an increased frequency and severity of pruritus.14, 15 Many other bile acid-based therapies in primary biliary cholangitis that are in development16 might also be associated with pruritus. Therefore, effective pruritus management in primary biliary cholangitis is likely to become increasingly important and challenging and new approaches are needed.
Ileal bile acid transporter (IBAT, also called apical sodium-dependent bile acid transporter [ASBT]) is an integral brush border membrane glycoprotein mainly expressed in the distal ileum.17, 18 The main physiological function of IBAT is reabsorption of bile acids and maintenance of their enterohepatic circulation. In cholestatic liver disease, ileal bile acid absorption is increased19, 20 and inhibiting ileal bile acid transport was proposed to prevent inappropriate conservation of bile acids.21 Using an IBAT inhibitor to reduce bile acid reabsorption and modulate the bile acid pool in the systemic circulation is an unexplored therapeutic strategy in primary biliary cholangitis, a condition in which retention of toxic hydrophobic bile acids is postulated to play a key pathogenetic role.
To date, published reports of IBAT inhibitor drugs include a study in healthy people (A4250),22 two reports in animal models of cholestasis (A4250 and SC435)23, 24 and a report of lopixibat chloride (formerly LUM001) in patients with primary biliary cholangitis and pruritus.25 GSK2330672 is a highly potent, soluble, minimally absorbed, selective inhibitor of the human IBAT. It has been assessed in animal models of type 2 diabetes mellitus (T2DM) and an early phase trial of T2DM patients.26, 27 In two phase 1 studies (59 healthy volunteers) it was well tolerated with a good safety profile at a dose range of 0·1 to 90 mg (unpublished data from clinical trial NCT01416324 and NCT01607385).
Here we report the first randomised, placebo-controlled, double-blind, crossover, phase 2 trial of an IBAT inhibitor in people with primary biliary cholangitis and pruritus. We postulated that GSK2330672 would interrupt enterohepatic circulation of bile acids and exert therapeutic benefit on pruritus associated with primary biliary cholangitis.
Section snippets
Study design and patients
BAT117213 was a phase 2a randomised, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat doses of GSK2330672 in patients with primary biliary cholangitis and symptoms of pruritus (figure 1). This study was done at two centres in the UK: Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, and University Hospitals Birmingham NHS Foundation Trust, Birmingham, in collaboration with the UK-PBC Consortium.28
Results
Between March 10, 2014, and Oct 7, 2015, we enrolled and randomised 22 patients. 21 patients completed all the planned study procedures as per protocol. One patient was withdrawn from the study due to withdrawal of consent in the placebo run-in period (figure 2). The safety population therefore comprised a total of the 22 randomly assigned patients, while the analysis population comprised 21 patients who completed all the planned study procedures as per protocol (although one patient did not
Discussion
This trial of GSK2330672 shows safety and efficacy of a first-in-class, novel agent in treating pruritus associated with primary biliary cholangitis. Despite the substantial symptom burden and need for better anti-pruritic drugs, little progress in developing new treatments for pruritus in primary biliary cholangitis has been made. We have attempted to fill this treatment gap with the first randomised, placebo-controlled, crossover trial of an IBAT inhibitor drug in patients with primary
