Efficacy and Safety of Belimumab in Patients With Active Systemic Lupus Erythematosus: A Randomised, Placebo-Controlled, Phase 3 Trial, placebo-controlled, phase 3 trialrticle name

Clinical Question

In patients with active systemic lupus erythematosus (SLE), does belimumab reduce disease activity?

Bottom Line

Belimumab improved SLE disease activity at week 52.

Major Points

Lupus is an incredibly heterogeneous disease and existing disease-modifying agents were often riddled with significant side effects and treatment failures. The search for therapies targeting the key pathogenesis of lupus has generally failed to demonstrate efficacy through randomized control trials, including rituximab.

The BLISS-52 trial is the first phase III randomized control trial on a targeted biological treatment that proves to be effective for SLE. The study demonstrated a reduction of SLE disease activity and disease flare with belimumab. Belimumab also demonstrated steroid-sparing activity, which is often an outcome of high interest for practicing clinicians. Moreover, improvement in SLE serological markers including C3, C4, dsDNA, and hypergammaglobulinaemia was demonstrated in a dose-dependent manner. In post hoc analyses subsequently, active disease, seropositivity, and lack of renal or CNS disease were felt to be useful predictors for sustained treatment response with belimumab. This led to the regulatory approval of the medication for the treatment of SLE, as well as guideline changes.

Guidelines

The 2019 EULAR update on SLE management suggests that in persistently active or flaring extrarenal disease, add-on belimumab should be considered.

Design

• Multicenter, double-blind, randomized, controlled trial
• N=865
  • Belimumab 1 mg/kg IV plus standard therapy on Days 0, 14, 28, and every 28 days thereafter through Week 48 (n=288)
  • Belimumab 10 mg/kg IV plus standard therapy on Days 0, 14, 28, and every 28 days thereafter through Week 48 (n=290)
  • Placebo + standard therapy (n=287)
• Setting: 90 centers in 13 countries in Latin America (Argentina, Brazil, Chile, Colombia, and Peru), Asia-Pacific (Australia, Hong Kong, India, Korea, Philippines, and Taiwan), and eastern Europe (Romania and Russia)
• Enrollment: May 2007 to May 2009
• Follow-up: 52 weeks
• Analysis: Intention-to-treat
• Primary outcome: SLE Responder Index (SRI) response rate at week 52
• Secondary outcome:
  • Percent of patients with a ≥ 4 point reduction in SELENA SLEDAI Score at week 52
  • Mean change in Physician's Global Assessment (PGA) at week 24
  • Mean change in Medical Outcomes 36-Item Short-Form Health Survey (SF-36) Physical Component Summary Score (PCS) at week 24
  • Percent of patients with ≥ 25% prednisone reduction to ≤ 7.5 mg/Day between week 40 and 52

Population

Inclusion Criteria

• 18 years and older
• Clinical diagnosis of SLE by ACR criteria
• Active SLE disease
• Autoantibody-positive
• On stable SLE treatment regimen

Exclusion Criteria

• Pregnant or nursing
• Have received treatment with any B cell-targeted therapy, a biological investigational agent in the past year or IV cyclophosphamide within 180 days of Day 0
• Have severe lupus kidney disease
• Have active central nervous system (CNS) lupus
• Have required management of acute or chronic infections within the past 60 days.
• Have current drug or alcohol abuse or dependence
• Have a historically positive test or test positive at screening for HIV, hepatitis B, or hepatitis C

