Background Treatments of chorea in patients with HD have limited efficacy and side-effects. AFQ056, a selective metabotropic glutamate receptor-5 antagonist shown to reduce levodopa-induced dyskinesia in PD, was hypothesised to reduce chorea in HD.
Objective To assess anti-choreatic efficacy, safety, and tolerability of AFQ056 (Mavoglurant) in HD.
Methods This was a 32-day randomised, double-blind, parallel-group, placebo (pbo)-controlled, proof-of-concept study. Patients were 30–85 years old, with HD (CAG ≥36) in clinical stage I–III, and maximal chorea sum score >10 in the UHDRS-TMS. Patients were randomised (1:1) to AFQ056 (Days 1–12, titration 25–150mg bid; Days 13–28, 150mg bid; Days 29–32, 50mg bid) or pbo. Primary objectives were to assess efficacy of AFQ056 vs pbo at Day 28 on UHDRS-TMS maximal chorea sum score and orientation index (non-dominant hand) from quantitative-motor (Q-Motor) grasping task and to assess safety and tolerability of AFQ056. Key secondary efficacy assessments included total UHDRS-TMS, UHDRS-TMS Luria score, UHDRS-TMS finger taps, and additional Q-Motor measures.
Results Overall 42 patients (mean age 55.2 years, HD duration 6.6 years) were randomised. At Day 28, there were no significant improvements on UHDRS-TMS maximal chorea sum score (p = 0.155) or orientation index (non-dominant hand, p = 0.626) in AFQ056-treated patients vs pbo. A significant reduction in Q-Motor speeded-tapping variability was observed favouring AFQ056 vs pbo (p = 0.011) and reverting at study end; this was accompanied by UHDRS-TMS finger-tapping scores showing a trend towards improvement. No significant treatment effects were observed at Day 28 on other key secondary endpoints. Adverse events were reported by 14 and 12 AFQ056- and pbo-treated patients, respectively.
Conclusions AFQ056 did not reduce involuntary choreatic movements in HD. The Q-Motor findings in speeded-tapping may reflect an improvement in fine motor coordination, but their clinical relevance is unknown. Overall, AFQ056 was well tolerated.
Study supported by Novartis Pharma AG.
- clinical trial