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Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 inhibitor (TYK2) approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib inhibits TYK2-mediated signaling of certain cytokines, such as type I interferons, involved in systemic lupus erythematosus (SLE). In the 48-week, double-blind, phase 2 trial (NCT03252587) in patients with active SLE, the 3 mg twice daily (BID) dose of deucravacitinib demonstrated greater efficacy compared with placebo for the primary endpoint of Systemic Lupus Erythematosus Responder Index-4 (SRI[4]) at week 32 and all key secondary endpoints, including Lupus Low Disease Activity State (LLDAS) response at week 48. Achievement and maintenance of LLDAS is associated with reduced risk of SLE-associated organ damage and mortality.Objectives:To further investigate LLDAS outcomes with deucravacitinib through post hoc subanalyses assessing median time to first LLDAS response, sustained time in LLDAS, and cumulative time in LLDAS.Methods:Patients with active SLE (N = 363) were randomized 1:1:1:1 to receive placebo or deucravacitinib 3 mg BID, 6 mg BID, or 12 mg once daily (QD). Exploratory outcomes included median time to first LLDAS response, the percentage of patients who achieved LLDAS for ≥ 3 or ≥ 5 consecutive visits, and the percentage of patients who achieved LLDAS for ≥ 20% or ≥ 50% of the time through week 48 using a prespecified nonresponder imputation. Time to first LLDAS response was estimated using the inverse Kaplan-Meier method (with LLDAS response as an event) followed by the stratified log-rank test for treatment comparison (P value). Odds ratios (ORs) were estimated from logistic regression with treatment group and stratification factors as fixed factors. Nominal P values for each treatment group compared with the placebo group were provided.Results:Median time to first LLDAS response was significantly shorter in all deucravacitinib groups compared with the placebo group (3 mg BID, 28.0 weeks: P = 0.0365 vs placebo; 6 mg BID, 40.1 weeks: P = 0.0004 vs placebo; 12 mg QD, 35.7 weeks: P = 0.0118 vs placebo). Median time to first LLDAS response was achieved in only 28 of 90 patients treated with placebo; therefore, median time to first LLDAS response was not estimable in the placebo group due to a < 50% probability of achieving LLDAS at any time point (Figure 1). The deucravacitinib 3 mg BID group had a significantly higher percentage of patients who achieved LLDAS for ≥ 3 visits compared with the placebo group (OR, 1.8; 95% CI, 0.9–3.7, P = 0.0430). A higher percentage of patients treated with any dose of deucravacitinib attained LLDAS for ≥ 3 or ≥ 5 visits compared with patients receiving placebo (Figure 2A). A higher percentage of patients treated with deucravacitinib attained LLDAS for ≥ 20% and ≥ 50% of cumulative observed time compared with patients receiving placebo (Figure 2B). The deucravacitinib 3 mg BID and 12 mg QD groups had significantly higher percentages of patients who achieved LLDAS for ≥ 20% of cumulative time compared with placebo (3 mg BID: OR, 3.5; 95% CI, 1.8–6.9; P = 0.0002; 12 mg QD: OR, 2.3; 95% CI, 1.1–4.5; P = 0.0098), and the 3 mg BID group also had a significantly higher percentage of patients who achieved LLDAS for ≥ 50% of cumulative time (3 mg BID: OR, 2.7; 95% CI, 1.2–6.2; P = 0.0091).Conclusion:Patients treated with deucravacitinib achieved LLDAS response earlier and demonstrated more sustained responses and greater cumulative time in LLDAS compared with patients receiving placebo. Given previously reported associations between LLDAS and improved clinical outcomes, including quality of life, these data support the continued evaluation of deucravacitinib in patients with SLE.Figure 1.Median time to first LLDAS responseFigure 2.Sustained LLDAS attainment for multiple consecutive visits and cumulative time in LLDASREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Stephanie V. Koebele, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Eric Morand AstraZeneca, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, Novartis, and Takeda, AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Takeda, and UCB, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Ravi Koti Employee of Syneos Health, providing statistical services to Bristol Myers Squibb, Thomas Wegman Bristol Myers Squibb, Bristol Myers Squibb, Ronald F. van Vollenhoven Roche, Pfizer, AbbVie, Galapagos, and Janssen, Pfizer, UCB, AstraZeneca, Biogen, Biotest, Celgene, Gilead, and Servier, AbbVie, Galapagos, and Janssen, Pfizer, UCB, UCB, Bristol Myers Squibb, Eli Lilly, and GSK.

