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A phase 3 trial of anifrolumab, a monoclonal antibody to type I interferon receptor subunit 1, showed benefit in a composite primary end point of lupus scores. A previous phase 3 trial failed to meet its primary objective but showed an effect in secondary end points.

Background Belimumab is a human monoclonal antibody that inhibits soluble B-Lymphocyte Stimulator and improves systemic lupus erythematosus (SLE) disease activity. Objectives This study was initiated to evaluate the use and efficacy of belimumab in academic SLE clinical practices. Methods An invitation to participate was sent to 16 physicians experienced in SLE Phase III clinical trials. All agreeing to participate completed a one-page questionnaire for each patient prescribed belimumab that includes demographic and SLE characteristics, and information about belimumab administration. The questionnaire completed every three months by the physicians also captured clinical responses and belimumab safety. Clinical response was defined as a ≥50% improvement in the initial clinical manifestation being treated without worsening in other organ systems. Results Of 16 invitations sent, nine investigators participated. Questionnaires on 150 patients treated with belimumab for at least 3 months were available for analysis. The mean age was 41.9±12.6 years. 92.0% were female, 67.1% White, 24.7% Black, 5.7% Asian, and 5.3% Hispanic. The average SLE disease duration was 12.2±8.2 years. Concomitant medications included: prednisone in 73.3% (mean dose of 12.2±10.9, 41.7% on ≥10 mg), antimalarials in 71.7%, and immunosuppressants in 66.3% (mycophenolate mofetil 34.2%, azathioprine 20.3%, methotrexate 11.8%). Only 3.7% of patients were not on any background SLE medications, 8.0% were on antimalarials alone. The dominant clinical manifestations driving treatment were arthritis in 69.5%, rash in 44.4%, and inability to taper steroids in 27.3%. Other SLE manifestations were serositis 16.0%, hematological 13.9%, and renal 10.7%. 65.2% of patients had ≥2 active manifestations. Of the 150 patients on belimumab for at least 3 months, 69 (46.0%) clinically responded by 3 months with marked improvement in arthritis and/or rash. Similarly, of the 112 patients on belimumab for at least 6 months for whom follow-up data were available, 54 (48.2%) clinically responded with improvements in arthritis, rash and/or nephritis. While the numbers are limited, black patients showed improvement at 6 months, with 19/26, 73% of patients responding, p=0.05. Conclusions These observational data support the use of belimumab across all racial/ethnic groups and efficacy similar to that reported in the Phase III trials. Relevant to physician and patient decision-making, improvement was seen as early as 3 months. Disclosure of Interest A. Askanase Consultant for: GlaxoSmithKline DOI 10.1136/annrheumdis-2014-eular.4343

Background Disease activity measures used in clinical studies of lupus, the SLEDAI (SLE Disease Activity Index) and BILAG (British Isles Lupus Assessment Group) are complicated and challenging due to potential scoring pitfalls, require extensive training and experience. This leaves a busy clinician with limited tools for tracking lupus patients to ensure quality care and documentation of treatment to target. The SELENA SLEDAI physician's global assessment (PGA) is simple to learn and efficient to use, but compresses assessment of moderate/severe disease into a small region of the scale, limiting the ability to evaluate change and performs no organ specific evaluation. The LFA (Lupus Foundation of America)-REAL is a pilot application composed of 7 anchored visual analogue scores (0-100mm each) representing the most common organs affected by lupus: mucocutaneous, neuropsychiatric, musculoskeletal, cardio- respiratory, renal, hematologic or “other” to be filled in for more rare conditions. Physicians select only the scale(s) for active organ(s) and rate disease severity using anchored landmarks based on the PGA: 0 = no disease, 1 = mild, 2 = moderate, 3 = most severe possible disease. Only features due to active lupus are rated. A total disease activity score represents the sum of scores for active organs, other organs default to zero. This enables both organ-specific distinctions and a much wider spectrum of change to be graded overall. Objectives This study is initiated to compare BILAG, SLEDAI and LFA-REAL disease activity scores. Methods A prospective real world clinic exercise was performed by evaluating 91 consecutive patients with SLE in 2 rheumatology clinics. SLEDAI, BILAG, and REAL scores were recorded. The level of agreement was determined by the strength of Spearman rank correlations. Results The study included 86 women and 5 men (mean age 42.1; 54% Caucasian, 31% African, 14% Asian, and 24% Hispanic). 70 (77%) patients were taking antimalarials, 53 (58%) immune modulators, and 40 (44%) prednisone (11>10 mg). 17 (19%) were rated as flaring. The median SLEDAI was 4.0 (0-28) and BILAG 2004 8.0 (0-32), representing a broad spectrum from minimal to severe disease. The median PGA (normalized to 100mm scaling) was 38mm (4-92) vs. the total REAL 50mm (0-268). 