“The initiation of the first Phase 3 efficacy trial in dialysis patients with CKD-aP is a key milestone in the development of KORSUVA injection as a potential novel treatment option for a significant unmet medical need in this patient population,” said Derek Chalmers, Ph.D., D.Sc., President and Chief Executive Officer of Cara Therapeutics. “Additionally, through the rest of this year, we will be working to expand our clinical development activities with KORSUVA beyond hemodialysis patients into additional renal, hepatic and dermatological patient populations.”
KALM-1 Phase 3 Trial Design
The Phase 3 U.S. study is a multicenter, randomized, double-blind, placebo-controlled 12-week treatment trial (with a 52-week open label extension phase) in the U.S. designed to evaluate the safety and efficacy of 0.5 mcg/kg of KORSUVA injection in 350 hemodialysis patients with moderate-to-severe pruritus.
The primary efficacy endpoint is the proportion of patients achieving at least a 3‑point improvement from baseline with respect to the weekly mean of the daily 24‑hour worst itching intensity numeric rating scale (NRS) score at week 12. In a completed Phase 2 trial, the proportion of patients with an improvement from baseline in the weekly mean worst itching intensity NRS score of ≥3 points at week eight was statistically significantly higher in the KORSUVA 0.5 mcg/kg group compared to the placebo group (64% vs. 29%; p<0.01)1.
Secondary endpoints of the Phase 3 trial include assessment of itch-related quality of life changes measured using validated self-assessment 5-D Itch and Skindex-10 scales, as well as the proportion of patients achieving >4-point improvement from baseline in weekly mean of the daily 24-hour worst itching NRS score at week 12.
The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. CR845/difelikefalin is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority.
CKD-aP is an intractable systemic itch condition that occurs with high frequency and intensity in patients with chronic kidney disease undergoing hemodialysis and peritoneal dialysis. Pruritus has also been reported in patients with stage III-V CKD who are not on dialysis. Aggregate, longitudinal, multi-country studies estimate the weighted prevalence of CKD-aP to be approximately 40 percent in patients with end-stage renal disease (ESRD), with approximately 25 percent of patients reporting severe pruritus. The majority of dialysis patients (approximately 60-70 percent) report pruritus, with 30 to 40 percent reporting moderate or severe pruritus2,3. Recent data from the ITCH National Registry Study showed that among those with pruritus, approximately 59 percent experienced symptoms daily or nearly daily for more than a year. Given its association with CKD/ESRD, most afflicted patients will continue to have symptoms for months or years with currently employed antipruritic treatments, such as antihistamines and corticosteroids, unable to provide consistent adequate relief. Moderate-to-severe chronic pruritus has repeatedly been shown to directly decrease quality of life, contribute to symptoms that impair quality of life (such as poor sleep quality), and is associated with depression4. CKD-aP is also an independent predictor of mortality among hemodialysis patients, mainly related to increased risk of inflammation and infections.
1. Data presentation at 2017 American Society of Nephrology’s Annual Meeting (Kidney Week 2017)
2. Pisoni RL, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2006; 21:3495-3505.
3. Ramakrishnan et al. Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms. International Journal of Nephrology and Renovascular Disease. 2014; 7: 1-12
4. Mathur V. et al. A longitudinal study of Uremic Pruritus in hemodialysis patients. Clin J Am Soc Nephrol. 2010; 5(8):1410-1419