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Evobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody-positive systemic lupus erythematosus (SLE).Patients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index-2000 score of 6 or more, were autoantibody-positive and on standard-of-care therapy. Randomization was 1:1:1:1 to oral evobrutinib 25 mg once daily (QD), 75 mg QD, 50 mg twice daily, or placebo. Primary efficacy endpoints were SLE responder index (SRI)-4 response at week 52 and SRI-6 response at week 52 in the high disease activity subpopulation. Safety endpoints included treatment-emergent adverse events (TEAEs).A total of 469 patients were randomized and received at least one dose of evobrutinib or placebo at the time of primary analysis. Mean (SD) age at baseline was 40.7 (±12.3) years; 94.9% of patients were female. Neither primary efficacy endpoint was met. All doses of evobrutinib were well tolerated, and there was no clear dose effect on the incidence of reported TEAEs, or serious TEAEs, including severe infections.This phase II, dose-ranging trial in SLE failed to show a treatment effect of evobrutinib versus placebo at any dose. Evobrutinib was generally well tolerated, with no dose effect observed for TEAEs. These results suggest that BTK inhibition does not appear to be an effective therapeutic intervention for patients with SLE.

Objective Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Methods Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment Results Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. Conclusion At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

BackgroundWe sought to examine the disease course of High Disease Activity Status (HDAS) patients and their different disease patterns in a real-world longitudinal cohort. Disease resolution till Lupus Low Disease Activity State (LLDAS) has been a general treatment goal, but there is limited information on this subset of patients who achieve this.MethodsAll consenting patients of the Monash Lupus Cohort who had at least 12 months of observation were included. HDAS was defined as SLEDAI-2K ≥ 10 ever, and HDAS episode as the period from the first HDAS clinic visit until attainment of LLDAS. We examined the associations of different HDAS patterns with the likelihood of damage accrual.ResultsOf 342 SLE patients, 151 experienced HDAS at least once, accounting for 298 HDAS episodes. The majority of HDAS patients (76.2%) experienced Recurrent HDAS (> 1 HDAS visit), and a smaller subset (47.7%) had Persistent HDAS (consecutive HDAS visits for longer than 2 months). Recurrent or Persistent HDAS patients were younger at diagnosis and more likely to experience renal or serositis manifestations; persistent HDAS patients were also more likely to experience neurological manifestations. Baseline SLEDAI greater than 10 was associated with longer HDAS episodes. Recurrent and Persistent HDAS were both associated with an increased likelihood of damage accrual. The total duration of HDAS episode greater than 2 years and experiencing multiple HDAS episodes (≥4) was also associated with an increased likelihood of damage accrual (OR 1.80, 95% CI 1.08–2.97,p= 0.02, and OR 3.31, 95% CI 1.66–13.26,p= 0.01, respectively).ConclusionHDAS episodes have a highly variable course. Recurrent and Persistent HDAS, and longer duration of HDAS episodes, increased the risk of damage accrual. In addition to a major signifier of severity in SLE, its resolution to LLDAS can determine the subsequent outcome in SLE patients.

OBJECTIVE Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS Among those with low LDL concentrations ( 4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

Objectives Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

Background: Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies published on biologics complicate the decision on the most appropriate biologic for a given disease. We aim to address this problem by publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. This article assesses the safety and efficacy of atacicept, a recombinant fusion protein consisting of the binding portion of transmembrane activator and CAML interactor (TACI; also known as tumor necrosis factor receptor superfamily member 13B), which is able to bind the cytokines B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Objective: To evaluate atacicept's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 118 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, ten articles were finally included in a narrative synthesis. Conclusions: Atacicept failed to show an effect in multiple sclerosis, optic neuritis, rheumatoid arthritis, and systemic lupus erythematosus. In patients with systemic lupus erythematosus, atacicept led to increased infection rates, but this adverse effect was not seen in the other treated diseases.

The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus effort to identify, prioritise and address top barriers in lupus impacting diagnosis, care, treatment and research. To conduct this process, the ALPHA Project convened a multistakeholder Global Advisory Committee (GAC) of lupus experts and collected input from global audiences, including patients. In phase I, the ALPHA Project used expert interviews and a global survey of lupus experts to identify and categorise barriers into three overarching pillars: drug development, clinical care and access to care. In phase II, reported here, the GAC developed recommended actionable solutions to address these previously identified barriers through an in-person stakeholder meeting, followed by a two-round scoring process. Recommendations were assessed for feasibility, impact and timeline for implementation (FIT), where potential FIT component values were between 1 and 3 and total scores were between 3 and 9. Higher scores represented higher achievability based on the composite of the three criteria. Simplifying and standardising outcomes measures, including steroid sparing as an outcome (drug development) and defining the lupus spectrum (clinical care) ranked as the highest two priority solutions during the GAC meeting and received high FIT scores (7.67 and 7.44, respectively). Leveraging social media (access to care) received the highest FIT score across all pillars (7.86). Cross-cutting themes of many solutions include leveraging digital technology and applying specific considerations for special populations, including paediatrics. Implementing the recommendations to address key barriers to drug development, clinical care and access to care is essential to improving the quality of life of adults and children with lupus. Multistakeholder collaboration and guidance across existing efforts globally is warranted.

