Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in moderate to severe plaque psoriasis: evaluation of lipid parameters in the phase 3 POETYK PSO-1 and PSO-2 trials Mark Lebwohl,1 Bruce Strober,2 Misti Linaberry,3 Kim Hoyt,3 Subhashis Banerjee,3 Renata M Kisa,3 Nehal N Mehta4 1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Yale University School of Medicine, New Haven, and Central Connecticut Dermatology, Cromwell, CT, USA; 3Bristol Myers Squibb, Princeton, NJ, USA; 4The George Washington University School of Medicine, Washington, DC, USA Presented at the Winter Clinical Dermatology Conference - Hawaii®, January 13-18, 2023, Kohala Coast, HI, and Winter Clinical - MiamiTM, February 17-20, 2023, Miami, FL This is an encore of the 2022 Fall Clinical Dermatology Conference poster Email for Mark Lebwohl, MD: lebwohl@aol.com This poster may not be reproduced without written permission from the authors. Synopsis • Tyrosine kinase 2 (TYK2) is an intracellular enzyme that mediates signaling of cytokines (interleukin-23 and Type I interferons) involved in psoriasis pathogenesis1 • Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy2 based on results from the phase 3 POETYK PSO-1 and PSO-2 trials3,4 • Plaque psoriasis is associated with hypertriglyceridemia and metabolic syndrome,5,6 and the frequency of hypertriglyceridemia increases with plaque psoriasis severity7 — Triglycerides ≥150 mg/dL are among the clinical characteristics used to identify patients with metabolic syndrome8 — The American Academy of Dermatology recommends that patients with plaque psoriasis be informed about their increased risk of metabolic syndrome and have frequent lipid screenings, especially when the disease is severe5 • In clinical trials enrolling patients with moderate to severe plaque psoriasis, treatment with deucravacitinib was associated with slight increases (~10 mg/dL) in mean triglyceride levels in the absence of any changes in mean cholesterol levels2 • In the absence of atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus, the American Academy of Cardiology9 recommends: — Diet and lifestyle optimization in adults with fasting triglycerides ≥150 mg/dL and <500 mg/dL — Consideration of initiation or intensification of statin therapy in adults with persistently elevated fasting triglycerides ≥150 mg/dL and <500 mg/dL and a calculated ASCVD risk ≥5% Objective • To report changes in lipid parameters in patients enrolled in POETYK PSO-1 and PSO-2 and treated with: — Placebo, deucravacitinib, or apremilast over 16 weeks — Deucravacitinib continuously for 52 weeks Methods Study designs • POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) were phase 3, 52-week, double-blind, randomized, placebo- and active comparator (apremilast)-controlled trials conducted globally (Figure 1) — Enrolled patients with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] ≥12; static Physician’s Global Assessment [sPGA] ≥3; body surface area involvement ≥10%) were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily during Weeks 0–16 — Blinded treatment switches occurred at Week 16 and Week 24 • Patients receiving placebo crossed over to deucravacitinib at Week 16 • Patients receiving apremilast who failed to meet trial-specific efficacy thresholds in POETYK PSO-1 (≥50% reduction from baseline in PASI [PASI 50]) and in POETYK PSO-2 (≥75% reduction from baseline in PASI [PASI 75]) were switched to deucravacitinib at Week 24 • Patients receiving