SYNOPSIS • Notalgia Paresthetica (NP) is a common sensory neuropathy of the back characterized by chronic pruritus1 • There are no approved therapies for NP • Difelikefalin (DFK) activates kappa-opioid receptors on peripheral sensory neurons and suppresses itch predominantly by a neuromodulatory effect – Intravenous (IV) DFK is approved for the treatment of moderate-to-severe pruritus in adults with chronic kidney disease undergoing hemodialysis2-5 o IV DFK is not addictive and is not a controlled substance – Oral DFK is being developed across numerous chronic pruritic conditions6 OBJECTIVE • Here we report the results of the phase 2 study (KOMFORT; NCT04706975) evaluating oral DFK for the treatment of moderate-to-severe pruritus in subjects with NP METHODS Study Design • KOMFORT was conducted in adults with a clinically confirmed diagnosis of NP • The study design is shown in Figure 1 Primary Endpoint • The primary endpoint was the change from baseline in the weekly mean of the daily 24-hour Worst Itch-Numeric Rating Scale (WI-NRS) at week 8 Other Endpoints  • ≥4-Point improvement in WI-NRS  • Complete response in WI-NRS – Defined as WI-NRS score of 0 or 1 for at least 70% of the daily non-missing WI-NRS scores for the week • Safety assessments Figure 1. KOMFORT: Phase 2 Study Design 8 Weeks TREATMENTRUN-IN 7 Days END OF TREATMENT 1:1 RandomizationSCREEN Baseline Mean WI-NRS ≥5 Placebo BID 4-Week Active Extension Ongoing Oral DFK 2 mg BID BID, twice daily. RESULTS • A total of 126 subjects were randomized (placebo, n=63; DFK, n=62) • Baseline demographics and disease characteristics were similar between groups (Table 1) – Subjects were predominantly white and female, and the mean age was approximately 60 years in both treatment groups Table 1. Baseline Demographics and Disease Characteristics Characteristic Placebo (n=63) DFK 2 mg (n=62) Age, mean (SD), y 60.2 (11.8) 59.3 (12.4) Female, n (%) 42 (66.7) 48 (77.4) Race, n (%) White 56 (88.9) 49 (79.0) Black 4 (6.3) 10 (16.1) Other/Not reported 3 (4.8) 3 (4.8) BMI, mean (SD), kg/m2 28.7 (5.2) 29.7 (5.8) Duration of notalgia paresthetica, mean (SD), y 8.2 (7.4) 8.9 (10.4) WI-NRS score, mean (SD) 7.6 (1.4) 7.6 (1.4) Moderate (≥5 – <7), n (%) 20 (31.7) 21 (33.9) Severe (≥7), n (%) 43 (68.3) 41 (66.1) BMI, body mass index. Efficacy • DFK resulted in a significant reduction from baseline in the weekly mean WI-NRS score at week 8 (primary efficacy outcome: DFK, 4.0; placebo, 2.4; P=0.001; Figure 2) Figure 2. Primary Endpoint: Change From Baseline in WI-NRS at Week 8 -5 -4 -3 -2 -1 0 ** Week LS M ea n C ha ng e Fr om B as el in e (W I-N R S ) Baseline 1 2 3 4 5 6 7 8 Placebo (n=63) DFK 2 mg (n=62)*** *** *** ** *** *** ** P=0.001 at Week 8 *P<0.05; **P<0.01; ***P<0.001 vs placebo. Analysis conducted in ITT population. LS means from mixed effects model with repeated measures with terms for treatment, week, treatment by week interaction, and baseline WI-NRS score. Bars indicate standard error. Missing data were imputed using multiple imputation under missing-at-random assumption. ITT, intent to treat; LS, least squares. • Reduction in itch intensity was observed with DFK at day 1 compared with placebo (Figure 3) • A significantly greater proportion of subjects achieved a ≥4-point improvement in WI-NRS score at week 8 with DFK vs placebo (Figure 4) • At week 8, a significantly greater proportion of subjects receiving DFK achieved a complete response (WI-NRS of 0 or 1 on at least 70% of the daily non-missing WI-NRS scores for the week) compared with placebo (Figure 5) Figure 3. Change From Baseline in Daily WI-NRS During Week 1 -5 -4 -2 -3 -1 0 1 Day LS M ea n C ha ng e Fr om B as el in e (W I-N R S ) Baseline P=0.001 ** 1 2 3 4 5 6 7 Placebo (n=63) DFK 2 mg (n=62) * ** * * on Day 7 ** *P<0.05; **P<0.01; ***P<0.001 vs placebo. Analysis conducted in ITT population. LS means from mixed effects model with repeated measures with terms for treatment, day, treatment by day interaction, and baseline WI-NRS score. Bars indicate standard error. Missing data were imputed using multiple imputation under missing-at-random assumption. Figure 4. Achievement of ≥4-Point Improvement in WI-NRS 1 8 7 8 11 16 19 18 3 30 43 44 44 41 41 41 0 10 20 30 40 50 1 2 3 4 5 6 7 8 Week Placebo (n=63) DFK 2 mg (n=62) *** *** *** ** * ** ** S ub je ct s, % *P<0.05; **P<0.01; ***P<0.001. Analysis conducted in ITT population. Estimated percentages from a logistic regression with terms for treatment and baseline WI-NRS score. Subjects with missing weekly WI-NRS scores for a particular week due to early termination were categorized as non-responders. No adjustments for multiplicity were made for the secondary or exploratory outcomes. Figure 5. Achievement of Complete Responsea in WI-NRS 0 10 20 30 40 50 1 2 3 4 5 6 7 8 Week Placebo (n=63) DFK 2 mg (n=62) S ub je ct s, % * ** ** * * ** * ** * 1 2 3 3 3 7 5 12 0 0 18 21 22 19 20 22 *P<0.05; **P<0.01; ***P<0.001. Analysis conducted in ITT population. aComplete response was defined as WI-NRS score of 0 or 1 for at least 70% of the daily non-missing WI-NRS scores for the week. Estimated percentages from a logistic regression with terms for