A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis

Abstract

BackgroundAccumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat.MethodsOverweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids.ResultsAll 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0–4) to 2 (0–8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of − 0.70 mmol/L (range − 2.8 to 0.4) and − 0.6990 mmol/L (− 3.341 to 0.570), respectively.ConclusionsThis study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis.Trial registrationClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).Electronic supplementary materialThe online version of this article (10.1186/s40360-018-0200-y) contains supplementary material, which is available to authorized users.

Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study

“…32 Phase I studies have demonstrated that volixibat is not metabolized, is minimally absorbed and is effective at reducing serum cholesterol in overweight and obese adults. 18,26,27 The increases in faecal BA excretion and serum C4 levels observed in these phase I studies support the proposed mechanism of action of volixibat in patients with NASH. It is also important that volixibat was found to reduce fasting glucose levels significantly compared with placebo in patients with type 2 diabetes mellitus (T2DM) 26 because there is a close association between NASH and T2DM.…”

“…21,22 Consistent with this mechanism of action, increases in serum levels of 7a-hydroxy-4-cholesten-3-one (7aC4, also known as C4; a biomarker of BA synthesis) and decreases in serum cholesterol levels are observed following administration of ASBT inhibitors, including volixibat. [23][24][25][26][27] In the treatment of NASH, volixibat may reduce the pathogenic accumulation of cholesterol in the liver by reducing the levels of BAs returning to the liver via enterohepatic recirculation and by stimulating de novo production of BAs from free cholesterol in the liver and serum. This may have therapeutically beneficial anti-inflammatory, anti-steatotic and antifibrotic effects.…”

Intestinal Absorption of Bile Acids in Health and Disease

“…Currently, there are several ASBT inhibitors in development, though none have been approved by the FDA as of this writing. In addition to their potential for lowering plasma LDL cholesterol (see above), these small molecule inhibitors have shown promise in preclinical and clinical studies for the treatment of chronic constipation (65,78,276,348), NASH (289,310), type 2 diabetes mellitus (71,249,379,426), and cholestatic pruritus (24,153,264). It will be interesting to see how these promising drug candidates fare in future clinical trials.…”

Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis

“… 95 Volixibat, an apical sodium-dependent bile-acid transporter inhibitor, was shown as safe and tolerable among overweight and obese healthy individuals. 96 In fact, volixibat was selected for fast track by the US Food and Drug Administration and a phase II clinical trial was underway to detect its efficacy among patients with NASH, with a primary endpoint of improvement in NAFLD activity score without worsening of fibrosis. 94 However, just recently, the phase II trial for volixibat was discontinued, without any further explanation for the possible causes.…”