Abstract Details

Title Safety, Tolerability and Anti-Dyskinetic Efficacy of Dipraglurant, a Novel mGluR5 Negative Allosteric Modulator (NAM) in Parkinson's Disease (PD) Patients with Levodopa-Induced Dyskinesia (LID)

Topic Movement Disorders

Presentation(s) S23 - (-)

Poster/Presentation
Number 004

Objective

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 AUC0-3) on Day 14 (- 33% ,placebo - 14%; p = 0.042). Day 28 dipraglurant peak mAIMS = -3.8, AUC0-3 = -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.

Authors/Disclosures
Francois Tison, MD, PhD (CHU Bordeaux) PRESENTER	No disclosure on file
Franck Durif, MD, PhD	No disclosure on file
Jean Christophe Corvol, MD (GH Pitie Salpetriere)	No disclosure on file
Enrique Alvarez, MD, PhD (University of Colorado)	Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Alvarez has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene/BMS. The institution of an immediate family member of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon.
	No disclosure on file
Claudia Trenkwalder, MD (Center For Parkinsonism and Movement Disorders)	No disclosure on file
Mark F. Lew, MD, FAAN (USC School of Medicine)	Dr. Lew has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Supernus. Dr. Lew has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for kyowa. Dr. Lew has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for neurocrine. Dr. Lew has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acorda. Dr. Lew has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Lew has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RegenXBio. Dr. Lew has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurocrine. Dr. Lew has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Kyowa. Dr. Lew has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for acorda. The institution of Dr. Lew has received research support from MJFF. Dr. Lew has received research support from NIH.
Stuart H. Isaacson, MD, FAAN (Parkinson's Dis & Mov Dis Ctr of Boca Raton)	The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Acadia. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sunovion. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for acorda. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Supernus. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurocrine. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kyowa. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for adamas. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neuroderm. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. The institution of Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for amneal. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurocrine. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for adamas. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lundbeck. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Supernus. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acadia. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amneal. Dr. Isaacson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie.
Charlotte G. Keywood, MBBS (Zambon SPA)	No disclosure on file
Olivier Rascol, MD, PhD (Departments of Clinical Pharmacology and Neurosciences-CIC9302/INSERM 825)	Dr. Rascol has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AbbVie, Acorda, Aguettant, Alkahest, AlzProtect, Apopharma, Astrazeneca, Axovant, Bial, Biogen, Britannia, Buckwang, Centogene, Cerevel, Clevexel, Contera, GE Healthcare, Handltherapeutic, Ionis, Irlab, Jazz, Kyowa, LGD Nuvamid, Lundbeck, Merck, Merz, MundiPharma, Neuralight, Neuratris, Neuroderm, Novartis, ONO Pharma, Orion Pharma, Osmotica, Oxford Biomedica, Parexel, PD Neurotechnology, Pfizer, Polycaps, Prexton, Roche Therapeutics, Sanofi, Scienture, Servier,Sombiotech, Sunovion, Supernus, Synagile, Thelonius Mind, Takeda, Théranexus, Teva, Tools4patient, UCB, Vision 2 voice, XenoPort, XO, Zambon . Dr. Rascol has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie, Acorda, Aguettant, Alkahest, AlzProtect, Apopharma, Astrazeneca, Axovant, Bial, Biogen, Britannia, Buckwang, Centogene, Cerevel, Clevexel, Contera, GE Healthcare, Handltherapeutic, Ionis, Irlab, Jazz, Kyowa, LGD Nuvamid, Lundbeck, Merck, Merz, MundiPharma, Neuralight, Neuratris, Neuroderm, Novartis, ONO Pharma, Orion Pharma, Osmotica, Oxford Biomedica, Parexel, PD Neurotechnology, Pfizer, Polycaps, Prexton, Roche Therapeutics, Sanofi, Scienture, Servier,Sombiotech, Sunovion, Supernus, Synagile, Thelonius Mind, Takeda, Théranexus, Teva, Tools4patient, UCB, Vision 2 voice, XenoPort, XO, Zambon . Dr. Rascol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIAL. Dr. Rascol has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MEDIZIN ACADEMY. The institution of Dr. Rascol has received research support from Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020).

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