This first-in-human, phase 1, double-blind, placebo-controlled study evaluated the safety, tolerability, immunogenicity, pharmacokinetics, and exploratory efficacy of a selective ErbB4 agonist, JK07, in patients with heart failure with reduced ejection fraction (HFrEF). In these patients on optimal goal-directed medical therapy, JK07 was generally safe and well tolerated at dose levels up to 0.09 mg/kg. There was a trend toward increased incidence and severity of treatment-emergent adverse events observed at the highest dose of 0.27 mg/kg. Consistent with prolonged effects seen with transient exposure to neuregulin-1 in previous phase 1 investigations, improvements in left ventricular ejection fraction lasting up to 180 days after infusion were observed. These findings support continued clinical investigation of JK07 in heart failure. (Study of JK07 in Subjects With Heart Failure With Reduced Ejection Fraction; NCT04210375).

Plain Language SummaryWhat is this summary about?This plain language summary describes the results of the phase 2 study called PAISLEY which tested deucravacitinib, a new medicine under investigation before approval, in people living with lupus. In this trial, researchers wanted to find out if deucravacitinib would be safe and reduce the symptoms and disease activity in people living with lupus. PAISLEY looked at the type of lupus known as systemic lupus erythematosus, shortened to SLE.What happened in the study?The study included 363 people from 17 countries who had SLE and were between 18 and 75 years of age. The participants were divided into 4 groups at random. One group was given placebo (a fake or dummy pill that contains no medicine) and the other 3 groups took deucravacitinib, a pill taken by mouth. Each of the groups taking deucravacitinib took a different dose, either 3 milligrams (mg) twice daily, 6 mg twice daily, or 12 mg once daily. After 32 and 48 weeks, researchers measured the number of people in each group who had improvements in their SLE symptoms and disease activity, as measured by different tests. They also looked at any side effects people experienced, which may or may not have been caused by the medicine.What do the results mean?After 32 weeks of treatment, SLE symptoms and disease activity improved in more people in each of the deucravacitinib dose groups compared with the people taking placebo (the dummy pill). After 48 weeks of treatment, SLE symptoms and disease activity were still improved in more people taking deucravacitinib compared with people taking placebo, and this was measured in several different ways. The best results were seen in people taking deucravacitinib 3 mg twice daily. The number of serious side effects was similar for people taking deucravacitinib and those taking placebo. The most common side effects that were seen in people taking deucravacitinib were infections such as sore throat, cough, or bronchitis (upper respiratory tract), infltion in the nose (nasopharyngitis), headaches, and urinary tract infections. More people taking deucravacitinib than placebo had acne, rash, and cold sores (oral herpes). These were not serious and did not have any long-term effects on patient health or lead to patients stopping treatment.How to say (double click sound icon to play sound)... Systemic lupus erythematosus: SIS-teh-MIC LOO-puhs Eh-RE-the-ma-TOE-susDeucravacitinib: doo-KRAV-a-sih-ti-nibEnzyme: EN-zimeInterferon: in-tur-FER-onPlacebo: pluh-SEE-bohTyrosine kinase: TY-ruh-seen KY-naysTYK2: TIK-tu

Background Tyrosine kinase 2 (TYK2) mediates signaling of key cytokines (eg, Type 1 IFNs, IL-23, and IL-12) involved in lupus 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 in a phase 2 trial in patients with active SLE (PAISLEY; NCT03252587).3 This analysis evaluated the effect of deucravacitinib on biomarkers of TYK2-mediated pathways, B cell pathways, and serological biomarkers in patients in the phase 2 PAISLEY SLE trial. Methods The 48-week PAISLEY trial randomized 363 patients with SLE 1:1:1:1 to placebo or deucravacitinib 3 mg twice daily (BID), 6 mg BID, or 12 mg once daily (QD). Whole blood transcripts, serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry. Results With deucravacitinib treatment, significant reductions were observed in IFNα (at week 48) and IFNλ (week 2 through week 48), and IFNγ was numerically lower after week 12. Deucravacitinib, but not placebo, reduced IFN-regulated gene (IRG) expression as well as expression of cytokines and chemokines downstream of IFN activity, including BAFF, CXCL10, and MCP2 (figure 1). IFNλ, CXCL10, CCL19, and MCP2 were significantly reduced in the BID-dosed arms as early as 2 to 3 days after dose initiation. With deucravacitinib treatment, lymphocyte and neutrophil counts and complement levels increased, while markers associated with B cell activation and differentiation including BLC (CXCL13), CD38 (gene expression), and autoantibodies were reduced. Conclusions Deucravacitinib suppressed IFN production, IRG expression, IFN-inducible proteins, B cell pathway markers, and serological biomarkers, consistent with clinical symptom improvements in SLE patients treated with deucravacitinib. Suppression of both IFN and B cell pathways suggests a broad reduction in lupus pathophysiology. These results provide a molecular framework for understanding how deucravacitinib modifies molecular networks in SLE. References Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol. 2022 Nov 11 (Epub ahead of print).