Background and Aims Analysis of serum or plasma from patients with IgA nephropathy (IgAN) has confirmed the presence of elevated levels of circulating immune complexes containing Gd-IgA1 (Czerkinsky 1986). New sensitive and reasonably specific noninvasive tests are emerging to guide the therapeutic strategy that is applicable to all stages of IgAN (Suzuki 2014). Here we are reporting the fit for purpose validation of an ELISA method for the quantitative determination of Gd-IgA1 in human serum samples to support biomarker investigations in clinical studies of Merck KGaA, Darmstadt. Method The assay was developed based on a commercially available immunoassay kit. The dynamic range of the calibration curve was determined from 1.56 ng/mL (LLOQ) to 100 ng/mL (ULOQ). With a minimum required dilution of 200-fold and standard assay volume of 50.0 μL, the range of the method in matrix was from 312 ng/mL to 20, 000 ng/mL. In assay validation phase, multiple validation parameters were evaluated, which included minimum required dilution (MRD), calibration curve, matrix effect, Intra- & Inter run accuracy & precision, selectivity, and parallelism. Additional validation parameters include sample stability (short/long term, freeze-thaw) and batch-to-batch comparison. Results All samples measured for intra & Inter - assay precision, accuracy, fulfilled the specifications according to the acceptance criteria. The selectivity was assessed using blank serum matrix from 10 individuals: the result indicated that matrix components in serum did not interfere with the detection of Gd-IgA1. Parallelism assessment was performed successfully for both samples from healthy donors and IgAN patient samples up to dilution factor (DF) 3200 (serum samples from healthy donors were determined up to DF 1600). All DF-corrected results within the assay range were determined with %CV ≤ 30.0%. Batch to batch comparison was assessed successfully based on the known shelf life of the kit. Short term stability using QC samples were given for up to 24hrs at room temperature. Freeze-thaw stability was given for up to 3 cycles at -20°C±5°C and -75°C±15°C. The investigations were performed according to general guidelines for method validation and applicable regulations. The results of investigated validation parameters fulfilled the requirements and recommendations, generally accepted for bioanalytical projects. Conclusion The present validation qualified the method for the quantitative determination of Gd-IgA1 in human serum samples from clinical studies.

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria >1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN. Method This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels. Results Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported. Conclusion These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.

Objective To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL–mediated B cell activation, in patients with systemic lupus erythematosus (SLE). Methods ADDRESS II is a 24‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody‐positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI‐4) at week 24. Results The intent‐to‐treat (ITT) population included 306 patients. There was a trend toward an improved SRI‐4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio [OR] 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI‐4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI‐4 and SRI‐6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo. Conclusion Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.

Objective To characterize the overall safety profile of atacicept, we conducted an integrated analysis of pooled safety data from all 17 clinical studies to date. Methods Three data sets were used to investigate safety endpoints: a double-blind placebo-controlled set (n = 1568), an SLE set (n = 761) and a full analysis set (n = 1845; including all 17 studies). Results Of 1568 patients in the double-blind placebo-controlled-set, 30.8% received placebo, and 8.2, 24.5 and 36.5% received atacicept 25, 75 and 150 mg, respectively. Treatment-emergent adverse event (TEAE) rates (adjusted by treatment-exposure) were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality. Serious infection and serious TEAE rates were similar for atacicept and placebo. The TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9/100 patient-years). In the full analysis set, 11 deaths occurred during treatment. Across indications, exposure-adjusted mortality rates/100 patient-years (95% CI) were 3.60 (0.90, 14.38), 0.34 (0.05, 2.43) and 1.18 (0.49, 2.82) with atacicept 25, 75 and 150 mg, respectively, and 0.44 (0.06, 3.12) with placebo. In SLE patients, exposure-adjusted mortality rates were 1.45 (0.54, 3.87) with atacicept 150 mg and 0.78 (0.29, 2.07) across all atacicept-treated patients. No deaths occurred with atacicept 75 mg or placebo. In the SLE and double-blind placebo-controlled sets, pharmacodynamic effects of atacicept were not associated with increased infection rates. Conclusion The results of this integrated safety analysis support further development and evaluation of atacicept in selected patients for whom potential benefits might outweigh risks.

Background: The Phase 2/3 APRIL-SLE study evaluated the safety and efficacy of atacicept, a dual inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), in systemic lupus erythematosus (SLE). Objectives: The goal of this post-hoc analysis was to use cell-based gene signatures on gene expression data from the APRIL-SLE study to identify clusters of patients with potential to flare and to assess clusters for differences in treatment effects of atacicept vs placebo. Methods: A published immune cell deconvolution algorithm (Abbas et al, 2009) was applied to whole-blood gene expression data from APRIL-SLE patients to identify relative proportions of 17 immune cell types. Patients were then grouped into clusters based on these immune cell profiles using a k-medoid clustering algorithm and were compared to each other based on patient characteristics, biomarkers and clinical efficacy. In addition, baseline expression and change in expression of putative APRIL-responder genes were compared among clusters. APRIL-responder genes were identified by combining differential expression results from the APRIL-SLE study (Week 52 vs Day 1 randomization) and tabalumab (targets BLyS only) Phase 3 studies (Week 52 vs baseline; GSE88887). Results: Patient gene expression data (N=105; placebo, n=30; atacicept 75 mg, n=40; atacicept 150 mg, n=35) were used to group patients into five main clusters (P1-P5) by predominant characteristic cells: P1, T helper cells; P2, plasma cells; P3, neutrophils and B cells; P4, B cells; P5, activated dendritic cells. Patients in P2 and P5 were more likely to have positive anti-dsDNA antibodies (≥30 IU/ml), elevated BLyS; ≥1.6 ng/ml, and high interferon gene signature in the blood than other those in other clusters. Patients in P2 were most likely to have low complement C3 and C4 levels. Placebo-group flare rates in P2 (100%), P4 (100%) and P5 (83%) were markedly higher than in P1 (33%) and P3 (29%). In P2, P4, and P5 the median time-to-flare was much lower with placebo (85, 98.5, and 115.5 days, respectively) than with atacicept 150 mg (over 364 days for all three clusters). A comparison of differentially-expressed genes from clinical studies of SLE patients treated with atacicept and tabalumab revealed possible APRIL-responder genes: SDC1, PARM1 and MZB1. These genes had a higher baseline expression in P2 and P4 compared with other clusters. SDC1 was reduced from baseline more in P2, P4, and P5 after atacicept treatment, while PARM1 and MZB1 decreased after atacicept treatment in P2 and P4. Conclusion: These post-hoc analyses revealed different subsets of SLE patients based on their molecular profiles. Atacicept may have different treatment effects in the identified patient subsets vs placebo, providing insights into potential mechanisms of flare in SLE. References: [1] Abbas AR, Wolslegel K, Seshasayee D, Modrusan Z, Clark HF. Deconvolution of blood microarray data identifies cellular activation patterns in systemic lupus erythematosus. PLoS ONE. 2009;4(7):e6098. Disclosure of Interests: Eileen Samy Employee of: Current employees of EMD Serono, Matthew Studham Employee of: Current employees of EMD Serono, Amy Kao Employee of: Current employees of EMD Serono, Philipp Haselmayer Employee of: Current employee of Merck KGaA, Peter Chang Employee of: Current employees of EMD Serono, P. Alexander Rolfe Employee of: Current employees of EMD Serono, David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Julie DeMartino Shareholder of: Shares in Merck & Co, Employee of: Current employees of EMD Serono; Past employee of Merck & Co. & Roche, Robert Townsend Employee of: Current employees of EMD Serono