deucravacitinib who achieved PASI 75 at Week 24 in POETYK PSO-2 were re-randomized (1:1) to continue deucravacitinib or to switch to placebo (withdrawal); patients receiving apremilast who achieved PASI 75 were switched to placebo Figure 1. POETYK PSO-1 and PSO-2 study designs POETYK PSO-1 (N = 666) Deucravacitinib 6 mg QDPlacebo (n = 166) Deucravacitinib 6 mg QDULN-300 mg/dL; >ULN-7.75 mmol/L 150-300 mg/dL (1.71-3.42 mmol/L) 2 >300-400 mg/dL; >7.75-10.34 mmol/L >300-500 mg/dL (>3.42-5.7 mmol/L) 3 >400-500 mg/dL; >10.34-12.92 mmol/L >500-1000 mg/dL (>5.7-11.4 mmol/L) 4 >500 mg/dL; >12.92 mmol/L >1000 mg/dL (>11.4 mmol/L); life-threatening consequences aDefined in these analyses as 200 mg/dL. CTCAE, Common Terminology Criteria for Adverse Events; ULN, upper limit of normal. Results Patient population • A total of 666 and 1020 patients were randomized in the POETYK PSO-1 and PSO-2 trials, respectively, and were included in this analysis Changes in lipid parameters from baseline to Week 16 • Baseline means for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were similar across treatment groups (Table 2) • Mean changes in total cholesterol, HDL cholesterol, and LDL cholesterol were small across treatment groups and not clinically meaningful (Table 2) • Baseline mean triglyceride levels were near the upper limit of normal (ULN; 150 mg/dL) across treatment groups (Table 2) • There were slight increases (~10 mg/dL) in mean triglyceride levels with deucravacitinib treatment (Table 2) Table 2. Changes in lipid parameters from baseline to Week 16 (pooled POETYK PSO-1 and PSO-2) Parameter Placebo Deucravacitinib 6 mg QD Apremilast 30 mg BID n Mean (SD/SEa) n Mean (SD/SEa) n Mean (SD/SEa) Total cholesterol, mg/dLb Baseline 419 189.4 (39.03) 842 189.1 (39.24) 422 190.1 (37.15) Week 16 357 190.4 (38.55) 755 192.5 (40.42) 369 187.8 (36.70) Change 357 -0.1 (1.27) 755 2.6 (0.97) 369 -2.8 (1.26) HDL cholesterol, mg/dL Baseline 419 49.5 (15.50) 842 50.4 (15.16) 422 50.5 (17.23) Week 16 357 48.5 (13.49) 755 51.7 (15.80) 369 51.9 (18.46) Change 357 -0.9 (0.39) 755 0.9 (0.28) 369 0.5 (0.38) LDL cholesterol, mg/dL Baseline 419 110.8 (33.77) 842 109.8 (34.90) 421 111.5 (32.32) Week 16 347 112.8 (33.37) 733 110.2 (35.97) 360 109.2 (32.37) Change 347 0.7 (1.15) 733 -0.2 (0.84) 359 -2.5 (1.11) Triglycerides, mg/dL Baseline 419 149.5 (106.77) 842 146.6 (92.04) 422 145.9 (93.81) Week 16 357 149.8 (88.95) 755 157.1 (104.02) 369 137.7 (80.80) Change 357 0.4 (4.77) 755 10.3 (3.15) 369 -6.8 (3.24) aSD is reported for baseline and Week 16 means; SE is reported for mean change from baseline. bTotal cholesterol = HDL + LDL + 20% triglycerides. BID, twice daily; HDL, high-density lipoprotein; LDL, low-density lipoprotein; QD, once daily; SD, standard deviation; SE, standard error. • Worsening of hypercholesterolemia was observed with comparable frequency among patients treated with placebo, deucravacitinib, and apremilast (10.6%, 11.7%, and 8.4%, respectively); nearly all shifts were 1 grade (Table 3) • Most deucravacitinib-treated patients maintained the same or shifted to a lower grade of hypercholesterolemia from baseline to Week 16 (Table 3) Table 3. Shifts in grade of hypercholesterolemia from baseline to Week 16 (pooled POETYK PSO-1 and PSO-2) Parameter Baseline grade Grade at Week 16, n (%) Total patients0 1 2 3 4 Placebo 0 182 (82.7) 38 (17.3) 0 (0.0) 0 (0.0) 0 (0.0) 220 1 31 (22.8) 105 (77.2) 0 (0.0) 0 (0.0) 0 (0.0) 136 2 0 (0.0) 1 