Shares in Cara Therapeutics (NASDAQ:CARA) have been on a tear since the company reported in March that an IV formulation of its CR845 controlled chronic itch in kidney disease patients. Today, however, shares are giving back some of their gains following tepid results for an oral formulation of CR845 that was studied in osteoarthritis patients.
Preventing pain differently
Unlike opioids that work by binding to the mu-opioid receptors in the central nervous system, CR845 targets kappa-opioid receptors in the peripheral nerves that are closer to the source of pain. CR845 also has a hard time crossing the blood-brain barrier, so it may pose less of a risk of abuse than opioids.
In March, management reported data from part A of a phase 2/3 study in kidney disease patients showing that IV CR845 improves uremic pruritis, or chronic itch. Chronic itch is common in patients with end-stage kidney failure who require dialysis, and it can significantly impair their quality of life.
Currently, uremic pruritis is treated with corticosteroids and antihistamines, but that approach has proven inadequate for many people. Given the negative impact on patients and the need for new treatments, the U.S. Food and Drug Administration granted IV CR845 breakthrough designation for this indication earlier this month. This status doesn't guarantee an FDA approval someday, but it does mean that the FDA will work closely with Cara Therapeutics to improve its chances for a speedy review if phase 3 trials pan out.
An eventual approval of IV CR845 in this indication could translate into a big commercial opportunity because about 60% of the 468,000 Americans with kidney failure who are on dialysis suffer from uremic pruritis, and up to 40% of patients consider their condition moderate to severe.
Coming up shy
Optimism that CR845 could also effectively control pain in other indications, including osteoarthritis, has been a big reason for Cara Therapeutics' recent rally. Unfortunately, yesterday management reported that a phase 2b study evaluating an oral formulation of CR845 in patients with hip and knee pain failed.
The study enrolled 476 patients and evaluated three doses (1 mg, 2.5 mg, and 5 mg) of oral CR845, but only the 5 mg dose showed statistically significant evidence of working, and it was only effective in hip-pain patients.
Overall, patients in the hip and knee groups had a mean reduction of joint pain of 35% versus placebo; however, the p-value of 0.111 suggests the improvement was not statistically significant. In hip-pain patients, there was a 39% reduction in pain with a p-value of 0.043. Management is understandably focusing on that data point as evidence of a win.
As a refresher, a p-value of 0.05 or less indicates that a result is not attributable to chance alone, and the lower the better when it comes to clinical trials.
What's up next?
All systems remain go for a registration-ready study of IV CR845 in uremic pruritis, but the future is murkier for oral CR845 in osteoarthritis. The hip-pain patient data could heavily influence a phase 3 trial, but I'd feel more comfortable with such a trial panning out if the p-value were 0.01, not flirting with 0.05. Yes, anything under 0.05 points to a statistically significant result, but 40% of phase 3 trials fail, and frankly, I'd like more wiggle room than 0.043 provides.
Nevertheless, an argument could be made that oral CR845 can carve out an important role in treating hip pain in osteoarthritis patients, particularly considering data from the trial on the use of rescue pain medication (drugs intended to relieve symptoms quickly) and the number of people reporting that pain was "very much improved" or "much improved." There was a 41% reduction in rescue pain medication use among patients with osteoarthritis of the hip, and the pain improvement measure on the patient global assessment score has a p-value of less than 0.006 versus placebo. This suggests that oral CR845 could reduce the use of opioids in these patients, and that many patients saw a meaningful benefit.
It will be a while before we get results from late-stage studies of IV CR845 in uremic pruritis and oral CR845 in osteoarthritis, so for now, investors should shift their focus to the ongoing study of IV CR845 in post-operative pain. Earlier this month, an independent monitoring committee recommended after interim analysis that this study continue.