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.

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

“…Our observation that evoked glutamate release is reduced in p11KO mice provides additional support for a blunted glutamatergic neurotransmission in these mice. Because both 5-HT 1A/B R agonists and mGluR5 antagonists have shown antidyskinetic properties in PD patients with LIDs (22,23), it will be important to further delineate the pathways whereby p11 influences serotonergic and glutamatergic mechanisms underlying LIDs.…”

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

“…These selective mGlu 5 NAMs have shown exciting efficacy across preclinical models (Emmitte, 2011;Christopoulos, 2014;Nickols and Conn, 2014) and in clinical development for the treatment of multiple CNS disorders (Berg et al, 2011;Jacquemont et al, 2011;Nickols and Conn, 2014;Lindemann et al, 2015).…”

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

“…Modulation of DA, glutamate,adenosine, and other systems has been explored in various animal models of LIDs [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145].…”

“…MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one), a novel mGluR5 modulator, has been found to have high efficacy in a rat model of LIDs without any detrimental effects on motor performance, as determined by open field and rotarod tests [133]. Other mGluR5 inhibitors, such as AFQ056 and dipraglurant, have been found in animal models to improve LIDs, but it is not clear whether these findings will translate into similar improvement in patients with PD [11,134].…”