Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement

Nicolas Guérard; Daniel Oder; Peter Nordbeck; Christian Zwingelstein; Olivier Morand; Richard W.D. Welford; Jasper Dingemanse; Christoph Wanner

doi:10.1002/cpt.790

journal article Aug 28, 2017

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement

Nicolas Guérard Daniel Oder Peter Nordbeck

Christian Zwingelstein Olivier Morand Richard W.D. Welford Jasper Dingemanse Christoph Wanner

Clinical Pharmacology & Therapeutics Vol. 103 No. 4 pp. 703-711 · Wiley

View at Publisher Save 10.1002/cpt.790

Abstract

Lucerastat is a glucosylceramide synthase inhibitor aimed at reducing production of glycosphingolipids (GSLs), including those accumulating in Fabry disease. The safety, tolerability, pharmacodynamics, and pharmacokinetics of oral lucerastat were evaluated in an exploratory study in patients with Fabry disease. In this single‐center, open‐label, randomized study, 10 patients received lucerastat 1,000 mg b.i.d. for 12 weeks in addition to enzyme replacement therapy (ERT; the lucerastat group). Four patients with Fabry disease received ERT only. Eight patients reported 17 adverse events (AEs) in the lucerastat group. No clinically relevant safety abnormalities were observed. The mean (SD) levels of the plasma GSLs, glucosylceramide, lactosylceramide, and globotriaosylceramide, were significantly decreased from baseline in the lucerastat group (‐49.0% (16.5%), ‐32.7% (13.0%), and ‐55.0% (10.4%), respectively). Lucerastat 1,000 mg b.i.d. was well tolerated in patients with Fabry disease over 12 weeks. A marked decrease in plasma GSLs was observed, suggesting clinical potential for lucerastat in patients with Fabry disease.

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References

Details

Published: Aug 28, 2017
Vol/Issue: 103(4)
Pages: 703-711
License: View

Authors

N

Nicolas Guérard

Department of Global Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland

D

Daniel Oder

Fabry Center for Interdisciplinary Therapy (FAZiT), Comprehensive Heart Failure Center (CHFC), and Department of Internal Medicine I, Divisions of Cardiology and Nephrology, University Hospital Würzburg Würzburg Germany

P

Peter Nordbeck

Fabry Center for Interdisciplinary Therapy (FAZiT), Comprehensive Heart Failure Center (CHFC), and Department of Internal Medicine I, Divisions of Cardiology and Nephrology, University Hospital Würzburg Würzburg Germany

C

Christian Zwingelstein

Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd Allschwil Switzerland

O

Olivier Morand

Department of Global Clinical Science Idorsia Pharmaceuticals Ltd Allschwil Switzerland

R

Richard W.D. Welford

DD Biology, Translational Science, Idorsia Pharmaceuticals Ltd Allschwil Switzerland

J

Jasper Dingemanse

Department of Global Clinical Pharmacology Idorsia Pharmaceuticals Ltd Allschwil Switzerland

C

Christoph Wanner

Fabry Center for Interdisciplinary Therapy (FAZiT), Comprehensive Heart Failure Center (CHFC), and Department of Internal Medicine I, Divisions of Cardiology and Nephrology, University Hospital Würzburg Würzburg Germany

Funding

Actelion Pharmaceuticals

Cite This Article

Nicolas Guérard, Daniel Oder, Peter Nordbeck, et al. (2017). Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement. Clinical Pharmacology & Therapeutics, 103(4), 703-711. https://doi.org/10.1002/cpt.790

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement

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