BackgroundTyrosine kinase 2 (TYK2) mediates cytokine pathways (eg, Type I IFN) linked with systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis [1,2]. Deucravacitinib was efficacious compared with placebo in a phase 2 SLE trial [3].ObjectivesTo develop a customized IFN 5-gene signature score, assess the pharmacodynamic effects of deucravacitinib on the IFN score, and evaluate the score’s association with SLE disease activity and clinical response in the phase 2 trial.MethodsPatients with active SLE were randomized equally to oral placebo or deucravacitinib (3 mg BID, 6 mg BID, or 12 mg QD). DxTerity chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes from whole blood. IFN genes were selected based on distribution, correlations, hierarchical clustering, and consistency of k-means clusters. Serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry. SRI(4) and BICLA were measured at weeks 32 and 48.ResultsAn IFN 5-gene (MX1, HERC5, IFIT1, RSAD2, and EIF2AK2) signature score was identified and used to classify patients into IFN-high or IFN-low subgroups (Figure 1). Higher baseline IFN score was associated with higher baseline SLEDAI and CLASI disease activity scores, higher levels of IFN activity biomarker (eg, IFNα, IFNλ, BAFF, CXCL10) and anti-dsDNA, and lower complement and lymphocyte counts. Baseline IFN score was not predictive of SRI(4) response. A higher baseline IFN score was associated with a significantly higher probability of BICLA response with deucravacitinib 3 mg BID relative to placebo (P=0.014). Deucravacitinib reduced the IFN score from weeks 4 through 44 by >50%.ConclusionThese data support the IFN 5-gene signature score as a biomarker to classify patients with SLE into IFN-high or IFN-low subgroups; however, clinical response by IFN score was inconsistently improved (Table 1). IFN-regulated gene expression performs well as a pharmacodynamic biomarker to confirm deucravacitinib mechanism of action and to aid in phase 3 dose selection.References[1]Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29-39.[2]Strober B, et al. J Am Acad Dermatol. 2023;88(1):40-51.[3]Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print).Table 1.Clinical response at week 32PlaceboN = 90Deucravacitinib3 mg BIDN = 91Deucravacitinib6 mg BIDN = 93Deucravacitinib12 mg QDN = 89SRI(4) response rate, n/N (%)IFN High21/65 (32.3)47/76 (61.8)37/73 (50.7)35/69 (50.7)IFN Low10/25 (40.0)8/15 (53.3)11/20 (55.0)5/20 (25.0)BICLA response rate, n/N (%)IFN High18/65 (27.7)39/76 (51.3)31/73 (42.5)30/69 (43.5)IFN Low13/25 (52.0)7/15 (46.7)13/20 (65.0)7/20 (35.0)BICLA, British Isles Lupus Assessment Group‒Based Composite Lupus Assessment; BID, twice daily; IFN, interferon; QD, once daily; SRI, Systemic Lupus Erythematosus Responder Index.AcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsChun Wu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yanhua Hu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mary K. Crow Consultant of: AMPEL BioSolutions, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Grant/research support from: Gilead Sciences, Amit Saxena Grant/research support from: AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Kezar Life Sciences, Cristina Arriens Speakers bureau: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, Kezar, Grant/research support from: AstraZeneca, Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Adrian Coles Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian M. Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis [1,2]. Deucravacitinib binds to the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind to the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587) [3].ObjectivesThis analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE.MethodsIn the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC50 was determined by in vitro whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48.ResultsDeucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib Cmax was 8-fold lower than JAK 1/3 IC50 and 47-fold lower than JAK 2/2 IC50 (Figure 1). In the E-R analyses, the probability of achieving SRI(4) and BICLA at week 32 increased with increasing deucravacitinib CminSS, with 3 mg BID providing near-maximal response. The E-R relationship for infection and infestation was relatively flat, while skin and subcutaneous tissue disorders increased with increasing deucravacitinib CminSS. These E-R relationships were similar at week 48.ConclusionDeucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events.References[1]Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29-39.[2]Strober B, et al. J Am Acad Dermatol. 2023;88(1):40-51.[3]Morand E, et al. Arthritis Rheumatol. 