The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

Role of Barrington's nucleus in the activation of rat locus coeruleus neurons by colonic distension.

The locus coeruleus (LC)-noradrenergic system, which has been implicated in arousal and attention, is activated by visceral stimuli such as colon and bladder distension. Neurons of Barrington's nucleus (the pontine micturition center) have been identified which project to both the LC and preganglionic column of the lumbosacral spinal cord. Thus, Barrington's nucleus is positioned to coordinate brain noradrenergic activity with pelvic visceral functions. The aim of this study was to determine whether LC activation by colonic distension was mediated by projections from Barrington's nucleus to the LC in the rat. Lesions of Barrington's nucleus were performed unilaterally by local injection of ibotenic acid (microg/microl, 90 nl) 10 days prior to recording: (i) ipsilateral spontaneous LC discharge rate; (ii) LC responses to colonic distension; and (iii) LC responses to sciatic nerve stimulation. In some rats LC activation by hypotensive challenge was also examined. Lesions of Barrington's nucleus significantly reduced LC activation by colon distension from a magnitude of 26.6+/-6% increase in discharge rate (n=8) to 6.9+/-3% (n=6), while having no effect on basal LC discharge rate. In contrast, LC responses to sciatic nerve stimulation were not altered in rats with lesions of Barrington's nucleus and LC neurons were still activated by hypotensive challenge. These results support the hypothesis that Barrington's nucleus selectively relays input from pelvic visceral afferents to the LC. This may serve as a limb in a circuit designed to coordinate central and peripheral responses to pelvic visceral stimuli.