ObjectiveEpratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).MethodsPatients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti–double‐stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI‐2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG‐2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5–60 mg/day). BILAG‐2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12‐week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG‐based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG‐2004 score, no worsening in the BILAG‐2004 score, SLEDAI‐2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders.ResultsIn the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified.ConclusionIn patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Objective EMBODY 1 (ClinicalTrials.gov identifier: NCT01262365) and EMBODY 2 (ClinicalTrials.gov identifier: NCT01261793) investigated the efficacy and safety of epratuzumab, a CD22‐targeted humanized monoclonal IgG antibody, in patients with systemic lupus erythematosus (SLE). The studies showed no significant difference from placebo in primary or secondary clinical outcome measures but did demonstrate B cell–specific immunologic activity. The aim of this post hoc analysis was to determine whether epratuzumab had a different clinical efficacy profile in SLE patients with versus those without an associated diagnosis of Sjögren's syndrome (SS).MethodsThe efficacy and safety of epratuzumab were compared between 2 patient subpopulations randomized in EMBODY 1 and 2: SLE patients with and those without a diagnosis of associated SS. British Isles Lupus Assessment Group (BILAG) total score, BILAG‐based Combined Lupus Assessment (BICLA) clinical response to treatment, biologic markers (including B cells, IgG, IgM, and IgA), and safety were assessed.ResultsA total of 1,584 patients were randomized in the EMBODY 1 and EMBODY 2 trials; 113 patients were anti‐SSA positive and had a diagnosis of associated SS, and 1,375 patients (86.8%) had no diagnosis of associated SS (918 patients were randomized to receive epratuzumab and 457 to receive placebo). For patients with associated SS, but not those without associated SS, a higher proportion of patients receiving epratuzumab achieved a BICLA response and a reduction from baseline in BILAG total score. B cell reduction was faster in patients with associated SS. The sensitivity of B cells to epratuzumab as measured by the mean concentration producing 50% of the maximum B cell count depletion was lower for patients with associated SS (9.5 μg/ml) versus the total EMBODY population (87.1 μg/ml). No difference in the frequency of adverse events in those receiving placebo was reported.ConclusionPatients with SLE and associated SS treated with epratuzumab showed improvement in SLE disease activity, which was associated with bioactivity, such as decreases in B cell number and IgM level.

An independent cross-sectional survey assessed systemic lupus erythematosus (SLE) disease and treatment burden. Variables included medication classes prescribed, disease activity, flare occurrences, treatment satisfaction, and validated measures of health-related quality of life (HRQoL), fatigue and work productivity. Of 886 eligible patients (mean age 41.3 years, 89% female), 515 completed the survey. One-third reported moderate-to-severe disease activity, and 31% had flared in the last 12 months. Higher severity of disease activity (moderate-to-severe) was associated with 2 medication classes prescribed and treatment regimens that included corticosteroids (CS) (both p < 0.0001). Patients receiving CS reported lower EQ-5D scores (p ¼ 0.0019) and higher fatigue levels (p < 0.001), and both patients (p ¼ 0.0019) and physicians (p ¼ 0.0001) were less likely to report satisfaction with treatment regimens including CS. Among responders eligible for work (n ¼ 456), severity of disease activity (moderate-tosevere vs. mild) was associated with unemployment (52.9% vs. 40.8%; p ¼ 0.0189), greater impairment in work productivity (36% vs. 21%; p ¼ 0.0003) and participation in daily activities (41% vs. 21%; p < 0.0001). This survey confirms that SLE and current treatment options substantially impair patients' health status and work productivity. Physician-and patientreported satisfaction with current treatment regimens, despite poorly controlled disease activity, indicate they are resigned to the limitations of available SLE treatment regimens. Lupus (2013) 22, 819-826.

Objective. The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). Methods. Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. Results. A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n 5 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. Conclusion. Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

BackgroundEpratuzumab is a humanized monoclonal antibody (mAb) that targets the B cell-specific protein CD22 and is currently in Phase 3 clinical trials in patients (pts) with systemic lupus erythematosus (SLE). Epratuzumab is not a B cell depleting mAb and its mechanism of action involves immunomodulation of B cells, for example by inducing loss of B Cell Receptor (BCR)-related proteins from the cell surface, and inhibiting signaling through the BCR.1,2ObjectivesThis analysis aimed to understand the effect of epratuzumab on B cell pharmacodynamics, both in Cynomolgus monkeys and in SLE pts enrolled in the Phase 2b EMBLEM™ study (NCT00624351), and its open-label extension (OLE) SL0008 (NCT00660881).MethodsCynomolgus monkeys (n=10 per group) received 0, 10, 60 or 160mg/kg epratuzumab IV for 5 cycles, where each cycle consisted of 4 once-weekly doses of epratuzumab followed by 4 treatment-free weeks. In EMBLEM™, pts were treated with placebo or 1 of 5 cumulative doses (cd) of epratuzumab (200mg–3600mg cd over the 12-week study; n=37–39 per group). In the OLE, all pts (n=203) received 2400mg cd epratuzumab. Blood samples withdrawn at various time points were analyzed by flow cytometry using a panel of antibodies against cell surface markers (CD19, CD22, CD27, IgD, CD95) in order to identify B cell subsets.ResultsIn Cynomolgus monkeys, treatment at all dose levels induced a partial but dose-independent decrease in B cell counts. The maximum decrease in B cell counts (∼50%) was achieved for all dose levels during the second cycle of dosing and did not increase with further cycles of dosing. The B cell decreases were maintained during the treatment-free weeks, but there was evidence for recovery after the last dose. In EMBLEM™ there was a small (10–15%) median decrease in the proportion of naïve B cells and a quantitatively similar increase in memory B cell proportions in pts treated with epratuzumab but not placebo, which did not appear to be dose-dependent. During OLE, total B cell numbers continued to decline, reaching a median decrease of 50–60% after 9–12 months of epratuzumab treatment before stabilizing with no further decrease. There was a rapid decrease (∼80%) of CD22 expression on all B cell subsets, which was maintained throughout the OLE. In vitro data demonstrated a bell-shaped concentration response, suggestive of a requirement for bivalency. Finally, there was a gradual decline in the numbers of CD27-/IgD- B cells expressing CD95 throughout the OLE, from 41% at EMBLEM™ baseline to 27% at OLE Year 2.ConclusionsEpratuzumab treatment of both Cynomolgus monkeys and SLE pts induced a protracted but defined reduction (∼50%) in the number of peripheral blood B cells over time, although the kinetics were somewhat faster in monkeys. In pts, CD22 expression was rapidly lost on all B cell subsets, and the loss maintained throughout the OLE. There was a gradual decline with epratuzumab treatment in the numbers of an activated memory B cell subset previously shown to be elevated in SLE and increased during lupus flare...