AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials.
ABSTRACT Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinson's disease patients with levodopa-induced dyskinesia. Two randomized, double-blind, placebo-controlled, parallel-group, in-patient studies for Parkinson's disease patients with moderate to severe levodopa-induced dyskinesia (study 1) and severe levodopa-induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25-150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4-day down-titration. Primary outcomes were the Lang-Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinson's Disease Rating Scale-part III (both studies). Secondary outcomes included the Unified Parkinson's Disease Rating Scale-part IV items 32-33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056-treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang-Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinson's Disease Rating Scale-part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056-treated patients in study 1, and 3 patients (2 AFQ056-treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy. © 2011 Movement Disorder Society.
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Conference Paper: Absorption and disposition of mavoglurant (AFQ056) in healthy volunteers[Show abstract] [Hide abstract]
ABSTRACT: Mavoglurant (AFQ056) is a selective mGluR5 antagonist under development for treatment of Parkinson`s disease-associated L-Dopa-induced dyskinesia and Fragile X syndrome. In the present work, the absorption and disposition of [14C]-radiolabeled mavoglurant were investigated in four healthy male volunteers after a single oral dose of 200 mg. Total radioactivity was determined in plasma, urine and feces. Mavoglurant was quantified in plasma by LC-MS/MS. Metabolite profiles were achieved in plasma and excreta by HPLC and radioactivity detection. The mavoglurant metabolite structures were elucidated by mass spectrometry, wet-chemical and enzymatic methods, NMR and comparison with reference compounds. For the metabolite profiling, the novel linked platecrane automated system was used, increasing significantly throughput. Sample analyses for this study were completed in a more efficient manner, as compared when using standard methods. Results: [14C]mavoglurant was absorbed with a Tmax of 2.6h and an oral bioavailability of ≥ 50% .The biotransformation of mavoglurant involved two main pathways: A) hydroxylation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6); B) hydroxylation of the phenyl ring leading to a hydroxylated metabolite (M3). The elimination of mavoglurant was fast and occurred predominantly by oxidative metabolism. The subjects were mainly exposed to mavoglurant and five metabolites (M6, M15, M18, M14, M30). Drug related material was excreted mostly in feces (58.6% of dose) and urine (36.7% of dose). After 7 days, the balance of excretion was almost complete (95.3% of dose).19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;
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ABSTRACT: No curative therapy is available for Parkinson's disease; therefore, one of the main goals of treatment is to control motor symptoms, often via the use of levodopa (also known as L-dopa). However, prolonged levodopa treatment in Parkinson's disease has been associated with the development of motor fluctuations and the occurrence of levodopa-induced dyskinesias (LIDs).American Health and Drug Benefits 09/2012; 5(6):347-58.
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ABSTRACT: Anti-glutamatergic drugs can relieve Parkinson's disease (PD) symptoms and decrease l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID). This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5) receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA, and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the l-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.Frontiers in neurology. 01/2014; 5:144.