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Peterschmitt MJ, Saiki H, Hatano T, et al. 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. J Parkinsons Dis. 2021;doi: 10.3233/JPD-212714.
Peterschmitt, M. J., Saiki, H., Hatano, T., Gasser, T., 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., Marek, K., Schapira, A. H. V., Scherzer, C. R., Simuni, T., Giladi, N., Sardi, S. P., Fischer, T. Z. (2021). 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. Journal of Parkinson's disease, . https://doi.org/10.3233/JPD-212714
Peterschmitt, M Judith, et al. "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." Journal of Parkinson's disease vol. (2021). doi: https://doi.org/10.3233/JPD-212714
Peterschmitt MJ, Saiki H, Hatano T, Gasser T, Isaacson SH, Gaemers SJM, Minini P, Saubadu S, Sharma J, Walbillic S, Alcalay RN, Cutter G, Hattori N, Höglinger GU, Marek K, Schapira AHV, Scherzer CR, Simuni T, Giladi N, Sardi SP, Fischer TZ. 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. J Parkinsons Dis. 2021 Dec 10; doi: 10.3233/JPD-212714. Epub 2021 Dec 10. PMID: 34897099.
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J Parkinsons Dis. 2021 Dec 10; doi: 10.3233/JPD-212714. Epub 2021 Dec 10.

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.

Journal of Parkinson's disease

M Judith Peterschmitt, Hidemoto Saiki, Taku Hatano, Thomas Gasser, Stuart H Isaacson, Sebastiaan J M Gaemers, Pascal Minini, Stéphane Saubadu, Jyoti Sharma, Samantha Walbillic, Roy N Alcalay, Gary Cutter, Nobutaka Hattori, Günter U Höglinger, Kenneth Marek, Anthony H V Schapira, Clemens R Scherzer, Tanya Simuni, Nir Giladi, Sergio Pablo Sardi, Tanya Z Fischer,

Affiliations

  1. Sanofi, Cambridge, MA, USA.
  2. Kitano Hospital, The Tazuke Kofukai MedicalResearch Institute, Osaka, Japan.
  3. Juntendo University, Tokyo, Japan.
  4. Neurologische Universitätsklinik, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  5. Parkinson's Disease and Movement Disorders Center, Boca Raton, FL, USA.
  6. Sanofi Genzyme, Amsterdam, Netherlands.
  7. Sanofi, Chilly-Mazarin, France.
  8. Sanofi, Bridgewater, NJ, USA.
  9. Department of Neurology and the Taub Institute, Columbia University Medical Center, New York, NY, USA.
  10. University of Alabama at Birmingham, School of Public Health, Birmingham, AL, USA.
  11. German Center for Neurodegenerative Diseases (DZNE), Munich, and Department of Neurology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
  12. Department of Neurology, Hannover Medical School, Hannover, Germany.
  13. Institute for Neurodegenerative Disorders, New Haven, CT, USA.
  14. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
  15. Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA.
  16. Northwestern University, Chicago, IL, USA.
  17. Neurological Institute, Tel Aviv Medical Center, Sackler School of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

PMID: 34897099 DOI: 10.3233/JPD-212714

Abstract

BACKGROUND: 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.

OBJECTIVE: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD).

METHODS: 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.

RESULTS: 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.

CONCLUSION: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Keywords: GBA-PD; MOVES-PD; Parkinson’s disease; Venglustat (GZ/SAR402671); glucocerebrosidase gene (GBA); glucosylceramide (GL-1); glucosylceramide synthase (GCS) inhibition

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