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.

Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, 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, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods. RESULTS: The geometric mean ratios of EE 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, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.

The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) pathology, including the accumulation of amyloid beta (Aß) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aß, including CNP520 (umibecestat), a ß-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aß immunotherapy, are in clinical development in preclinical AD. METHODS: The Alzheimer's Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60-75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer's Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. DISCUSSION: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

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

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-ß (Aß), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aß 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) Aß in rats and dogs, and Aß 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 Aß reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.

Central representation of bladder and colon revealed by dual transsynaptic tracing in the rat: substrates for pelvic visceral coordination.

The neurocircuitry underlying regulation of bladder and distal colon function by Barrington's nucleus (the pontine micturition centre) was investigated in rats by identifying neurons which were transsynaptically labelled from these viscera, with pseudorabies virus (PRV) or genetically modified forms of PRV [PRV-beta-galactosidase (PRV-beta-Gal) and PRV-green fluorescent protein (PRV-GFP)]. PRV injection into the bladder or the colon of separate rats suggested an overlap in the distribution of bladder- and colon-related neurons in Barrington's nucleus, as well as a topographical arrangement whereby dorsal neurons were bladder-related and ventral neurons were colon-related. In rats injected with PRV-beta-Gal into one viscera and PRV-GFP into another, neurons in the major pelvic ganglion and lumbosacral spinal cord were primarily single-labelled at relatively early survival times. With longer survival times many double-labelled neurons (>70%) appeared in Barrington's nucleus, suggesting that individual Barrington's nucleus neurons are synaptically linked to preganglionic parasympathetic neurons which independently innervate the colon or the bladder. In addition to these dual-labelled neurons, Barrington's nucleus neurons which were single-labelled from either viscera were observed and these exhibited a viscerotopic organization consistent with the single-labelling studies. Together, these findings suggest the existence of three neuronal populations in Barrington's nucleus, one which is synaptically linked to both the bladder and the colon and the other two populations which are specifically linked to either viscera. These anatomical substrates may underlie the central coordination of bladder and colon function and play a role in disorders characterized by a coexistence of bladder and colonic symptoms.

Convergent responses of Barrington's nucleus neurons to pelvic visceral stimuli in the rat: a juxtacellular labelling study.

Barrington's nucleus impacts on bladder and distal colon function and relays pelvic visceral information to the forebrain. This study investigated processing of information from the bladder and the distal colon by Barrington's nucleus in the rat. The responses of individual Barrington's nucleus neurons to bladder and/or colon distention were characterized using extracellular recording and the recorded neurons were identified using juxtacellular labelling. Most neurons within Barrington's nucleus (79%) were activated by bladder distention, consistent with its role as a pontine micturition centre. Although no neurons were selectively responsive to colon distention, the majority of bladder-responsive neurons (73%) were also activated by colon distention. In a second study, Barrington's nucleus neurons were characterized with respect to their response to colon distention and their immunoreactivity for the stress-related neuropeptide corticotropin-releasing factor (CRF). Of 30 labelled neurons in the central part of Barrington's nucleus, 53% were activated by colon distention and 63% of these were CRF-ir. This is the first report demonstrating that Barrington's nucleus neurons are responsive to colon distention. The results provide evidence for convergence of information from the bladder and the colon onto individual Barrington's nucleus neurons. Taken with evidence that many Barrington's nucleus neurons are synaptically linked to the bladder and colon, the present study suggests a role for these neurons in coordinating peripheral parasympathetic and central responses to both viscera and implicate CRF as a neurotransmitter in this function. Dysfunctions in this circuit may underlie the coexistence of colon and bladder symptoms observed in functional bowel disorders.