Background Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for treatment of adults with plaque psoriasis. In PAISLEY, a 48-week, phase 2, randomized controlled trial (NCT03252587) that assessed deucravacitinib in patients with active systemic lupus erythematosus (SLE), a greater proportion of patients receiving deucravacitinib achieved SLE Responder Index-4 responses at Weeks 32 and 48 vs placebo. Patient-reported outcomes (PROs) were collected as exploratory endpoints at 48 weeks. Methods Patients with SLE (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 (SF-36). Missing data were imputed using control-based pattern imputation. Results are descriptive. Results Baseline characteristics were comparable across groups (table 1). At Week 48, greater mean changes from baseline in pain and fatigue were reported with deucravacitinib 3 mg BID, 6 mg BID, and 12 QD vs placebo (figure 1). Mean improvements in pain and fatigue were greater than minimum clinically important differences (MCIDs) of −1.0 and −4.0, respectively, with all doses of deucravacitinib vs only pain with placebo. 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], 4.7 [2.7]; PROMIS Fatigue: 52.4 [10.2], 52.6 [10.0], 51.9 [10.6], 54.4 [10.9]; SF-36 physical component: 44.7 [10.0], 44.6 [9.3], 45.1 [11.0], 41.5 [10.5]; and SF-36 mental component scores: 46.7 [12.6], 46.3 [13.1], 47.3 [12.6], 45.2 [12.9]. Additional subgroup analyses are ongoing. Conclusions Patients with SLE receiving deucravacitinib reported improvements over placebo in NRS pain, fatigue, and health-related quality of life at Week 48.

Background CTLA-4 is highly expressed on most regulatory T cells (Tregs) but only upregulated in effector T cells following activation. Emerging evidence suggests anti-tumor activity of antibodies targeting CTLA-4 may be modulated by the local presence of NK cells. Interleukin 15 (IL-15) is a pleiotropic cytokine important in both innate and adaptive immunity. The IL-15/IL-15Rα complex can stimulate adjacent cells through the IL-2Rβ/γ complex. JK08 is a recombinant fusion protein consisting of two functional elements - a fully human monoclonal antibody directed against CTLA-4 and a protein complex consisting of human IL-15 and the Sushi domain of human IL-15Rα. JK08 is intended to widen the therapeutic window for IL-15 cytokine-mediated cancer therapy and CTLA-4-targeted antibody-mediated cancer therapy by local activation and expansion of NK cells at sites of Tregs, and by IL-15 enhancement of the activity and potency of the proximal CTLA-4 antibody, mirroring the endogenous trans-presentation orientation. Preclinical studies demonstrate JK08 can elicit ADCC-mediated killing of CTLA-4-expressing cells and interact with IL-2Rβ on NK & CD8+ T cells to promote robust T cell proliferation independent of IL-15Rα expression, suggesting that JK08 could effectively activate IL-2Rβ/γC-expressing cells preferentially at sites of Tregs and achieve enhanced anti-tumor responses including through ADCC-mediated depletion of T regulatory cells. In vivo studies show JK08 induces robust NK and CD8+ T cell expansion in cynomolgus monkeys and anti-tumor activity in syngeneic murine models. Methods The Phase 1/2 study of JK08 will enroll patients with advanced relapsed/refractory solid tumors. The study will employ an accelerated 3+3 escalation design to explore the safety, PK, immuno-regulatory activity, and preliminary anti-tumor activity of JK08. Patients will receive treatment with JK08 subcutaneously once weekly until confirmed disease progression or intolerable toxicity. Tumor specific expansion cohorts will be initiated once dose and schedule are established from dose escalation, with plans to further advance development in combinations. Response will be assessed every 9 weeks per RECIST v1.1.

