Deucravacitinib, an Oral, Selective Tyrosine Kinase 2 (TYK2) Inhibitor, Versus Placebo and Apremilast in Moderate to Severe Plaque Psoriasis: Efficacy Analysis by Baseline Disease Characteristics From the Phase 3 POETYK PSO-1 and PSO-2 Trials Joseph F Merola,1 Howard Sofen,2 Diamant Thaçi,3 Carle Paul,4 Shinichi Imafuku,5 Subhashis Banerjee,6 Elizabeth Colston,6 Jonghyeon Kim,6 John Throup,6 April W Armstrong7 1Brigham and Women’s Hospital, Brigham Dermatology Associates, Harvard Medical School, Boston, MA, USA; 2UCLA School of Medicine, Los Angeles, CA, USA; 3University of Lübeck, Lübeck, Germany; 4Larrey University Hospital, Paul Sabatier University, Toulouse, France; 5Fukuoka University Hospital, Fukuoka, Japan; 6Bristol Myers Squibb, Princeton, NJ, USA; 7University of Southern California, Los Angeles, CA, USA Introduction • Deucravacitinib — Novel, oral, selective tyrosine kinase 2 (TYK2) inhibitor with a unique mechanism of action distinct from Janus kinase (JAK) 1/2/3 inhibitors (Figure 1)1 • Binds to the TYK2 regulatory domain with high selectivity and inhibits TYK2 via an allosteric mechanism1 — ≥100-fold greater selectivity for TYK2 vs JAK 1/3 and ≥2000-fold greater selectivity for TYK2 vs JAK 2 in cells1,2 • Inhibits TYK2-mediated signaling of cytokines involved in psoriasis pathogenesis (eg, interleukin [IL]-23, IL-12, and Type I interferons)1 Figure 1. Mechanism of action of deucravacitinib Deucravacitinib (allosteric inhibitor) Regulatory domain Catalytic domain ATP-binding active site (other kinase inhibitors) TYK2 ATP, adenosine triphosphate; TYK2, tyrosine kinase 2. • Deucravacitinib has demonstrated good efficacy and tolerability in Phase 2 trials in patients with moderate to severe plaque psoriasis3 and with active psoriatic arthritis4 • In 2 pivotal Phase 3 trials in patients with moderate to severe plaque psoriasis, POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751), a significantly greater proportion of patients achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) score and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (0/1) at Week 16 with deucravacitinib compared with placebo or apremilast5 Objective • The present analyses were performed to evaluate the efficacy of deucravacitinib at Week 16 by prespecified baseline disease characteristics in the Phase 3 POETYK PSO-1 and PSO-2 trials Methods Key design elements • The POETYK PSO-1 and PSO-2 study designs are shown in Figure 2 • Key eligibility criteria — Adults with moderate to severe plaque psoriasis — PASI ≥12, sPGA ≥3, body surface area (BSA) ≥10% — Stratified by geographic region, body weight, and prior biologic use • Coprimary endpoints were the proportion of patients who achieved PASI 75 and sPGA 0/1 responses vs placebo at Week 16 • Data from subgroups with the following predefined baseline disease characteristics in PSO-1 and PSO-2 were pooled and analyzed for the coprimary endpoints vs placebo and vs apremilast at Week 16: — Moderate vs severe disease • PASI score: 12−20 vs ≥20 • sPGA score: 3 vs 4 • BSA involvement: 10%−20% vs >20% — Disease duration: <10 y vs ≥10 y — Age at disease onset subgroups: <18 y, 18−39 y, ≥40 y • Additional subgroups for age at disease onset (<18 y, 18−39 y, 40−55 y, >55 y) and disease duration (1−5 y, 5−15 y, 15−20 y, >20 