Background: We conducted an integrated analysis of pooled safety data from all 17 atacicept clinical studies across multiple indications to date. Objectives: To characterize the overall safety profile of atacicept. Methods: Analyses were based on 3 pooled datasets: double-blind placebo (PBO)-controlled set (DBPC-S) (n=1568; key endpoint: treatment-emergent AEs [TEAEs]); systemic lupus erythematosus set (SLE-S; n=761; key endpoints: IgG change and serious infection rates, and mortality); and full analysis set (FA-S; n=1845; key endpoint: exposure-adjusted mortality). Results: Of 1568 patients (DBPC-S), 30.8% received PBO, and 8.2%, 24.5% and 36.5% received atacicept 25, 75 and 150 mg. Overall, baseline characteristics were balanced across treatment arms. Treatment exposure in patient-years (py) was similar with PBO and atacicept 75 and 150 mg but was lower with 25 mg (Table). Exposure-adjusted TEAE rates were generally higher with atacicept vs PBO; serious TEAE and infection rates were similar with atacicept and PBO (Table). TEAE-related discontinuation rates were higher with atacicept vs PBO (16.1 vs 10.9/100 py). In the SLE-S and DBPC-S, pharmacodynamic effects of atacicept (eg on IgG) were not associated with an increase in infection rates. Across all studies (FA-S), 11 patients died during treatment. Across all indications, exposure-adjusted mortality rates/100 py (95% CI) were 3.60 (0.90–14.38), 0.34 (0.05–2.43), 1.18 (0.49–2.82) for atacicept 25, 75 and 150 mg, and 0.44 (0.06–3.12) for PBO. In SLE patients, exposure-adjusted mortality rates/100 py were 1.45 (0.54–3.87) with atacicept 150 mg and 0.78 (0.29–2.07) across all atacicept-treated patients. The underlying disease and other causes were potential confounders in most cases. Conclusion: In this integrated safety analysis of atacicept, no consistent association was found between atacicept dose and specific TEAEs or mortality. These results support further development and evaluation of atacicept in patients in whom potential benefits may outweigh risks. Disclosure of Interests: Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Roberto Bassi Employee of: Current employees of EMD Serono, Peter Chang Employee of: Current employees of EMD Serono, Amy Kao Employee of: Current employees of EMD Serono, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Victor Ona Employee of: Current employees of EMD Serono, Patricia Fleuranceau-Morel Employee of: Current employees of EMD Serono

Background The Phase II/III APRIL-SLE study evaluated the safety and efficacy of atacicept in systemic lupus erythematosus (SLE). The goal of this post-hoc analysis was to use cell-based gene signatures on the APRIL-SLE gene expression data to identify clusters of patients with potential to flare and to assess for difference in treatment effect of atacicept vs placebo. Methods A published immune cell deconvolution algorithm was applied to whole-blood gene expression data from APRIL-SLE to identify relative proportions of 17 immune cell types. Patients were then grouped into clusters based on these immune cell profiles using a k-medoid clustering algorithm, and were compared to each other based on patient characteristics, biomarkers and clinical efficacy. In addition, the baseline expression and change in expression of putative APRIL-responder genes were compared among the clusters. APRIL-responder genes were identified by combining differential expression results from the APRIL-SLE study (Week 52 vs. Day 1 randomization) and tabalumab Phase III studies (Week 52 vs. Baseline; GSE88887). Results Patient gene expression data (N=105; Placebo: N=30; atacicept 75 mg: N=40; atacicept 150 mg N=35) was used to group patients into 5 main clusters (P1-P5) by predominant characteristic cells: P1, T helper cells; P2, plasma cells; P3, neutrophils and B cells; P4, B cells; P5, activated dendritic cells. Patients in P2 and P5 were more likely to have positive anti-dsDNA antibodies (≥30 IU/ml) and elevated BLyS (≥1.6 ng/ml), as well as high IFN gene signature in the blood. Patients in P2 were more likely to have low complement C3 and C4 levels. In P2, P4, and P5 clusters the flare rate in the placebo group was significantly higher than in P1 and P3. In P2 and P4, atacicept 150mg treatment group showed delayed time to flare and reduced flare rate as compared with the placebo group. A comparison of differentially-expressed genes from clinical studies of SLE patients on atacicept (targets BLyS & APRIL) vs tabalumab (targets BLyS) revealed possible APRIL-responder genes: SDC1, PARM1 and MZB1. These genes have a higher baseline expression in the P2 and P4 compared to other clusters. SDC1 was reduced more in P2, P4, and P5 after atacicept treatment, while PARM1 and MZB1 decreased after atacicept treatment in P2 and P4. Conclusions These post-hoc analyses revealed different subsets of SLE patients based on their molecular profiles, which identified patient subsets that might have differential treatment effect of atacicept vs placebo, and provided insights into potential mechanisms of flare. Funding Source(s): Merck KGaA, Darmstadt, Germany

