SHELTON, Conn.—Cara Therapeutics Inc., a biotechnology company focused on developing and commercializing new chemical entities designed to selectively target peripheral kappa opioid receptors, announced recently the successful completion of a Phase 1b trial of an intravenous (IV) formulation of CR845 in dialysis patients. The repeat dosing of IV CR845 over one week was observed to be safe and well tolerated across a fivefold dose range, and the trial established a dosing regimen for the ongoing Phase 2 trial in dialysis patients with uremic pruritus. The company expects to report top-line data from this trial in the first half of 2015.
“The completion of this Phase 1b trial and initiation of the Phase 2 study in uremic pruritus is an important step in establishing the potential clinical utility of CR845 in this area of significant unmet medical need,” said Dr. Frédérique Menzaghi, vice president of research and development at Cara Therapeutics. “We are particularly encouraged that preliminary data from this trial indicate that CR845 effectively reduced ‘worst itching’ scores in those subjects who entered the study with ongoing moderate-to-severe uremic pruritus.”
There are currently no approved therapeutics in the United States for uremic pruritus, an intractable type of itch that is generally resistant to conventional treatments and diminishes the quality of life for almost half of all kidney dialysis patients.
Opiate analgesics can act through three different types of opioid receptors called mu, delta and kappa, explains Dr. Derek Chalmers, president and CEO of Cara Therapeutics. “Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu receptor, which is located in the central nervous system (CNS). This CNS action induces pain relief, but is also associated with a wide array of unpleasant side effects, such as nausea and vomiting, respiratory depression and a high risk of addiction,” he tells DDNews.
“CR845 differs from other opioids because it works on kappa opioid receptors that are localized on peripheral nerve endings. As such, CR845 does not enter patients’ brains and does not cause side effects, such as euphoria, respiratory depression, nausea and vomiting. CR845 has the potential to offer a new and safer approach to the treatment of pain,” he concludes.
The Phase 1b trial was a double-blind, randomized, placebo-controlled trial designed to evaluate the safety and pharmacokinetics (PK) of IV CR845 in 24 hemodialysis patients. IV CR845 was administered as a bolus dose (0.5 µg-2.5 µg/kg) after each dialysis session up to three times a week (t.i.w.). PK analysis indicated that IV CR845 exhibited dose linear increases in Cmax and AUC with an approximate tenfold increase in AUC across doses in these dialysis patients compared to normal subjects.
IV CR845 was observed to be safe and well tolerated over the one-week dosing period with no serious adverse events (AEs) reported. The most common AEs were transient facial tingling and headache. Although uremic pruritus was not an inclusion criterion for randomization, three subjects entered the trial with “worst itching” baseline scores in the moderate-to-severe range, more than four on a 10-point visual analog scale (VAS). All three subjects received t.i.w. dosing of IV CR845 (two subjects at 1 µg/kg, one at 2.5 µg/kg) and ended the one-week dosing period with reported “worst itching” scores of one or less.
“We are very encouraged that our clinical data to date in hemodialysis patients indicate that CR845 may provide a novel therapeutic approach for patients suffering the burden of chronic pruritus associated with chronic kidney disease,” said Chalmers. “The ability to broaden the potential clinical utility of CR845 beyond pain into the spectrum of conditions associated with chronic pruritus is a significant opportunity, and we look forward to seeing the data from this additional set of patients with uremic pruritus next year.”
The ongoing Phase 2 trial will measure the efficacy of IV CR845 compared to placebo in reducing the intensity of itch in dialysis patients with baseline “worst itching” scores of four or greater over a two-week dosing period. The primary endpoint of the study will be the change from baseline in the average “worst itching” scores during the second week of treatment, as recorded on a VAS. Secondary endpoints will focus on quality-of-life measures associated with pruritus burden using a series of previously validated self-assessment scales. The study will enroll a total of 60 dialysis patients at multiple sites in the United States.
In multiple randomized, double-blind, placebo-controlled Phase 2 trials in patients undergoing laparoscopic hysterectomy or bunionectomy procedures, IV CR845 treatment resulted in statistically significant reductions in pain intensity and opioid-related side effects. In over 400 subjects dosed to date, IV CR845 was observed to be safe and well tolerated, without incurring the dysphoric and psychotomimetic side effects that have been reported with centrally acting kappa opioid receptor agonists. In a human abuse liability trial, IV CR845 met the primary endpoint showing highly statistically significant reductions (p < 0.0001) in scores for “drug liking,” as well as “feeling high,” “overall liking” and “take drug again” when compared to intravenous pentazocine, a Schedule IV opioid analgesic.
“Based on CR845’s success in clinical trials thus far,” Chalmers states, “we see markets ranging from postoperative and chronic pain to uremic and general pruritus. Worldwide postoperative pain market sales are estimated to be more than $5.9 billion, and additional opportunities exist in the acute/chronic pain market. Further, results of a recent physician survey we conducted show that a majority of physicians (84 percent) reported they were likely to extremely likely to prescribe oral CR845 for their patients with moderate-to-severe pain.”
Commenting on the Cara studies, Canaccord Genuity analyst Corey Davis said, “While still the single largest pharma market in volume terms, a potent alternative to opioids for pain has remained elusive. Cara seems to have found the most promising candidate—a highly selective kappa-opioid receptor agonist—CR854.
“We have certainly seen our fair share of pain drug trials, and the K drugs in general have virtually all failed. For this reason, we use a very high 45-percent discount rate in deriving our $20 target. However, if the Ph3 IV and/or the Ph2 oral trials are successful, we would argue very strongly that a much lower discount rate should be applied.”