AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study

Abstract

AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13-week, double-blind, placebo-controlled study. Patients with Parkinson's disease and moderate-to-severe levodopa (l-dopa)-induced dyskinesia who were receiving stable l-dopa/anti-parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26-item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056-treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, -2.8; 95% confidence interval [CI], -5.2, -0.4; P = 0.007). Based on final actual doses, there was a dose-response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, -3.6; 95% CI, -7.0, -0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, -0.7; 95% CI, -1.1, -0.2; P = 0.003; 200 mg daily: difference, -0.5; 95% CI, -0.8, -0.1; P = 0.005). No significant changes were observed on the 26-item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti-dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials.

Designing Clinical Trials for Dystonia

“…A third strategy that has led to specific targets for therapeutic trials has come from studies of drugs that suppress levodopa-induced dyskinesias in Parkinson's disease or its animal models. Dyskinesias sometimes have a dystonic quality, and negative allosteric modulators of metabotropic glutamate receptor mGluR5 appear to specifically suppress dystonic dyskinesias in animal models [25,26]. These observations raise the intriguing possibility that this category of drugs may suppress dystonia in other disorders, but further studies are needed.…”

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

“…The development of mavoglurant or AFQ056 [methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl) ethynyl]octahydro-1H-indole-1-carboxylate] (Vranesic et al, 2014) for the treatment of dyskinesia induced by L-DOPA (L-3,4-dihydroxyphenylalanin) (Stocchi et al, 2013) has been discontinued in view of its reported insufficient efficacy (Petrov et al, 2014). More recently, the clinical development of mavoglurant and basimglurant for fragile X syndrome (FXS) also has been discontinued because neither drug improved the clinical phenotype of patients (FRAXA mavoglurant posting, FRAXA basimglurant posting), an unexpected result in view a strong hypothesis (Krueger and Bear, 2011;Michalon et al, 2012;Scharf et al, 2015).…”

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

“…Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias. To moderate this uncontrolled signaling or neuronal excitability, several approaches have been explored such as reducing D1R surface expression (29,30), dampening overactive intracellular signaling (20,23,31,32), and inhibiting A2A (33,34), mGluR5 (35)(36)(37) or NMDA receptors (24,25,(38)(39)(40). Although these targets have clinical potential, several drugs to these targets have either failed clinical trials or have the potential to affect other key CNS physiological processes.…”