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The discovery and development of belimumab: the anti-BLyS-lupus connection.

ABSTRACT: For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to take calculated risks, a devoted cadre of patients and physicians and a healthy dose of serendipity. Collectively, these efforts have provided a model for the development of a new generation of drugs to treat the broad manifestations of SLE. However, as a substantial percentage of SLE patients do not respond to belimumab, further research is needed to better characterize the pathogenetic mechanisms of SLE, identify additional therapeutic targets, and develop effective and nontoxic novel agents against these targets.

SUBMITTER: Stohl W

PROVIDER: S-EPMC3264947 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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The discovery and development of belimumab: the anti-BLyS-lupus connection.

Stohl William W Hilbert David M DM

Nature biotechnology 20120109 1

For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to ...[more]

PMID: 22231104

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Project description:Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels???2?ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS???2?ng/mL. Efficacy and safety of belimumab 10?mg/kg were examined in patients with BLyS???2?ng/mL and <?2?ng/mL.Data from BLISS-52 and -76 (N?=?1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS???2?ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ??4-point reduction in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup.Baseline predictors of BLyS???2?ng/mL included positive anti-Smith (??15 U/mL), low complement (C) 3 (<?900?mg/L), anti-double-stranded DNA (anti-dsDNA) 80-200 and ??200?IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10?mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS???2?ng/mL group (24.1%, p?<?0.0001) compared with BLyS?<?2?ng/mL (8.2%, p?=?0.0158). Results were similar for???4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10?mg/kg versus placebo in the BLyS???2?ng/mL group (p?=?0.0002). AEs were similar across treatment arms and BLyS subgroups.Positive anti-Smith, low C3, anti-dsDNA???80?IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS???2?ng/mL. Monitoring these factors could identify patients with BLyS???2?ng/mL who are at risk of flare.

Project description:BackgroundElevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE.MethodsIn BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare.ResultsOf 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman's rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p < 0.0001). The proportion of SRI4 responders was higher with belimumab versus placebo in all subgroups, but the difference reached statistical significance in the medium BLyS mRNA tertile (odds ratio [OR] 2.17; 95% CI 1.16, 4.04; p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups.ConclusionsThis post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Dataset Information

The discovery and development of belimumab: the anti-BLyS-lupus connection.

Publications

The discovery and development of belimumab: the anti-BLyS-lupus connection.

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