Cara avoids placebo pitfall with second pivotal win


Cara Therapeutics today announced a second successful pivotal study of its lead anti-itch project, Korsuva, in dialysis patients with pruritus. Still, a much stronger placebo response in Kalm-2 made the win slightly less convincing than in Kalm-1, and caused secondary quality-of-life endpoints to miss significance. The potential for a derailing placebo effect is a big concern for indications like pruritus, as Cara found to its cost late last year when a trial of a follow-on oral formulation was weakened by the control arm. The company’s shares slumped 35% on that news and have never really recovered; investors appear to have written off oral Korsuva, which has greater potential than the injected version used in Kalm-1 and 2. Opinions could shift if an interim statistical analysis on a phase II atopic dermatitis trial, due in the second quarter, yields positive signals; analysts at Stifel believe that this represents the biggest commercial opportunity for oral Korsuva. Either way, Cara plans to file the intravenous project, which is partnered with Vifor in Europe, with global regulators in the coming months. The sellside is pencilling in launch next year and sales of $275m by 2024, according to EvaluatePharma.

Korsuva IV pivotal programme 
  Kalm-2 (Global) Kalm-1 (US only)
  Korsuva (n=235) placebo (n=236) Korsuva (n=189) Placebo (n=189)
≥ 3 improvement in WI-NRS at week 12* 54% 42% 51% 28%
  p=0.02 p=0.000019
Change from baseline in weekly mean WI-NRS  -3.1 -2.4 -3.2 -2.0
  p<0.05 p<0.001
≥4 improvement in WI-NRS at week 12 41% 28% 39% 18%
  p=0.01 p=0.000032
5D-itch (QoL measure, change from baseline) -4.4 -3.9 -5.0 -3.7
  nominal p=0.002 p<0.001
Skindex-10 (QoL measure, change from baseline) -15.3 -15 -17.2 -12.0
  p=0.171 (non significant) p<0.001
*Primary endpoint. WI-NRS = worst itching intensity numeric rating scale. Source: company presentations & NEJM. 


Cara's pruritus programme
Study Enrolment Trial ID Notes
Phase 3
Kalm-2 IV Korsuva in dialysis patients 474
Hit primary, missed secondary endpoints
Kalm-1: IV Korsuva in dialysis patients 378 NCT03422653 Hit primary and secondary endpoints
Phase 2
Oral Korsuva in primary biliary cholangitis  60 NCT03995212 Data due 2020
Oral Korsuva in atopic dermatitis  240 NCT04018027 Interim stats analysis Q2'20; topline 2020
Oral Korsuva in chronic kidney disease  271 NCT03617536 Hit primary endpoint, missed secondary

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