BMS-986165, an Oral, Selective Tyrosine Kinase 2 (TYK2) Inhibitor: Evaluation of Changes in Laboratory Parameters in Response to Treatment in a Phase 2 Trial in Psoriasis Patients Kenneth Gordon,1 Kim Papp,2 Melinda Gooderham,3 Akimichi Morita,4 Peter Foley,5 Diamant Thaçi,6 Sudeep Kundu,7 Renata Kisa,7 Lan Wei,7 Subhashis Banerjee7 1Medical College of Wisconsin, Milwaukee, WI, USA; 2Clinical Research and Probity Medical Research Inc, Waterloo, ON, Canada; 3SKiN Centre for Dermatology, Queen’s University and Probity Medical Research, Peterborough, ON, Canada; 4Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 5The University of Melbourne, St Vincent’s Hospital Melbourne & Probity Medical Research, Skin & Cancer Foundation Inc, Melbourne, VIC, Australia; 6Research Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany; 7Bristol-Myers Squibb Company, Princeton, NJ, USA Conclusions • There were no consistent differences observed between placebo and BMS-986165 treatment groups in any hematologic parameters, serum chemistry (hepatic, renal, or lipid) parameters, or serum Ig isotype levels • In addition, there were no clear dose-dependent changes observed with BMS-986165 for any of the laboratory parameters investigated • Results of 4 large ongoing Phase 3 trials of BMS-986165 (NCT03624127 [POETYK-PSO-1], NCT03611751 [POETYK-PSO-2], NCT04167462 [POETYK-PSO-3], and NCT03924427) and the long- term extension study (NCT04036435) in patients with moderate to severe plaque psoriasis will provide long-term safety and laboratory data Introduction • TYK2 activates intracellular signal transducer and activator of transcription (STAT)-dependent signaling pathways of specific cytokines, including interleukin (IL)-23, IL-12, and Type I interferons, that are involved in the pathogenesis of psoriasis and other immune-mediated disorders1–5 • BMS-986165, an oral, selective TYK2 inhibitor with a unique mode of binding to the pseudokinase domain of the enzyme rather than the ATP binding site of the active kinase domain targeted by other tyrosine kinase inhibitors, provides high functional selectivity for TYK22,6 • In a 12-week, Phase 2 trial (NCT02931838) in adults with moderate to severe plaque psoriasis, BMS-986165 demonstrated a dose-dependent improvement in Psoriasis Area and Severity Index (PASI) 75 response and a favorable safety profile7 — At Week 12, PASI 75 responses were highest (67–75%) at doses from 3 mg twice daily (BID) up to 12 mg once daily (QD) versus placebo (7%; P<0.001; primary endpoint) Objective • The objective of this post hoc analysis of the Phase 2 trial was to assess the effect of BMS-986165 on laboratory parameters Methods Patient population and study design • The Phase 2 trial included adult patients with plaque psoriasis for 6 months and a body mass index of 18–40 kg/m2, who were eligible for phototherapy or systemic therapy and had moderate to severe disease as defined by affected body surface area ≥10%, PASI score ≥12, and static Physician’s Global Assessment score ≥37 • Patients were randomized to 1 of 5 oral doses of BMS-986165 (3 mg every other day, 3 mg QD, 3 mg BID, 6 mg BID, 12 mg QD) or placebo7 • The treatment period was 12 weeks, with an additional 30-day off-treatment follow-up period for safety7 Laboratory assessments • Assessments of clinical laboratory parameters included hematologic parameters, C-reactive protein, metabolic parameters (creatinine, creatine phosphokinase [CPK], glucose, total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglyceride levels), and immunoglobulin (Ig) levels. Other laboratory parameters were measured but are not presented here • Mean (standard deviation [SD]), median (interquartile range), or median (range) absolute values for laboratory parameters are reported for the placebo group and the most clinically effective BMS-986165 doses (ie, doses ≥3 mg BID). For this ad hoc analysis on the intention-to-treat cohort, data are shown for the 12-week treatment period Results Patient population • Of the 267 patients who were randomized and received treatment in the Phase 2 trial, 45 patients each received placebo, BMS-986165 3 mg BID, or BMS-986165 6 mg BID, and 44 received BMS-986165 12 mg QD and were included in this analysis • Patient demographics and baseline disease characteristics