2022 Nov 11 (Epub ahead of print).AcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsTakafumi Ide Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Manoj Chiney Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Huynh Yen Thanh Bach Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vineet Goti Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Bindu Murthy Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Qihong Zhao Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Urvi Aras Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib inhibits TYK2-mediated signaling of certain cytokines, such as type I interferons (IFNs), involved in systemic lupus erythematosus (SLE). Patients with SLE have common molecular manifestations, including elevated IFN and B-cell activity, elevated autoantibody levels, and reduced complement levels. In the 48-week, double-blind, phase 2 PAISLEY trial (NCT03252587) in patients with active SLE, deucravacitinib 3 mg twice daily (BID) met its primary endpoint of SLE Responder Index-4 (SRI[4]) response rate at week 32 and all secondary endpoints at week 48. A deeper understanding of cellular and molecular mechanisms is important in the development of optimized therapies for patients with SLE.Objectives:To perform a gene set enrichment and cellular deconvolution analysis on RNA-sequencing data from the PAISLEY trial to identify additional mechanistic insights into the effect of deucravacitinib in SLE.Methods:RNA-sequencing was performed on samples collected from patients with active SLE who were randomized 1:1:1:1 in PAISLEY to placebo (n=90) or deucravacitinib 3 mg BID (n=91), or 6 mg BID (n=93), or 12 mg QD (once daily) (n=89). Samples were analyzed up to the primary endpoint at 32 weeks. Pharmacodynamic and differential gene expression analysis was conducted using linear mixed-effects models for Differential Expression for Repeated Measures (DREAM) in R. Single-sample gene set enrichment analysis (ssGSEA) was performed using public predefined gene modules from MSigDB Hallmark and BloodGen3. xCell was used to digitally portray the blood cellular heterogeneity landscape.Results:Compared to placebo, pharmacodynamic analysis of whole transcriptome profiles identified 73, 122, and 392 genes modulated by deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD groups, respectively, at week 32 (adjusted p < 0.05). Many IFN-regulated genes were normalized by deucravacitinib treatment. ssGSEA and cellular deconvolution further identified SLE-relevant gene sets modulated by deucravacitinib (Figure 1). Gene sets representing naive and memory B lymphocytes were marginally increased, consistent with the increase in circulating lymphocytes. In contrast, plasma cell modules were reduced (Figure 2A). Regulatory T cell gene sets were increased in SLE compared with healthy controls, and further increased with deucravacitinib treatment (Figure 2B); in contrast, Th1 gene expression was marginally decreased. Gene expression associated with several myeloid cell types was reduced by deucravacitinib, including macrophage and activated dendritic cell (DC) (Figure 2C and D) signatures; complement gene signatures were also decreased. In contrast, conventional DC and immature DC signatures increased.Conclusion:RNA sequencing whole blood transcriptome profiling revealed expected, as well as novel, gene expression changes in deucravacitinib-treated subjects. As expected, deucravacitinib normalized expressions of IFN-regulated genes and reduced plasma cell gene signatures. Surprisingly, deconvolution revealed normalization of dendritic cell populations and increased regulatory T cell gene signature. These findings are consistent with the robust efficacy observed.Figure 1.Changes in gene sets identified by xCell deconvolutionFigure 2.Transcript scores according to predicted cell composition via ssGSEA or xCell for (A) plasma cells; (B) regulatory T cells; (C) activated dendritic cells; (D) macrophages across the timepoints of the studyREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Angela R. Eder, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Edward M. Vital AstraZeneca, Bristol Myers Squibb, UCB, Roche, Novartis, Lilly, AbbVie, Otsuka, Aurinia, Pfizer, AstraZeneca, Sandoz, Cristina Arriens AstraZeneca and Aurinia, AstraZeneca and Bristol Myers Squibb; Advisory or review panel: AstraZeneca, Aurinia, Bristol Myers Squibb, GSK, and Kezar, J Michelle Kahlenberg AstraZeneca, Eli Lilly, GSK, Bristol Myers Squibb, Avion Pharmaceuticals, Provention Bio, Aurinia Pharmaceuticals, Ventus Therapeutics, Exo Therapeutics, DangerBio, and Boehringer Ingelheim, Q32 Bio, Celgene/Bristol Myers Squibb, Ventus Therapeutics, Rome Therapeutics, and Janssen, Mary K. Crow AMPEL BioSolutions, AstraZeneca, Bristol Myers Squibb, GSK, and Lilly, Gilead Sciences, Amit Saxena AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, GSK, and Kezar Life Sciences, Chun Wu Bristol Myers Squibb, Bristol Myers Squibb, Yanhua Hu Bristol Myers Squibb, Bristol Myers Squibb, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Adrian Coles Bristol Myers Squibb, Bristol Myers Squibb, Ian M. Catlett Bristol Myers Squibb, Bristol Myers Squibb.