Background Low disease activity (LDA) and remission are important goals in the treatment of patients with SLE.1 2 Lupus Low Disease Activity State (LLDAS) is associated with reduced damage accrual,2 and has been shown to be a feasible clinical trial endpoint.3 In patients with high disease activity (HDA; SLEDAI-2K ≥10) enrolled in the ADDRESS II study, atacicept improved SLE responder index (SRI)-6 response rates and flare prevention at Week 24 vs placebo. Atacicept also demonstrated an acceptable safety profile.4 We present a post-hoc analysis of data from ADDRESS II and its long-term extension, describing 48-week LDA and remission rates in patients with HDA at Screening. Methods In ADDRESS II, patients were randomized (1:1:1) to weekly subcutaneous atacicept 75 or 150 mg or placebo for 24 weeks. Atacicept-completers continued at the same dose in the extension study, while placebo-treated patients were switched to atacicept 150 mg (placebo/atacicept 150 mg). This post-hoc analysis assessed: LDA (SLEDAI-2K ≤2), LLDAS (SLEDAI-2K ≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment [PGA] ≤1, prednisone-equivalent ≤7.5 mg/day, and stable immunosuppressants),2 and remission (clinical SLEDAI-2K=0, PGA Results Of 306 ADDRESS II patients, 158 (51.6%) had HDA at Screening. At Week 24, 42.4% achieved SRI-6, 23.4% attained LDA, 15.8% LLDAS and 10.8% remission. At Week 48, 52.5% achieved SRI-6, 26.6% attained LDA, 19.0% LLDAS and 10.8% remission. Among 83 patients with HDA at Screening who had an SRI-6 response at Week 48, 49.4% (n=41) attained LDA, 34.9% (n=29) LLDAS and 20.5% (n=17) remission. At 48 weeks, LDA, LLDAS and remission rates were higher in patients treated with atacicept 150 mg vs atacicept 75 mg and vs placebo/atacicept 150 mg (figure 1). Conclusions ADDRESS II patients with HDA at Screening who received atacicept 150 mg were more likely to attain LDA, LLDAS and remission at Week 48 than those treated with atacicept 75 mg or placebo/atacicept 150 mg. These endpoints were more stringent and discriminatory than SRI-6, confirming LLDAS, LDA, and remission to be robust and meaningful endpoints for SLE trials. In addition, these data further support future studies of atacicept in SLE. Funding Source(s): Merck KGaA, Darmstadt, Germany References Van Vollenhoven et al. Ann Rheum Dis 2017. Franklyn et al. Ann Rheum Dis 2016. Morand et al. Ann Rheum Dis 2018. Merrill et al. Arthritis Rheum 2018.

Background We conducted an integrated analysis of pooled safety data from all 17 atacicept clinical studies across multiple indications to date, to characterize the safety profile of atacicept. Methods Analyses were based on 3 pooled datasets: double-blind placebo-controlled (DBPC) set (n=1568; key endpoint: treatment-emergent AEs [TEAEs]); SLE set (n=761; key endpoint: IgG change and serious infection rates); and full analysis set (n=1845; key endpoint: exposure-adjusted mortality). Results Of 1568 patients in the DBPC set, 30.8% received placebo, 8.2% atacicept 25 mg, 24.5% atacicept 75 mg and 36.5% atacicept 150 mg. Overall, baseline characteristics were balanced across treatment arms. Treatment exposure was similar with placebo and atacicept 75 and 150 mg (278.3, 225.0 and 286.7 patient-years, respectively), but was lower with atacicept 25 mg (51.5 patient-years). Exposure-adjusted TEAE rates were generally higher with atacicept vs placebo, with no consistent association between atacicept dose and cardiac arrhythmias, serious and severe infections or injection site reactions (table 1). Serious infection and serious TEAE rates were similar between atacicept and placebo. TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9 per 100 patient-years). In the SLE set, there was no association between reduced IgG levels and increased infection rates. Across all studies (full analysis set), 11 patients died during treatment (10 atacicept [0.5%], 1 placebo [0.1%]). Infection-related deaths in the DBPC set are shown in the table 1. Exposure-adjusted mortality rates per 100 patient-years were 3.60 (95% CI: 0.90–14.38) with atacicept 25 mg, 0.34 (95% CI: 0.05–2.43) with 75 mg, 1.18 (95% CI: 0.49–2.82) with 150 mg, and 0.44 (95% CI: 0.06–3.12) with placebo. Conclusions Results from this pooled analysis clarify the benefit-risk relationship for atacicept, which is being further evaluated in additional clinical studies in IgA nephropathy and SLE. Funding Source(s): Merck KGaA, Darmstadt, Germany

An autoimmune disease is a disorder in which the body’s immune system attacks itself. The dysregulation of the immune system associated with systemic autoimmune diseases can affect various organs systems, including the brain. This chapter will review the neuropsychological involvement and the resulting cognitive changes associated with three systemic autoimmune or rheumatic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (SS). Diagnosis, neuropsychological assessment, and treatment planning are challenging since most of the disease manifestations are nonspecific. Due to the abundant literature on cognitive dysfunction in SLE as compared to the other two diseases, the discussion of cognition is focused mainly in SLE.