33 patients were rated moderate-severe (≥1.5 on SLEDAI landmarks). Their median PGA was 66mm (42) vs. REAL score100mm (218), confirming a wider distinction potential of comparative scores. The total REAL correlated well with PGA, SLEDAI, and BILAG summary scores (correlation coefficient =0.90, 0.82, and 0.93, respectively; p<0.0000002 for all). Individual REAL scores for commonly involved organs (musculoskeletal and mucocutaneous) correlated with the corresponding BILAG domain scores at 0.92 and 0.94 (p<0.0000002). The REAL index took only a few seconds to score. Conclusions The REAL is a simple, intuitive measure of disease severity that performs reliably at 2 clinics. The advantages over PGA are ability to distinguish involvements of different organ systems and allow for a greater range in moderate/severe disease. Community input, refinement and formal validation of the REAL with raters who are not as familiar with BILAG and SLEDAI is planned. The final product of this work (amenable to paper scoring or encripted electronic application) could help improve treatment justification, documentation of progress and standards of care for lupus patients. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4504

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

BackgroundSystemic lupus erythematosus (SLE) clinical trials are challenged by high placebo response rates. Subgroup analyses of historic SLE clinical trial data have identified acute flares with normal complement levels as potential predictors of high placebo response.ObjectivesTo assess the treatment effect of dapirolizumab pegol (DZP; a polyethylene glycol conjugated antigen-binding fragment lacking a functional Fc domain, which inhibits the CD40–CD40 ligand interaction) in patients from the phase 2b trial in SLE,[1] who fulfilled one or both of the characteristics identified as potential predictors of placebo response.MethodsPost hoc analyses were performed on data from a phase 2b trial (NCT02804763), in which patients received placebo or DZP (6/24/45 mg/kg), alongside standard of care (SOC) for 24 weeks.[1] Efficacy was compared between two subgroups: (1) acute flare with low C3/C4 or persistent disease activity, vs (2) acute flare without low C3/C4. In the subgroup analyses, disease activity at screening was defined using British Isles Lupus Assessment Group (BILAG) 2004 item level scores either as acute flare (worsening/new symptoms) or persistent (symptoms rated as the same) based on the past 4 weeks compared with the 4 weeks prior to those, and low C3/C4 was defined as below the lower limit of normal at screening. Outcomes assessed were BILAG-based Composite Lupus Assessment (BICLA) response, SLE Responder Index-4 (SRI-4) response, and change from baseline in Physician’s Global Assessment (PGA) at Week 24. Binary outcomes were analysed using logistic regression (p-values reported for odds ratio vs acute flare without low C3/C4), and continuous outcomes were analysed using mixed models with repeat measures (p-values reported for difference vs acute flare without low C3/C4).ResultsFigure 1a and 1b show BICLA responses in the subgroups over time; similar patterns were seen for the other outcomes. At Week 24, higher BICLA response rates were achieved across all treatment arms in the acute flare without low C3/C4 subgroup compared with the other subgroup (Figure 1c). This pattern was particularly evident in patients receiving SOC plus placebo, where there was a significant 3-fold difference in BICLA response rates between the subgroups (80.0% vs 24.2%; p=0.005). Patients who received SOC plus placebo in the acute flare without low C3/C4 subgroup also achieved numerically higher SRI-4 response rates than the acute flare with low C3/C4 or persistent disease activity subgroup. A similar pattern was observed for patients who received SOC plus 6 mg/kg DZP; however, comparable SRI-4 response rates were observed between subgroups in patients who received SOC plus 24/45 mg/kg DZP (Figure 1d). At Week 24, greater changes from baseline in PGA were achieved in patients receiving SOC plus placebo in the acute flare without low C3/C4 subgroup than in the acute flare with low C3/C4 or persistent disease activity subgroup (least squares mean: −42.0 vs −24.9; p=0.0268). Comparable changes in PGA were seen between subgroups for patients receiving SOC plus DZP (Figure 1e).ConclusionDespite the limited sample size, patients with acute flare with normal complement levels were more likely to achieve responses to SOC plus placebo, diminishing the DZP treatment effect. These data suggest that SLE trial design may need to consider baseline clinical and serologic activity patterns to adequately assess treatment efficacy.Reference[1]Furie RA. Rheumatology (Oxford) 2021;60:5397–407.AcknowledgementsFunded by UCB Pharma and Biogen Inc. Medical writing support provided by Costello Medical and funded by UCB Pharma and Biogen Inc.Disclosure of InterestsAnca Askanase Consultant of: AbbVie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB Pharma, Grant/research support from: AstraZeneca, BMS, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB Pharma, Christian Stach Shareholder of: UCB Pharma, Employee of: UCB Pharma, Claire Brittain Shareholder of: UCB Pharma, Employee of: UCB Pharma, George Stojan Employee of: UCB Pharma, Richard Furie Consultant of: Biogen Inc. and UCB Pharma, Grant/research support from: Biogen Inc. and UCB Pharma.