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib selectively inhibits TYK2-mediated signaling of certain cytokines, such as type I interferons, involved in SLE. The 48-week, double-blind, phase 2 PAISLEY trial (NCT03252587) of deucravacitinib in patients with active SLE met its primary and secondary endpoints, with deucravacitinib 3 mg twice daily (BID) demonstrating superiority to placebo in the primary endpoint of SLE Responder Index-4 (SRI[4]) response at week 32 and all secondary endpoints at week 48.1Objectives:To evaluate the efficacy of deucravacitinib 3 mg BID vs placebo at week 48 by baseline demographics and disease characteristics in subgroups of patients in the PAISLEY trial.Methods:Patients with active SLE were randomized 1:1:1:1 to placebo (n = 90) or deucravacitinib 3 mg BID (n = 91), 6 mg BID (n = 93), or 12 mg once daily (n = 89). Key secondary endpoints were assessed at week 48 in the PAISLEY trial, including SRI[4] response rate, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response rate, a ≥ 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (CLASI-50) in patients with a CLASI activity score of ≥ 10 at baseline, and a ≥ 50% reduction in active (swollen + tender) joint count (JC-50) from baseline in patients with an active 40-joint count of ≥ 6 at baseline. Response rates were reported with a prespecified nonresponder imputation method for missing values or patients who took prespecified prohibited medications;1 the 2-sided 95% CI was based on the asymptotic (including continuity correction) method. For each secondary endpoint, response rates were analyzed according to baseline demographics and disease characteristics, including race, glucocorticoid (GC) use, baseline SLE Disease Activity Index-2000 (SLEDAI-2K) score, and disease duration. The 3 mg BID dose generated the optimal benefit-risk profile vs placebo; therefore, for this analysis, this dose was determined to be representative of the efficacy of the drug. All analyses were conducted post hoc and were descriptive.Results:Baseline demographics and disease characteristics were well balanced between the placebo and treatment arms. Overall, SRI[4] and BICLA response rates increased with deucravacitinib 3 mg BID vs placebo at week 48, regardless of patient race, GC use at baseline, baseline SLEDAI-2K score, or disease duration (Figure 1). Similarly, CLASI-50 and JC-50 response rates increased with deucravacitinib 3 mg BID vs placebo in these subgroups (Figure 2). Data interpretation for some subgroups was limited by low patient numbers.Conclusion:In the phase 2 PAISLEY trial, deucravacitinib 3 mg BID was associated with improved SRI[4], BICLA, CLASI-50, and JC-50 response rates at week 48 in multiple patient subgroups with select baseline demographics and disease characteristics. These findings will be validated in the ongoing phase 3 trials of deucravacitinib in SLE.REFERENCES:[1] Morand E, et al. Arthritis Rheumatol 2023;75:242–252.Figure 1.SRI[4] and BICLA response rates at week 48 by baseline demographics and disease characteristicsFigure 2.CLASI-50 and JC-50 response rates at week 48 by baseline demographics and disease characteristicsAcknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Angela R. Eder, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Eric Morand AstraZeneca, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, Novartis, and Takeda, AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Takeda, and UCB, Cristina Arriens AstraZeneca, Aurinia, AstraZeneca, Aurinia, Bristol Myers Squibb, GSK, Kezar, AstraZeneca and Bristol Myers Squibb, Laura Geraldino-Pardilla Aurinia, Bristol Myers Squibb, Ann E. Clarke Bristol Myers Squibb, Otsuka, Roche, AstraZeneca, GSK, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Thomas Wegman Bristol Myers Squibb, Bristol Myers Squibb, Ravi Koti Syneos Health, providing statistical services to Bristol Myers Squibb, Subhashis Banerjee Bristol Myers Squibb, Bristol Myers Squibb, Ronald F. van Vollenhoven Pfizer, Roche, Pfizer, AbbVie, Galapagos, Janssen, UCB, AbbVie, Galapagos, Janssen, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, Bristol Myers Squibb, GSK, Eli Lilly, UCB, Pfizer.