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 Total 213 144 0 0 0 357 Deucravacitinib 6 mg QD 0 387 (82.5) 81 (17.3) 1 (0.2) 0 (0.0) 0 (0.0) 469 1 64 (22.7) 212 (75.2) 6 (2.1) 0 (0.0) 0 (0.0) 282 2 0 (0.0) 4 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 Total 451 297 7 0 0 755 Apremilast 30 mg BID 0 205 (87.2) 30 (12.8) 0 (0.0) 0 (0.0) 0 (0.0) 235 1 41 (31.1) 90 (68.2) 1 (0.8) 0 (0.0) 0 (0.0) 132 2 0 (0.0) 2 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 Total 246 122 1 0 0 369 Light pink shading indicates a shift of 1 grade; dark pink shading indicates a shift of >1 grade. BID, twice daily; QD, once daily. • Grade ≥3 hypertriglyceridemia occurred in several patients in each treatment group at Week 16 (Table 4) • Worsening shifts in hypertriglyceridemia >1 grade were observed in 1.4%, 1.2%, and 0.3% of patients treated with placebo, deucravacitinib, and apremilast, respectively (Table 4) • Most deucravacitinib-treated patients maintained the same or shifted to a lower grade of hypertriglyceridemia from baseline to Week 16 (Table 4) — Of the 34 deucravacitinib-treated patients with grade 2 or 3 hypertriglyceridemia at baseline, 19 improved to grade 0 or 1 at Week 16 • No patient exhibited pancreatitis or a major adverse cardiovascular event associated with grade 4 hypertriglyceridemia • No adverse event related to increased triglycerides was reported as serious or led to treatment discontinuation Table 4. Shifts in grade of hypertriglyceridemia from baseline to Week 16 (pooled POETYK PSO-1 and PSO-2) Parameter Baseline grade Grade at Week 16, n (%) Total patients0 1 2 3 4 Placebo 0 195 (86.7) 26 (11.6) 4 (1.8) 0 (0.0) 0 (0.0) 225 1 37 (35.9) 56 (54.4) 9 (8.7) 1 (1.0) 0 (0.0) 103 2 4 (15.4) 14 (53.8) 7 (26.9) 1 (3.8) 0 (0.0) 26 3 0 (0.0) 2 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 4 0 (0.0) 0 (0.0) 0 (0.0) 1 (100.0) 0 (0.0) 1 Total 236 98 20 3 0 357 Deucravacitinib 6 mg QD 0 381 (78.2) 99 (20.3) 6 (1.2) 1 (0.2) 0 (0.0) 487 1 66 (28.3) 135 (57.9) 31 (13.3) 1 (0.4) 0 (0.0) 233 2 2 (6.7) 16 (53.3) 7 (23.3) 4 (13.3) 1 (3.3) 30 3 0 (0.0) 1 (25.0) 2 (50.0) 1 (25.0) 0 (0.0) 4 4 0 (0.0) 0 (0.0) 1 (100.0) 0 (0.0) 0 (0.0) 1 Total 449 251 47 7 1 755 Apremilast 30 mg BID 0 210 (87.5) 29 (12.1) 1 (0.4) 0 (0.0) 0 (0.0) 240 1 42 (40.4) 56 (53.8) 6 (5.8) 0 (0.0) 0 (0.0) 104 2 2 (8.7) 12 (52.2) 7 (30.4) 2 (8.7) 0 (0.0) 23 3 0 (0.0) 0 (0.0) 2 (100.0) 0 (0.0) 0 (0.0) 2 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 Total 254 97 16 2 0 369 Light pink shading indicates a shift of 1 grade; dark pink shading indicates a shift of >1 grade. BID, twice daily; QD, once daily. Changes in lipid parameters in patients treated with deucravacitinib continuously from baseline to Week 52 • Mean changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides among patients treated with deucravacitinib continuously for 52 weeks were small and not clinically meaningful (Figure 2) • The exposure-adjusted incidence rate (EAIR) for “blood cholesterol increased” as an adverse event over Weeks 0-52 was 0.2/100 person-years (PY) with deucravacitinib compared with 0.4/100 PY with placebo and 0 with apremilast • The EAIR for “blood triglycerides increased” as an adverse event over Weeks 0-52 was 1.0/100 PY with deucravacitinib compared with 0.4/100 PY with placebo and 1.3/100 PY with apremilast • No patient discontinued deucravacitinib due to a lipid-related adverse event Figure 2. Change in lipid parameters among patients treated