Background:Lupus nephritis (LN) is characterized by proteinuria, which is not only a marker of active kidney inflammation, but also a driver of progressive kidney injury. Early reduction in proteinuria following treatment initiation has been shown to be a predictor of long-term kidney survival and overall mortality. The AURA-LV and AURORA 1 clinical trials have shown that voclosporin-based triple therapy with lower-dose MMF, and low-dose glucocorticoids (GCs) led to early and significant reductions in proteinuria with an acceptable safety profile. However, dual-immunosuppressive regimens containing high-dose glucocorticoids (GCs) and higher doses (>2 g/day) of mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) are still frequently used for the management of active LN in the belief that they may be more efficacious and safer.Objectives:To compare the safety and efficacy of a voclosporin-based, triple immunosuppressive regimen to a dual-immunosuppressive regimen for the treatment of active LN, we analyzed outcomes in propensity-matched participants from the ALMS, AURA-LV, and AURORA 1 studies. We hypothesized that a voclosporin-based, triple therapy approach would reduce exposure to the toxicities associated with higher doses of GCs, MMF, and IVC, resulting in an improved safety profile without compromising efficacy.Methods:All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months.Results:Propensity matching identified 179 participant pairs with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants in ALMS over the 6-month period. More participants in AURA-LV and AURORA 1 reported hypertension and anemia. Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; a greater number of events of GFR decreased were reported by AURA-LV/AURORA 1 participants. The incidence of serious AEs was similar across groups. UPCR ≤0.5 mg/mg was achieved by 52% of voclosporin-treated participants compared to 41.1% of IVC- or MMF-treated participants of ALMS; the median time to this endpoint for the voclosporin group was 142 days; a median time was not determinable for ALMS participants as less than 50% achieved the endpoint within the study period (hazard ratio [HR] 1.41; 95% confidence interval [CI] 1.03, 1.94; p=0.0324; Table 1, Figure 1). More voclosporin-treated participants achieved a 50% reduction in UPCR from baseline at any point during the study; this endpoint was met significantly earlier by voclosporin-treated patients as well (29 vs. 84 days; HR 1.88, 95% CI 1.48, 2.39; p<0.0001).Conclusion:Participants treated with voclosporin in combination with low-dose GCs and MMF 2g/day demonstrated an improved safety profile and earlier reductions in proteinuria compared to participants treated with high-dose GCs and MMF up to 3 g/day or IVC. These findings support the recommendation that a voclosporin-based, triple-immunosuppressive regimen should be considered as an initial therapy in patients with active LN.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Anca Askanase Consultant for Aurinia Pharmaceuticals Inc., AstraZeneca, GSK plc., Eli Lilly, Kenneth C. Kalunian: None declared, Maria Dall’Era Consultant for Annexon Biosciences, AstraZeneca, Aurinia Pharmaceuticals Inc., Biogen, GSK plc., and Pfizer, Grant/research support from Annexon Biosciences, GSK plc., Neil Solomons Shareholder of Aurinia Pharmaceuticals Inc., Former employee of Aurinia Pharmaceuticals Inc., Lucy Hodge Shareholder of Aurinia Pharmaceuticals, Inc., Employee of Aurinia Pharmaceuticals, Inc., Matt Truman Consultant for Aurinia Pharmaceuticals, Inc., Ernie Yap Shareholder of Aurinia Pharmaceuticals Inc., Employee of Aurinia Pharmaceuticals Inc.