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib inhibits TYK2-mediated signaling of certain cytokines, such as type I interferons, involved in systemic lupus erythematosus (SLE). A 48-week, double-blind, phase 2 trial (NCT03252587) in patients with active SLE showed that the 3 mg twice daily (BID) dose of deucravacitinib demonstrated greater efficacy than placebo for the primary endpoint of Systemic Lupus Erythematosus Responder Index-4 (SRI[4]) at week 32 and all key secondary endpoints, including a ≥ 50% reduction in CLASI activity score (CLASI-50) among patients with moderate to severe skin involvement at baseline (CLASI activity score ≥ 10).Objectives:This subanalysis further assessed the efficacy of deucravacitinib in treating cutaneous manifestations of SLE in patients with moderate to severe skin involvement at baseline.Methods:Patients with active SLE and a baseline CLASI score of ≥ 10 who received placebo (n = 24) or deucravacitinib 3 mg BID (n = 23), 6 mg BID (n = 25), or 12 mg once daily (QD; n = 29) were included in these analyses. All subanalyses were descriptive. Response rates in patients who achieved a sustained CLASI-50 response from weeks 32 through 48, a ≥ 70% reduction in CLASI activity score (CLASI-70) at week 48, and CLASI-50 by SLE cutaneous manifestation subtype were calculated using a nonresponder imputation. The 2-sided 95% CI for response rate was calculated based on the asymptotic method. Investigators used Systemic Lupus International Collaborating Clinics criteria to classify patients in ≥ 1 subcategory (acute, subacute, chronic, or discoid) at screening; all patients classified as discoid were included in the chronic subgroup. Biopsy confirmation was not required for this study.Results:More patients receiving deucravacitinib sustained CLASI-50 for 5 consecutive visits between weeks 32 and 48 (placebo, 12.5%; deucravacitinib 3 mg BID, 56.5%; 6 mg BID, 36.0%; 12 mg QD, 58.6%; Figure 1A) and achieved CLASI-70 at week 48 (placebo, 8.3%; deucravacitinib 3 mg BID, 65.2%; 6 mg BID, 36.0%; 12 mg QD, 58.6%) than patients receiving placebo (Figure 1B). Analysis by cutaneous manifestation suggested that patients receiving deucravacitinib achieved CLASI-50 at week 48 more often than patients receiving placebo in all subtypes assessed (acute: placebo, 15.0%; deucravacitinib 3 mg BID, 68.4%; 6 mg BID, 54.2%; 12 mg QD, 60.0%; subacute: placebo, 0.0%; deucravacitinib 3 mg BID, 100.0%; 6 mg BID, 33.3%; 12 mg QD, 80.0%; chronic: placebo, 18.2%; deucravacitinib 3 mg BID, 72.7%; 6 mg BID, 46.2%; 12 mg QD, 64.3%; discoid: placebo, 25.0%; deucravacitinib 3 mg BID, 71.4%; 6 mg BID, 45.5%; 12 mg QD, 66.7%; Figure 2A). Patient visual findings demonstrate changes with deucravacitinib treatment from baseline to week 48 (Figure 2B).Conclusion:Among those with moderate to severe skin involvement at baseline, more patients receiving deucravacitinib were able to achieve improvements in skin overall and sustain CLASI-50 from weeks 32 through 48 than patients receiving placebo. CLASI-50 achievement was more frequent among patients treated with deucravacitinib in all cutaneous subtypes assessed than among patients treated with placebo.Figure 1.Sustained CLASI-50 response and CLASI-70 achievement at week 48 in patients with a CLASI activity score of ≥ 10 at baselineFigure 2.CLASI-50 achievement at week 48 by cutaneous manifestation subtype and patient visual findingsREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Stephanie V. Koebele, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Cristina Arriens AstraZeneca and Aurinia, AstraZeneca, Aurinia, Bristol Myers Squibb, GSK, Kezar, AstraZeneca, Bristol Myers Squibb, Ronald F. van Vollenhoven Pfizer, AbbVie, Galapagos, Janssen; Roche, UCB, Pfizer, AbbVie, Galapagos, Janssen, AbbVie, Galapagos, Janssen, UCB, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, Pfizer, Bristol Myers Squibb, GSK, Eli Lilly, UCB, Alice B Gottlieb Amgen, AnaptysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, DICE Therapeutics, Eli Lilly, Janssen, Novartis, Sanofi, UCB, XBiotech, AnaptysBio, MoonLake Immunotherapeutics AG, Novartis, Bristol Myers Squibb, UCB Pharma (all paid to Icahn School of Medicine at Mount Sinai), Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Ravi Koti Employee of Syneos Health, providing statistical services to Bristol Myers Squibb, Thomas Wegman Bristol Myers Squibb, Bristol Myers Squibb, Victoria P. Werth Celgene, MedImmune, Resolve, Genentech, Idera, Janssen, Eli Lilly, Biogen, Bristol Myers Squibb, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Serono, CSL Behring, Principia, Crisalis, Viela Bio, argenx, Kirin, AstraZeneca, AbbVie, GSK, Cugene, UCB, Corcept, Beacon Bioscience, Celgene, Janssen, Biogen, Gilead, AstraZeneca, Viela, Amgen, Lupus Research Alliance/Bristol Myers Squibb.

