Background: Chronic kidney disease–associated pruritus (CKD-aP) in patients undergoing hemodialysis (HD) is a common and distressing condition and seriously impairs quality of life (QoL). Difelikefalin, a selective kappa-opioid receptor agonist, decreases intensity of pruritus in HD patients. The antipruritic effect of difelikefalin may be due to activation of kappa opioid receptors on immune cells and peripheral sensory neurons. This presentation reports the results from the KALM-1 and KALM-2 phase 3 trials that supported the recent US approval of difelikefalin (KORSUVA) for the treatment of moderate to severe CKD-aP in adults undergoing hemodialysis. Study Design: In KALM-1 and KALM-2 trials, subjects were randomized (1:1) to receive intravenous (IV) difelikefalin (0.5 mcg/kg) or placebo 3 times/week for 12 weeks followed by a 52-week open-label extension. Trial participants were adults with moderate-to-severe CKD-aP undergoing HD in North America, Europe, and the Asia-Pacific region. Efficacy Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch- related QoL (Skindex-10 and 5-D Itch scales). Results: There were 851 subjects randomized (difelikefalin: 426; placebo: 425) between the KALM-1 and KALM-2 trials. Mean age of subjects was 58.7 years; the proportion of subjects aged ≥65 years was 33%. Most subjects were male and White. The mean HD duration was 4.6 years, and the mean duration of pruritus was 3.2 years. Approximately 40% of subjects reported the use of anti-pruritic medications at baseline. The most commonly used anti-pruritic medications were diphenhydramine, hydroxyzine, hydrocortisone, cetirizine, and clemastine. Gabapentinoids were used for itch by <2% of subjects, although approximately 20% of subjects were using gabapentinoids for all indications. In KALM-1 and KALM-2, difelikefalin showed significant and clinically meaningful itch reduction (≥3-point WI-NRS reduction) versus placebo (51.0% vs 27.6% and 54.0% vs 42.2%, respectively) at week 12. The onset of treatment effect was rapid (1 week). A pooled analysis demonstrated that difelikefalin reduced itch regardless of age, sex, anti-itch medication use, presence of specific medical conditions, and gabapentin or pregabalin use. In both trials, difelikefalin also improved itch-related QoL based on assessments with Skindex-10 and 5-D Itch. Greater proportions of difelikefalin-treated subjects achieved clinically meaningful decreases (≥5 points) in 5-D Itch scores versus placebo, with a sustained treatment effect observed up to 64 weeks. The most commonly reported adverse events, occurring in ≥2% of subjects receiving difelikefalin and with ≥1% higher incidence than placebo, were diarrhea, dizziness, nausea, gait disturbance including falls, hyperkalemia, headache, somnolence, and mental status changes. These were mostly mild or moderate, with few leading to discontinuation. Incidence rates of TEAEs, serious TEAEs, and discontinuations due to TEAEs did not increase with long-term exposure. The mortality rate during long-term exposure was within the mortality rates reported in the literature for hemodialysis patients. Conclusions: Results from KALM 1 and KALM 2 trials demonstrate rapid, sustained efficacy of difelikefalin, with consistent results in diverse populations of patients. Difelikefalin presented an acceptable safety profile and was generally well tolerated with long-term use. Intravenous difelikefalin provides an effective and safe treatment option for adults with CKD-aP undergoing HD and may address an unmet treatment need in these patients.