Cenerimod is an orally active, selective sphingosine 1-phosphate (S1P) 1 receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). The Phase 2 CARE study (NCT03742037) did not meet its primary endpoint after adjustment for multiplicity, but patients treated with cenerimod 4 mg showed reduced disease activity versus placebo after 6 months.[1] Along with prior findings that type-1 interferon (IFN-1) activation is a robust biomarker of SLE disease activity and that an elevated IFN-1 signature associates with autoantibodies and more severe disease, cenerimod reduces plasma levels of IFN-α and leads to decreased circulating B and T cells in patients with SLE, suggesting effects on both innate and acquired immune responses. These post-hoc analyses evaluated the efficacy of cenerimod in subpopulations of patients with SLE. CARE randomised 427 patients with SLE to once-daily cenerimod (0.5, 1, 2 or 4 mg) or placebo. At month (M) 6, patients receiving 4 mg cenerimod were re-randomised to placebo or cenerimod 2 mg for the subsequent 6 months, while all other groups continued their initially assigned treatment to M12. The primary endpoint was change from baseline to M6 in SLEDAI-2K score modified to exclude leukopenia (mSLEDAI-2K) due to the mechanism of action of cenerimod. Post-hoc analyses were performed in patients with high IFN-1 gene expression signature or anti-dsDNA levels ≥30 IU/mL. IFN-1 gene expression signature was based on the expression of four genes (IFI27, RSAD2, HERC5, IFIT1). Primary results from the CARE study were presented at ACR 2022.[1] The primary endpoint was not met (nominal P=0.0291 for cenerimod 4 mg vs placebo). At baseline, 207 patients (51%) in CARE had high IFN-1 gene expression signature, including 36 (45%) and 40 (50%) randomised to cenerimod 4 mg and placebo, respectively. Anti-dsDNA antibody levels ≥30 IU/mL were noted in 86 patients (20%), including 21 (25%) and 15 (17%) for cenerimod 4 mg and placebo, respectively. There was an association between high IFN-1 gene expression signature and high anti-dsDNA levels, with more than 75% of patients with anti-dsDNA levels ≥30 IU/mL having high IFN-1 gene expression signature. Reduction in mSLEDAI-2K from baseline to M6 for the cenerimod 4 mg group was greater in patients with high IFN-1 gene expression signature and high anti-dsDNA antibody levels versus the overall population (Figure 1A). Similarly, the proportion of SRI-4 responders at M6 was higher in patients with high versus low IFN-1 gene expression signature (70% vs 41% for cenerimod 4 mg; 46% vs 43% for placebo). Patients with high IFN-1 gene expression signature treated with 4 mg cenerimod showed reduced IFN-α and anti-dsDNA levels at M6 versus baseline. At M6 resolution of alopecia was reported by more patients with high versus low IFN-1 gene expression signature (38% vs 26% for cenerimod 4 mg; 14% vs 7% for placebo), as were resolution of arthritis (57% vs 28% for cenerimod 4 mg; 38% vs 42% for placebo) and reduction in mucosal ulcers (80% vs 67% for cenerimod 4 mg; 41% vs 41% for placebo) on the mSLEDAI-2K. However, there was no treatment effect observed in rash. Treatment with cenerimod 4 mg resulted in greater reductions of disease activity versus placebo at M6 in patients with high IFN-1 gene expression signature or high anti-dsDNA antibody levels at baseline. Cenerimod treatment also reduced levels of IFN-α protein and anti-dsDNA antibodies in these patients. Two Phase 3 studies of cenerimod 4 mg in SLE are underway. [1]Askanase A et al. Efficacy and Safety of Cenerimod in Patients with Moderate to Severe Systemic Lupus Erythematosus (SLE): A Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled, Dose-Finding Phase 2b Trial. Arthritis Rheumatol 2022; 74 (suppl 9):3293–7. o This study was sponsored by Idorsia Pharmaceuticals Ltd. Medical writing support was provided by Anne Sayers (Idorsia Pharmaceuticals Ltd.) and funded by Idorsia Pharmaceuticals Ltd. We thank the patients for their participation and the CARE investigators for their involvement in patient care and contribution to the study. Anca Askanase Consultant of: Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer. Provention, Remegen and UCB, David D'Cruz Consultant of: GSK, UCB, Vifor, Kenneth Kalunian Consultant of: Abbvie, AstraZeneca, Amgen, Aurinia, Biogen, BMS, Eli Lilly, Equillium, Genentech/Roche, Gilead, GSK, Idorsia, KangPu, Kezar, Novartis, Pfizer, UCB, Joan Merrill Consultant of: AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, Grant/research support from: Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline, Sandra Navarra Speakers bureau: Janssen, GlaxoSmithKline, Roche, Consultant of: Astellas, AstraZeneca, Aurinia, Biogen, Boehringer Ingelheim, Idorsia, Grant/research support from: Novartis, Eli Lilly, Horizon Pharma, Clélia Cahuzac Employee of: Employee of Idorsia Pharmaceuticals Ltd., Peter Cornelisse Employee of: Employee of Idorsia Pharmaceuticals Ltd., Daniel Strasser Employee of: Employee of Idorsia Pharmaceuticals Ltd., Luba Trokan Employee of: Employee of Idorsia Pharmaceuticals Ltd., Ouali Berkani Employee of: Employee of Idorsia Pharmaceuticals Ltd. 