Novel and Emerging Therapies for Cholestatic Liver Diseases

Jordan Goldstein; Cynthia Levy


Liver International. 2018;38(9):1520-1535. 

In This Article

Treatment of Pruritus

ASBT Inhibitors: GSK2330672 & Marilixibat

Apical sodium-dependent bile acid transporter (ASBT) is a transporter on the apical border of the terminal ileum which reclaims about 90% of the bile acids.[103] 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.[16,104] The 2 ASBT inhibitors currently being studied are maralixibat and GSK2330672.

In a phase II trial of maralixibat + UDCA (CLARITY study), 66 PBC patients were treated for 13 weeks to determine the effect on itching. Despite improvement from baseline itching scores, no significant difference was observed in the magnitude of effect between the drug and placebo. Side effects included diarrhoea (61.9%), abdominal pain (23.8%) and nausea (23.8%).[105]

A phase IIa 14-day crossover study of GSK2330672 in 22 patients with PBC showed a significant reduction in pruritic symptoms. Besides the increased incidence of diarrhoea (7 patients in the GSK2330672 group vs one in the placebo group), there is concern for downstream effects such as vitamin deficiencies, gallstone formation and colonic inflammation.[106,107] A larger phase II study including 118 PBC patients is ongoing to confirm the beneficial effect on itching and further examine drug tolerability (NCT02966834).

Maralixibat was also evaluated in 27 patients with PSC (CAMEO study; NCT02061540). Data published on shows 25 of 27 patients experiencing adverse events, with the majority of the events being diarrhoea and other gastrointestinal symptoms. While secondary outcomes such as change in bilirubin (from 1.22 to 0.98), ALP (from 471.6 to 434.9) and ItchRO scores (from 15.00 to 7.23) all improved, these do not appear to be clinically meaningful. However, further analysis of the results is warranted.


Currently, underway in the Netherlands is the phase III FITCH trial, comparing placebo vs bezafibrate 400 mg daily over 3 weeks for the treatment of itching in 84 PBC patients (NCT02701166).[108]