Cara’s Phase III Success In CKD-Pruritus Puts NDA Filing In Sight
Executive Summary
Second Phase III study expected later this year, but Cara wants to discuss the possibility of accelerated filing with the US FDA. It also has an oral formulation in Phase II for less severe CKD patients.
Cara Therapeutics Inc. hit the primary endpoint and secondary endpoint along with multiple quality-of-life measures in the first of two Phase III trials for Korsuva, its intravenous therapy for moderate-to-severe pruritus in chronic kidney disease patients on dialysis. The company intends to discuss NDA filing plans with the US Food and Drug Administration later this year while awaiting data from a second pivotal trial.
Analysts called the top-line data from the 350-patient KALM-1 study unveiled on 29 May “a home run” and “significantly de-risking” for the first-in-class, selective kappa opioid receptor agonist. While KALM-1 was solely conducted at US sites, Cara expects data from the global KALM-2 trial during the second half of the year and also plans to discuss with the FDA the possibility of an accelerated filing based on findings so far.
Connecticut-based Cara licensed EU rights to the compound last May to Vifor Fresenius Medical Care Renal Pharma Ltd. in a deal that also gave the Swiss firm rights in South American and some Asia-Pacific markets other than Japan and South Korea. (Also see "Cara’s Partnership With Vifor Fresenius Provides Validation For Pruritis Drug Korsuva " - Scrip, 23 May, 2018.) That agreement also included a co-promotion and profit-sharing arrangement in the US under which the drug will be marketed to Fresenius SE & Co. KGaA dialysis centers with Cara booking the sales and splitting revenues from those sales evenly with Vifor Fresenius. Cara CEO Derek Chalmers told Scrip he estimates Fresenius covers about 38% of the US dialysis market, while Cara will retain full commercial rights in the rest of the US dialysis market.
“We thought that would diminish the launch risk for this product if we had a major dialysis provider that could help with the momentum of that launch and could get the drug onto its formularies rapidly,” Chalmers explained. “The conditions are good. It’s a 50/50 profit split, we aim to leverage their infrastructure within their clinics, and we book all sales.”
Cara has FDA breakthrough therapy designation for injectable Korsuva (CR845/difelikefalin) for the CKD-associated pruritus indication, which is one of the reasons Chalmers is hoping for an easy path through the agency. The company also has an oral formulation of Korsuva in Phase II – it sees the intravenous formulation as a product specific to the hemodialysis setting, while oral Korsuva could have broader application as an anti-pruritic in less severe renal disease, Chalmers noted.
NDA Filing Likely To Be Based On Both Phase III Trials
During an end of Phase II meeting with Cara, the FDA raised the possibility of approval in CKD-associated pruritus based on a single clinical trial. Chalmers said the company plans to discuss that possibility with the agency later this year, but sounded like he anticipates the filing ultimately will be based on data from the two Phase III studies. He expects a priority review and thinks Cara could get other concessions from FDA such as a safety requirement less than that standard 1,500 drug exposures needed for approval.
“It’s possible that we could get some concessions from the FDA if the KALM-1 data are [considered] statistically compelling, and that’s a conversation we plan to have at an FDA meeting later this year,” the exec said. “It’s the FDA’s decision how they treat these data – and if we get concessions at all – but once we have that meeting, we’ll certainly guide to the outcome of that and whether we can file this NDA in an accelerated fashion.”
Korsuva met the primary endpoint in KALM-1, which measured the percentage of patients achieving 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) compared to placebo over 12 weeks. In the study, 51% receiving Korsuva met that measure, compared to 28% in the placebo arm (p=0.000019).
Chalmers said the placebo effect was in line with what Cara had anticipated, as studies in pruritus and pain indications using patient self-assessment measures typically show a placebo response ranging between 20% and 30%. During its discussions with the FDA prior to beginning Phase III, Cara determined that a 2.5-point reduction in WI-NRS or greater would be clinically meaningful for patients, and rounded that number up to three points for the study. The responder analysis protocol based on that endpoint was the basis for the FDA awarding the breakthrough therapy designation for injectable Korsuva, the exec noted.
Other Endpoints May Bolster Efficacy Argument, Enhance Label
Korsuva also hit the study’s secondary endpoint, comparing study drug to placebo looking at patients with a four-point or greater improvement from baseline in WI-RNS. Thirty-nine percent of patients receiving Korsuva met that measure, compared with 18% in the placebo group (p=0.000032).
Cara also reported that Korsuva met statistical significance in KALM-1 on a pair of validated quality-of-life itch-related self-assessment tools. Patients experienced a 43% improvement in average total Skindex-10 score compared to placebo (p=0.0004) and a 35% improvement in average total 5-D itch score compared to placebo (p=0.0009).
Chalmers said Cara included the four-point improvement in WI-NRS endpoint in the trial to potentially bolster its argument for a robust therapeutic response with the FDA. “We wanted to show not only can we meet our predefined primary endpoint, but we can beat that and show good efficacy even at the four-point level,” he said. “That’s a discussion point that we can use with the FDA in relation to labeling.”
As for the quality-of-life measures, Cara hopes they might be included in the label’s clinical section. “That would indicate to end-users, clinicians, that this is a drug that not only reduces the level of pruritus in patients but also that patients perceive that benefit with an improvement in their quality of life scores,” Chalmers said.
In a note issued on 29 May, Laidlaw & Company analyst Francois Brisebois said the data de-risked Korsuva, and added that “we were particularly impressed with Korsuva’s ability to demonstrate statistically significant improvements in itch-related quality-of-life measures at 12 weeks.” The analyst also predicted that the KALM-1 data could have read-through for positive results in both KALM-2 and the ongoing Phase II study of oral Korsuva in non-dialysis CKD patients. Like KALM-2, the Phase II oral study is expected to read out during the second half of 2019.
Jefferies analyst Chris Howerton described the KALM-1 data as a “home run” for Cara in a 29 May note and also predicted read-through to the other two ongoing pruritus studies with Korsuva.
“This treatment effect was comparable to robust Phase II results, suggesting consistently high efficacy and good study conduct,” Howerton wrote. “Impressively, the significant separation of itch reduction vs. placebo started at week one, better than that observed in Phase II (at week four onwards).”
Beyond developing the IV formulation of Korsuva for pruritus in dialysis patients and the oral formulation in stage III-V CKD patients not only dialysis, Cara intends to launch Phase II studies with oral Korsuva in liver disease-related pruritus and in atopic dermatitis. It is also studying the drug in post-operative pain, but has put that work on the backburner to focus on pruritus, Chalmers said. (Also see "Cara Therapeutics' Stock Buoyed By Positive Korsuva Data For Post-Op Pain " - Scrip, 28 Jun, 2018.) As of the end of the past quarter, Cara had cash of about $156.1m on hand, which it expects to provide financial runway until the end of 2020.