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Clinical Trial
. 2021 Jan;10(1):86-98.
doi: 10.1002/cpdd.865. Epub 2020 Aug 26.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers

M Judith Peterschmitt  1 , Nigel P S Crawford  2 , Sebastiaan J M Gaemers  3 , Allena J Ji  4 , Jyoti Sharma  2 , Theresa T Pham  5
Affiliations
Clinical Trial

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers

M Judith Peterschmitt et al. Clin Pharmacol Drug Dev. 2021 Jan.

Abstract

Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0-24 ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.

Keywords: globotriaosylceramide (GL-3); glucosylceramide (GL-1); glucosylceramide synthase (GCS) inhibition; glucosylsphingosine (lyso-GL-1); monosialodihexosylganglioside (GM3); substrate reduction therapy; venglustat (GZ/SAR402671; Genz-682452).

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Conflict of interest statement

M.J.P., S.J.M.G., A.J.J., and J.S. are full‐time employees of Sanofi Genzyme. N.P.S.C. was a Sanofi employee at the time of the studies. T.T.P. is a full‐time employee of PPD Development, LLC, contracted by Sanofi Genzyme to perform the studies.

Figures

Figure 1
Figure 1
(A) Structure of venglustat, [(3S)‐1‐azabicyclo[2.2.2]octan‐3‐yl] N‐[2‐[2‐(4‐fluorophenyl)‐1,3‐thiazol‐4‐yl]propan‐2‐yl]carbamate (PubChem CID 60199242; National Center for Biotechnology Information. PubChem Database. Venglustat, CID=60199242, https://pubchem.ncbi.nlm.nih.gov/compound/Venglustat#section=2D-Structure [accessed on March 13, 2020]). (B) Mean (+ standard deviation) venglustat plasma concentrations in the single ascending‐dose study. Values below the lower limit of quantitation (LLOQ) were considered zero for this graph.
Figure 2
Figure 2
Mean (+ standard deviation) venglustat plasma concentrations on Day 1 (A) and Day 14 (B), and trough concentrations from Day 1 to Day 14 in the repeated ascending‐dose study (C). Values below the lower limit of quantitation (LLOQ) were considered zero for this graph
Figure 3
Figure 3
Mean (SEM) remaining of glucosylceramide (GL‐1; A), globostriaosylceramide (GL‐3; B), and GM3 ganglioside (GM3; C) in placebo, 5‐, 10‐, and 20‐mg dose groups (venglustat l‐malate, GZ402671) from Day 1 to Day 15 in the repeated ascending‐dose study
See this image and copyright information in PMC

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