Risk of severe SELENA-SLEDAI flares over 76 weeks was reduced with belimumab 1 mg/kg (34%;P= 0.023) and 10 mg/kg (23%;P= 0.13). efficacy endpoint: significantly greater SRI response at week 52 than placebo (43.2% versus 33.5%;P= 0.017); the rate with belimumab 1 mg/kg was 40.6% (P= 0.089). Week-76 response rates: 32.4%, 39.1%, and 38.5% with placebo, and belimumab 1 and 10 mg/kg, respectively. In post-hoc sensitivity analyses evaluating higher SELENA-SLEDAI thresholds, belimumab 10 mg/kg achieved better discrimination at weeks 52/76. Risk of severe SELENA-SLEDAI flares over 76 weeks was reduced with belimumab 1 mg/kg (34%;P= 0.023) and 10 mg/kg (23%;P= 0.13). Serious and severe adverse events including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. == Conclusion == Belimumab plus SOC significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well-tolerated in SLE. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects a variety of organ systems and markedly impairs health-related quality of life (14). While available therapies, such as corticosteroids, hydroxychloroquine, and immunosuppressive drugs, have improved the outcomes of patients with SLE, there remains a significant unmet need for safe and more effective treatments. A novel approach to address immune abnormalities in SLE ERK5-IN-1 is to inhibit B-lymphocyte stimulator (BLyS; also known as B-cell activating factor of the tumor necrosis factor ligand family), a key survival cytokine for B cells (58). Overexpression of BLyS promotes survival of B cells (including autoreactive B cells), whereas inhibition of BLyS results in autoreactive B-cell apoptosis (9,10). Elevated circulating BLyS levels are common in SLE, and ERK5-IN-1 correlate with increased SLE disease activity and elevated antidouble-stranded DNA (anti-dsDNA) antibody concentrations (1113). Belimumab is a fully human immunoglobulin (Ig)G1- monoclonal antibody that binds soluble human BLyS and inhibits its biologic activities. The clinical and pharmacodynamic effects of belimumab were evaluated in a phase 2 study in patients with active SLE who were receiving standard of care (SOC) ERK5-IN-1 therapies (14). Reductions in circulating CD20+B lymphocytes, short-lived plasma cells, and anti-dsDNA antibody titers were observed. A post-hoc analysis identified a subset of seropositive (antinuclear antibody [ANA] 1:80 and/or anti-dsDNA 30 IU/mL) patients (71.5% of the original cohort) in whom belimumab reduced SLE disease activity compared with placebo. In a 5-year, open-label extension of this study, improvement in SLE disease activity was sustained in the seropositive subset remaining on treatment (15). Furthermore, flare frequencies and autoantibody levels declined, and rates of adverse events (AEs), including infectious and serious AEs, remained stable or decreased over the 5-year ERK5-IN-1 period. Post-hoc analysis of the phase 2 results led to the development of the SLE Responder Index (SRI), which reflects improvement in disease activity using Mouse monoclonal to Fibulin 5 a global scoring system, while simultaneously requiring that there be no worsening of the disease in any organ system or by physician judgment (16). With the SRI at week 52 as the primary endpoint, belimumab was evaluated in two phase 3 trials comparing belimumab 1 and 10 mg/kg plus SOC with placebo plus SOC in patients with seropositive active SLE. In BLISS-52, a 52-week trial conducted primarily in Asia, South America, and Eastern Europe, belimumab was well tolerated, reduced SLE disease activity, prevented flares, improved serologic activity in serologically active patients, and reduced corticosteroid use (17). BLISS-76, the second phase 3 clinical trial of belimumab in SLE, was conducted primarily in North America and Europe. Treatment continued through week 72, with the final evaluation at week 76. The results on efficacy, safety, tolerability, and biologic markers are presented from the BLISS-76 trial. == PATIENTS AND METHODS == == Study design == In this phase 3, multicenter, ERK5-IN-1 randomized, double-blind, placebo-controlled trial, patients with SLE on SOC therapy were assigned to receive placebo, or belimumab 1 or 10 mg/kg by intravenous (IV) infusion over 1 hour on days 0, 14, and 28, and every 28 days through week 72. While the initiation of an immunosuppressive (IS) drug was prohibited during the trial, the addition of a new antimalarial (AM) drug and dose increases of concomitant IS or AM drugs were permitted until week 16. After week 16, however, the maximum doses of IS or AM drugs could be no greater than the higher of the baseline or week-16 dose. For corticosteroids, any dose was permitted.