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 plaque psoriasis.1 2 In a phase 2 trial in SLE patients on background standard therapy, deucravacitinib demonstrated efficacy vs placebo across multiple endpoints, including SRI(4) at week 32 (primary endpoint) and at week 48 (secondary endpoint), as well as BICLA at week 48 (secondary endpoint).3 This post-hoc analysis further evaluated efficacy and time to response with deucravacitinib vs placebo in these responses in the phase 2 trial. Methods This 48-week, double-blind trial (NCT03252587) randomized 363 patients with active SLE 1:1:1:1 to placebo or deucravacitinib 3 mg BID, 6 mg BID, or 12 mg QD. Endpoints included the proportions of patients achieving SRI(4), BICLA, and simultaneous (dual) SRI(4)/BICLA responses at weeks 32 and 48, proportions of patients with sustained responses through week 48 (responder at every visit from week 32 through week 48), and time to onset of responses. BICLA response, and therefore dual response, were measurable at the first visit after steroid taper completion (week 24 [day 168]). Analyses were descriptive. Results At weeks 32 and 48, SRI(4), BICLA, and dual response rates were numerically higher with deucravacitinib vs placebo (figure 1). Median time intervals to onset of SRI(4), BICLA, and dual responses were lower with deucravacitinib treatment compared with placebo (table 1). Median times to onset of dual response were 196–282 days with deucravacitinib. A higher percentage of patients treated with deucravacitinib sustained their SRI(4), BICLA, and dual responses through week 48 vs placebo (table 1). Conclusions Deucravacitinib treatment elicited higher and faster SRI(4), BICLA, and dual responses compared with placebo. Patients were more likely to sustain their treatment responses from weeks 32 through 48 with deucravacitinib treatment vs placebo. These data support the robust efficacy of deucravacitinib across multiple SLE response indices. References Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print).

Background Tyrosine kinase 2 (TYK2) mediates signaling of key cytokines (eg, type 1 IFNs, IL-23, and IL-12) involved in 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 demonstrated a favorable safety and efficacy profile in a phase 2 trial in patients with psoriatic arthritis[3] and a phase 2 trial in patients with active SLE (PAISLEY; NCT03252587).[4] Objectives This analysis evaluated the effect of deucravacitinib on biomarkers of TYK2-mediated pathways, B-cell pathways, and serological biomarkers in patients in the phase 2 PAISLEY SLE trial. Methods The 48-week PAISLEY trial randomized 363 patients with SLE 1:1:1:1 to placebo or deucravacitinib 3 mg twice daily (BID), 6 mg BID, or 12 mg once daily (QD). Whole blood transcripts, serum proteins, blood cell subsets, and antibody profiles at screening and baseline through week 48 were measured by immunoassays and flow cytometry. In a substudy, samples were collected from 83 subjects 22 to 114 hours after the initial dose. Samples from demographically matched healthy subjects were collected and measured for comparison. Results At screening, 42 genes/modules and 75 proteins were differentially expressed compared with healthy subjects, with fold change >1.5 and adjusted P value <0.05. With deucravacitinib treatment, significant reductions were observed in IFNα (at week 48) and IFNλ (week 2 through week 48), and IFNγ was numerically lower after week 12. Deucravacitinib significantly inhibited IFN-regulated gene (IRG) expression from week 4 through week 44 (Figure 1). Deucravacitinib, but not placebo, reduced expression of cytokines and chemokines downstream of IFN activity, including BAFF, CXCL10, and MCP2. Adjusted mean percent changes from baseline at week 48 after treatment with deucravacitinib 3 mg BID, 6 mg BID, or 12 mg QD were –26%, –31%, and –30% for MCP2 and –42%, –43%, and –48% for CXCL10, respectively. Selected cytokines and chemokines including IFNλ, CXCL10, CCL19, and MCP2 were significantly reduced in the BID-dosed arms as early as 2 to 3 days after dose initiation. With deucravacitinib treatment, lymphocyte and neutrophil counts and complement levels increased, while markers associated with B-cell activation and differentiation including BLC (CXCL13), CD38 (gene expression), and autoantibodies were reduced. Conclusion Deucravacitinib suppressed IFN production, IRG expression, IFN-inducible proteins, B-cell pathway markers, and serological biomarkers, consistent with clinical symptom improvements in SLE patients treated with deucravacitinib. Suppression of both IFN and B-cell pathways suggests a broad reduction in lupus pathophysiology. These results provide a molecular framework for understanding how deucravacitinib modifies molecular networks in SLE and support the continued investigation of deucravacitinib as a treatment for SLE in phase 3 trials. 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]Mease PJ, et al. Ann Rheum Dis. 2022;81:815-822. [4]Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print). Acknowledgements This clinical trial was sponsored by Bristol Myers Squibb. Disclosure of Interests J Michelle Kahlenberg Consultant of: Q32 Bio, Celgene/Bristol Myers Squibb, Ventus Therapeutics, Rome Therapeutics, and Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Bristol Myers Squibb, Avion Pharmaceuticals, Provention Bio, Aurinia Pharmaceuticals, Ventus Therapeutics, and Boehringer Ingelheim., Ignacio Sanz Shareholder of: Kyverna, Consultant of: Exagen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Kyverna, and Visterra, Chun Wu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yanhua Hu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Jin Hyang Kim Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian M. Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.

Deucravacitinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune‐mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open‐label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12‐mg tablet and an intravenous microdose infusion of 0.1‐mg carbon‐13 and nitrogen‐15–labeled deucravacitinib ([13C2, 15N3] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3‐ and 12‐mg dose levels in 20 subjects. The absolute oral availability of deucravacitinib in the tablet formulation was near complete at approximately 99%. The total clearance (254 mL/min) was low relative to hepatic blood flow, and volume of distribution (∼140 L) was greater than total body water, indicating extravascular distribution. Deucravacitinib systemic exposure (maximum plasma concentration, area under the plasma drug concentration curve from time zero to the time of the last quantifiable nonzero concentration, and area under the plasma drug concentration–time curve from time zero extrapolated to infinity) after administration of the tablet formulation were similar to the capsule at the tested 3‐ and 12‐mg doses. In both studies, deucravacitinib was safe with no clinically relevant changes in laboratory values, electrocardiogram parameters, or vital signs.

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 plaque psoriasis [1,2]. Deucravacitinib demonstrated efficacy across multiple outcome measures, including achievement of ≥50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-50), in a phase 2 trial in patients with systemic lupus erythematosus (SLE) [3] and is being investigated in two phase 3 trials (NCT05617677; NCT05620407). Patients with discoid and/or subacute cutaneous lupus erythematosus (DLE/SCLE) have elevated expression of Type I interferons (IFN) [4]. Deucravacitinib mediates signaling of Type I IFN, IL-12, and IL-23 and may be an effective treatment for patients with DLE/SCLE [5]. Objectives Results of this ongoing phase 2 trial (NCT04857034) will characterize the efficacy and safety of deucravacitinib compared with placebo in patients with active DLE/SCLE with or without SLE. Methods This phase 2, global, randomized, double-blind, placebo-controlled trial is enrolling adults (aged 18-75) with biopsy-confirmed clinical diagnosis of DLE/SCLE. Key eligibility criteria and study design are depicted below (Figure 1). Eligible patients will be randomized (1:1:1) to treatment with placebo or deucravacitinib (dose 1 or 2) for 16 weeks. At week 16, all patients randomized to placebo will be rerandomized (1:1) to treatment with deucravacitinib dose 1 or 2 until week 52. Patients originally randomized to deucravacitinib will continue treatment until week 52. The primary and secondary endpoints are depicted below (Table 1). This trial will also assess the safety and tolerability of 2 doses of deucravacitinib, exploratory efficacy endpoints, patient-reported outcomes, and pharmacodynamics. Results Planned enrollment is 75 total patients (25 per double-blind treatment group) in 8 countries in North and South America, Europe, and Asia-Pacific regions. Conclusion This phase 2 trial will characterize the efficacy, safety, and tolerability of deucravacitinib in patients with active DLE/SCLE. 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). [4]Braunstein I, et al. Br J Dermatol. 2012;166(5):971-975. [5]Burke JR, et al. Sci Transl Med. 2019;11(502):eaaw1736. Acknowledgements This study was sponsored by Bristol Myers Squibb. Disclosure of Interests Victoria P. Werth Consultant of: Celgene, Medimmune, Resolve, Genentech, Idera, Janssen, 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, and Beacon Bioscience, Grant/research support from: Celgene, Janssen, Biogen, Gilead, AstraZeneca, Viela, Amgen, and Lupus Research Alliance/BMS, Joseph F. Merola Consultant of: AbbVie, Amgen, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB., Jörg Wenzel Consultant of: GSK, Incyte, Spirig, AstraZeneca, Bristol Myers Squibb, Medac, Biogen, Novartis, LEO, Kyowa Kirin, Janssen, Bayer, Merck/Serono, Roche, Pfizer, ArrayBio, and Amgen, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Harini Kothari Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Richard Meier Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Malavi Madireddi Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shimon Korish Shareholder of: Bristol Myers Squibb, Employee of: 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 plaque psoriasis.¹−² Deucravacitinib demonstrated efficacy across multiple outcome measures, including achievement of ≥50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-50), in a phase 2 trial in patients with systemic lupus erythematosus (SLE)³ and is being investigated in two phase 3 trials (NCT05617677; NCT05620407). Patients with discoid and/or subacute cutaneous lupus erythematosus (DLE/SCLE) have elevated expression of Type I interferons (IFN).4 Deucravacitinib mediates signaling of Type I IFN, IL-12, and IL-23 and may be an effective treatment for patients with DLE/SCLE.5 Results of this ongoing phase 2 trial (NCT04857034) will characterize the efficacy and safety of deucravacitinib compared with placebo in patients with active DLE/SCLE with or without SLE. Methods This phase 2, global, randomized, double-blind, placebo-controlled trial is enrolling adults (aged 18–75) with biopsy-confirmed clinical diagnosis of DLE/SCLE. Key eligibility criteria and study design are depicted below (figure 1). Eligible patients will be randomized (1:1:1) to treatment with placebo or deucravacitinib (dose 1 or 2) for 16 weeks. At week 16, all patients randomized to placebo will be rerandomized (1:1) to treatment with deucravacitinib dose 1 or 2 until week 52. Patients originally randomized to deucravacitinib will continue treatment until week 52. The primary and secondary endpoints are depicted below (table 1). This trial will also assess the safety and tolerability of 2 doses of deucravacitinib, exploratory efficacy endpoints, patient-reported outcomes, and pharmacodynamics. Results Planned enrollment is 75 total patients (25 per double-blind treatment group) in 8 countries in North and South America, Europe, and Asia-Pacific regions. Conclusions This phase 2 trial will characterize the efficacy, safety, and tolerability of deucravacitinib in patients with active DLE/SCLE. References Armstrong A, et al. J Am Acad Dermatol 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol 2022 Nov 11 (Epub ahead of print). Braunstein I, et al. Br J Dermatol 2012;166(5):971–975. Burke JR, et al. Sci Transl Med 2019;11(502):eaaw1736.

