Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double‐Blind, Placebo‐Controlled Trials

Abstract

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.

Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling

“…It has been suggested that a high placebo response and early rescue of nonresponders with increased doses of glucocorticoids might have confounded the data from the trial [87, 88]. Although disappointing, these results reflect to a large extent the complexity and diversity of the pathology of SLE and suggest that perhaps some, but not all, SLE patients would benefit from Emab therapy.…”

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

“…An unconjugated anti-CD22 monoclonal antibody (Epratuzumab) has also shown clinical efficacy in multiple clinical trials involving B-cell lymphomas (non-Hodgkin, acute lymphoblastic leukemia, and diffuse large B-cell lymphoma)(32–36). Epratuzumab showed positive results in early Phase II clinical trials(37–40), but failed to meet the primary endpoint in two larger Phase III trials(41). Despite the fact that Epratuzumab did not have a robust signal in Phase III trials, the mechanism by which it modulates B-cell function continues to be a topic of interest, with a recent study showing that this antibody can augment responses to TLR7.…”

Use of Biologics in Sjögren's Syndrome

“…27 However, results from a phase II randomized controlled trial presented at the 2015 ACR meeting in San Francisco failed to demonstrate any efficacy of epratuzumab in lupus. 28 In pSS, one open-label study including 16 patients who received 4 monthly infusions with epratuzumab reported significant responses in half of the patients. 29 Efficacy was assessed by a composite endpoint involving the Schirmer test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate, and IgG.…”