Despite the higher placebo response than a previous, identically designed experiment turned up, Cara Therapeutics Inc.’s Kalm-2 phase III study of Korsuva (CR-845/difelikefalin) for injection handily reached its primary endpoint in hemodialysis patients with moderate to severe chronic kidney disease-associated pruritus (CKD-aP).

Top-line data with the drug, a kappa opioid receptor agonist partnered with Vifor Fresenius Medical Care Renal Pharma Ltd., of Gallen, Switzerland, showed that the proportion of patients on 0.5 mcg/kg of Korsuva who achieved a three-point or greater improvement from baseline in the weekly mean of the daily 24-hour Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12 was 54% vs. 42% for patients on placebo (p=0.02). CKD-aP is an intractable, systemic itch condition that occurs with high frequency and intensity in patients undergoing hemodialysis.

On the key secondary endpoint, the proportion of patients on 0.5 mcg/kg of Korsuva who gained a four-point or greater improvement from baseline in the weekly mean of the daily 24-hour WI-NRS score at week 12 was 41% vs. 28% for patients on placebo (p=0.01). On itch-related quality of life (QoL) measures, Korsuva patients experienced a 12% and 29% numerical improvement in the average total Skindex-10 and total 5-D Itch scores, respectively, which did not meet statistical significance.

Piper Sandler analyst David Amsellem was pleased, noting in a report that “though the placebo response in Kalm-2 was noticeably higher than that of Kalm-1, some variability is to be expected, given that these are subjective patient-reported outcome measures (also bearing in mind that Kalm-2 had ex-U.S. sites).” He saw “a clear path to FDA approval” for the compound, and marketing clearance will be sought in the U.S. as well as Europe in the second half of this year.

Wainwright analyst Oren Livnat said the Kalm-2 data should quell shareholder jitters. “We’ve repeatedly highlighted that investor sentiment is too pessimistic” related to the drug, he said in a report. Mixed phase II results in December with oral Korsuva “spooked” investors, but “we continue to see peak sales potential over $500 million in the U.S. (ex-U.S. revenue is upside),” and he called Vifor Fresenius the “perfect” commercial partner. Kalm-2 was originally planned to enroll 350 patients but was upsized to a planned 430 upon the interim conditional powering analysis, “likely due to higher placebo response and/or variability in the data,” he said. The final sign-up number was 473.

During Stamford, Conn.-based Cara’s conference call on the results, analyst Christopher Howerton asked about the placebo response. CEO Derek Chalmers said the firm “took quite some time with the FDA to define what a reduction threshold in [WI-NRS] means with respect to clinical meaningfulness, and that was an analysis we performed empirically on our phase II data,” which determined that a reduction of three-point drop “is very much clinically meaningful.” He said the company “had that [placebo] discussion with respect to the oral data. One possibility here – and it remains a possibility, at least as a contributing factor in Kalm-2 – is that there may be some expectation bias on behalf of the patients, related to the previous experience of some of these sites in either our Kalm-1 phase III study or the intravenous [I.V.] phase II. There was a small minority number of sites we used in Kalm-2 in the U.S. that also had experience previously with Korsuva injection [during] other trials. It’s always a possibility that you can be the enemy of your own success here.” The efficacy response was “very robust, regardless of the issues related to variable placebo,” he said. Chief Medical Officer Joana Goncalves pointed out that “in the clinic, nobody is actually measuring pruritus numerically. It’s more subjective. How is your itch? Is it bothering you? When the drug is available, that's how it will be assessed and measured, not placebo response rates from a clinical study.”

Chalmers elaborated on the QoL measures. That’s “not something that's going to be on the label” and Cara is not “crucially relying on” such findings. In any case, the company can “certainly combine the data” from Kalm-1 and Kalm-2 and have regulators look at them together, he said.

The drug was generally well-tolerated with a safety profile consistent with Kalm-1 and with the Korsuva clinical program. Overall, the incidence of adverse events (AEs) and serious AEs were similar across the Korsuva and placebo groups. The most common treatment-emergent AEs reported in >5% of patients were diarrhea (8.1% Korsuva vs. 5.5% placebo), falling (6.8% Korsuva vs. 5.1% placebo), vomiting (6.4% Korsuva vs. 5.9% placebo), nausea (6.4% Korsuva vs. 4.2% placebo) and dizziness (5.5% Korsuva vs. 5.1 % placebo).

In the marketing push, Vifor Fresenius will be promoting to all Fresenius clinics and affiliated physicians, with Cara taking the rest of the market. “We model the target population as approximately the 35% of 500,000 dialysis patients with moderate or severe pruritus,” analyst Livnat wrote. Fresenius centers treat about 38% of all dialysis patients, and the firm already has a sales force promoting end-stage renal disease drugs. Targeted are physicians that already have close ties and economic relationships with Fresenius dialysis centers. “We model over 70% peak penetration into those practices, and about half that peak penetration in the rest of the non-Fresenius market. That yields total penetration of about 50% of over 90,000 patients on I.V. Korsuva by 2027.”

Cara signed the deal with Fresenius in May 2018, banking $50 million in up-front cash and an equity investment of $20 million through the acquisition of common stock at a price of about $17 per share – a premium of about 47% to the previous day’s closing price. Under the terms, Cara is eligible for $470 million more, including $30 million if regulatory milestones are hit and as much as $440 million if tiered, sales-related commercial goals are reached in Fresenius’ region, which excludes the U.S., Japan and South Korea.

Shares of Cara (NASDAQ:CARA) moved little on the Kalm-2 news, closing at $15.42, up 60 cents.

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