Background:The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus initiative to identify, prioritize and address top barriers in lupus drug development, clinical care and access to care. The Lupus Foundation of America convenes ALPHA with Tufts Center for the Study of Drug Development and a Global Advisory Committee of lupus experts representing clinician-scientists, industry and patients.Objectives:Collect global patient input to determine alignment with the lupus clinician-scientist community on prior published consensus of top lupus barriers.Methods:A 23-question online Qualtrics survey was developed to identify challenges across lupus diagnosis, clinical care and research participation. The survey, available in English, Spanish, Korean and simplified Chinese, was fielded in November 2019 to people with lupus and caregivers of children Results:Analysis included only consented responses with ≥ 68% survey completion (n=3,447) received across 83 countries. 95% were female with a mean age of 45. Respondents reported being White (57%), Black or of African descent (14%), Hispanic or Latino (18%) and Asian (10%). 65% resided in the US while 35% resided in countries outside of the US. 97% were people with lupus while 3% were caregivers to children Highest ranked challenges were similar globally and across children and adults: medication side effects, lack of treatment options and high out-of-pocket costs. Managing side effects ranked significantly higher (pConclusion:This global survey revealed that medication side effects and lack of effective treatments are top challenges for people with lupus, including children. Most respondents were never asked by their doctors to participate in a clinical trial, which may explain difficulties in trial recruitment. These barriers are consistent with prior published barriers identified by the clinician-scientist community.Acknowledgments:ALPHA sponsors: EMD Serono, GSK, Aurinia, MallinckrodtDisclosure of Interests:Karin Tse: None declared, Yaritza Peña: None declared, Kathleen Arntsen: None declared, Sang-Cheol Bae: None declared, Lauren Bloch Consultant of: Faegre Drinker Consulting is a division of Faegre Drinker Biddle & Reath, a law and consulting firm that represents patient advocacy organizations and sponsors developing drugs, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca, Bradley Dickerson Employee of: Aurinia, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Kenneth Getz: None declared, Amy Kao Employee of: EMD Serono, Susan Manzi: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Sandra Raymond: None declared, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Laura Schanberg Grant/research support from: Sobi, BMS, Consultant of: Aurinia, UCB, Sanofi, Victoria Werth Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, Consultant of: Biogen, Gilead, Janssen, Abbvie, GSK, Resolve, AstraZeneca, Amgen, Eli Lilly, EMD Serono, BMS, Viela, Kyowa Kirin, Joan Von Feldt Shareholder of: GSK, Employee of: GSK, David Zook Consultant of: Faegre Drinker Consulting is a division of Faegre Drinker Biddle & Reath, a law and consulting firm that represents patient advocacy organizations and sponsors developing drugs, Leslie Hanrahan: None declared

ObjectiveDisease severity in SLE is an important concept related to disease activity, treatment burden and prognosis. We set out to evaluate if high disease activity status (HDAS), based on ever attainment of a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) disease activity score of ≥10, is an indicator for disease severity in SLE.MethodsUsing prospectively collected data, we assessed the association of HDAS with sociodemographic and disease characteristics and adverse clinical outcomes using logistic regression or generalised estimating equations.ResultsOf 286 patients with SLE, who were observed for a median (range) of 5.1 years (1–10.8 years), 43.7% experienced HDAS at least once during the observational period. Autoantibody positivity, particularly anti-dsDNA and anti-Sm positivity, were associated with increased likelihood of HDAS. Age ≥45 years at diagnosis was associated with reduced likelihood of HDAS (p=0.002). Patients with HDAS had higher Physician Global Assessment score (>1: OR 8.1, p0.001), higher corticosteroid exposure (corticosteroid dose in highest quartile: OR 7.7, 95% CI 3.9 to 15.3; pConclusionsHDAS is associated with more severe disease, as measured by higher disease activity across time, corticosteroid exposure and damage accrual. The occurrence of HDAS may be a useful prognostic marker in the management of SLE.

Background Atacicept targets the B-cell stimulating factors BLyS and APRIL, and is currently in clinical development for the treatment of patients (pts) with active, auto-antibody positive SLE. Objectives Here, we evaluated integrated nonclinical, clinical and exposure-response (E-R) data from atacicept studies to determine an appropriate atacicept dose for a Phase (P) III study in SLE pts with high disease activity (HDA). Methods Nonclinical efficacy and pharmacokinetic (PK)/pharmacodynamic data for atacicept were obtained from two murine models: An F1 hybrid NZBWF1/J spontaneous SLE model (given mouse Fc-protein control or mouse TACI-Fc 5 mg/kg intraperitoneal [IP] three times per week) and a 4-Hydroxy-3-nitrophenylacetyl-Keyhole Limpet Haemocyanin (NP-KLH) vaccinated C57BL/6 model to assess immunomodulation (given control protein 10 mg/kg or atacicept 1, 3 or 10 mg/kg IP every third day). Clinical PK, efficacy, safety and E-R data were obtained from a PI PK study in healthy participants (Study 022; single dose atacicept: 25, 75 or 150 mg) and two PII studies in pts with autoantibody-positive SLE (APRIL-SLE [EudraCT 2007–003698–13] and ADDRESS II [EudraCT 2013–002773–21]; randomization [1:1:1] to once weekly [QW] subcutaneous [SC] injections of atacicept [75 or 150 mg] or placebo [PBO]). In APRIL-SLE, the primary endpoint was the proportion of pts with BILAG A/B flare over 52 weeks. In ADDRESS II, the primary endpoint was SRI-4 response at Week 24. SRI-6 response was analysed post-hoc in pts with HDA (SLEDAI-2K≥10) at Screening. A population PK model was established using data from the PI and PII studies. Population PK model-derived exposure vs probability of clinical response (BILAG A/B flare, SRI-4, SRI-6) was assessed, and an exploratory analysis of exposure vs safety performed. Results TACI-Fc 5 mg/kg prevented proteinuria development and glomerular damage in the F1 hybrid NZBWF1/J spontaneous SLE model. Anti-KLH IgG decreased markedly in atacicept-treated NP-KLH vaccinated mice (>50% reduction vs control protein at all doses), with mean atacicept serum trough concentrations (Cmin) of ~2.3 µg/mL (1 mg/kg),~5 µg/mL (3 mg/kg) and ~8.5 µg/mL (10 mg/kg). In post-hoc analyses of the proportion of pts with BILAG A/B flare and time to flare in APRIL-SLE, and SRI-4 and SRI-6 response in SLE pts with HDA in ADDRESS II, treatment with atacicept 150 mg QW demonstrated greater clinical response vs PBO. In both studies, atacicept E-R relationships based on population PK-derived exposure were observed. For maximal flare reduction, an atacicept exposure of AUC ≥1 mg*hr/mL was identified. This exposure was more achievable with 150 than 75 mg (60% vs 15% probability) and corresponded to an atacicept Cmin of 5 µg/mL, which was similar to the Cmin values observed in the NP-KLH vaccinated mouse model. Both atacicept 150 and 75 mg had acceptable safety profiles in SLE pts, with no apparent E-R relationship observed for serious infections. Conclusions Integrated nonclinical, clinical and E-R data demonstrate an acceptable benefit-risk profile for atacicept in SLE pts with HDA and support the selection of the 150 mg QW dose for a PIII study. Disclosure of Interest J. Shen Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), O. Papasouliotis Employee of: Merck Institute for Pharmacometrics, Lausanne, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany), E. Samy Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), P. Haselmayer Employee of: Merck KGaA, P. Chang Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), V. Ona Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), A. Kao Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany)