y) were analyzed post hoc • Differences between treatment groups were calculated using a stratified Cochran-Mantel-Haenszel test • Missing data were imputed with nonresponder imputation This poster may not be reproduced without written permission from the authors.Email for Joseph F Merola, MD: jfmerola@bwh.havard.edu Figure 2. Study designs POETYK PSO-1 (N=666) POETYK PSO-2 (N=1020) Deucravacitinib 6 mg QDPlacebo (n=166) Deucravacitinib 6 mg QD20, n (%) 167 (39.7) 368 (43.7) 181 (42.9) 716 (42.5) BSA, mean (SD) (overall) 25.3 (16.1) 26.4 (15.8) 27.6 (16.4) 26.4 (16.0) BSA 10%−20%, n (%) 226 (53.7) 421 (49.9) 200 (47.4) 847 (50.2) BSA >20%, n (%) 195 (46.3) 422 (50.1) 222 (52.6) 839 (49.8) aAge at disease onset and disease duration were not reported for 1 patient in the placebo arm of PSO-2. BSA, body surface area; PASI, Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assessment. Efficacy • In the overall populations, significantly greater proportions of patients receiving deucravacitinib vs placebo and vs apremilast achieved PASI 75 and sPGA 0/1 responses at Week 16 in each study (Figure 3)5 Figure 3. PASI 75 and sPGA 0/1 responses at Week 16 for PSO-1 and PSO-2 58.4 53.0 12.7 9.4 35.1 39.8 0 10 20 30 40 50 60 70 80 90 100 PSO−1 PSO−2 P A SI 7 5 r e sp on se , % PASI 75 53.6 49.5 7.2 8.6 32.1 33.9 0 10 20 30 40 50 60 70 80 90 100 PSO−1 PSO−2 sP G A 0 /1 r e sp o n se , % sPGA 0/1 Deucravacitinib Placebo Apremilast PASI 75, ≥75% reduction from baseline in Psoriasis Area and Severity Index; sPGA 0/1, static Physician’s Global Assessment score of 0 or 1. • Pooled data from PSO-1 and PSO-2 demonstrated a consistent and favorable treatment benefit by PASI 75 and sPGA 0/1 responses for deucravacitinib compared with placebo and apremilast in all prespecified baseline disease subgroups at Week 16: — Disease severity by PASI, sPGA, and BSA — Disease duration — Age of disease onset (Figure 4 and Figure 5) Figure 4. PASI 75 response at Week 16: PSO-1 and PSO-2 pooled analysis − efficacy of deucravacitinib vs placebo and apremilast in prespecified subgroups Deucravacitinib Placebo Apremilast 0 10 20 30 40 50 60 Difference vs placebo (95% CI) 0 10 20 30 40 50 60 Difference vs apremilast (95% CI) Baseline PASI ≤20 Baseline PASI >20 Baseline sPGA score 3 (moderate) Baseline sPGA score 4 (severe) Baseline BSA involvement 10%−20% Baseline BSA involvement >20% Duration of disease <10 y Duration of disease ≥10 y Age at disease onset <18 y Age at disease onset 18−39 y Age at disease onset ≥40 y Difference (95% CI) 40.8 (34.9−46.8) 49.1 (42.4−55.8) 43.4 (38.3−48.5) 49.9 (40.7−59.0) 39.5 (33.0−46.0) 49.6 (43.6−55.6) 46.5 (38.5−54.5) 43.5 (38.2−48.9) 45.4 (36.2−54.6) 43.1 (36.9−49.3) 46.8 (37.9−55.7) Difference (95% CI) Patients, n Placebo Deucravacitinib Apremilast 15.7 (8.1−23.2) 254 475 241 19.0 (10.2−27.7) 167 368 181 16.2 (9.7−22.7) 345 665 335 20.0 (7.6−32.4) 75 178 87 16.6 (8.4−24.8) 226 421 200 17.7 (9.7−25.7) 195 422 222 19.9 (9.1−30.7) 119 261 112 16.1 (9.3−22.9) 301 582 310 16.1 (4.8−27.4) 102 208 112 19.8 (12.0−27.7) 205 438 215 13.2 (1.0−25.3) 113 197 95 Deucravacitinib vs placebo Deucravacitinib vs apremilast Missing data were imputed with nonresponder imputation. BSA, body surface area; PASI 75, ≥75% reduction from baseline in Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assessment. Figure 