A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson’s Disease.
Mov Disord.. 2016-05-23; 31(9): 1373-1380
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1. Mov Disord. 2016 Sep;31(9):1373-80. doi: 10.1002/mds.26659. Epub 2016 May 23.
A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant
for Levodopa-Induced Dyskinesia in Parkinson’s Disease.
Tison F(1)(2)(3)(4), Keywood C(5), Wakefield M(5), Durif F(6)(7), Corvol
JC(6)(8), Eggert K(9), Lew M(10), Isaacson S(11), Bezard E(12)(13), Poli SM(5),
Goetz CG(14), Trenkwalder C(15), Rascol O(6)(16).
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(3)Service de Neurologie, CHU de Bordeaux, Bordeaux, France.
(4)NS-Park/FCRIN Network, UMS 015, Toulouse, France.
(5)Addex Pharma SA, Plan Les Ouates, Switzerland.
(6)NS-Park/FCRIN Network, UMS 015, Toulouse, France.
(7)Neurology Service, A, Hôpital Gabriel Montpied, Clermont Ferrand, France.
(8)Sorbonne Universités and UPMC Univ Paris 06, INSERM UMRS-1127 and CIC-1422;
CNRS UMR-7225; AP-HP; and ICM, Hôpital Pitié-Salpêtrière, Paris, France.
(9)Universitätsklinikum Giessen und Marburg, Klinik für Neurologie, Marburg,
(10)Department of Neurology USC/Keck School of Medicine, Los Angeles, California,
(11)Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton,
(12)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
(13)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(14)Rush University Medical Center, Dept. of Neurological Sciences, Movement
Disorder Section, Chicago, Illinois, USA.
(15)Paracelsus Elena Klinik, centre for Parkinson’s Disease & Movement Disorders,
(16)CIC9302, Departments of Clinical Pharmacology and Neurosciences and NeuroToul
COEN Center; INSERM, University Hospital of Toulouse and University of Toulouse
3, Toulouse, France.
BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator
dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The
objective of this study was to assess the safety, tolerability (primary
objective), and efficacy (secondary objective) of dipraglurant on
levodopa-induced dyskinesia in Parkinson’s disease (PD).
METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized
(2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily
to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to
severe levodopa-induced dyskinesia. Safety and tolerability were assessed based
on clinical and biological examination and adverse events recording. Secondary
efficacy outcome measures included the modified Abnormal Involuntary Movement
Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a
RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There
were no major safety concerns. Two subjects did not complete the study because of
adverse events. Most frequent adverse events included dyskinesia, dizziness,
nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia
(modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04)
and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day
14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant
was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844
ng/mL on day 28.
CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first
administration to PD patients. Its efficacy in reversing levodopa-induced
dyskinesia warrants further investigations in a larger number of patients. © 2016
International Parkinson and Movement Disorder Society.
© 2016 International Parkinson and Movement Disorder Society.
PMID: 27214664 [Indexed for MEDLINE]