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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:Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) responses are the most common primary endpoints in systemic lupus erythematosus (SLE) randomized controlled trials (RCTs). Discordance between SRI-4 and BICLA effect sizes in RCTs has engendered skepticism about the utility of these composite indices.Objectives:In this post hoc analysis of 2 SLE RCTs, we examined concordance in SRI-4 and BICLA outcome measures among participants receiving placebo and standard of care (SOC) and explored reasons for SRI-4 and BICLA discordance.Methods:This analysis included data from participants on SOC with evaluable BICLA and SRI-4 response enrolled in the placebo arms of the EXPLORER (n=87; NCT00137969)1 and ATHOS (n=80; NCT02908100)2 RCTs. SRI-4 and BICLA data from Weeks 24 and 52 in EXPLORER and Weeks 24 and 48 in ATHOS were analyzed. Both RCTs had the entry criterion of an SLE Disease Activity Index (SLEDAI) score of ≥6. The trials applied 2 different corticosteroid taper protocols: EXPLORER had an oral corticosteroid target dose of prednisone (or equivalent) of ≤10 mg/d by Week 12 and ≤5 mg/d by Week 52, and ATHOS had a target of <10 mg/d by Weeks 12 and 36. Disease activity was measured using BILAG and SELENA-SLEDAI in EXPLORER and BILAG-2004 and SLEDAI-2K in ATHOS. For this analysis, participants were classified as either responders or nonresponders based on the SRI-4 and BICLA composite indices, as well as the presence of an intercurrent event, and concordance and discordance frequencies between SRI-4 and BICLA were determined. Overall concordance between SRI-4 and BICLA was estimated by the Cohen κ score.Results:In EXPLORER, SRI-4 placebo response rates were greater than BICLA response rates, whereas in ATHOS, SRI-4 and BICLA placebo response rates were similar (Figure 1). Across both trials, SRI-4 and BICLA placebo responses ranged from 40.2% to 45.0% and 29.9% to 47.5%, respectively. At Weeks 24 and 48/52, SRI-4 and BICLA concordance was 0.43 and 0.46 in EXPLORER and 0.60 and 0.54 in ATHOS, respectively (Figure 2). Discordance between SRI-4 and BICLA varied by trial (range, 25.3%-26.4% in EXPLORER and 20.0%-22.5% in ATHOS). In EXPLORER, SRI-4+/BICLA− discordance was high at 18.4% at Week 52. In ATHOS, the low SRI-4+/BICLA− discordance of 12.5% was in line with the similar SRI-4 and BICLA responses at Week 48.Conclusion:Discordance between SRI-4 and BICLA in the EXPLORER and ATHOS trials varied, with the largest difference found in SRI-4 and BICLA placebo responders at Week 52 in EXPLORER; however, the trials cannot be directly compared due to differences in the use of rescue therapies and variants of instruments used. Potential reasons for discordance within studies warranting further evaluation include differences in how domain-specific changes are captured in the SLEDAI and BILAG instruments, especially with regard to the musculoskeletal, mucocutaneous and serologic domains. While BILAG does not capture any immunologic changes (eg, low complement or elevated anti–double-stranded DNA antibody), it does enable capture of partial improvement in each domain, whereas the SLEDAI instruments only permit a binary (present or absent) response for each disease manifestation. As such, BICLA has the advantage over SRI-4 in better detecting partial—but clinically meaningful—changes in SLE disease activity. Evaluating patient-level data inclusive of patient-reported outcomes may also provide insights into the reasons for the SRI-4+/BICLA− discordance.REFERENCES:[1] Merril JT, et al. Arthritis Rheumatol. 2010;62(1):222-233.[2] Isenberg D, et al. Arthritis Rheumatol. 2021;73(10):1835-1846.Acknowledgements:Funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd.Disclosure of Interests:Anca Askanase has been an investigator and/or consultant for AbbVie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly and Company, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Edward M. Vital has received consulting fees from Roche/Genentech, AstraZeneca, Otsuka, Novartis, Eli Lilly and Company, Pfizer, Merck, AbbVie and UCB., Oliver Meier is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Armando Turchetta is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Huiyan (Ashley) Mao is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Justine Maller is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Jorge A. Ross Terres is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Maria Dall’Era reports professional services for Genentech, Aurinia, GSK, AstraZeneca and Eli Lilly and Company.

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.