continuously with deucravacitinib during Weeks 0-52 (pooled POETYK PSO-1 and PSO-2) 0.5 0.9 1.5 1.5 -30 -20 -10 0 10 20 30 0 8 16 24 52 HDL cholesterol 692 642 609 577 523n = M e an ± S E , m g/ d L Baseline mean (SD) = 49.7 (14.59) 1.8 2.2 3.7 3.3 0 10 20 30 40 50 0 8 16 24 52 Total cholesterola 692 642 609 577 523n = Baseline mean (SD) = 189.0 (39.16) M e an ± S E , m g/ d L Weeks Weeks Weeks Weeks 12.0 10.7 13.2 13.1 0 10 20 30 40 50 60 70 80 90 100 0 8 16 24 52 692 642 609 577 523 Triglyceridesb n = Baseline mean (SD) = 148.4 (93.76) M e an ± S E , m g/ d L -0.5 0.1 -0.7 -30 -20 -10 0 10 20 30 0 8 16 24 52 LDL cholesterol 692 623 591 558 507n = Baseline mean (SD) = 110.0 (35.17) M e an ± S E , m g/ d L -0.6 SOTYKTUTM US prescribing information values at Weeks 16 and 52 reflect a mixed population including crossover patients2,b aTotal cholesterol = HDL + LDL + 20% triglycerides. bThe values presented here are limited to patients enrolled in POETYK PSO-1 and PSO-2 who received deucravacitinib continuously for 52 weeks. SOTYKTU™ (deucravacitinib) prescribing information notes that mean triglyceride levels increased by 10.3 mg/dL and by 9.1 mg/dL during the 16-week and 52-week treatment periods, respectively, in the combined population from the 2 studies. The label values were derived from all patients who were taking deucravacitinib at Week 16 or at Week 52 from both POETYK PSO-1 and PSO-2 studies. Some of the latter had received placebo or apremilast in a previous treatment period per the individual study designs. HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; SE, standard error. • Most patients treated with deucravacitinib continuously for 52 weeks maintained the same or shifted to a lower grade of hypercholesterolemia from baseline to Week 52 (Table 5) — There was one 2-grade increase in hypercholesterolemia from baseline to Week 52 Table 5. Shifts in grade of hypercholesterolemia among patients treated continuously with deucravacitinib during Weeks 0-52 (pooled POETYK PSO-1 and PSO-2) Parameter Baseline grade Grade at Week 52, n (%) Total patients0 1 2 3 4 Deucravacitinib 6 mg QD 0 253 (80.8) 59 (18.8) 1 (0.3) 0 (0.0) 0 (0.0) 313 1 45 (21.4) 161 (76.7) 4 (1.9) 0 (0.0) 0 (0.0) 210 2 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 3 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 4 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 Total 298 220 5 0 0 523 Light pink shading indicates a shift of 1 grade; dark pink shading indicates a shift of >1 grade. QD, once daily. • Most patients treated with deucravacitinib continuously for 52 weeks maintained the same or shifted to a lower grade of hypertriglyceridemia from baseline to Week 52 (Table 6) — Grade ≥3 hypertriglyceridemia events were rare and were limited to those with elevated triglycerides at baseline — Shifts >1 grade were observed in 1.9% of patients Table 6. Shifts in grade of hypertriglyceridemia among patients treated continuously with deucravacitinib during Weeks 0-52 (pooled POETYK PSO-1 and PSO-2) Parameter Baseline grade Grade at Week 52, n (%) Total patients0 1 2 3 4 Deucravacitinib 6 mg QD 0 241 (73.0) 84 (25.5) 5 (1.5) 0 (0.0) 0 (0.0) 330 1 49 (29.9) 97 (59.1) 14 (8.5) 4 (2.4) 0 (0.0) 164 2 1 (4.0) 10 (40.0) 12 (48.0) 1 (4.0) 1 (4.0) 25 3 0 (0.0) 2 (66.7) 0 (0.0) 1 (33.3) 0 (0.0) 3 4 0 (0.0) 0 (0.0) 1 (100.0) 0 (0.0) 0 (0.0) 1 Total 291 193 32 6 1 523 Light pink shading indicates a shift of 1 grade; dark pink shading indicates