An Oral, Selective Tyrosine Kinase 2 Inhibitor, BMS-986165, Reduced Absolute Psoriasis Area and Severity Index in a Phase 2 Trial in Psoriasis Bruce Strober,1 Alice B. Gottlieb,2 Diamant Thaçi,3 Luis Puig,4 Matthew J. Colombo,5 Sudeep Kundu,5 Renata Kisa,5 Subhashis Banerjee5 1Yale University, New Haven, CT, and Central Connecticut Dermatology Research, Cromwell, CT, USA; 2Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Research Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany; 4Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; 5Bristol-Myers Squibb Company, Princeton, NJ, USA Conclusions • This analysis suggests that BMS-986165 elicits a rapid response and is efficacious in achieving an absolute PASI of ≤2 in approximately 50% of patients and an absolute PASI ≤1 in approximately 30% of patients with moderate to severe plaque psoriasis — As mentioned earlier, an absolute PASI of ≤2 has been shown to be clinically meaningful for clinical and HRQoL outcomes2 — Mean percentage change from baseline in absolute PASI at Week 12 was approximately 80% in BMS-986165–treated patients • Five ongoing Phase 3 trials in plaque psoriasis (NCT03624127, NCT03611751, NCT04167462, NCT03924427, and NCT04036435) involving BMS-986165 treatment will evaluate this further over a longer duration and in larger patient cohorts • PASI ≤2 has the potential to be an alternative therapeutic goal to percent PASI improvements and sPGA scores for patients with moderate to severe plaque psoriasis Introduction • Plaque psoriasis is a debilitating, chronic, immune-mediated skin disorder that impairs patients’ health- related quality of life (HRQoL) and productivity1 • Treatment outcomes for plaque psoriasis based on the absolute Psoriasis Area and Severity Index (PASI) are indicative of an individual patient’s disease severity at the time of analysis2 — Absolute PASI may be more clinically meaningful than percentage change in PASI from baseline captured by scores such as PASI 75 (≥75% reduction from baseline PASI)2 — Although a consensus therapeutic target has yet to be defined, a recent analysis reported that attainment of an absolute PASI of ≤2 translates to meaningful improvements in clinical and HRQoL outcomes2 • Previous studies have demonstrated that an absolute PASI ≤2 correlates with PASI 90 (≥90% improvement from baseline PASI), static Physician’s Global Assessment (sPGA) score of 0/1 (range, 0–5; higher scores indicate greater disease severity), and Dermatology Life Quality Index (DLQI) of 0/1 (range, 0–30; higher scores indicate worse HRQoL)2 • BMS-986165 is an oral, selective, allosteric inhibitor of tyrosine kinase 2 (TYK2), an intracellular enzyme involved in key cytokine signaling pathways in plaque psoriasis pathogenesis3 — In a Phase 2, double-blind, randomized trial in patients with moderate to severe plaque psoriasis (NCT02931838), 67%–75% of patients treated with BMS-986165 at doses of 3 or 6 mg twice daily (BID) or 12 mg once daily (QD) achieved PASI 75 at Week 12 (primary endpoint) vs 7% with placebo (P<0.001)3 — BMS-986165 had a favorable safety and tolerability profile, and was associated with low rates of treatment discontinuation3 Objective • This post hoc analysis of the Phase 2 trial compared the efficacy of BMS-986165 vs placebo based on absolute PASI over time up to Week 12 Methods Inclusion criteria • Adults with body mass index of 18–40 kg/m2 • Moderate to severe plaque psoriasis for ≥6 months affecting ≥10% of body surface area — PASI ≥12 (range, 0–72; higher scores indicate greater disease severity) — sPGA ≥3 • Eligible for phototherapy or systemic therapy Exclusion criteria • Diagnosis of nonplaque psoriasis or other immune-mediated condition requiring concomitant systemic immunosuppressant therapy • History or evidence of specific infections (eg, HIV or hepatitis B or C infection) or risk of tuberculosis • Previous lack of response to any therapeutic agent targeting the TYK2 pathway (eg, interleukin-12/-23 pathways) Treatment • Patients were randomized equally to 1 of 5 oral doses of BMS-986165 (3 mg every other day, 3 mg QD, 3 mg BID, 6 mg BID, or 12 mg QD) or matching oral placebo for 12 weeks Study endpoints • This post hoc analysis assessed the following efficacy endpoints in the 3 most effective BMS-986165 dose groups (3 mg BID, 6 mg BID, 12 mg QD) vs placebo — Mean absolute PASI over time — Mean percentage change from baseline in absolute PASI over time — Percentage of patients at Week 12 who achieved an absolute PASI of ≤1, ≤2, ≤3, and ≤5 Statistical analysis • This post hoc efficacy analysis was performed in the efficacy analysis population • Absolute PASI over time and within predefined categories are expressed as patient numbers and percentages • Patients who discontinued the treatment regimen early or who had a missing value at any time point had outcomes imputed as a nonresponse at that time point, regardless of response status at time of discontinuation Results Baseline demographics and disease characteristics • 179 patients were included in this post hoc analysis (BMS-986165 groups, n=134; placebo, n=45) • Baseline demographics and disease characteristics of patients in each dose group are presented in Table 1 — Most patients were male (58%–82% across treatment groups), mean patient age was 43–47 years, and mean body mass index was 27–30 kg/m2 — Baseline mean PASI was similar across treatment groups (18–19) • Median disease duration was 13–20 years and 41%–44% of patients had received prior biologic therapy Table 1. Baseline demographics and disease characteristics3 BMS-986165 Characteristica Placebo (n=45) 3 mg BID (n=45) 6 mg BID (n=45) 12 mg QD (n=44) Demographic characteristics Mean age, y 46 ± 12 46 ± 15 43 ± 13 47 ± 12 Male sex, n (%) 37 (82) 26 (58) 35 (78) 30 (68) Race, n (%) White 40 (89) 39 (87) 35 (78) 37 (84) Asian 5 (11) 5 (11) 9 (20) 6 (14) Other 0 1 (2) 1 (2) 1 (2) Body weight, kg 96 ± 21 84 ± 18 84 ± 19 88 ± 24 Body mass index, kg/m2 30 ± 6 28 ± 5 27 ± 5 29 ± 5 Clinical characteristics Median (range) disease duration, y 18 (2–48) 13 (1–61) 15 (1–55) 20 (1–47) Prior use of biologic therapy, n (%) 20 (44) 19 (42) 20 (44) 18 (41) PASIb 19 ± 6 19 ± 8 18 ± 6 18 ± 5 DLQIc 13 ± 7 13 ± 5 11 ± 6 13 ± 7 Body surface area, % 24 ± 13 24 ± 15 25 ± 13 21 ± 12 From N Engl J Med, Papp K, Gordon K, Thaçi D, et al, Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis, 379(14):1313-1321. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission. BID, twice daily; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; QD, once daily. aValues are means ± SD unless otherwise noted. Data have been rounded to the nearest integer. Percentages may not total 100 because of rounding. bPASI ranges from 0–72, with higher scores indicating greater severity of psoriasis. cDLQI scores range from 0–30, with higher scores indicating worse quality of life. Absolute PASI • BMS-986165 was associated with lower absolute PASI compared with placebo up to Week 12 (Figure 1) — Each of the 3 BMS-986165 doses evaluated resulted in similar levels of improvement in median absolute PASI over time 2020 PA & NP Fall Clinical Dermatology Conference, November 13–15, 2020, Orlando, Florida Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from the authors of this poster. References 1. Weigle N, McBane S. Am Fam Physician. 2013;87(9):626-633. 2. Puig L et al. Acta Derm Venereol. 2019;99(11):971-977. 