Journal Article

DZNE-2022-00152

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial.

Peterschmitt, M. J. ; Saiki, H. ; Hatano, T. ; Gasser, T.DZNE* ; Isaacson, S. H. ; Gaemers, S. J. M. ; Minini, P. ; Saubadu, S. ; Sharma, J. ; Walbillic, S. ; Alcalay, R. N. ; Cutter, G. ; Hattori, N. ; Höglinger, G. U.DZNE* ; Marek, K.Extern* ; Schapira, A. H. V. ; Scherzer, C. R. ; Simuni, T. ; Giladi, N. ; Sardi, S. P. ; Fischer, T. Z. ; Investigators, M.-P. (Collaboration Author)

2022
IOS Press Amsterdam

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Please use a persistent id in citations: doi:10.3233/JPD-212714

Abstract: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor.Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD).Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics.Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants.Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Aged, 80 and over (MeSH) ; Enzyme Inhibitors: adverse effects (MeSH) ; Glucosylceramidase: genetics (MeSH) ; Glucosylceramides (MeSH) ; Humans (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Parkinson Disease: drug therapy (MeSH) ; Parkinson Disease: genetics (MeSH) ; Young Adult (MeSH) ; GBA-PD ; MOVES-PD ; Parkinson’s disease ; Venglustat (GZ/SAR402671) ; glucocerebrosidase gene (GBA) ; glucosylceramide (GL-1) ; glucosylceramide synthase (GCS) inhibition

Note: (CC BY-NC)

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Coordinator of Clinical Parkinson Research (AG Höglinger 2)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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