were generally similar across treatment groups7 Laboratory parameters • Hematologic parameters, including numbers of lymphocytes and neutrophils, platelet count, and hemoglobin levels, remained within normal ranges for placebo and BMS-986165-treated patients over 12 weeks of treatment (Figure 1) • Other hematologic parameters assessed, including numbers of erythrocytes, leukocytes, and natural killer cells, were also within normal ranges (data not shown) Figure 1. Hematologic parameters at baseline and on treatment for all randomized and treated patients who received BMS-986165 3 mg BID, 6 mg BID, or 12 mg QD or placebo M e an ( SD ) ly m p h o cy te n u m b e r, 1 0 3 c e ll s/ µL Week 3 2 1 0 0 2 4 6 8 10 12 Week 0 2 4 6 8 10 12 Week 0 2 4 6 8 10 12 Week 0 2 4 6 8 10 12 A M e an ( SD ) n e u tr o p h il n u m b e r, 1 0 3 c e ll s/ µL 10 4 2 0 B M e an ( SD ) h e m o gl o b in , g/ d L 18 4 2 0 C M e an ( SD ) p la te le t co u n t, 1 0 9 c e ll s/ L 350 100 50 0 D 8 6 8 6 12 10 16 14 200 150 300 250 Lymphocyte number Neutrophil number Hemoglobin Platelet count Placebo (n=45) BMS-986165 12 mg QD (n=44)BMS-986165 6 mg BID (n=45)BMS-986165 3 mg BID (n=45) Data shown are for the 12-week treatment period. BID=twice daily; QD=every day; SD=standard deviation. • Serum levels of C-reactive protein, creatinine, glucose, total cholesterol, HDL-C, and triglycerides remained within normal ranges during the 12-week trial period (Table 1; Figure 2). For patients with LDL-C values available, no increase was observed over 12 weeks of treatment (data not shown) • Increases in CPK observed at 12 weeks in the placebo and BMS-986165 groups were asymptomatic, mostly Grade 1 or 2, and were observed in 12/44 (27%) patients who received placebo and 57/221 (26%) who received BMS-986165 Table 1. C-reactive protein, creatinine, and glucose levels at baseline and on treatment for all randomized and treated patients who received BMS-986165 3 mg BID, 6 mg BID, or 12 mg QD or placebo BMS-986165 Absolute values Placebo (n=45) 3 mg BID (n=45) 6 mg BID (n=45) 12 mg QD (n=44) C-reactive protein, mg/L Baseline 3.863 (3.9629), n=45 4.344 (6.3423), n=45 3.397 (5.0866), n=44 3.159 (3.5864), n=41 Week 4 3.128 (2.8095), n=44 3.623 (5.1206), n=42 4.413 (6.2391), n=39 3.517 (3.8205), n=44 Week 12 4.046 (3.4668), n=31 4.910 (8.1941), n=43 2.638 (3.2964), n=39 3.426 (5.2116), n=41 Creatinine, mg/dL Baseline 0.846 (0.1535), n=45 0.849 (0.1957), n=45 0.797 (0.1400), n=45 0.778 (0.1503), n=44 Week 4 0.858 (0.1443), n=44 0.845 (0.1790), n=42 0.784 (0.1371), n=39 0.801 (0.1515), n=44 Week 12 0.808 (0.1210), n=32 0.843 (0.1788), n=43 0.794 (0.1382), n=39 0.788 (0.1553), n=41 Glucose, mg/dL Baseline 96.3 (21.03), n=45 99.3 (44.34), n=45 115.2 (79.93), n=45 98.3 (26.09), n=44 Week 12 96.5 (16.14), n=31 100.0 (38.47), n=43 109.1 (51.36), n=39 100.8 (27.12), n=41 Data are means (SD). Data shown are for the 12-week treatment period. BID=twice daily; QD=every day; SD=standard deviation. 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. Watford WT et al. Immunol Rev. 2004;202:139-156. 2. Tokarski JS et al. J Biol Chem. 2015;290:11061-11074. 3. Volpe E et al. Nat Immunol. 2008;9:650-657. 4. Geremia A et al. J Exp Med. 2011;208:1127-1133. 5. Tucci M et al. Clin Exp Immunol. 2008;154:247-254. 6. Gillooly K et al. Arthritis Rheumatol. 2016;68(suppl10):abstract 11L. 7. Papp K et al. N Engl J Med. 2018;379:1313-1321. 8. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. November 27, 2017. Available at: https://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick Reference_5x7.pdf (accessed January 20, 2020). Acknowledgments • This work was sponsored by Bristol-Myers Squibb Company. Professional medical writing and editorial assistance was provided by Catriona McKay, PhD, and creative assistance during layout was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ; both were funded by Bristol-Myers Squibb Company. Relationships and Activities • KG: Grant support and consulting fees: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, UCB; Consulting fees: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, Sun Pharma. • KP: Speakers bureau: AbbVie, Amgen, Astellas, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Leo, Merck Sharp & Dohme, Novartis, Pfizer, Valeant; Grant/research