OBJETIVO: Analizar la eficacia, seguridad, dosificación, interacciones medicamentosas, así como consideraciones económicas y terapéuticas de belimumab, un estimulador de linfocitos B (BLyS) inhibidor en investigación. BASES DE DATOS: Revisión sistemática con búsqueda en inglés en MEDLINE (1966 - agosto 2010) utilizando los términos: belimumab, Benlysta, estimuladores de linfocitos B, los inhibidores específicos de BLyS y lupus eritematoso sistémico (LES). Se revisaron comunicados de prensa y bibliografías para obtener más información y citas. SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Belimumab fue - por primera vez - identificado y estudiado como una proteína humana blanco en 1999. Por lo tanto, todos los ensayos clínicos publicados y resúmenes que evalúan la seguridad y eficacia de belimumab para el tratamiento del LES, además artículos de revisión desde 1999 fueron evaluados para su inclusión. Datos adicionales fueron extraídos del sitio web del fabricante y de documentos de la Food and Drug Administration (FDA). SÍNTESIS DE DATOS: Tratamientos actuales del LES atacan sitios inespecíficos para reducir la inflamación y suprimir el sistema inmunológico. Belimumab es sitio específico, la IgG1 humana, estimulador e inhibidor monoclonal del linfocito B. Actualmente, en fases tardías de investigación para el tratamiento del LES. Ensayos fase 3, no publicados, han reportado resultados estadísticamente significativos para outcomes primarios al comparar belimumab (10 mg/kg) más tratamiento estándar con placebo en pacientes seropositivos con LES. En general, belimumab ha sido relativamente bien tolerado, con tasas de interrupción y eventos adversos similares a placebo. Si belimumab es aprobado por la FDA, su lanzamiento al mercado de EE.UU se espera en el 2011. CONCLUSIONES: Belimumab ha demostrado beneficios significativos para pacientes con LES en los pocos ensayos fase 3 publicados. Sin embargo, quedan dudas respecto a la población de pacientes óptima, la duración del tratamiento, rol en la terapia y efectos colaterales a largo plazo.

BACKGROUND: Belimumab, a monoclonal antibody that inhibits B-lymphocyte stimulating protein, was the first biologic agent approved for, and the first drug approved in 55 years for, the treatment of systemic lupus erythematosus (SLE) by the US Food and Drug Administration (FDA). OBJECTIVE: This article reviews the current research on belimumab and provides recommendations on its use in the treatment of SLE. METHODS: The Cochrane Library, EBSCO, IPA, MEDLINE, and SCOPUS were searched for research published from January 2000 to November 2011, using the search terms belimumab, Benlysta, and Lympho-Stat B. Selection criteria included peer-reviewed original research articles on the pharmacology, pharmacokinetic properties, drug interactions, and clinical efficacy and tolerability of belimumab in the treatment of SLE. Abstracts from the annual meetings of major rheumatology medical organizations and societies were searched and reviewed for new content. Additional information on belimumab was obtained from the manufacturer, from the FDA, and from other sources. MEDLINE was also used to select clinical studies and therapeutic guidelines on SLE therapy. RESULTS: The literature search identified 1 Phase II and 2 Phase III studies that compared belimumab (1, 4, and 10 mg/kg/dose IV on days 0, 14, and 28; then every 28 days) to placebo in patients with active SLE on concurrent therapies. Patients with active lupus nephritis or neuropsychiatric lupus were excluded. In a Phase II, 52-week study, 24-week mean Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores were decreased by 19.5% with belimumab versus 17.2% with placebo (P = NS). Median time to first flare was 67 days with belimumab versus 83 days with placebo (P = NS). In seropositive patients, 52-week mean SELENA-SLEDAI scores were decreased by 28.8% with belimumab versus 14.2% with placebo (P < 0.05), and physician's global assessment scores were improved by 32.7% with belimumab versus 10.7% with placebo (P < 0.05). Two Phase III studies were performed in seropositive SLE patients. In a Phase III, 52-week study, the rates of response (a reduction of ≥4 points on the SLE Response Index [SRI]) at week 52 were 51% and 58% with belimumab 1 and 10 mg/kg/dose, respectively, versus 44% with placebo (both, P < 0.05). In a Phase III, 76-week study, the rates of response, as measured using SRI, at week 52 were 42.8% and 46.5% with belimumab 1 and 10 mg/kg/dose versus 35.3% with placebo (P = NS and P < 0.001); at 76 weeks, response rates were 42.1% and 41.4% with belimumab 1 and 10 mg/kg/dose versus 33.8% with placebo (P < 0.05 and P = NS). The tolerability data from these studies did not suggest any overall differences between belimumab and placebo. CONCLUSIONS: Based on the findings from the present review, belimumab appears to be efficacious and generally well-tolerated and in the treatment of SLE other than lupus nephritis or neuropsychiatric lupus. Additional clinical and economics studies are needed to determine the most appropriate place for belimumab in the treatment of SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

RECORD STATUS: None CITATION: Belimumab for the treatment of systemic lupus erythematosus.. Catalan Agency for Health Information, Assessment and Quality (CAHIAQ -formerly CAHTA).