5. sPGA 0/1 response at Week 16: PSO-1 and PSO-2 pooled analysis − efficacy of deucravacitinib vs placebo and apremilast in prespecified subgroups Patients, n 0 10 20 30 40 50 60 Difference vs apremilast (95% CI) 0 10 20 30 40 50 60 Difference vs placebo (95% CI) Baseline PASI ≤20 Baseline PASI >20 Baseline sPGA score 3 (moderate) Baseline sPGA score 4 (severe) Baseline BSA involvement 10%−20% Baseline BSA involvement >20% Duration of disease <10 y Duration of disease ≥10 y Age at disease onset <18 y Age at disease onset 18−39 y Age at disease onset ≥40 y Difference (95% CI) 40.9 (35.0−46.7) 46.0 (40.0−52.1) 42.1 (37.3−47.0) 48.1 (39.9−56.3) 39.8 (33.4−46.2) 46.7 (41.2−52.1) 45.6 (37.9−53.2) 41.8 (36.7−47.0) 40.2 (31.1−49.3) 44.4 (38.5−50.2) 43.4 (34.8−52.0) Difference (95% CI) Placebo Deucravacitinib Apremilast 17.9 (10.5−25.4) 254 475 241 17.7 (9.2−26.3) 167 368 181 17.1 (10.7−23.4) 345 665 335 20.3 (8.2−32.3) 75 178 87 17.7 (9.6−25.9) 226 421 200 17.8 (10.0−25.6) 195 422 222 20.6 (10.1−31.1) 119 261 112 16.5 (9.9−23.2) 301 582 310 17.0 (5.9−28.1) 102 208 112 20.0 (12.3−27.8) 205 438 215 14.2 (2.2−26.2) 113 197 95 Deucravacitinib vs placebo Deucravacitinib vs apremilast Missing data were imputed with nonresponder imputation. BSA, body surface area; PASI, Psoriasis Area and Severity Index; sPGA 0/1, static Physician’s Global Assessment score of 0 or 1. • Analysis of pooled data from PSO-1 and PSO-2 demonstrated favorable efficacy for deucravacitinib against placebo and apremilast across most post hoc subgroups with additional strata (Figure 6 and Figure 7) Figure 6. PASI 75 response at Week 16: PSO-1 and PSO-2 pooled analysis − efficacy of deucravacitinib vs placebo and apremilast in post hoc subgroups 0 10 20 30 40 50 60 Difference vs placebo (95% CI) Age at disease onset >55 y Age at disease onset 40−55 y Age at disease onset 18−39 y Age at disease onset <18 y Duration of disease ≥20 y Duration of disease 15−<20 y Duration of disease 5−<15 y Duration of disease 1−<5 y Difference (95% CI) 46.7 (29.8−63.7) 47.3 (36.9−57.7) 43.1 (36.9−49.3) 45.4 (36.2−54.6) 39.0 (31.7−46.4) 49.4 (38.2−60.5) 48.7 (41.5−55.9) 42.9 (28.3−57.5) Patients, n Placebo Deucravacitinib Apremilast 25 55 25 88 142 70 205 438 215 102 208 112 167 327 167 64 125 62 139 293 146 Difference (95% CI) −2.6 (−26.9 to 21.8) 20.2 (6.1−34.2) 19.8 (12.0−27.7) 16.1 (4.8−27.4) 11.6 (2.4−20.8) 18.1 (3.1−33.1) 22.9 (13.3−32.5) 19.1 (1.2−37.0) 48 94 42 Deucravacitinib vs placebo Deucravacitinib vs apremilast -35 -25 -15 -5 5 15 25 35 Difference vs apremilast (95% CI) Missing data were imputed with nonresponder imputation. PASI 75, ≥75% reduction from baseline in Psoriasis Area and Severity Index. Figure 7. sPGA 0/1 response at Week 16: PSO-1 and PSO-2 pooled analysis − efficacy of deucravacitinib vs placebo and apremilast in post hoc subgroups 0 10 20 30 40 50 60 Difference vs placebo (95% CI) Difference (95% CI) Age at disease onset >55 y 46.7 (31.2−62.1) Age at disease onset 40−55 y 42.5 (32.3−52.6) Age at disease onset 18−39 y 44.4 (38.5−50.2) Age at disease onset <18 y 40.2 (31.1−49.3) Duration of disease ≥20 y 37.8 (30.7−44.9) Duration of disease 15−<20 y 47.4 (36.7−58.1) Duration of disease 5−<15 y 45.7 (38.8−52.7) Duration of disease 1−<5 y 45.9 (32.7−59.1) -35 -25 -15 -5 5 15 25 35 Difference vs apremilast (95% CI) Difference (95% CI) Patients, n Placebo Deucravacitinib Apremilast −4.2 (−28.9 to 20.6) 25 55 25 20.4 (6.9−34) 88 142 70 20.0 (12.3−27.8) 205 438 215 17.0 (5.9−28.1) 102 208 112 12.6 (3.6−21.7) 167 327 167 18.3 (3.5−33.1) 64 125 62 23.3 (14.0−32.6) 139 293 146 23.0 (5.6−40.3) 48 94 42 Deucravacitinib vs placebo Deucravacitinib vs apremilast Missing data were imputed with nonresponder imputation. sPGA 0/1, static Physician’s Global Assessment score of 0 or 1. Conclusions • Patients treated with deucravacitinib had PASI 75 and sPGA 0/1 responses that were superior to placebo and apremilast across nearly all prespecified and post hoc baseline disease parameters, including measures of baseline disease severity, duration of psoriasis, and age at disease onset • Taken together with the primary results from the Phase 3 POETYK trials,5 these findings suggest that deucravacitinib has the potential to become a treatment of choice and new standard of care for patients with moderate to severe plaque psoriasis References 1. Burke JR et al. Sci Transl Med 2019;11:1-16. 2. Wrobleski ST et al. J Med Chem 2019;62:8973-8995. 3. Papp K et al. N Engl J Med 2018;349:1313-1321. 4. Mease PJ et al. Presented at the Annual Scientific Meeting of the American College of Rheumatology; November 5-9, 2020. 5. Armstrong A et al. Presented at the Annual Meeting of the American Academy of Dermatology; April 23-25, 2021. Acknowledgments • These clinical trials were sponsored by Bristol Myers Squibb. Professional medical writing from Lisa Feder, PhD, and editorial assistance were provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and were funded by Bristol Myers Squibb. Relationships and Activities • JFM: Consultant and/or investigator: Amgen, AbbVie, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB • HS: Clinical investigator: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Leo Pharma, Novartis, and Sun Pharma • DT: Advisory board, principal investigator, and lecture fees: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DS Pharma, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche-Posay, Samsung, Sandoz-Hexal, Sanofi, and UCB • CP: Grant support and consultant fees: AbbVie, Almirall, Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Leo Pharma, Merck, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and UCB • SI: Grants and personal fees: AbbVie, Eisai, Janssen, Kyowa Hakko Kirin, Leo Pharma, Maruho, Sun Pharma, Taiho Yakuhin, Tanabe Mitsubishi, Torii Pharmaceutical, and Yakuhin; Personal fees: Amgen, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, and UCB • SB, EC, JK, and JT: Employees and shareholders: Bristol Myers Squibb • AWA: Grants and personal fees: AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Leo Pharma, and Novartis; Personal fees: Boehringer Ingelheim/Parexel, Celgene, Dermavant, Genentech, GlaxoSmithKline, Menlo Therapeutics, Merck, Modernizing Medicine, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Science 37, Sun Pharma, and Valeant; Grant support: Dermira, Kyowa Hakko Kirin, and UCB, outside the submitted work Presented at the Fall Clinical Dermatology Conference®; October 21−24, 2021; Las Vegas, NV, and Virtual This is an encore of the 2021 EADV 30th Congress poster