Background:Deucravacitinib, a first-in-class, oral, selective, allosteric tyrosine kinase 2 inhibitor, targets select immune pathways relevant to systemic lupus erythematosus (SLE) and is approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. In the 48-week, double-blind, phase 2 PAISLEY trial in patients with active SLE (NCT03252587), a greater proportion of patients randomized to deucravacitinib 3 mg twice daily (BID) met the primary endpoint of SLE Responder Index-4 (SRI[4]) response and all key secondary endpoints, including global disease activity measures.Objectives:This post hoc subanalysis focuses on the efficacy of deucravacitinib in musculoskeletal manifestations of SLE in the PAISLEY study.Methods:Patients receiving standard of care were randomized 1:1:1:1 to placebo (n = 90) or deucravacitinib 3 mg BID (n = 91), 6 mg BID (n = 93), or 12 mg once daily (QD; n = 89). A 40-joint count (JC) measured joint swelling, tenderness, or both. Outcomes included achievement of ≥ 50% reduction (JC-50) and 100% reduction (JC-100) in active joint count (swollen + tender; AJC-50 and AJC-100, respectively), swollen joint count (SJC), and tender joint count (TJC) in patients with ≥ 6 joints involved at baseline or patients with any joint involvement at baseline. Responses were reported using a prespecified nonresponder imputation. The 2-sided 95% CI for responses was calculated using the asymptotic (including continuity) method. Results were descriptive.Results:At week 32 (primary endpoint analysis time point), more patients with ≥ 6 active joints at baseline receiving deucravacitinib achieved AJC-50 vs those receiving placebo (placebo, 45.3%; deucravacitinib 3 mg BID, 63.5%; 6 mg BID, 64.6%; 12 mg QD, 56.5%; Figure 1A), in line with previously reported JC-50 findings at week 48. Patients with any joint involvement at baseline receiving deucravacitinib achieved AJC-50 more often than those receiving placebo (week 32: placebo, 48.3%; deucravacitinib 3 mg BID, 63.3%; 6 mg BID, 63.4%; 12 mg QD, 53.4%) through week 48 (Figure 1B). AJC-100 results were similar to AJC-50 results in both populations through week 48 (Figures 1C and 1D). Consistent patterns of higher JC-50 and JC-100 responses with deucravacitinib were observed in separate analyses of SJC and TJC through week 48 (Figure 2).Conclusion:Deucravacitinib was associated with reductions in joint counts vs placebo using a range of assessment time points, different joint assessments, and different cutoffs for musculoskeletal involvement at baseline.Figure 1.AJC-50 and AJC-100 responses from baseline through week 48Figure 2.JC-50 and JC-100 responses at week 48 for SJC and TJC assessmentsREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Stephanie V. Koebele, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Marilyn Pike AstraZeneca, Bristol Myers Squibb, Pfizer, UCB, Amit Saxena AstraZeneca, Bristol Myers Squibb, Eli Lilly, GSK, Kezar Life Sciences, Richard A. Furie Bristol Myers Squibb, Bristol Myers Squibb, Peter Nash AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Servatus, UCB, Thomas Dörner AbbVie, Aurinia, Bristol Myers Squibb, Eli Lilly, Novartis, Sanofi, UCB, AbbVie, Novartis, Bristol Myers Squibb, Janssen, Roche/Genentech, Sanofi, Eli Lilly, UCB, Deutsche Forschungsgemeinschaft, EU Horizon/HarmonicSS, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Ravi Koti Employee of Syneos Health, providing statistical services to Bristol Myers Squibb, Subhashis Banerjee Bristol Myers Squibb, Bristol Myers Squibb, Thomas Wegman Bristol Myers Squibb, Bristol Myers Squibb, Joan Merrill AbbVie, Alexion, Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb, EMD Serono, Equillium, Genentech, Gilead, GSK, IQVIA, Janssen, Eli Lilly, LFA, Merck, Provention, RemeGen, Sanofi, Takeda, Zenas.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in the US, EU, and other countries for treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. In PAISLEY, a 48-week, phase 2, randomized controlled trial that assessed deucravacitinib in patients with active systemic lupus erythematosus (SLE), a greater proportion of patients receiving deucravacitinib treatment achieved SLE Responder Index-4 (SRI[4]) responses at Weeks 32 and 48 vs placebo.Objectives:To assess the impact of deucravacitinib on patient-reported outcomes (PROs) in patients with active SLE.Methods:All patients met Systemic Lupus International Collaborating Clinics classification criteria, were seropositive for antinuclear antibody, anti-double-stranded DNA, or anti-Smith antibody, and had Systemic Lupus Erythematosus Activity Index 2000 total score ≥6 points and clinical score ≥4 points. Patients (N = 363) were randomized 1:1:1:1 to placebo (n = 90) or deucravacitinib 3 mg twice daily (BID; n = 91), 6 mg BID (n = 93), or 12 mg once daily (QD; n = 89). Patients assessed pain levels on a numeric rating scale (NRS) and completed the Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue 7a Short Form and 36-Item Short Form Health Survey (SF-36). Patient-reported assessments were recorded on Day 1 regardless of the assessment time relative to the first dose of study medication. Missing data were imputed using control-based