a shift of >1 grade. QD, once daily. Conclusions • In the phase 3 POETYK PSO-1 and PSO-2 trials, mean changes in the lipid panel from baseline to Week 16 were minimal across the placebo, deucravacitinib, and apremilast groups, and none was clinically meaningful — A 10.3 mg/dL increase in mean triglyceride levels from a baseline mean of 146.6 mg/dL in the deucravacitinib group was accompanied by very few worsening shifts in hypertriglyceridemia >1 grade per CTCAE • A large majority of patients treated continuously with deucravacitinib for 52 weeks maintained their baseline grade or shifted to a lower grade of hypercholesterolemia or hypertriglyceridemia at Week 52 — Fewer than 2% of patients had worsening shifts >1 grade from baseline to Week 52 — No patient discontinued deucravacitinib due to a lipid-related adverse event • Clinical guidelines recommend diet and lifestyle optimization for most low-risk adults with fasting triglycerides ≥150 mg/dL and <500 mg/dL, with consideration of initiation or intensification of pharmacotherapy in those with persistent elevations and a calculated ASCVD risk ≥5%9 — These guidelines would apply to most patients with moderate to severe plaque psoriasis due to the high incidence of hypertriglyceridemia/metabolic syndrome in these patients References 1. Burke JR, et al. Sci Trans Med. 2019;11:eaaw1736. 2. SOTYKTU™ (deucravacitinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; September 2022. 3. Armstrong AW, et al. J Am Acad Dermatol. 2023;88:29-39. 4. Strober B, et al. J Am Acad Dermatol. 2023;88:40-51. 5. Elmets CA, et al. J Am Acad Dermatol. 2019;80:1073-1113. 6. Teklu M, et al. J Am Acad Dermatol. 2021;84:1329-1338. 7. Langan SM, et al. J Invest Dermatol. 2012;132:556-562. 8. Grundy SM, et al. Circulation. 2004;109:433-438. 9. Virani SS, et al. J Am Coll Cardiol. 2021;78:960-993. Acknowledgments • This study was sponsored by Bristol Myers Squibb • Writing and editorial assistance was provided by Liz Rockstein, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, funded by Bristol Myers Squibb • The authors thank the patients and investigators who participated in these trials Disclosures • ML: Research funds on behalf of Mount Sinai: AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen, Ortho Dermatologics, Regeneron, and UCB; Consultant: Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Arena, Aristea, Arrive Technologies, Avotres, BiomX, Boehringer Ingelheim, Brickell Biotech, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, CorEvitas’ (Corrona) Psoriasis Registry, Dermavant, Dr Reddy’s Laboratories, Evelo Biosciences, Evommune, Forte Biosciences, Helsinn Therapeutics, Hexima, Leo Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica • BS: Consultant (honoraria): AbbVie, Almirall, Amgen, Arcutis, Arena, Aristea, Asana, Boehringer Ingelheim, Bristol Myers Squibb, Connect Biopharma, Dermavant, Eli Lilly, Equillium, GlaxoSmithKline, Immunic Therapeutics, Janssen, Leo Pharma, Maruho, Meiji Seika Pharma, Mindera, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, Ventyxbio, and vTv Therapeutics; Speaker: AbbVie, Eli Lilly, Janssen, and Sanofi Genzyme; Co-scientific director (consulting fee): CorEvitas' (Corrona) Psoriasis Registry; Investigator: AbbVie, Cara Therapeutics, CorEvitas' (Corrona) Psoriasis Registry, Dermavant, Dermira, and Novartis • ML, KH, SB, and RMK: Employees and shareholders: Bristol Myers Squibb • NNM: Consultant: Abcentra, Amgen, and Novartis