F. Tison, F. Durif, J. Corvol
Feb 12, 2013
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Influential Citations
17
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Journal
Neurology
Abstract
OBJECTIVE: Evaluation of the safety, tolerability and anti-dyskinetic profile of dipraglurant in PD patients with LID. BACKGROUND: Dipraglurant a novel mGluR5 NAM, reduced levodopa-induced chorea and dystonia in MPTP macaques. DESIGN/METHODS: Randomised, double-blind placebo-controlled study in 76 male and female PD patients with moderate or severe LID. Four weeks treatment, dose titration from 50 mg o.d. on Day 1, to 50 mg t.d.s. by Day 14, and 100 mg t.d.s. by Day 21. LID severity was measured on Day 0 (pre-randomisation) and on treatment Days 1, 14 and 28 by (mAIMS) performed every 30 minutes for 3 hours following a single usual levodopa dose. Diary data of “on”, “off” and sleep time were collected weekly. Major efficacy variables were analysed by ANOVA. RESULTS: Patient characteristics and LID severity were matched in the dipraglurant (N = 52; male 26, mean age 64 years) and placebo groups (N = 24; male 12, mean age 62.5 years). No significant changes in safety monitoring parameters were observed including nervous system AEs (dipraglurant 52%, placebo 46%). Dipraglurant significantly reduced peak dose mAIMS on Day 1 (50mg) (- 2.4 , placebo -0.5, p = 0.042) and on Day 14 (100 mg) (-3.9 placebo -1.5; p = 0.038) and across the 3 hour post-dose period (mAIMS AUC 0-3 ) on Day 14 (– 33% ,placebo – 14%; p = 0.042). Day 28 dipraglurant peak mAIMS = -3.8, AUC 0-3 = -28%, (placebo -2.6 and -21% p = ns). Dipraglurant did not affect levodopa efficacy (UPDRS Part III). Dipraglurant increased daily “on” time without dyskinesia +1.25, +1.8, +2.0 and +2.3 hours in Weeks 1, 2, 3 and 4 and reduced daily “off” time, by 50 minutes at Week 4. CGIC dyskinesia reported more improvement for dipraglurant (p = 0.05). CONCLUSIONS: Dipraglurant demonstrated good safety and tolerability in PD patients. The clinical efficacy seen, warrants further investigation. Supported by: Addex Pharma S.A. and Michael J Fox Foundation. Disclosure: Dr. Tison has received personal compensation for activities with GlaxoSmithKline, Inc., Novartis, Boehringer Ingelheim Pharmaceuticals, Inc. and UCB Pharma as a speaker and/or participant on an advisory board. Dr. Durif has nothing to disclose. Dr. Corvol has nothing to disclose. Dr. Eggert has received personal compensation for activities with UCB Pharma, Novartis, GlaxoSmithKline, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Teva Neuroscience, Roche, Orion, and Solvay. Dr. Eggert has received research support from UCB Pharma, Novartis, GlaxoSmithKline, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Teva Neuroscience, Roche, Orion, and Solvay. Dr. Trenkwalder has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Mundipharm, UCB Pharma, and Teva Neuroscience. Dr. Trenkwalder has received research support from Mundipharm and Novartis. Dr. Lew has received personal compensation for activities with Boehringer-Ingelheim, Teva, Solstice Neurosciences, Ipsen, BI, Novartis, Schering Plough, GSK, Merz, and Abbott. Dr. Lew has received research support from NIH, Abbott/Solvay, Schering Plough, Parkinson9s Study Group, Michael J. Fox Foundation, Allon Therapeutics, Addex, Takeda Pharmaceuticals, Synosia Pharmaceuticals, and the National Parkinson9s Disease Foundation. Dr. Isaacson has received personal compensation for activities with Allergan, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Chelsea, GE Healthcare, GlaxoSmithKline, Inc., Ipsen, Lundbeck Research USA, Inc., Merz Pharma, Novartis, Teva Neuroscience, and UCB Pharma. Dr. Isaacson has received research support from Acadia, Adamas, Addex, Allergan, Inc., Biotie, Boehringer Ingelheim Pharmaceuticals, Inc., Chelsea, Eisai Inc., GlaxoSmithKline, Inc., Ipsen, Merck & Co., Inc., Merz Pharma, Michael J. Fox Foundation, Neurogen, the National Institutes of Health, Novartis, Pfizer Inc, Santhera, Schering-Plough Corporation, Schwarz, Serono, Inc., Solstice, Synosia, Solvay, Teva Neuroscience, UCB Pharma, Valeant Pharmaceuticals, and Vernalis. Dr. Keywood has received personal compensation for activities with Addex Pharma SA as an employee. Dr. Rascol has received personal compensation for activities with GlaxoSmithKline, Inc., UCB Pharma, Teva Neuroscience, Lundbeck Research USA, Abbott Laboratories Inc. and Novartis as a participant and/or consultant. Dr. Rascol has received research support from Lundbeck Research USA and UCB Pharma.