Opioid analgesics can act through three different types of opioid receptors, called mu, delta, and kappa. Morphine, the most widely used opioid analgesic, acts primarily via activation of the mu opioid receptor located in the central nervous system (CNS). This CNS action induces pain relief but is also associated with a wide array of CNS-mediated side effects including nausea/vomiting, sedation, respiratory depression, and abuse liability. As a way to avoid these undesirable CNS and mu opioid mediated side effects, there has been an effort to develop opioids which activate peripheral kappa opioid receptors present on sensory nerves, immune cells and the dorsal root ganglion (DRG). Such compounds, Kappa Opioid Receptor Agonists (KORAs), are thought to have the potential to provide pain relief (peripheral opioid analgesia) without producing significant CNS and mu-opioid mediated side effects.
The First Potential Kappa Opioid Receptor Agonist: CR845
Cara Therapeutics is developing the first peripherally acting kappa opioid receptor agonist (KORA) called CR845. CR845 is a potent peripheral kappa opioid receptor agonist with high selectivity over other opioid receptors in the body. The degree of kappa receptor selectivity displayed by CR845 ranks as best-in-class compared to all other previously developed compounds for this therapeutic target. Moreover, CR845 displayed no significant affinity for any other non-opioid known receptors.
CR845 exhibits potent analgesic, anti-pruritic (anti-itch) and anti-inflammatory properties in both human and animals. Since CR845 is intrinsically poor at penetrating the blood-brain barrier, it has shown to produce little to no CNS-mediated side effects that one sees with traditional CNS-acting mu opioids like nausea/vomiting, sedation, respiratory depression, abuse, addiction or euphoria.
Dr. Derek Chalmers CEO Cara Therapeutics
CR845 has been formulated both as an IV and oral formulation and it has been studied for both pain and pruritus (itch). IV CR845 was also studied in a Phase 2 trial for uremic pruritus, a severe itch that develops in upwards of 60-70% of dialysis patients. The study was a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy of I.V. CR845 (1.0 mcg/kg) compared to placebo in reducing the intensity of itch in dialysis patients over a two-week dosing period.
In the study, patients receiving I.V. CR845 experienced a 54 percent greater reduction in worst itch scores than those receiving placebo (p-value = 0.016).
To date, it has shown analgesic, anti-pruritic properties in 5 different Phase 2 studies for acute postoperative pain (IV formulation in laparoscopic hysterectomy and bunionectomy), chronic pain (oral formulation in osteoarthritis) and pruritus (IV for uremic pruritus). Additionally, it has been studied in a human abuse liability (HAL) study which supports the view that CR845 is unlikely to be recreationally abused or lead to physical dependence. In a human abuse liability trial, I.V. CR845 demonstrated statistically significant reductions in “drug liking,” “feeling high,” “overall liking,” and “take drug again” scores in comparison to I.V. pentazocine, a Schedule IV analgesic.
An oral formulation of CR845 is currently being evaluated in a Phase 2b study in osteoarthritis patients and was shown in a Phase 2a study to be well tolerated with twice a day dosing for two weeks, with evidence of decreasing pain scores during that time period.