Objective To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). Methods In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. Results ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. Conclusions Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. Trial registration number NCT03881059.

Purpose Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons, IL-23, and IL-12, key cytokines involved in lupus pathogenesis. Deucravacitinib (DEUC) is an oral, selective, allosteric TYK2 inhibitor with a unique mechanism of action, distinct from Janus kinase (JAK) 1/2/3 inhibitors, and has demonstrated a favorable safety and efficacy profile in patients with moderate to severe plaque psoriasis and in psoriatic arthritis. This study assessed efficacy and safety of DEUC in patients with active systemic lupus erythematosus (SLE). Methods This was a 48-week (wk), randomized, double-blind, placebo (PBO)-controlled, phase 2 trial (NCT03252587). Eligible patients met the Systemic Lupus International Collaborating Clinics (SLICC) criteria, were seropositive (ANA/anti-dsDNA/anti-Sm), and had a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6 and ≥1 British Isles Lupus Assessment Group (BILAG) index A or ≥2 BILAG B manifestations from the musculoskeletal or mucocutaneous domain. Patients on standard background medications were randomized 1:1:1:1 to PBO or DEUC (3 mg BID, 6 mg BID, 12 mg QD). Oral corticosteroid tapering to 7.5 mg/day was required from wks 8–20, and further tapering was optional from wks 32–40. The primary endpoint was the proportion of patients achieving SRI(4) at wk 32. Key secondary endpoints at wk 48 included SRI(4), BICLA, LLDAS, CLASI-50, and change from baseline in active (tender and swollen) joint count. Results A total of 363 patients were randomized, with baseline demographic and disease characteristics being similar across treatment groups. Of randomized patients, 275 (76%) completed 48 wks of treatment. The primary endpoint at wk 32 was met, with significantly greater proportions of patients in the DEUC 3 mg BID and 6 mg BID groups vs PBO achieving SRI(4) responses (PBO: 34.4%; DEUC 3 mg BID: 58.2%, P=0.0006; DEUC 6 mg BID: 49.5%, P=0.021; DEUC 12 mg QD: 44.9%, P=0.078). SRI(4) response was sustained across all DEUC groups up to 48 wks (Figure). At wk 48, the DEUC 3 mg BID group demonstrated statistical significance in BICLA, LLDAS, CLASI-50, and active joint count, and the two other DEUC groups demonstrated clinically meaningful differences vs PBO (Figure 1). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between DEUC and PBO groups (Table 1). Most common AEs (≥10%) with DEUC were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major adverse cardiac events, thrombotic events, systemic opportunistic infections, or active tuberculosis occurred. Malignancies were rare with similar rates across all groups (Table 1). No meaningful laboratory abnormalities in mean levels of hematology and chemistry laboratory parameters were observed. Conclusion In patients with active SLE, DEUC showed statistically significant and sustained clinical efficacy in SRI(4), improvement across multiple composite and organ-specific measures up to 48 wks, and was well tolerated. DEUC shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion. The placebo-corrected change from baseline for the QT interval corrected for heart rate using the Fridericia method (QTcF), ECG parameters, and safety measures were evaluated. A clinically meaningful QTcF prolongation of >10 milliseconds was not found for deucravacitinib at tested doses. Assay sensitivity was demonstrated by the observation of known