Background Low disease activity (LDA) and remission are consummate goals of SLE treatment.1 Lupus Low Disease Activity State (LLDAS) is associated with reduced damage accrual,2 and has been shown to be a feasible clinical trial endpoint.3 In the Phase IIb ADDRESS II study,4 atacicept improved SRI-6 response rates and flare prevention at Week (Wk) 24 vs placebo (PBO), in patients with High Disease Activity (HDA; SLEDAI-2K≥10) at Screening, with an acceptable safety profile. Objectives Post-hoc analysis of ADDRESS II and its long-term extension to describe 48-wk rates of LDA and remission in patients with HDA at Screening. Methods Pts were randomised 1:1:1 to weekly subcutaneous PBO or atacicept 75 or 150 mg for 24 wks in ADDRESS II. Completers entered the extension study at the same dose, except PBO patients who switched to atacicept 150 mg (PBO/atacicept 150 mg). This analysis includes: LDA (SLEDAI-2K≤2); LLDAS (SLEDAI–2K≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment [PGA]≤1, prednisone-equivalent ≤7.5 mg/day, and stable immunosuppressants); and remission (clinical SLEDAI-2K=0, PGA Results Of 306 ADDRESS II pts, 158 (52%) had HDA at entry; 42.4% achieved SRI-6, 23.4% LDA, 15.8% LLDAS and 10.8% remission at Wk 24. At Wk 48, 52.5% achieved SRI-6, 26.6% LDA, 19.0% LLDAS and 10.8% remission. Among the 83 HDA patients with an SRI-6 response at Wk 48, LDA, LLDAS, and remission represented increasingly stringent subsets (49.4% [n=41] attaining LDA, 34.9% [n=29] LLDAS, and 20.5% [n=17] remission). LDA, LLDAS and remission rates were higher in patients treated with atacicept 150 mg vs 75 mg and PBO/atacicept 150 mg (table 1; figure 1). Conclusions At 48 wks, patients entering the ADDRESS II study with HDA who received atacicept 150 mg were more likely to attain LDA, LLDAS and remission than those treated with 75 mg or PBO/atacicept 150 mg. These endpoints were more stringent and discriminatory than SRI-6, confirming LLDAS, LDA, and remission to be robust and meaningful endpoints for SLE trials, and adding further support for future studies of atacicept in SLE. References [1] Van Vollenhoven, et al. Ann Rheum Dis2017. [2] Franklyn, et al. Ann Rheum Dis2016. [3] Morand, et al. Ann Rheum Dis2018 (in press). [4] Merrill, et al. Arthritis Rheum2017. Disclosure of Interest E. Morand Grant/research support from: AstraZeneca/Medimmune, Janssen, UCB and BMS, Consultant for: EMD Serono, AstraZeneca/Medimmune, and Janssen, J. T. Merrill Grant/research support from: GSK and BMS (investigator-initiated studies), Consultant for: EMD Serono, Lilly, GSK, Anthera and Biogen; • Clinical Trial Data Management/Analysis/QA Services for Celgene and Xencor, D. A. Isenberg Consultant for: EMD Serono (consulting fees have been passed to a local arthritis charity), A. H. Kao Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), C. Vazquez–Mateo Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), S. Wax Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), P. Chang Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), K. Pudota Employee of: EMD Serono Research and Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), C. Aranow Grant/research support from: EMD Serono Research and Development Institute, Inc., D. Wallace Consultant for: Merck KGaA

Purpose Atacicept targets the B-cell stimulating factors, BLyS and APRIL, and has shown evidence of clinical response in patients with SLE. The 24 week Phase II ADDRESS II (NCT01972568) Study and its long-term extension (LTE; NCT02070978) provided data on disease activity with up to 48 weeks of atacicept treatment. Methods In ADDRESS II, patients were randomised (1:1:1) to receive weekly atacicept (75 or 150 mg SC injection) or placebo (PBO) for 24 weeks. Those who completed treatment were eligible to enter the LTE, to either continue on the same atacicept dose (atacicept groups), or switch from PBO to atacicept 150 mg (PBO/150 mg). The SLE flare analysis from both studies are reported here. Results The ITT population of ADDRESS II included 306 patients; 158 of whom met the predefined high disease activity (HDA) criterion (SLEDAI-2K≥10 at Screening). Of the 262 patients who completed the ADDRESS II, 253 entered the LTE. At 24 weeks in the PBO-controlled trial, cumulative incidence of severe flare was significantly reduced with atacicept 75 mg vs PBO by BILAG A (HR 0.24; p=0.0186), and with atacicept 150 mg vs PBO by SFI (HR 0.18; p=0.002). There was no difference in moderate-to-severe flare by BILAG A/2B. In the HDA subpopulation, incidence of severe flare at 24 weeks was significantly reduced with both atacicept doses vs PBO by BILAG A (75 mg HR 0.08, p=0.002; 150 mg HR 0.32, p=0.038) and SFI (75 mg HR 0.33, p=0.029; 150 mg HR 0.19, p=0.004). Incidence of moderate-to-severe flare by BILAG A/2B was significantly reduced with atacicept 150 mg vs PBO (HR 0.34, p=0.032). At 48 weeks, risk of severe flare by SFI was significantly lower with atacicept 150 mg vs the PBO/150 mg in both the ITT and HDA populations (figure 1); significant flare reductions were seen with atacicept 75 mg by BILAG A, and with both atacicept doses by BILAG A/2B vs PBO/150 mg, in the HDA subpopulation. Conclusions In this 24 week, double-blind, PBO-controlled trial, atacicept treatment was associated with significant flare reductions compared with PBO. Rates of flare continued to be low in atacicept-treated patients between weeks 24–48. Most flares occurred in HDA patients in the PBO group.

