scholarly journals Impact of concomitant medication use on belimumab efficacy and safety in patients with systemic lupus erythematosus

Lupus ◽  
2016 ◽  
Vol 25 (14) ◽  
pp. 1587-1596 ◽  
Author(s):  
A Schwarting ◽  
M A Dooley ◽  
D A Roth ◽  
L Edwards ◽  
A Thompson ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Concomitant Medication ◽  
Safety Data ◽  
Standard Of Care ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Systemic Lupus ◽  
Two Phase ◽  
Over Time

Practicing physicians have requested efficacy and safety data for belimumab, when used with specific systemic lupus erythematosus (SLE) medications. This was a post hoc analysis of pooled efficacy and safety data from patients who received belimumab 10 mg/kg plus standard of care (SoC) or placebo (SoC) in two Phase III, randomized trials, BLISS-52 and BLISS-76. Patients were categorized into four groups based on baseline concomitant medication usage: steroids only; antimalarials (AM) only; steroids + AM; or steroids + AM + immunosuppressants (IS). The primary endpoint was the SLE Responder Index (SRI) at Week 52. SRI over time and individual SRI components were secondary endpoints. Time to first flare and changes in concomitant medications were exploratory endpoints. Safety was assessed using adverse event (AE) reporting. Across 834 patients, steroids + AM was the largest group ( n = 346, 41.5%) and AM only was the smallest ( n = 77, 9.2%). Disease duration was shortest in the steroids + AM group (5.7 years vs 6.4–7.1 years); SELENA-SLEDAI scores were similar across groups. At Week 52, the percentage of SRI responders was greatest in the steroids + AM group for belimumab 10 mg/kg (59%) compared with placebo (44%); treatment response and SRI component improvements were also observed across other groups. The probability of experiencing an SLE flare was reduced in the steroids-only group for patients who received belimumab 10 mg/kg compared with placebo (64.3% vs 78.1%; hazard ratio 0.64; 95% confidence interval: 0.42–0.96). There was little or no change in daily AM or IS dose in any group. For all groups, there was a general decrease in steroid dose over time; a quarter to a third of patients experienced decreased steroid doses at Week 52. The overall safety profile was similar across treatment arms and concomitant medication groups, with the exception of serious AEs in the steroids + AM group (belimumab 10 mg/kg 16%, placebo 8%). The efficacy and safety of belimumab in combination with SoC was demonstrated for various groupings of steroids, AM and IS. These findings may improve the understanding of the safety and efficacy of adding belimumab to different treatments.

scholarly journals Sub-Setting Systemic Lupus Erythematosus by Combined Molecular Phenotypes Defines Divergent Populations in Two Phase III Randomized Trials

Rheumatology ◽  
2021 ◽  
Author(s):  
Michelle Petri ◽  
Steven D Watts ◽  
Richard E Higgs ◽  
Matthew D Linnik
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Concomitant Medication ◽  
Medication Use ◽  
The United States ◽  
Molecular Biomarkers ◽  
Combinatorial Analysis ◽  
Phase Iii ◽  
Systemic Lupus

Abstract Objectives Heterogeneity of systemic lupus erythematosus (SLE) patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity. Methods Combinations of IFN(high/low), anti-dsDNA(+/-), C3 and C4(low/normal) were used to subset n = 1747 patients from two randomized phase 3 trials. A dichotomous classification scheme defined SLE(+) as: IFNhigh, anti-dsDNA(+), C3(low) and/or C4(low). SLE(-) required all of the following: IFNlow, anti-dsDNA(-), C3(normal) and C4(normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement. Results The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE(-) population and n = 1500 patients in the SLE(+) population. The SLE(-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE(+) had more hematologic, renal and vascular involvement. There was lower concomitant medication use in the SLE(-) population for corticosteroids and immunosuppressants, except for methotrexate. Time to severe flare was significantly longer in SLE(-) vs SLE(+) (p < 0.0001) and SRI-4 response rate was significantly lower in SLE(-) vs SLE(+) (p = 0.00016). The United States had more SLE(-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%). Conclusion Combinatorial analysis of 4 molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis.

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

2012 ◽  
Vol 3 (3) ◽  
pp. 209-222
Author(s):  
Cristina Pamfil ◽  
Antonis Fanouriakis ◽  
Dimitrios T Boumpas
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Standard Of Care ◽  
Lessons Learned ◽  
Phase Iii ◽  
Systemic Lupus ◽  
Novel Therapy ◽  
Key Factor ◽  
B Cell Homeostasis

Systemic lupus erythematosus is the prototypic autoimmune disease with a broad range of clinical manifestations and a complex pathogenesis. B-cells hold a central role in its pathogenesis, not only as autoantibody producing cells, but also by producing other inflammatory mediators and by presenting autoantigens to autoreactive T cells. BlyS, a soluble ligand of the TNF cytokine family, is a key factor affecting B-cell homeostasis and survival and its blockade ameliorated the disease in animal models and preclinical studies of SLE. Following an unsuccessful phase II trial of belimumab, a monoclonal antibody targeting BlyS, two large phase III studies in patients with mild-to-moderate disease, BLISS-52 and BLISS-76, met their primary endpoints showing better efficacy of the drug over standard of care alone. To this end, development of a novel more sensitive responder index and improvements in study designs were crucial. As a result, belimumab became the first drug to get approval for the treatment of SLE after more than 50 years. In this paper we discuss the rationale, development, indications, lessons learned, pitfalls and challenges for this novel therapy and point-out to additional issues that need to be addressed in the future.http://dx.doi.org/10.7175/rhc.v3i3.206

scholarly journals Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials

2012 ◽  
Vol 71 (11) ◽  
pp. 1833-1838 ◽  
Author(s):  
Susan Manzi ◽  
Jorge Sánchez-Guerrero ◽  
Joan T Merrill ◽  
Richard Furie ◽  
Dafna Gladman ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Specific Inhibitor ◽  
Phase Iii ◽  
Systemic Lupus ◽  
Two Phase ◽  
Organ Systems ◽  
Phase Iii Trials ◽  
Organ Domain

ObjectiveTo evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity.MethodsData obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) organ domain scores.ResultsAt baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA–SLEDAI, and immunological by SELENA–SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA–SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA–SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA–SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains.ConclusionsBelimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.

scholarly journals Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison

RMD Open ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e001747
Author(s):  
Hermine I Brunner ◽  
Carlos Abud-Mendoza ◽  
Masaaki Mori ◽  
Clarissa A Pilkington ◽  
Reema Syed ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Response Rate ◽  
Activity Index ◽  
Adult Patients ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Systemic Lupus ◽  
Link Type

ObjectiveTo assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).MethodsWe performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III).ResultsSRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies.ConclusionsThese analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE.Trial registration numbersPLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).

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