A Cara Therapeutics drug developed to treat the severe itching experienced by patients receiving hemodialysis has met the main goal of a second late-stage study, setting up the experimental medicine for regulatory filings in the US and Europe.
Cara (NASDAQ: CARA) is testing its injectable drug, difelikefalin (Korsuva), in patients who have moderate-to-severe chronic kidney disease. According to the company, an estimated 40 percent of these patients experience pruritus, which is a persistent and intense itching sensation on their skin. Steroids and antihistamines are among the treatments prescribed for pruritus but there are no therapies approved in the US or Europe that specifically address the condition.
The Cara drug is designed to hit kappa opioid receptors, which play a role in itching and pain. Stamford, CT-based Cara says its drug blocks the neurons associated with sensing pruritus. The drug is designed to target peripheral receptors rather than those in the central nervous system, and to hit kappa receptors while avoiding mu receptors, another opioid receptor subtype. Cara contends that this selective approach avoids triggering addiction or respiratory depression, side effects associated with opioid receptor-targeting drugs.
The data announced Tuesday were from a global Phase 3 study that enrolled 475 patients who were randomly assigned to receive difelikefalin or a placebo. The main goal was to show a three point or greater improvement from baseline after 12 weeks as measured by an itching intensity scale. Cara said that 54 percent of patients treated with its drug met that mark, versus 42 percent of those given a placebo. On the secondary goal of showing a four point or greater improvement in the weekly average score at week 12, 41 percent in the treatment group achieved that mark compared to 28 percent in the placebo arm.
In a measure of quality of life, patients treated with difelikefalin showed improvement in the average of the total scores of two itching assessments. But the change was not enough to be statistically significant, Cara said. The injection was well tolerated by patients; the most common serious side effects reported in the clinical trial were diarrhea, falls, vomiting, nausea, and dizziness.
The results released Tuesday come nearly a year after Cara released positive data from its first Phase 3 study of difelikefalin. Based on the results of both studies, the company is now preparing to submit its drug for review by US and European regulators in the second half of this year.
Speaking on a conference call Monday, CEO Derek Chalmers said that a higher placebo response in the second Phase 3 study compared to the first one was not a surprise. In the first Phase 3 study, conducted with only US patients, the placebo response was seen in 28 percent of patients. With the second study drawing from a more diverse patient pool spanning the world, Chalmers said an increase in placebo response was expected. But he added that the drug achieved statistical significance according to measures agreed upon by the company and the FDA.
“We took quite some time with the FDA to define what a reduction threshold in [the itching score] means with respect to clinical meaningfulness, and that was an analysis we performed empirically on our Phase 2 data,” Chalmers said. “From that analysis, it’s clear that a three-point reduction is very much clinically meaningful for a hemodialysis patient suffering from pruritus.”
As for the drug falling short of statistical significance in improving quality of life, Chalmers said that those measures will not be part of the drug’s label and Cara is not relying on them for regulatory approval.
Pruritus has proven to be a tough target as drug developers have been stymied by high placebo responses. Menlo Therapeutics (NASDAQ: MNLO) tried to treat it with a small molecule, serlopitant, designed to block neurokinin 1 receptor, a nerve signaling path for itching. But after reporting three clinical trial failures for the compound this year, the Bridgewater, NJ-based company announced earlier this month that it would stop further research on the drug.
New Haven, CT-based Trevi Therapeutics (NASDAQ TRVI) aims to treat pruritus with a drug that targets both kappa and mu receptors, activating the former and blocking the latter. The compound, an extended-release formulation of nalbuphine hydrochloride, is an opioid. But the company says since the drug blocks mu receptors, it reduces the risk of abuse associated with drugs that activate those receptor subtypes. Trevi initially reported mixed results from Phase 2 tests of its drug in pruritus associated with the skin disorder prurigo nodularis. Preliminary data from a Phase 2b/3 study are expected in the second half of this year, the company said in its annual report.
Trevi has also advanced its drug to Phase 2b/3 tests in chronic kidney disease-associated pruritus, which is sometimes called uremic pruritus. Trevi says in the regulatory filing that it is “not actively developing nalbuphine ER for uremic pruritus at this time based on our evaluation of the market dynamics, but may consider resuming development in the future.”
In 2018, Cara licensed global rights to difelikefalin to Vifor Fresenius Medical Care Renal Pharma (VFMCRP), a unit of Switzerland-based Vifor Pharma. That deal excludes the US, Japan, and South Korea. If the drug wins FDA approval, Cara has a profit-sharing agreement with VFMCRP that calls for the companies to work together to commericalize the treatment in Fresenius Medical Care’s 2,400 North America dialysis clinics. For other US clinics, Cara holds all promotional rights and will keep profits from those sales.