OBJECTIVE: Systemic lupus erythematosus (SLE) is treated with anti-inflammatory and immunosuppressive drugs and off-label biologics. Belimumab is the first biologic approved after 50 years as an add-on therapy for active disease. This paper summarizes a health technology assessment performed in Italy. METHODS: SLE epidemiology and burden were assessed using the best published international and national evidences and efficacy and safety of belimumab were synthesized using clinical data. A cost-effectiveness analysis was performed by a lifetime microsimulation model comparing belimumab to standard of care (SoC). Organizational and ethical implications were discussed. RESULTS: Literature review showed that SLE affects 47 per 100,000 people for a total of 28,500 patients in Italy, 50% of whom are affected by active form of the disease despite SoC. These patients, if autoantibodies and anti-dsDNA positive with low complement, are eligible for belimumab. SLE determines work disability and a 2-5-fold increase in mortality. Belimumab with SoC may prevent 4,742 flares in three years being cost-effective with an incremental cost-effectiveness ratio of €32,859 per quality adjusted life year gained. From the organizational perspective, the development of clear and comprehensive clinical pathways is crucial. CONCLUSIONS: The assessment supports the use of belimumab into the SLE treatment paradigm in Italy.

RECORD STATUS: None CITATION: National Horizon Scanning Centre. Belimumab (Benlysta) for active systemic lupus erythematosus Birmingham: National Horizon Scanning Centre (NHSC). Horizon Scanning Technology Briefing. 2009

The treatment of belimumab plus standard therapy in patients with systemic lupus erythematosus (SLE) has been studied extensively in recent years. Our aim was to estimate the efficacy and safety of this therapy compared with placebo plus standard therapy in patients with SLE. METHODS: PubMed, Web of Science, Embase, Chinese Biomedical Literature Database (CBM, Chinese), and Wanfang Database (Chinese) were searched for all randomized clinical trials that mainly studied the efficacy and safety of belimumab plus standard therapy before June 2015. We extracted or calculated the rate of the SLE Response Index and adverse event rate at 52 weeks in all the included studies. The odds ratio (OR) with 95% CI between the 2 groups in this meta-analysis was conducted by using a random-effects model. Sensitivity and publication bias analyses were also performed. All statistical tests were performed by using Stata software version 12.0 (StataCorp., College Station, Texas). FINDINGS: In the overall samples (4 studies, N = 4692 ), a significantly higher SLE Response Index rate at 52 weeks was found in belimumab plus standard therapy group compared with the placebo plus standard therapy group in all studies (OR = 1.49; 95% CI, 1.26-1.77 ; P < 0.001 ). When assessed with the incidence of serious adverse events, the data revealed that there was no significant difference between the 2 groups, with pooled OR = 1.08; 95% CI, 0.83-1.39; P = 0.573; OR = 1.23; 95% CI, 1.02-1.48; P = 0.029; and OR = 1.07; 95% CI, 0.88-1.29; P = 0.506. IMPLICATIONS: The results suggest that treatment with belimumab plus standard therapy is more effective than placebo plus standard therapy in SLE patients, which represents major progress in the treatment of SLE. Regardless of the statistical analyses, further research is necessary to optimize treatment effects.

RECORD STATUS: This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database. CITATION: IQWiG. Belimumab – Nutzenbewertung gemäß § 35a SGB V. [Belimumab - Benefit assessment according to § 35a Social Code Book V (dossier assessment)] Cologne: Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). IQWiG Berichte 128. 2012

RECORD STATUS: None CITATION: Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus.. NIHR Health Technology Assessment programme.

OBJECTIVES: To undertake a systematic review and meta-analysis to investigate clinical effectiveness of belimumab for patients with systemic lupus erythematosus (SLE) and antinuclear and/or anti-double-stranded DNA (dsDNA) autoantibodies. METHODS: We searched eight electronic databases and reference lists for randomised controlled trials (RCTs) of belimumab against placebo or best supportive care. Quality assessment and random effects meta-analysis were undertaken. DESIGN: A meta-analysis of RCTs. PARTICIPANTS: 2133 SLE patients. PRIMARY AND SECONDARY OUTCOME MEASURES: SLE Responder Index (SRI) at week 52. RESULTS: Three double-blind placebo-controlled RCTs (L02, BLISS-52 BLISS-76) investigated 2133 SLE patients. BLISS-52 and BLISS-76 trials recruited patients with antinuclear and/or anti-dsDNA autoantibodies and demonstrated belimumab effectiveness for the SRI at week 52. Ethnicity and geographical location of participants varied considerably between BLISS trials. Although tests for statistical heterogeneity were negative, BLISS-52 results were systematically more favourable for all measured outcomes. Meta-analysis of pooled 52-week SRI BLISS results showed benefit for belimumab (OR 1.63, 95% CI 1.27 to 2.09). By week 76, the primary SRI outcome in BLISS-76 was not statistically significant (OR 1.31, 95% CI 0.919 to 1.855).