Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response

Abstract

ObjectivesTo identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets.MethodsThe BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect.ResultsPooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA–SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA–SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life.ConclusionsThese findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline.ClinicalTrials.govidentifiers NCT00424476 and NCT00410384

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

“…BAFF-transgenic mouse studies demonstrated that overexpression of BAFF results in development of SLE-like autoimmune pathology including increased autoantibody production (46)(47)(48). Belimumab (Benlysta), a specific inhibitor of BAFF, shows significant efficacy in evidence-based clinical trials for SLE, further supporting the role of BAFF in SLE pathology (49)(50)(51)(52)(53)(54).…”

Impact of standard of care treatments and disease variables on outcomes in systemic lupus erythematosus trials: analysis from the Lupus Foundation of America Collective Data Analysis Initiative

“…An exploratory analysis of patients with higher disease activity at baseline suggested lower response rates with placebo plus SOC in these sicker patients (11), as is suggested by the data reported here. Several analyses have confirmed that subsets of SLE patients, definable by serology, race, or disease activity as likely to be more ill and have less response to SOC even in aggressively treated placebo groups (8,9,(12)(13)(14). Additional data suggest that less aggressive background treatments can lower response rates in moderately ill SLE patients (7-9, 15, 16), leaving room to determine whether a targeted treatment with potential ceiling response rate of 40%-50% may be effective.…”

Developing novel drugs for systemic lupus erythematosus. Lessons learned from the belimumab trials

“…As a result, to show a statistically significant reduction in severe flare rates with belimumab, the size of the study had to be extended. Pooled analysis of both BLISS trials suggested that belimumab may be particularly effective in patients with higher disease activity at baseline (characterized by a SELENA-SLEDAI ≥ 10, anti-dsDNA positivity or hypocomplementemia), or in patients requiring treatment with corticosteroids [33]. These findings may further help define the profile of patients with enhanced potential to response to a given biological therapy in clinical practice or future trials.…”

“…To this end, suitable patients should be considered to be those who are seropositive and with at least moderate disease severity (SLEDAI > 6) despite receiving optimal treatment [33]. Such patients with smoldering disease are not uncommon in clinical practice and, more importantly, they tend to accumulate damage over time.…”