pattern imputation. Results were descriptive.Results:Baseline characteristics were comparable across groups. At Week 48, greater mean changes from Day 1 in pain and fatigue were reported with deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD vs placebo, including achievement of the minimal clinically important differences (MCID) of −1 and −4 for both pain and fatigue with all doses of deucravacitinib vs for pain only with placebo (Figure 1). Patients treated with deucravacitinib reported greater achievement of changes associated with MCID for pain (−1), fatigue (−4), and SF-36 MCS and PCS (−2.5) vs placebo (Table 1). Mean scores (SD) at Week 48 numerically improved with deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD vs placebo, respectively: Pain NRS: 3.6 (2.7), 3.7 (2.6), 3.6 (2.8), and 4.7 (2.7); PROMIS Fatigue: 52.4 (10.2), 52.6 (10.0), 51.9 (10.6), and 54.4 (10.9); SF-36 PCS: 44.7 (10.0), 44.6 (9.3), 45.1 (11.0), and 41.5 (10.5); and SF-36 MCS: 46.7 (12.6), 46.3 (13.1), 47.3 (12.6), and 45.2 (12.9).Conclusion:Patients with SLE who received deucravacitinib reported improvements over patients who received placebo on pain and fatigue, and in health-related quality of life at Week 48.REFERENCES:NIL.Acknowledgements:This study was sponsored by Bristol Myers Squibb.Disclosure of Interests:Marta Mosca AstraZeneca, Bristol Myers Squibb, GSK, Lilly, Otsuka, and UCB, Laurent Arnaud AbbVie, Alexion, Alpine, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Grifols, Janssen, LFB, Kezar Life Sciences, Lilly, Medac, Novartis, Oséus, Pfizer, Roche-Chugaï, and UCB, Anca Askanase AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, GSK, Idorsia, Janssen, Lilly, Pfizer, and UCB, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Brandon Becker Bristol Myers Squibb, Bristol Myers Squibb, Shalabh Singhal Bristol Myers Squibb, Former employee Bristol Myers Squibb, Subhashis Banerjee Bristol Myers Squibb, Bristol Myers Squibb, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Jiyoon Choi Bristol Myers Squibb, Bristol Myers Squibb, Adrian Coles Bristol Myers Squibb, Bristol Myers Squibb, Vibeke Strand AbbVie, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Biosplice, Bioventus, Blackrock Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Chemocentryx, Equillium, Eupraxia, Flexion, Galápagos, Genentech/Roche, Gilead, GSK, Horizon Therapeutics, Ichnos Sciences, Inmedix, Janssen, Kiniksa, Kypha, Eli Lilly, Merck, MiMedx, Novartis, Pfizer, Regeneron, Rheos Medicines, Samsung, Sandoz, Sanofi, Scipher, Servier, SetPoint Medical, Spherix, Tonix, and UCB.

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of moderate to severe plaque psoriasis. The 48-week, double-blind, phase 2 PAISLEY trial in patients with active SLE (NCT03252587) met its primary endpoint and all key secondary endpoints at the deucravacitinib 3-mg-twice daily (BID) vs placebo.Objectives:In this post-hoc analysis, response rates over time were evaluated for ≥50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score from baseline in patients with a baseline CLASI score ≥10 (CLASI-50), ≥50% reduction in active (swollen + tender) joint count in patients with ≥6 active joints at baseline (AJC-50), and other key secondary endpoints.Methods:Patients with active SLE receiving standard of care were randomized 1:1:1:1 to placebo (n = 90), deucravacitinib 3 mg twice daily (BID; n = 91), 6 mg BID (n = 93), or 12 mg once-daily (QD; n = 89). Previous reporting from PAISLEY used strict nonresponder imputation criteria with several conditions considered a nonresponse applied after week 20, including not achieving a glucocorticoid dose ≤7.5 mg/day by week 20, resulting in different imputation methods used before vs after week 20. Here, we characterize disease activity improvement in 2 key lupus manifestations, imputing only missing data as nonresponse (M=NR) through week 48 and assessing response rate kinetics using the same imputation method throughout.Results:Patients receiving deucravacitinib had numerically higher CLASI-50 response rates vs placebo starting at week 4 (placebo, 4.2%; 3 mg BID, 21.7%; 6 mg BID, 8.0%; 12 mg QD, 27.6%) (Figure 1A); robust differences were maintained through week 48. Numerical differences in AJC-50 response rates were first observed at week 8 (placebo, 54.7%; 3 mg BID, 69.8%; 6 mg BID, 73.8%; 12 mg QD, 59.7%) and became more notable from week 24 (Figure 1B). Differences in responses of both organs were maintained with deucravacitinib beyond week 20, after the protocol-mandated glucocorticoid taper.Conclusion:These data suggest that higher response rates with deucravacitinib vs placebo occur early on for mucocutaneous and somewhat later for musculoskeletal manifestations. Permitted concomitant glucocorticoid use may partially explain the placebo group responses. Robust differences were seen after the glucocorticoid taper, further supporting the efficacy of deucravacitinib.Figure 1.Response rates from weeks 4 to 48 in patients with active SLEREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Angela R. Eder, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Ronald F. van Vollenhoven Pfizer, Roche, UCB, Pfizer, AbbVie, Galapagos, and