QT effects of moxifloxacin in the study. Deucravacitinib had no clinically relevant effect on other parameters and was generally well tolerated. The majority of adverse events (AEs) were mild, and all AEs resolved by study's end. Three treatment-related serious AEs of pharyngitis, cellulitis, and lymphadenopathy occurred in 1 subject following administration of deucravacitinib 12 mg, but resolved by end of study. This study demonstrated that a single oral dose of deucravacitinib 12 or 36 mg did not produce a clinically relevant effect on the corrected QT interval or other measured ECG parameters in healthy adults.

Introduction: Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons and IL-23, key cytokines involved in systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for the treatment of adults with plaque psoriasis. This analysis assessed the efficacy and safety of deucravacitinib in patients with active SLE. Methods: This 48-week, double-blind, phase 2 trial (NCT03252587) randomized patients 1:1:1:1 to deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD) or placebo. Oral corticosteroid tapering was required from weeks 8-20; further tapering was optional from weeks 32-40. The primary endpoint was the proportion of patients achieving SLE Responder Index-4 (SRI[4]) at week 32. Key secondary endpoints at week 48 included percentage of patients achieving SRI(4) and decrease of ≥50% from baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50), in patients with baseline CLASI ≥10. Change from baseline in CLASI Activity Score (CLASI-A) over time was also assessed. Results: Of 363 randomized patients, 275 (76%) completed 48 weeks of treatment. Baseline demographic and disease characteristics were balanced across treatment groups, with baseline mean CLASI-A scores ranging from 8.0 to 8.6. The primary endpoint at week 32 was met, with significantly greater proportions of patients in deucravacitinib 3 mg BID and 6 mg BID groups vs placebo achieving SRI(4) responses (placebo: 34.4%; deucravacitinib 3 mg BID: 58.2%, P=0.0006; 6 mg BID: 49.5%, P=0.021; 12 mg QD: 44.9%, P=0.078). Patients treated with deucravacitinib demonstrated improvement across all secondary endpoints compared with placebo. In patients with CLASI ≥10 at baseline, greater mean changes from baseline in CLASI-A were observed in deucravacitinib vs placebo over 48 weeks of treatment (placebo: 16.7%; deucravacitinib 3 mg BID: 69.6%, P=0.0006; 6 mg BID: 56.0%, P=0.0058; 12 mg QD: 62.1%, P=0.0009). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between deucravacitinib and placebo groups. Most common AEs with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major adverse cardiac events, thrombotic events, systemic opportunistic infections, or active tuberculosis occurred. Conclusion: Deucravacitinib demonstrated sustained, meaningful clinical efficacy in SRI(4), improvement in mucocutaneous activity as measured by CLASI-A responses, and was well tolerated in patients with active SLE up to 48 weeks.

Objective To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). Methods Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI‐4) response at week 32. Secondary outcomes assessed at week 48 included SRI‐4, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI‐50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. Results At week 32, the percentage of patients achieving SRI‐4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI‐50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. Conclusion Deucravacitinib treatment elicited higher response rates for SRI‐4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE. image