treatment and baseline WI-NRS score. Subjects with missing weekly WI-NRS scores for a particular week due to early termination were categorized as non-responders. No adjustments for multiplicity were made for the secondary or exploratory outcomes. A Phase 2 Study of Oral Difelikefalin for Moderate-to-Severe Pruritus in Subjects With Notalgia Paresthetica (KOMFORT) Brian S. Kim, MD, MTR1; Robert Bissonnette, MD, FRCPC2; Kristine Nograles, MD3; Catherine Munera, PhD3; Nilam Shah, PharmD3; Alia Jebara, MD3; Joshua Cirulli, PharmD3; Joana Goncalves, MD3; Mark Lebwohl, MD1 1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Innovaderm Research, Montreal, QC, Canada; 3Cara Therapeutics, Stamford, CT, USA Presented at: the Fall Clinical Dermatology Conference; October 20–23, 2022; Las Vegas, NV Safety • All adverse events (AEs) in DFK-treated subjects were mild to moderate in severity (Table 2) • The most common treatment-emergent AEs (TEAEs) leading to discontinuation were dizziness (n=5; 8.1%) and nausea (n=4; 6.5%) in the DFK group and abdominal pain (n=2, 3.2%) in the placebo group • Headache, dizziness, constipation, and increased urine output were more commonly reported in subjects treated with DFK (Table 3) Table 2. Summary of TEAEs Subjects, n (%) Placebo (n=63) DFK 2 mg (n=62) ≥1 TEAE 32 (50.8) 35 (56.5) ≥1 Serious TEAE 0 0 TEAEs leading to discontinuation of trial regimen 4 (6.3) 12 (19.4) Safety analyses were conducted in the safety population, which was defined as all randomized subjects who received ≥1 dose of study drug based on actual treatment received. Table 3. Most Commonly Reported TEAEs TEAEs (≥5% frequency), n (%) Placebo (n=63) DFK 2 mg (n=62) Nausea 7 (11.1) 8 (12.9) Abdominal paina 8 (12.7) 7 (11.3) Headache 3 (4.8) 7 (11.3) Dizziness 2 (3.2) 7 (11.3) Constipation 4 (6.3) 6 (9.7) Increased urine outputb 1 (1.6) 5 (8.1) Safety analyses were conducted in the safety population, which was defined as all randomized subjects who received ≥1 dose of study drug based on actual treatment received. aIncludes the preferred terms abdominal pain, upper abdominal pain, abdominal discomfort, and lower abdominal pain. bIncludes increased urine output and pollakiuria. CONCLUSIONS • The phase 2 KOMFORT study demonstrated that oral DFK significantly reduced itch intensity compared with placebo in subjects with NP • The onset of action was evident at day 1 and maintained through week 8 • A significantly greater proportion of subjects receiving DFK vs placebo achieved a complete response • DFK was generally well tolerated • The most commonly reported AEs were headache, transient dizziness, constipation, and increased urine output • The results of this phase 2 trial support the role of kappa-opioid receptor activation for the control of neuropathic itch • These findings underscore that DFK has the potential to fill a significant unmet need and warrants further clinical development in NP REFERENCES 1. Ellis C. Dermatol Pract Concept. 2013;3:3-6. 2. Fishbane S, et al. N Engl J Med. 2020;382:222-232. 3. Topf J, et al. Kidney Med. 2022;4(8):100512. 4. Korsuva. Package insert. Cara Therapeutics, Inc.; 2021. 5. Kapruvia. Summary of product characteristics. Vifor Fresenius Medical Care Renal Pharma France; 2022. 6. Kim BS, et al. Oral difelikefalin reduces pruritus in atopic dermatitis. Presented at: the 30th European Academy of Dermatology and Venereology Congress; September 29–October 2, 2021. ACKNOWLEDGMENTS This study was sponsored by Cara Therapeutics. The authors thank the study investigators and patients who participated in this study. We also gratefully acknowledge Illyce Nunez, PhD, and Callie Grimes, PhD (Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ), for medical writing and editorial support, which was funded by Cara Therapeutics, under the direction of the authors. CORRESPONDENCE Mark Lebwohl – lebwohl@aol.com DISCLOSURES BSK: AbbVie, Abrax Japan, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Escient Pharmaceuticals, Galderma, GlaxoSmithKline, Granular Therapeutics, Incyte, LEO Pharma, Lilly, Pfizer, Recens Medical, Regeneron, Sanofi, Trevi Therapeutics – consulting. Cara Therapeutics and LEO Pharma – research grant. RB: AbbVie, Arcutis, Arena Pharma, Asana BioSciences, Bellus Health, Bluefin Biomedicine, BioMimetix, Boehringer Ingelheim, Boston, Brickell, Cara Therapeutics, Clexio, Dermavant, Eli Lilly, EMD Serono, Evidera, Galderma, GlaxoSmithKline, Incyte, Inmagene Bio, Janssen, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Novartis, Pfizer, Ralexar, RAPT Therapeutic, Regeneron, Respivant, Sanofi, Sienna, Target RWE, and Vyne Therapeutics – advisor, consultant, speaker, investigator, and/or research grant. Innovaderm Research – employee and shareholder. KN, CM, NS, AJ, JC, & JG: Cara Therapeutics, Inc. – employment. ML: Mount Sinai – employee. AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Cara Therapeutics, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB – research funds. Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Inc., Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd., LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica – consultant.