NGX267, a functionally selective muscarinic (M1) agonist, was found to be safe and well tolerated when given orally to healthy male volunteers once-daily for four consecutive days.
In two previous Phase I trials, NGX267, administered as single oral doses, was shown to be well-tolerated in healthy young adult males, as well as in healthy elderly males and females.
The purpose of the Phase I trial was to investigate the safety, tolerability and pharmacokinetics of multiple doses of NGX267 and to confirm data from previous studies in which the compound demonstrated evidence of muscarinic receptor stimulation as measured by increases in salivary flow.
A total of 60 healthy males, between the ages of 18 and 55, were enrolled in the double-blind, placebo-controlled trial conducted at one center in Belgium. In a series of sequential dosing cohorts, subjects received a single oral dose of either 10, 20, 30 or 35mg of NGX267 once-daily for four consecutive days.
NGX267 was well-tolerated at doses up to and including 30mg, a dose range believed to be effective for treating memory and cognitive disturbances. TorreyPines plans to initiate a Phase II dose-ranging trial in cognitive impairment associated with schizophrenia (CIAS) during the first half of 2008.
A secondary objective was to obtain quantitative measures of salivary flow, prior to and at multiple time points post-dosing, as a peripheral biomarker for stimulation of the muscarinic receptor. In the study, increases in peak and total salivary flow were detected for NGX267 in comparison to placebo. These effects increased linearly with dose, were maintained over four days of dosing, and within subject peak increases in salivary flow correlated with peak plasma levels of NGX267.
“The data from this study are promising, given the low incidence of adverse events at potentially therapeutic doses for treating CIAS,” said Neil Kurtz, president and CEO of TorreyPines. “In addition, the data not only confirm earlier findings that NGX267 increases salivary flow, but also demonstrates that the effect is seen at multiple dose levels and maintained after repetitive dosing. In addition to our planned Phase II study in CIAS, we will consider initiating a small proof of concept study for xerostomia early next year.”