Purpose Atacicept targets the B-cell stimulating factors BLyS and APRIL, and has been shown to reduce SLE disease activity. Methods APRIL-SLE (NCT00624338) and ADDRESS II (NCT01972568) were phase II, multicenter studies in patients (pts) with autoantibody-positive SLE randomised (1:1:1) to weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO). In APRIL-SLE, pts had BILAG A/B flare at Screening that was reduced to BILAG C/D before randomization using corticosteroids; the primary endpoint was BILAG A/B flare over 52 weeks. In ADDRESS II, pts had SLEDAI-2K≥6 at Screening; the primary endpoint was SRI-4 response at Week 24. SLE responder index (SRI)−6 response was analysed post-hoc in high disease activity (HDA; SLEDAI-2K≥10) pts. Population pharmacokinetic (PK) model-derived exposure vs the probability of response (BILAG A/B flare, SRI-4, SRI-6), exploratory analysis of exposure vs safety, and population model simulations of serum IgG were analysed. Results Exposure-response modelling suggests a relationship between atacicept exposure and SLE clinical response [figure 1], including serum IgG changes from baseline. The optimal atacicept exposure was AUCtau,ss ≥~1 mg.hr/mL, which is more achievable with weekly SC doses of atacicept 150 mg than 75 mg across a range of body weights. Body weight-based dosing is unlikely to offer any value over a fixed 150 mg dose, based on comparable predicted clinical response. In HDA pts, greater reductions in serum IgG from baseline corresponded to a higher probability of SRI-6 response. Greater IgG reductions from baseline were associated with higher atacicept exposure; however, even at the highest exposure range, mean IgG reductions did not exceed ~40%. There was no association between serious/severe infections and exposure by PK quartile. Conclusions Exposure-response modelling indicated robust relationships between atacicept exposure and clinical response or IgG levels, supporting the proposed mechanism of action for atacicept. Atacicept 150 mg weekly SC is likely to provide an effective level of exposure with an acceptable safety profile. There was no evidence of an increased risk of severe or serious infections at higher exposures. Based on these results, the 150 mg dose merits further evaluation.

Purpose Atacicept targets B-cell stimulating factors, BLyS and APRIL. ADDRESS II (NCT01972568) investigates the efficacy and safety of atacicept in SLE. Methods In this Phase IIb multicenter study, patients with active (SLEDAI-2K≥6), autoantibody-positive SLE on standard of care therapy received weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO) for 24 weeks. The primary endpoint was proportion of patients achieving SLE responder index (SRI)−4 response at week 24. Other endpoints included SRI-5 through SRI-8 response and low disease activity (LDA) attainment, defined as LDA-1 (SLEDAI-2K≤2), LDA-2 (SLEDAI-2K≤2 and prednisone-equivalent ≤7.5 mg/day), or LLDAS (SLEDAI–2K≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment≤1, prednisone-equivalent ≤7.5 mg/day, and stable maintenance doses of immunosuppressants). A pre-defined subset of patients was also evaluated, with high disease activity (HDA: SLEDAI-2K≥10 at Screening). Differences in clinical response between patients treated with atacicept and PBO at Week 24 were analysed using odds ratio estimated from logistic regression. Results The ITT population included 306 patients, and 158 had HDA. There was a trend towards improved SRI-4 response with atacicept vs PBO at Week 24 (p=ns in primary analysis; screening visit as baseline, BL). In a pre-specified sensitivity analysis using study day 1 as BL, a significantly larger proportion of patients on atacicept achieved SRI-4 response at week 24. In the HDA subpopulation, there were significant improvements in SRI-4,–5, −6,–7 and −8 response rates and attainment of LDA with atacicept 150 mg vs PBO (table 1). Atacicept was associated with increased serum C3 and C4, and decreased IgG, IgA, IgM and anti-dsDNA antibodies over time. Rates of treatment emergent adverse event (TEAE) and serious TEAEs were similar among groups. The most frequent serious TEAEs were infections but the incidence was not increased in the atacicept groups vs PBO. Conclusions Atacicept showed evidence of efficacy in SLE with a dose-dependent reduction of SLE disease activity in patients with HDA. Atacicept was associated with an acceptable safety profile. These results also suggest that more discriminatory endpoints will be useful for future SLE clinical trials.

Objective Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci. Methods In stage 1, we conducted a new GWAS of SLE in a North American case–control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3. Results As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10−8). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10−7) and at 8p23/BLK (P = 8.1 × 10−6). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10−8), which was replicated in stage 3. Conclusion Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.

