François Tison1,2,3,4, Charlotte Keywood5, Mark Wakefield5, Franck Durif6,7, Jean-Christophe Corvol6,8, Karla Eggert9, Mark Lew10, Stuart Isaacson11, Erwan Bezard12,13, Sonia-Maria Poli5, Christopher G Goetz14, Claudia Trenkwalder15, Olivier Rascol6,16. 1. Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. francois.tison@chu-bordeaux.fr. 2. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. francois.tison@chu-bordeaux.fr. 3. Service de Neurologie, CHU de Bordeaux, Bordeaux, France. francois.tison@chu-bordeaux.fr. 4. NS-Park/FCRIN Network, UMS 015, Toulouse, France. francois.tison@chu-bordeaux.fr. 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, Germany. 10. Department of Neurology USC/Keck School of Medicine, Los Angeles, California, USA. 11. Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA. 12. Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. 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, Kassel, Germany. 16. CIC9302, Departments of Clinical Pharmacology and Neurosciences and NeuroToul COEN Center; INSERM, University Hospital of Toulouse and University of Toulouse 3, Toulouse, France.
Abstract
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 single dose. 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.
RCT Entities:
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 single dose. 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 PDpatients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients.
Authors: Angela Arsova; Thor C Møller; Line Vedel; Jakob Lerche Hansen; Simon R Foster; Karen J Gregory; Hans Bräuner-Osborne Journal: Mol Pharmacol Date: 2020-05-01 Impact factor: 4.436
Authors: Andrew S Felts; Alice L Rodriguez; Ryan D Morrison; Anna L Blobaum; Frank W Byers; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte Journal: Bioorg Med Chem Lett Date: 2018-04-22 Impact factor: 2.823
Authors: Andrew S Felts; Alice L Rodriguez; Ryan D Morrison; Katrina A Bollinger; Daryl F Venable; Anna L Blobaum; Frank W Byers; Analisa Thompson Gray; J Scott Daniels; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte Journal: Bioorg Med Chem Lett Date: 2017-09-20 Impact factor: 2.823
Authors: Wen Yuan Luo; Su Qian Xing; Ping Zhu; Chen Guang Zhang; Hui Min Yang; Nicholas Van Halm-Lutterodt; Li Gu; Hong Zhang Journal: Neurotherapeutics Date: 2019-07 Impact factor: 7.620
Authors: Andrew S Felts; Katrina A Bollinger; Christopher J Brassard; Alice L Rodriguez; Ryan D Morrison; J Scott Daniels; Anna L Blobaum; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley Journal: Bioorg Med Chem Lett Date: 2018-11-10 Impact factor: 2.823