The biopharmaceutical company Paion AG reported the first human data of its intravenous sedative/anaesthetic CNS 7056. The phase-I proof of concept study compared intravenous CNS 7056 to placebo and a standard dose of midazolam, the current gold standard for procedural sedation. The anticipated favourable profile was observed and no safety issues were raised. Volunteers treated with increasing doses of CNS 7056 were successfully sedated at the higher dose cohorts as expected and recovered to full consciousness rapidly.
A total of 81 subjects were enrolled in the double-blind placebo- and midazolam- controlled phase-I study. The study was designed to explore the safety, tolerability and pharmacokinetics of single ascending doses of CNS 7056 in healthy volunteers. Efficacy was ascertained by assessing the sedation of the volunteers by standardized methods. Midazolam-treated volunteers were included to allow an initial assessment of the comparative efficacy and safety profile of CNS 7056. The stopping criterion for the study was pre-determined as more than 50 per cent of the volunteers reaching loss of consciousness for more than 5 minutes. In the ninth out of 10 planned doses this criterion was met. No serious adverse events occurred, even at doses that induced unconsciousness.
Dose dependent sedation, with a rapid onset of effect, was observed after administration of CNS 7056 at doses of 0.05 mg/kg and higher. Doses of CNS 7056 (0.075 – 0.20 mg/kg) that induced peak sedation levels similar to or greater than those achieved with midazolam (0.075 mg/kg) showed a markedly shorter duration of sedative effect with recovery from sedation within approximately 10 minutes compared to approximately 40 minutes for midazolam. The peak sedative effect of CNS 7056 was reached within four minutes in these dose groups, with initial onset of sedation being observed after approximately one minute. For midazolam, the peak effect was reached after approximately 15 minutes. Duration and depth of sedation increased with higher doses of CNS 7056, while the recovery was still earlier as compared to midazolam.
The company now plans one study with healthy volunteers in colonoscopies and one study with patients undergoing upper gastrointestinal endoscopies. Both studies are expected to start no later than Q3 2009.
CNS 7056 is an ester and pre-clinical studies showed that it is rapidly hydrolysed by tissue esterases to an inactive metabolite. This mechanism of deactivation should result in a more predictable onset and offset profile compared to that seen with drugs that are predominantly metabolized by the liver and, secondly, a lower risk of pharmacokinetic drug interactions. Pharmacokinetic analysis from the current phase-I study confirmed that CNS 7056 was rapidly converted to its inactive metabolite in man. The plasma clearance of CNS 7056 was approximately three times more rapid than the clearance of midazolam. The pharmacokinetic profile of CNS 7056 was linear within the dose range examined.
Paion will now progress to the next stage of development and start seeking a partner for territories outside Japan in parallel to the commencement of phase-II. In Japan, CNS 7056 is partnered with Ono Pharmaceuticals. Wolfgang Söhngen, CEO of Paion commented, "The positive data meet our expectations. We are positive that CNS 7056 could be a valuable alternative for procedural sedation by avoiding the potential for prolonged or overly deep sedation thus potentially reducing the intensity of supervision needed. We will seek ways to explore its potential also in other indications. It was especially re-assuring to see that sedation, to the level of unconsciousness, could be achieved without safety concerns. Paion's management and project team are proud to see that these results confirm our high expectations for the potential of this compound, which was in the pre-clinical development phase when we completed the CeNeS acquisition last summer."