An analgesic with ‘significant potential’

STAMFORD, Conn.—Cara Therapeutics Inc., a biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus, announced top-line results from a Phase 2b trial of an oral tablet formulation of their peripherally selective kappa opioid agonist, CR845, in patients with osteoarthritis (OA) of the knee or hip. CR845 is an opioid analgesic, but it differs greatly from traditional opioids (e.g., morphine, oxycodone).

 

Existing opioid therapies work by activating mu opioid receptors, which are located within the central nervous system (CNS). This CNS action induces effective pain relief, but is also associated with side effects like respiratory depression, nausea and vomiting, sedation and addiction. CR845, on the other hand, works by activating kappa opioid receptors, which are found on peripheral nerve endings. By avoiding the CNS, CR845 shows promise in effectively relieving pain while minimizing the risk of undesirable side effects and abuse liability.

 

In a human abuse liability (HAL) trial comparing CR845 with intravenous pentazocine, a Schedule IV opioid analgesic, CR845 demonstrated significantly lower “drug liking,” “feeling high” and “overall liking” scores when compared to pentazocine. These HAL results underscore the view that CR845 is unlikely to be recreationally abused or lead to physical dependence.

 

“Developing effective analgesics that lack the high abuse potential and serious side effects of currently available drug classes remains the most pressing need in chronic pain,” said Dr. Ajay D. Wasan, professor of anesthesiology and psychiatry and vice chair for pain medicine in the Department of Anesthesiology at theUniversity of Pittsburgh Medical Center (UPMC). “The magnitude of the reduction in mean joint pain scores observed in all patients in this trial together with an encouraging safety profile underscores the significant potential of CR845 as a new therapeutic approach for the treatment of chronic inflammatory pain.”

 

Acute and chronic pain represent very large markets, with an estimated 140 million prescriptions written for treatments addressing moderate-to-severe chronic pain in the United States in 2013 alone. A majority of those written were for OxyContin and the Fentanyl patch, two mu-acting opioid analgesics widely associated with high abuse potential. With more than 60 million post-surgical patients every year in the United States, there’s a huge need for a different approach to managing postoperative pain.

 

The Phase 2b trial was a randomized, double-blind, placebo-controlled trial of three tablet strengths of CR845—1 mg, 2.5 mg and 5 mg—dosed twice a day (BID) over an eight-week treatment period in 476 patients with osteoarthritis of the hip or knee experiencing moderate-to-severe pain. CR845-treated patients reported a statistically significant 39-percent reduction in their daily pain intensity score using a numerical rating scale (NRS) once titrated to a 5 mg dose.

 

A goal of the trial was to inform the patient population and dose range for subsequent trials based on statistically significant efficacy and safety over placebo. Where 1 and 2.5 mg doses didn’t elicit significant mean join paint scores compared to placebo, the 5 mg dose showed a statistically significant 39-percent reduction in the pain of patients with osteoarthritis of the hip. Given these results, Cara Therapeutics anticipates using 5 to 10 mg tablet doses in the next Phase 2 trial, pending discussion with the FDA.

 

“We believe that the present trial of oral CR845 has highlighted the potential of a peripherally acting kappa agonist to provide clinical benefit in a chronic pain population, and we’re pleased that statistical significance was achieved for the 5.0 mg dose in patients with OA of the hip,” commented Joseph Stauffer, chief medical officer of Cara Therapeutics. “The drug was observed to be well tolerated over the treatment period, and this overall data set will inform both our dose selection and patient population in designing our next trial of oral CR845 in OA patients.”

 

Cara Therapeutics is focused on developing oral CR845 for chronic pain and intravenous CR845 for acute postoperative pain. In addition, the company is developing CR845 for chronic kidney disease-associated pruritus (itch), another area of unmet need and large market potential, for which it recently received Breakthrough Therapy designation from the FDA. Following a full analysis of the Phase 2b trial data, Cara will meet with the FDA to determine next steps, including a subsequent Phase 2 adaptive trial of oral CR845 using the increased dose range (5 to 10 mg), with more exposures in patients with osteoarthritis of the hip.