Janssen, UCB, Pfizer, AbbVie, Galapagos, and Janssen, AstraZeneca, Biogen, Biotest, Celgene, Gilead, and Servier, Bristol Myers Squibb, GSK, and Eli Lilly, UCB, Joseph F. Merola AbbVie, Amgen, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB, Kathryn H. Dao Bristol Myers Squibb, Piotr Leszczyński Novartis, AbbVie, AstraZeneca, Bristol Myers Squibb, Pfizer, and UCB, Bristol Myers Squibb, Marilyn Pike AstraZeneca, Bristol Myers Squibb, Pfizer, and UCB, Samantha Pomponi Bristol Myers Squibb, Bristol Myers Squibb, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Matthew J. Colombo Bristol Myers Squibb, Bristol Myers Squibb, Ravi Koti Employee of Syneos Health and provides statistical services to Bristol Myers Squibb, Subhashis Banerjee Bristol Myers Squibb, Bristol Myers Squibb, Thomas Wegman Bristol Myers Squibb, Bristol Myers Squibb, Eric Morand AstraZeneca, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, Novartis, and Takeda, AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Takeda, and UCB.

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis [1,2]. Deucravacitinib demonstrated efficacy across the primary endpoint and all key secondary endpoints in a phase 2 trial in patients with systemic lupus erythematosus (SLE) [3].ObjectivesHere, we describe 2 phase 3 trials currently underway to assess the efficacy and safety of deucravacitinib in patients with active SLE. These phase 3 trials have been designed to replicate the successful elements of the phase 2 trial, including its glucocorticoid-tapering strategy and rigorous management structure [3].MethodsIn these phase 3, randomized, double-blind, placebo-controlled, global trials (POETYK SLE-1 [NCT05617677], POETYK SLE-2 [NCT05620407]), adults (aged 18-75) with active SLE on background standard-of-care treatment will be randomized (1:1) to placebo or deucravacitinib for 52 weeks of double-blind treatment (Figure 1). Patients on glucocorticoids will be instructed to taper, unless significant disease activity is present, to a threshold dose level during the double-blind treatment period. At week 52, patients may choose to continue in a 104-week open-label extension phase, in which all patients receive deucravacitinib. Key eligibility criteria and study design are depicted below (Figure 1). The primary endpoint of SLE Responder Index (SRI[4]) and all secondary endpoints will be assessed at week 52 (Table 1). Safety and tolerability will be assessed throughout the trial.ResultsPlanned randomization in each trial includes 490 patients (245 per treatment group) in 27 countries across North and South America, Europe, and Asia-Pacific.ConclusionThe phase 3 POETYK SLE trials will further evaluate the efficacy and safety of deucravacitinib, an oral, selective, TYK2 inhibitor, in patients with active SLE.References[1]Armstrong A, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02256-3.[2]Strober B, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02643-3.[3]Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print). doi: 10.1002/art.42391.Table 1.Primary and Secondary Endpoints Assessed at Week 52Primary Endpoint • Proportion of patients who achieve an SLE Responder Index (SRI[4]) responseSecondary Endpoints • Proportion of patients who achieve a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response • Proportion of patients with simultaneous achievement of SRI(4) and BICLA response (dual responders) • Proportion of patients who achieve a ≥ 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50) among patients with CLASI activity score ≥ 10 at baseline • Proportion of patients who achieve Lupus Low Disease Activity State (LLDAS) • Proportion of patients maintaining ≤ 7.5 mg/day glucocorticoid dose from weeks 24 to 52 • Proportion of patients who achieve a ≥ 50% reduction in active joints (Joint-Count 50) among patients with ≥ 6 active joints at baseline • Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scoreAcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsCristina Arriens Speakers bureau: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, Kezar, AstraZeneca and Aurinia, Grant/research support from: AstraZeneca and Bristol Myers Squibb, Anca Askanase Consultant of: Abbvie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Idorsia, Janssen, Pfizer, and UCB, Richard Furie Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Eric F. Morand Consultant of: AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, Gilead, Novartis, and Servier, Grant/research support from: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, and UCB, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, Janssen, Pfizer, UCB, Consultant of: UCB, Pfizer, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, AbbVie, Galapagos, and Janssen, Grant/research support from: Bristol Myers Squibb, Eli Lilly, Pfizer, UCB, Roche, and GlaxoSmithKline, Kevin Connors Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Monica Davey Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vaishali Shah Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Anna Stevens Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Wegman Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.