CR665 is the lead clinical development candidate from a series of highly selective peripheral kappa opioid receptor agonists. In preclinical studies, CR665 was highly selective for the peripheral kappa opioid receptor.
Preclinical animal studies suggest that CR665 is a potent analgesic compound. In addition, unlike currently marketed opioids, CR665 does not produce inhibition of intestinal transit (ileus), induce respiratory depression, or elicit signs of addiction in animal models. Preclinical studies also indicate that CR665 possesses anti-inflammatory activities.
The Phase Ia single-centre clinical trial evaluated the safety, tolerability, pharmacokinetic profile, and pharmacological activity of CR665 in a double-blind, randomised, placebo-controlled, single escalating intravenous dose study in 60 healthy male and female volunteers.
CR665 was shown to be safe at all doses investigated, with no apparent gender differences, and no reports of serious side effects or adverse central nervous system activity.
Linear, dose-proportional increases in systemic exposure to CR665 were observed. Relatively low doses of CR665 resulted in plasma levels at or above the plasma levels of drug expected to be associated with clinical analgesic efficacy.
In addition, the pharmacological activity of CR665 at peripheral kappa receptors was confirmed utilizing a quantitative endocrine biomarker, which demonstrated receptor activation at relatively low doses of the drug candidate.
"These preliminary results are consistent with CR665's peripheral mechanism of action," said Frederique Menzaghi, Cara's vice president of research and development.
"The results have not only confirmed our expectations in relation to the safety of CR665 but have also provided evidence of kappa receptor activation at much lower drug doses than predicted from preclinical animal studies," he added.
In a recent interview with the Wall Street Reporter magazine, Derek Chalmers, president and CEO, spoke about his hopes for the company's drug candidate CR665, and its potential impact within the pain market.
"The difficulty for the industry in producing a molecule which selectively interacts with the Kappa receptors on sensory nerve endings is that it is selective for the peripheral sites and doesn't enter the CNS."
"It happens to be that those kappa receptors in the CNS produce side effect such as anxiety and dysphoria," he added.
Chalmers added that the therapeutic window was very narrow because they've relied on molecules, which don't show high peripheral selectivity. On average, the peripheral selectivity for those molecules was somewhere between two and twenty in terms of factor of selectivity over central nervous system effects.
Commenting on the postoperative pain market, in which CR665 was being developed for, Chalmers said: "It's a large market. Most of the activity really relates to companies looking at re-formulations of older opioid molecules, and those re-formulations may have enhanced half-life, they many be more applicable to the acute setting in terms of administration."
"But at the end of the day, all of those formulations really suffer from the same problems as the older non-selective opioid molecules, and that relates to side effects, both centrally and also in terms of the gastrointestinal side effects."