support: AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, AstraZeneca, Baxalta, Boehringer Ingelheim, Bristol- Myers Squibb, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Leo, MedImmune, Meiji Seika Pharma, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant; Consultant: AbbVie, Akros, Amgen, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, Leo, Meiji Seika Pharma, Merck Sharp & Dohme, Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant; Honoraria: AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene, Coherus, Eli Lilly, Forward Pharma, Galderma, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Takeda, UCB, Valeant; Scientific officer/steering committee/advisory board: AbbVie, Akros, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Valeant. • MG: Speakers bureau, consultant, investigator/advisor: AbbVie, Akros, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Hakko Kirin, Leo Pharma, Merck, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant. • AM: Grant/research support, consultant, speakers bureau: AbbVie, Eli Lilly, Janssen, Kyowa Hakko Kirin, Leo Pharma, Maruho, Mitsubishi-Tanabe, Novartis. • PF: Speakers bureau, consultant, investigator, advisor, travel grants: 3M/iNova/Valeant, Abbott/AbbVie, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celtaxsys, Cutanea, Dermira, Eli Lilly, Galderma, GlaxoSmithKline/Stiefel, Janssen, LEO/Peplin, Novartis, Regeneron, Sanofi Genzyme, Schering-Plough/Merck Sharp & Dohme, Sun Pharma, UCB, Wyeth/Pfizer. • 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, 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. • SK, RK, LW, 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 2. Total cholesterol, HDL-C, triglyceride, and CPK levels at baseline and on treatment for all randomized and treated patients who received BMS-986165 3 mg BID, 6 mg BID, or 12 mg QD or placebo Baseline Week 12 Baseline Week 12 M e an ( SD ) to ta l ch o le st e ro l, m g/ d L 250 200 100 150 50 0 A M e an ( SD ) H D L- C , m g/ d L 70 20 10 0 B M e an ( SD ) tr ig ly ce ri d e s, m g/ d L 400 100 50 0 C M e an ( SD ) C P K , U /L 600 100 0 -100 20 4 6 Week 8 10 12 D 50 30 60 40 200 150 300 250 350 300 200 500 400 Total cholesterol HDL-C Triglycerides CPK Placebo (n=45) BMS-986165 3 mg BID (n=45) BMS-986165 6 mg BID (n=45) BMS-986165 12 mg QD (n=44) Placebo (n=45) BMS-986165 3 mg BID (n=45) BMS-986165 6 mg BID (n=45) BMS-986165 12 mg QD (n=44) Placebo (n=45) BMS-986165 3 mg BID (n=45) BMS-986165 6 mg BID (n=45) BMS-986165 12 mg QD (n=44) Baseline Week 12 Placebo (n=45) BMS-986165 12 mg QD (n=44) BMS-986165 6 mg BID (n=45) BMS-986165 3 mg BID (n=45) Data shown are for the 12-week treatment period. Protocol-defined ULNs for CPK were 180 U/L for females and 200 U/L for males. CTCAE elevations in CPK are defined as: Grade 1, >ULN to 2.5 x ULN; Grade 2, >2.5 x ULN to 5 x ULN; Grade 3, >5 x ULN to 10 x ULN; Grade 4, >10 x ULN.8 BID=twice daily; CPK=creatine phosphokinase; CTCAE=Common Terminology Criteria for Adverse Events; HDL-C=high-density lipoprotein cholesterol; QD=every day; SD=standard deviation; ULN=upper limit of normal. • Changes in CPK levels were not dose-dependent and there were no events resulting in discontinuation from the trial • Serum levels of IgE, IgA, IgM, and IgG also stayed within normal ranges (Figure 3) Figure 3. Immunoglobulin levels at baseline and on treatment for all randomized and treated patients who received BMS-986165 3 mg BID, 6 mg BID, or 12 mg QD or placebo Placebo (n=45) BMS-986165 12 mg QD (n=44)BMS-986165 6 mg BID (n=45)BMS-986165 3 mg BID (n=45) M e d ia n ( IQ R ) Ig E , kU /L WeekWeek 0 2 4 6 8 10 12 D M e d ia n ( IQ R ) Ig A , m g/ L 0 2 4 6 8 10 12 C M e d ia n ( IQ R ) Ig M , m g/ L Week 1500 0 0 2 4 6 8 10 12 B M e d ia n ( ra n ge ) Ig G , m g/ d L Week 3000 1000 500 0 0 2 4 6 8 10 12 A 500 10002000 1500 2500 IgEIgA IgMIgG 350 100 50 0 200 150 300 250 5000 1000 500 0 2000 1500 3000 3500 4000 4500 2500 Data are medians (IQR) or medians (range). Medians rather than mean data are shown due to skewing of data at the individual patient level. Data shown are for the 12-week treatment period. BID=twice daily; Ig=immunoglobulin; IQR=interquartile range; QD=every day; SD=standard deviation. http://www.globalbmsmedinfo.com