Objective To investigate the determinants of health care utilization and costs with use of glucocorticoid (GC) drugs among adult systemic lupus erythematosus (SLE) patients. Methods This cross-sectional study analyzed established SLE patients identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes from a large US insurance claims database in 2007–2011. Five patient groups were defined by their oral GC use during a 1-year period: non-GC users, 7.5 to ≤15 mg/day), or higher dosage (>15 mg/day). Annual health care utilization and costs were compared across these groups. Incremental costs of GC groups, calculated as the difference in total health care costs compared with those of the non-GC group, were estimated from multivariable regressions adjusting for demographic/clinical characteristics and stratified by concomitant immunosuppressant use. Results A total of 50,230 SLE patients were identified (52% non-GC users, 20%

Background Atacicept targets B-cell stimulating factors BLyS and APRIL, and has shown evidence of clinical response in SLE. Objectives Exploration of atacicept efficacy and safety in a pre-defined subpopulation of SLE patients with high disease activity (HDA, SLEDAI-2K ≥10 at Screening) in the phase IIb ADDRESS II study (NCT01972568). Methods Autoantibody positive patients on standard of care therapy were randomized 1:1:1 to double-blind weekly SC injections of atacicept 75 or 150 mg or placebo (PBO) for 24 weeks. Analyses of the HDA subpopulation are now reported. Results 52% of the ITT population had HDA (n=158: 52 PBO; 55 atacicept 75 mg; 51 atacicept 150 mg). 92% were female, 67% were white, and baseline characteristics were balanced between groups. At week 24 (Table 1; Figure 1), the proportion of SLE Responder Index (SRI)-4 (p Conclusions In SLE patients with HDA, Atacicept 150 mg demonstrated significant clinical responses and an acceptable safety profile. Acknowledgements The study was sponsored by EMD Serono Research & Development Institute Inc., USA (a business of Merck KGaA, Germany). Medical writing support was provided by Bioscript Science, UK, and funded by Merck KGaA. Disclosure of Interest J. Merrill Consultant for: received consulting fees from Anthera Pharmaceuticals, Lilly, EMD Serono, GlaxoSmithKline and Biogen, D. Wallace Consultant for: received consulting fees from EMD Serono, A. Kao Employee of: EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, C. Vazquez Mateo Employee of: EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, P. Fraser Employee of: EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, P. Chang Employee of: EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, D. Isenberg Consultant for: received consulting fees from EMD Serono

Background and aims Atacicept targets B-cell stimulating factors, BLyS and APRIL. ADDRESS II was a phase IIb, multicenter study (NCT01972568) investigating the efficacy and safety of atacicept in SLE. Methods Patients with active (SLEDAI-2K≥6), autoantibody-positive SLE receiving standard therapy were randomised to weekly subcutaneous injections of atacicept (75 or 150 mg) or placebo for 24 weeks. Results In the ITT population (n=306), there was a trend towards improved SRI-4 response rates with both atacicept doses vs placebo at Week 24 (primary analysis, Screening as baseline). In a sensitivity analysis using Day 1 as baseline, both atacicept doses significantly increased SRI-4 responses (Table 1). In patients with high disease activity (HDA, n=158), serologically active (SA) disease (n=84), or both (HDA SA, n=69), enhanced improvements in SRI-4 and SRI-6 response rates were seen with atacicept (Tables 1 and 2; Figure 1). Atacicept significantly reduced severe flares in the ITT (75 mg: BILAG A p=0.019; 150 mg: SLEDAI flare index [SFI] p=0.002) and HDA populations (75 mg: BILAG A HR=0.1, SFI HR=0.3; 150 mg: BILAG A HR=0.3, SFI HR=0.2; all p Conclusions Atacicept demonstrated evidence of efficacy in SLE, particularly in HDA and SA patients, with reduction in disease activity and severe flares, and showed a favourable safety profile.

ObjectiveLupus is a complex, heterogeneous autoimmune disease that has yet to see significant progress towards more timely diagnosis, improved treatment options for short-term and long-term outcomes, and appropriate access to care. The Addressing Lupus Pillars for Health Advancement (ALPHA) project is the first step in establishing global consensus and developing concrete strategies to address the challenges limiting progress.MethodsA Global Advisory Committee of 13 individuals guided the project and began barrier identification. Seventeen expert interviews were conducted to further characterise key barriers. Transcripts were analysed using Nvivo and a codebook was created containing a list of thematic ‘nodes’ (topics) and their descriptions. Findings were used to develop a final survey instrument that was fielded to a diverse, international stakeholder audience to achieve broad consensus.ResultsExpert interviews identified lupus heterogeneity as the primary barrier hindering advancement. Subsequent barriers were categorised into three areas: (1) Drug development. (2) Clinical care. (3) Access and value. The global survey received 127 completed responses from experts across 20 countries. Respondents identified barriers as high priority including the lack of biomarkers for clinical and drug development use, flawed clinical trial design, lack of access to clinicians familiar with lupus, and obstacles to effective management of lupus due to social determinants of care. Respondents also identified 30 autoimmune conditions that may be lupus-related based on overlapping features, shared autoantibodies and pathophysiology.ConclusionsALPHA is a comprehensive initiative to identify and prioritise the continuum of challenges facing people with lupus by engaging a global audience of lupus experts. It also explored views on lupus as a spectrum of related diseases. Conclusions from this effort provide a framework to generate actionable approaches to the identified high-priority barriers.

Systemic lupus erythematosus (SLE) is a multi-organ chronic autoimmune disease that can negatively affect patients’ health-related quality of life (HRQOL). This study evaluated HRQOL of SLE patients using questionnaires from the Patient-Reported Outcomes Measurement Information System (PROMIS) and Quality of Life in Neurological Disorders (Neuro-QoL). Individuals with SLE completed an online survey consisting of the PROMIS-29 health profile, PROMIS Psychosocial Illness Impact-Negative, and Neuro-QoL Applied Cognition. PROMIS and Neuro-QoL scores have a mean of 50 in the US general population. Patients self-rated SLE disease severity as negligible, mild, moderate, or severe. Of the 333 participants (mean age 45 years; 92% female; 26% Black; mean SLE disease duration 12 years, 56% with SLE disease severity as moderate or severe), mean HRQOL scores were worse than those of the general population by ≥0.5 SD with the greatest deficits observed in the domains of fatigue, applied cognition, psychosocial illness impact-negative, pain interference, and physical function. Greater SLE disease severity was associated with worse mean HRQOL scores (all p