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

Background: Accumulation 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.

Methods: Overweight 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.

Results: All 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.

Conclusions: This 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 registration: ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).

Keywords: Apical sodium-dependent bile acid transporter (ASBT); Cholesterol; LUM002; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity; SHP626; Volixibat.

Conflict of interest statement

Ethics approval and consent to participate

The study was conducted in accordance with International Conference for Harmonisation guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki, and other applicable local ethical and legal requirements. The study protocol was approved by an independent institutional review board (Crescent City Institutional Review Board) and regulatory agency before initiation. Each participant provided written informed consent before commencing any study-specific procedures.

Consent for publication

Not applicable.

Competing interests

All authors are employees of Shire and may own stock or stock options. This study was funded by Shire Development LLC. Volixibat is a Shire investigational medical product. Shire develops and markets treatments for gastrointestinal and metabolic diseases, including NASH.

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Figures

Fig. 1

Study design. Each cohort consisted of 12 participants (volixibat, n = 9; placebo, n = 3); details are shown for the volixibat arm only. Light-grey boxes indicate dose regimen options that were not undertaken. Bold text indicates alterations to planned doses. Cohorts 4 and onwards were each initiated after reviewing results from previous cohorts.*Study days are approximate. Cohort 2 treatment was to begin at least 4 days after cohort 1 treatment; cohort 3 treatment was to start after completion of treatment in cohort 2.†Changed from 80 mg q.d. following review of data from cohorts 1 and 2 to a descending dose titration of 80–40–20 mg q.d. ‡Results from cohorts 1–3 triggered the use of intermediate and reduced doses in cohorts 4 and 5, instead of increased doses. ¶Treatment of an optional second b.i.d. dose cohort was not undertaken. §Treatment of an optional second q.d. or b.i.d. dose titration cohort was not undertaken. AE, adverse event; b.i.d., twice daily; FBA, faecal bile acid; q.d., once daily

Fig. 2

Mean daily faecal bile acid excretion (a) at baseline and days 11–12, and (b) change from baseline to days 11–12. Baseline was days − 2 and − 1 for this data set. Data are from the pharmacodynamic analysis set. b.i.d., twice daily; CI, confidence interval; q.d., once daily; SD, standard deviation

Fig. 3

Absolute serum 7α-hydroxy-4-cholesten-3-one (C4) concentration at (a) baseline and 13 h after dosing on day 12, and (b) change from baseline to 13 h after dosing on day 12. Baseline was the last observation before the first dose of study drug. Data are from the pharmacodynamic analysis set. b.i.d., twice daily; CI, confidence interval; q.d., once daily; SD, standard deviation

Fig. 4

Daily frequency of bowel movements. Baseline was day − 1 for this data set. Squares represent medians; shaded bars represent ranges. Data are from the pharmacodynamic analysis set. b.i.d., twice daily; q.d., once daily