Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial

Abstract

BackgroundPathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002).MethodsParticipants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker).ResultsSixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM.ConclusionsVolixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).Electronic supplementary materialThe online version of this article (10.1186/s12876-017-0736-0) contains supplementary material, which is available to authorized users.

Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives

“…Furthermore, SC-435 improved insulin sensitivity and prevented hepatic accumulation of triglyceride. More recently, a randomized placebo-controlled trial demonstrated that Volixibat, another ASBT inhibitor, increased the excretion of fecal bile acid and serum levels of 7a-hydroxy-4-cholesten-3-one (a bile acid synthesis biomarker) in healthy adults and patients with type 2 diabetes mellitus [124], further supporting the mechanistic rationale for application of ASBT inhibitors to NASH treatment. Generally, research about the effect of ASBT inhibitors on NAFLD are focused on the preclinically mechanistic studies.…”

Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

“…All three IBAT inhibitors showed similar adverse events: dose-dependent diarrhea (up to 50, 100, and 83% with A4250, SHP626, and GSK2330672, respectively) and abdominal pain (up to 33, 78, and 17% with A4250, SHP626, and GSK2330672, respectively) ( Graffner et al, 2016 ; Ino et al, 2018 ; Tiessen et al, 2018 ).…”

“…SHP626, as compared with placebo, increased mean total fecal BA excretion about ∼1.6–3.2 times in healthy volunteers and ∼8 times in patients with T2DM. With SHP626, mean C4 concentrations increased by ∼1.3–5.3-fold from baseline to day 28 in healthy volunteers and twofold in T2DM patients ( Tiessen et al, 2018 ).…”

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

“…Overall, study data supported the anticipated effects of IBAT inhibition, that is, decreased hepatic and circulating bile acid levels accompanied by increased fecal bile acid excretion. [82][83][84][85][86] IBAT inhibitors are currently in development for a range of target indications across both paediatric (eg PFIC, ALGS and others) and adult (eg PBC, PSC, others) populations. In cholestatic liver diseases, preventing the return of bile acids to the liver via IBAT inhibition may relieve the inflammatory and fibrotic pressures driving tissue damage such that cholestasis and liver function may improve.…”