title: A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.
abstract: 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).
  
  
  
  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 single dose.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. francois.tison@chu-bordeaux.fr.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. francois.tison@chu-bordeaux.fr.|Service de Neurologie, CHU de Bordeaux, Bordeaux, France. francois.tison@chu-bordeaux.fr.|NS-Park/FCRIN Network, UMS 015, Toulouse, France. francois.tison@chu-bordeaux.fr.
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.affiliation: Addex Pharma SA, Plan Les Ouates, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Keywood
authors.affiliation: Addex Pharma SA, Plan Les Ouates, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Wakefield
authors.affiliation: NS-Park/FCRIN Network, UMS 015, Toulouse, France.|Neurology Service, A, Hôpital Gabriel Montpied, Clermont Ferrand, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Durif
authors.affiliation: NS-Park/FCRIN Network, UMS 015, Toulouse, France.|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.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: Universitätsklinikum Giessen und Marburg, Klinik für Neurologie, Marburg, Germany.
authors.forename: Karla
authors.initials: K
authors.lastname: Eggert
authors.affiliation: Department of Neurology USC/Keck School of Medicine, Los Angeles, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lew
authors.affiliation: Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Isaacson
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Addex Pharma SA, Plan Les Ouates, Switzerland.
authors.forename: Sonia-Maria
authors.initials: SM
authors.lastname: Poli
authors.affiliation: Rush University Medical Center, Dept. of Neurological Sciences, Movement Disorder Section, Chicago, Illinois, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Goetz
authors.affiliation: Paracelsus Elena Klinik, centre for Parkinson's Disease & Movement Disorders, Kassel, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.affiliation: NS-Park/FCRIN Network, UMS 015, Toulouse, France.|CIC9302, Departments of Clinical Pharmacology and Neurosciences and NeuroToul COEN Center; INSERM, University Hospital of Toulouse and University of Toulouse 3, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
mesh_terms: D000368:Aged; D015259:Dopamine Agents / Q000009:adverse effects*; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010300:Parkinson Disease / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*
chemical_list: D015259:Dopamine Agents; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D007980:Levodopa; C000596095:6-fluoro-2-(4-(pyridin-2-yl)but-3-yn-1-yl)imidazo(1,2-a)pyridine
keywords: Parkinson's disease; dipraglurant; levodopa-induced dyskinesia; mGluR5 antagonist; phase 2A