3. Papp K et al. N Engl J Med. 2018;379(14):1313-1321. Acknowledgments • This work was sponsored by Bristol-Myers Squibb Company. Professional medical writing from Ann Marie Fitzmaurice, PhD and editorial assistance were provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and were funded by Bristol-Myers Squibb Company. Relationships and Activities • BS: Honoraria or consultation fees: AbbVie, Almirall, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, GSK, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medac, Meiji Seika Pharma, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi-Genzyme, Sun Pharma, UCB; Speaker: AbbVie, Eli Lilly, Janssen, Ortho Dermatologics; Scientific Director (consulting fee): Corrona Psoriasis Registry; Investigator: AbbVie, Corrona Psoriasis Registry, Dermavant, Dermira. • ABG: Grant/research funding (paid to institution): Boehringer Ingelheim, Incyte, Janssen-Ortho, Novartis, UCB, XBiotech; Honoraria or consultation fees (paid to ABG): Abbott (AbbVie), Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Janssen Biotech, Janssen-Ortho, Leo Pharma, Lilly ICOS, Novartis, Sun Pharma, UCB, XBiotech, Avotres (no direct compensation received from Avotres); Stock options: XBiotech. • DT: Research support/principal investigator (clinical trials): AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Chugai, Dermira, DS-Pharma, Eli Lilly, Galderma, GSK, Janssen-Cilag, Leo Pharma, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, UCB; Consultant: AbbVie, Almirall, Celgene, Dignity, Galapagos, Leo Pharma, Maruho, Mitsubishi, Novartis, Pfizer, Xenoport; Lectures: AbbVie, Almirall, Amgen, DS-Pharma, Janssen, Leo Pharma, MSD, Novartis, Pfizer, La Roche-Posay, Sandoz-Hexal, Sanofi, Target-Solution, UCB; Scientific advisory board: AbbVie, Amgen, Celgene, DS-Pharma, Eli Lilly, Galapagos, Janssen-Cilag, Leo Pharma, Morphosis, MSD, Novartis, Pfizer, Sandoz, Sanofi, UCB. • LP: Grant/research support or participation in clinical trials (paid to institution): Abbvie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB; Honoraria or consultation fees (paid to LP): Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Eli Lilly, Fresenius Kabi, Gebro, Janssen, Leo Pharma, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung Bioepis, Sandoz, Sanofi, UCB; Speakers bureau: Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer. • MJC, SK, RK, and SB: Employees and shareholders of Bristol-Myers Squibb Company. To request a copy of this poster: Scan QR code via a barcode reader application Scientific Content on Demand QR codes are valid for 30 days after the congress date. Figure 1. Median absolute PASI through Week 12 0 5 10 15 20 25 35 30 40 45 A b so lu te P A SI Baseline Week 4 Week 8 Week 12 3 mg BIDPlacebo 6 mg BID 12 mg QD BMS-986165 BID, twice daily; PASI, Psoriasis Area and Severity Index; QD, once daily. • BMS-986165 was also associated with greater reductions in mean percentage change from baseline in absolute PASI than placebo from Week 1 to Week 12 (Figure 2) Figure 2. Mean percentage change from baseline in absolute PASI through Week 12 3 mg BIDPlacebo 6 mg BID 12 mg QD BMS-986165 0 2 6 104 8 12 Time (weeks) -90 -80 -70 -60 -50 -40 -30 -20 -10 0 M e an ± S E p e rc e n ta ge c h an ge f ro m b as e li n e i n a b so lu te P A SI BID, twice daily; PASI, Psoriasis Area and Severity Index; QD, once daily. • The percentages of patients achieving absolute PASI values of ≤1, ≤2, ≤3, and ≤5 at Week 12 were higher in the BMS-986165 groups than in the placebo group (Table 2) Table 2. Absolute PASI at Week 12 Patients achieving PASI threshold, % (intent-to-treat population) Absolute PASI Placebo (n=45) BMS-986165 3 mg BID (n=45) BMS-986165 6 mg BID (n=45) BMS-986165 12 mg QD (n=44) BMS-986165 combined (n=134) ≤1 0 24.4 33.3 34.1 30.6 ≤2 0 46.7 44.4 50.0 47.0 ≤3 2.2 57.8 53.3 63.6 58.2 ≤5 8.9 73.3 64.4 77.3 71.6 BID, twice daily; PASI, Psoriasis Area and Severity Index; QD, once daily. Patients who discontinued the treatment regimen early or who had a missing value at any time point had outcomes imputed as a nonresponse at that time point, regardless of response status at time of discontinuation. http://www.globalbmsmedinfo.com