$CARA Positive Data From Quantitative Phase 1 Trial

“We are very pleased that I.V. CR845 demonstrated no significant alteration in any measure of respiratory drive, even at doses five-fold greater than the projected therapeutic dose,” said Joseph Stauffer, D.O., M.B.A., Chief Medical Officer of Cara Therapeutics. “These data further underscore the overall clinical safety profile of CR845 for use in postoperative pain management and continue to differentiate it from traditional mu opioids.”

“There remains a clear unmet need for effective analgesic agents that lack the risk of serious, potentially fatal respiratory depression that is inherent in current opioids,” said Christopher Wu, M.D., Department of Anesthesiology and Critical Care, Johns Hopkins University. “The ability to administer I.V. CR845 without any direct effect on respiratory function is a significant advantage in the acute post-surgical care setting where patients are already at heightened risk of respiratory depression. CR845’s profile also aligns with the most recent standard of care guidelines for postoperative pain, which call for minimizing opioid-related side effects.”

Respiratory Safety Phase 1 Trial Design and Results

The Phase 1 trial was a randomized, double-blind, placebo-controlled, three-way crossover trial of two doses of I.V. CR845 (1.0 ug/kg, and 5.0 ug/kg) versus placebo on three measures of respiratory drive in 15 healthy volunteers. Each subject was randomized to one of three treatment sequences and was administered I.V. bolus placebo, CR845 (1.0 ug/kg) and CR845 (5.0 ug/kg) on sequential 24-hour periods, with CR845 at 5.0 ug/kg representing a projected five-fold supra-therapeutic dose. After each administration, and continuing through four hours post-dosing, end-tidal CO2 (ETCO2), oxygen saturation (SpO2) and respiratory rate were continuously monitored. The primary safety endpoints were: a >10 mmHg sustained (>30 seconds duration) increase in ETCO2 above baseline or to >50 mmHg, and a sustained reduction in SpO2 to <92 percent.

Mean ETC02 pre-dosing ranged from 36.1 ± 3.9 to 37.8 ± 2.9 mmHg across treatment groups. At one hour post-administration, ETC02 values for placebo, CR845 1.0 ug/kg and CR845 5.0 ug/kg treatment groups were numerically and statistically equivalent at 38.1 ± 2.8, 38.1 ± 3.1, and 38.3 ± 2.9 mmHg, respectively. Pre-treatment levels of SpO2 ranged from 98.3 percent ± 1.2 to 98.9 percent ± 1.0 and were measured at 97.8 percent ± 1.2, 98.2 percent ± 1.5 and 97.9 percent ± 1.0 for placebo, CR845 1.0 ug/kg and CR845 5.0 ug/kg treatment groups respectively, at one hour post-treatment. There were no statistically significant differences in any respiratory measures between groups throughout the four-hour observation period and no individual patient met the threshold for a respiratory safety event.

All reported treatment-emergent adverse events were previously reported with CR845 administration and were mild, resolving without intervention.

An oral presentation of this dataset will be part of the Journal Anesthesiology Symposium on Sunday, October 22, 2017 at the American Society of Anesthesiology (ASA) Annual Meeting in Boston, MA.

About Respiratory Depression

Respiratory depression is the most life-threatening side effect of conventional opioids, which act primarily at the mu opioid receptor subtype. Mu opioid receptors are present in high amounts in brainstem areas that control respiration, similar to midbrain and spinal areas that regulate pain perception. A wide variety of factors are involved in determining the effects of mu opioids on breathing, with high potency and speed of onset being well known risk factors, in addition to the presence of sedating medications, the site of surgery and surgical technique used, the presence of underlying disease, and the patient’s age, sex, genetics, and hormonal status, as well as arousal and pain, which can vary substantially between patients. Although death rates from opioid-induced respiratory arrest have declined in many hospitals due to more aggressive patient monitoring, it remains the leading concern of anesthesiologists and pain specialists (1). However, such monitoring is generally not available when patients are discharged home with powerful opioids, and the increasingly high rate of deaths associated with both opioid use and misuse is presently considered a national health crisis.