Effect of mavoglurant (AFQ056) on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women

Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18–40 years. In Period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In Period 2, OC was administered with a clinically relevant multiple-dose of 100 mg b.i.d. mavoglurant under-steady conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration and PK parameters Cmax and AUClast were estimated using noncompartmental methods. Results: The geometric mean ratios of EE PK parameters Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval [CI]: 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63 0.73), respectively. Conclusions: In conclusion, the EE PK was unchanged, whereas Cmax and AUClast of LNG was approximately 19% and 32% lower, respectively, when given with mavoglurant. Further investigation regarding the impact on contraceptive efficacy is warranted

Efficacy, Safety and Tolerability of AFQ056 for the treatment of chorea in patients with Huntington’s disease

OBJECTIVE To assess the anti-choreatic efficacy, safety and tolerability of AFQ056 in Huntington’s disease (HD). BACKGROUND HD is characterised by involuntary choreatic movements. Treatments of chorea have limited efficacy and side effects. AFQ056, a selective metabotropic glutamate-receptor-5 antagonist shown to reduce levodopa-induced dyskinesia in Parkinson’s disease, was hypothesized to reduce chorea in HD. DESIGN/METHODS 32-day, randomized, double-blind, parallel-group, placebo-controlled, proof-of-concept study. Patients were 30–85 years, with HD (CAG≥36) in clinical stage I–III, and a Unified HD Rating Scale-Total Motor Score (UHDRS-TMS) maximal chorea sum score >10. Patients were randomized (1:1) to AFQ056 (Days 1–12, titration from 25mg to 150mg twice-daily [bid]; Days 13–28, maintenance [150mg bid]; Days 29–32, down-titration [50 mg bid]) or placebo. Primary objectives were to assess the efficacy of AFQ056 versus placebo at Day 28 on the UHDRS-TMS maximal chorea sum score and the orientation index (non-dominant hand) from the quantitative-motor (Q-Motor) grasping task; and to evaluate 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 42 patients (mean age 55.2 years, HD duration 6.6 years) were randomized. At Day 28, there were no significant improvements on the UHDRS-TMS maximal chorea sum score (p=0.155) or orientation index (non-dominant hand, p=0.626) in AFQ056-treated patients versus placebo. A significant reduction in Q-Motor speeded-tapping variability was observed favouring AFQ056 versus placebo and reverting at study end ; this was accompanied by UHDRS-TMS finger-tapping scores exhibiting a trend towards improvement. No significant treatment effects were observed at Day 28 on other key secondary assessments. CONCLUSIONS AFQ056 did not reduce involuntary choreatic movements in HD. The Q-Motor finding in speeded-tapping may reflect an improvement in fine motor coordination, but the clinical relevance of this observation is unknown. Overall, AFQ056 was well-tolerated in HD

A randomized, placebo‐controlled trial of AFQ056 for the treatment of chorea in Huntington's disease

Background This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). Methods This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale–Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. Results Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. Conclusions AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation. © 2015 International Parkinson and Movement Disorder Societ

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease

Background This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). Methods This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale–Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. Results Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. Conclusions AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation. © 2015 International Parkinson and Movement Disorder Societ

The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimer's disease

Abstract The beta‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) initiates the generation of amyloid‐β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti‐Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE‐1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP‐transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose‐dependent Aβ reduction in the cerebrospinal fluid. Thus, long‐term, pivotal studies with CNP520 have been initiated in the Generation Program