Presented at the 2022 Fall Clinical Dermatology Conference®; October 20-23, 2022; Las Vegas, Nevada Background • Prurigo nodularis is a chronic inflammatory dermatologic condition characterized by intense pruritus and raised nodular lesions, papules, and/or plaques1 – The global prevalence of PN is estimated to be 730,0002 • Pruritus is a severe and often treatment-resistant symptom of PN3 • There are no approved pharmacologic therapies for patients with PN • κ- and μ-opioid receptors are critical mediators for itch, with important roles in the itch-scratch cycle and PN-related pruritus4 • Nalbuphine extended-release (NAL ER) is a dual-acting κ-opioid receptor agonist/μ-opioid receptor antagonist that acts centrally and peripherally4 – In contrast with activation of µ-opioid receptors, κ-opioid receptor activation is not associated with abuse or addiction5 • The IV formulation of nalbuphine is an unscheduled opioid (ie, not controlled under the Controlled Substances Act by the Drug Enforcement Agency) in the United States and most of Europe6,7 • NAL ER may improve the balance of κ- and μ-opioid receptor activity and therefore may be an oral treatment option for patients with PN-related pruritus8 Objective • To assess the antipruritic and lesion-reducing efficacy and safety of oral NAL ER in patients with PN in the phase 2b/3 PRISM trial Methods Study Design • PRISM (NCT03497975) was a randomized, double-blind, placebo-controlled, phase 2b/3 trial of adult patients with confirmed PN, ≥10 pruriginous nodules on ≥2 distinct anatomical areas, and WI-NRS score ≥7 • Participants received oral NAL ER 162 mg or placebo twice daily • The study consisted of a 2-week titration phase, a 12-week fixed-dose treatment phase, and a 2-week off-treatment safety phase • The primary end point was the percentage of responders who had ≥4-point reduction in WI-NRS score • Key secondary end points were: – LSM change from baseline in ItchyQoL – Participants with ≥1-category improvement in PAS question 5a (to assess improvement in PN skin lesions) Oral Nalbuphine Extended-Release Is Effective in Severe Prurigo Nodularis–Associated Pruritus: Results From a Phase 2b/3, Double-Blind, Placebo-Controlled Study Sonja Ständer,1 Elke Weisshaar,2 Jennifer L. Parish,3 Jacek C. Szepietowski,4 Adam Reich,5 Neil J. Korman,6 Enoch Bortey,7 Thomas R. Sciascia7 1Münster University Hospital, Münster, Germany; 2Ruprecht-Karls University, Heidelberg, Germany; 3Thomas Jefferson University, Philadelphia, PA, USA; 4Wroclaw Medical University, Wroclaw, Poland; 5University of Rzeszow, Rzeszow, Poland; 6University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 7Trevi Therapeutics, New Haven, CT, USA Results Table 1. Participant Demographics and Baseline Disease Characteristics NAL ER n = 168 Placebo n = 176 Age, mean ± SD, years 59.6 ± 13.3 55.9 ± 14.3 Female, n (%) 100 (59.5) 112 (63.6) Weight, mean ± SD, kg 85.7 ± 20.5 84.7 ± 20.9 Race, n (%) White Black or African American Native Hawaiian or Other Pacific Islander Asian Multiple 132 (78.6) 24 (14.3) 6 (3.6) 6 (3.6) 0 134 (76.1) 23 (13.1) 11 (6.3) 7 (4.0) 1 (0.6) Region, n (%) Europe North America 99 (58.9) 69 (41.1) 103 (58.5) 73 (41.5) Baseline disease WI-NRS,a mean ± SD ItchyQoL, mean ± SD No. of prurigo lesions,b n (%) 1-19 20-100 >100 8.6 ± 0.9 84.9 ± 15.7 17 (10.1) 101 (60.1) 50 (29.8) 8.7 ± 0.9 83.9 ± 16.2 22 (12.5) 93 (52.8) 61 (34.7) a For WI-NRS, the baseline value was calculated as the arithmetic mean of the daily WI-NRS values (≥5 measurements required) taken for eligibility review by site at the time of randomization. bStudy participation required ≥10 pruriginous nodules on ≥2 distinct anatomical areas. Safety Table 2. Safety NAL ER n = 168 Placebo n = 176 Titration Fixed-Dose Titration Fixed-Dose Participants who had ≥1 TEAE Treatment-related AEs 111 (66.1) 86 (51.2) 81 (48.2) 52 (31.0) 55 (31.3) 24 (13.6) 79 (44.9) 22 (12.5) Participants who had TEAEs leading to study discontinuation 33 (19.6) 23 (13.7) 5 (2.8) 7 (4.0) Participants who had any SAEsa 8 (4.8) 6 (3.4) TEAEs that had >15% incidence in any treatment armb Gastrointestinal disorders Nausea Constipation Nervous system disorders Dizziness Headache 84 (50.0) 51 (30.4) 26 (15.5) 81 (48.2) 51 (30.4) 26 (15.5) 37 (21.0) 16 (9.1) 7 (4.0) 28 (15.9) 5 (2.8) 14 (8.0) aNo SAEs were considered treatment related. bBy MedDRA SOC and PT. Efficacy Figure 1. Efficacy of NAL ER Versus Placebo in Patients With PN NAL ER 162 mg Placebo Key Secondary End Points Patients in the NAL ER group achieved significantly greater LSM change from baseline in ItchyQoL than those on placebo The proportion of patients in the NAL ER group achieving ≥1-category improvement from baseline in pruriginous lesions with excoriations/crustb was significantly greater than placebo Primary End Point The proportion of patients in the NAL ER group who had ≥4-point improvement from baseline in WI-NRSa score was significantly greater than in the placebo group WI-NRS ItchyQoL PAS 24.7% 13.9% 54.9% 38.0% −16.5 −9.1 70 30 20 P a rt ic ip a nt s W ho H a d ≥ 1- C a te g or y Im p ro ve m en t, % ( S E) Weeks 10 0 0 10 14 40 50 60 45.5 30.3 54.9 38.0 P = 0.0020 P = 0.0064 NAL ER Placebo 0 −5 −10 LS M C ha ng e Fr om B a se lin e (S E) Weeks −15 −20 0 6 10 14 −10.3 −6.7 −15.5 −7.3 −16.5 −9.1 P = 0.0399 P < 0.0001 P = 0.0002 NAL ER Placebo 35 30 25 R es p on d er s, % ( S E) 20 15 10 5 0 0 6 10 142 5.4 2.0 15.8 3.9 20.9 9.4 24.7 13.9 P = 0.0027 P = 0.0116 P = 0.0157 Primary End Point P = 0.1352 Weeks NAL ER Placebo aBased on 7-day WI-NRS scores. bAs measured by responses to PAS question 5a. Summary • The PRISM study met its primary end point and all key secondary end points – A significantly higher percentage of participants experienced an antipruritic response on week 14 with NAL ER (24.7%) versus placebo (13.9%) – Compared with placebo, NAL ER treatment also resulted in • Greater improvement in ItchyQoL at weeks 6, 10, and 14 • Greater improvement in pruriginous lesions with excoriations/crusts at weeks 10 and 14 • The safety profile of NAL ER was consistent with its known safety profile – A 36-week open-label study is ongoing to assess the long-term safety and efficacy • Use of NAL ER may provide a novel oral treatment approach References 1. Elmariah S et al. J Am Acad Dermatol. 2021;84(3):747-760. 2. Prurigo Nodularis – Market Insights, Epidemiology, and Market Forecast. Accessed September 14, 2022. https://www.delveinsight.com/report-store/ prurigo-nodularis-market 3. Steinke S et al. J Am Acad Dermatol. 2018;79(3):457-463. 4. Elmariah S et al. J Am Acad Dermatol. 2021;7:156-163. 5. Kim BS et al. Abstract presented at: Winter Clinical Dermatology Conference–Hawaii®; January 16-24, 2021; virtual. 6. Drug Enforcement Administration. Nalbuphine hydrochloride. Accessed September 14, 2022. https://www.deadiversion.usdoj.gov/drug_chem_ info/nalbuphine.pdf 7. WHO Expert Committee on Drug Dependence. World Health Organ Tech Rep Ser. 1989;775:1-48. 8. Weisshaar E et al. J Eur Acad Dermatol Venereol. 2021;36(3):453-461. Abbreviations ItchyQoL, Itchy Quality of Life; IV, intravenous; LSM, least squares mean; MedDRA, Medical Dictionary for Regulatory Activity; NAL ER, nalbuphine extended release; PAS, prurigo activity score; PN, prurigo nodularis; PT, preferred term; SAE, serious adverse event; SOC, system organ class; SD, standard deviation; SE, standard error; TEAE, treatment-emergent adverse event; WI-NRS, Worst Itch Numerical Rating Scale Acknowledgments Medical writing assistance was provided by Richard W. Davis IV, PhD, of ApotheCom (San Francisco, CA) and was funded by Trevi Therapeutics, Inc. (New Haven, CT). This study is sponsored by Trevi Therapeutics, Inc. Contact information Contact the author at sonja.staender@ukmuenster.de for questions or comments.