Baseline Characteristics

• Mean age 35-36.2 years
• Women 94-97%
• Balanced distribution of Indigenous American, White, Black American (smallest representation 3-4%), Asian, and Hispanic/Latino
• Mean disease duration 5-5.9 years
• Mean SELENA-SLEDAI 9.6-10, 48-55% having score ≥10
• BILAG domain with A or B scores: Mucocutaneous 58-60%, Musculoskeletal 51-55%, Haematological 18-19%, Renal 13-17%, Vasculitis 8-11%, General 8-10%, Neurological: <1%
• Proteinuria ≥2 g/24h: 7-9%
• ANA ≥1:80: 92-95%, Anti-dsDNA ≥30 IU/mL: 71-77%
• C3 < LLN (<0·9 g/L): 46-51%, C4 < LLN (<0·16 g/L): 56-62%
• Prednisone >7·5 mg/day at baseline: 96%
• Immunosuppressive drugs: 42-43%
• Antimalarial drugs: 64-70%

Interventions

• Randomized to low dose belimumab (1mg/kg), high dose belimumab (10mg/kg) and placebo (standard treatment)
• IV infusion of belimumab or placebo in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, along with the standard of care
• Patients were assessed every 4 weeks

• Standard of care medication changes:
  • No changes to immunosuppressive drugs (mycophenolate, azathioprine, or methotrexate) after 16 weeks
  • No changes to antimalarial drugs after 24 weeks
  • Prednisone dose was not restricted in the first 24 weeks, but required return to within 25% or 5 mg greater than the baseline dose, with no further increases for the remainder of the study
• Protocol prohibited medication addition:
  • New immunosuppressive
  • New biological drug
  • New antimalarial drug or angiotensin-converting-enzyme inhibitors after 4 months
  • New statins after 6 months

Outcomes

Comparisons are belimumab therapy vs. standard therapy.

Primary Outcomes

SRI-4 response rate at week 52 (vs. placebo, 44%)

belimumab 1 mg/kg (51%, OR 1.55; 95% CI 1.10–2.19; p=0.0129)

belimumab 10 mg/kg (58%, OR 1.83 95% CI 1.30–2.59; p=0.0006)

Secondary Outcomes

SELENA-SLEDAI score reduction by 4 points (vs. placebo 46%)

belimumab 1 mg/kg (53%, OR 1.51 95%CI 1.07–2.14; p=0.0189)

belimumab 10 mg/kg (58%, OR 1.71 95%CI 1.21–2·41; p=0.0024)

No new BILAG A or no more than 1 new B flare (vs. placebo 73%)

belimumab 1 mg/kg (78%, OR 1.38 95%CI 0.93–2.04; p=0·1064)

belimumab 10 mg/kg (81%, OR 1.62 95%CI 1.09–2.42; p=0.0181)

No worsening in PGA score (vs. placebo 69%)

belimumab 1 mg/kg (79%, OR 1.68 95%CI 1.15–2.47; p=0.0078)

belimumab 10 mg/kg (80%, OR 1.74 95%CI 1.18–2.55; p=0.0048)

Health-related quality of life at week 24 (SF-36 PCS score, absolute change from baseline vs. placebo 3.26 SE 0.54)

belimumab 1 mg/kg (3.39, SE 0.53 Treatment difference 0.13 95%CI −0.95 to 1.21; p=0.8127)

belimumab 10 mg/kg (3.34, SE 0.55 Treatment difference 0.08 95%CI (−1.00 to 1.15; p=0.8870)

Prednisone dose reduced by ≥25% to ≤7·5 mg/day during week40-52 (vs. placebo 12%)

belimumab 1 mg/kg (21%, OR 1.89 95%CI 1.08–3.31; p=0.0252)

belimumab 10 mg/kg (19%, OR 1.75 95%CI 0.99–3.08; p=0.0526)

Additional Outcomes

Normalization of C3 (vs. placebo 14%)

belimumab 1 mg/kg (23%, p=0.146)

belimumab 10 mg/kg (34%, p=0.0005)

Normalization of C4 (vs. placebo 19%)

belimumab 1 mg/kg (36%, p=0.0024)

belimumab 10 mg/kg (43%, p<0.0001)

Nomralization of hypergammaglobulinaemia (vs. placebo 19%)

belimumab 1 mg/kg (50%, p<0.0001)

belimumab 10 mg/kg (49%, p<0.0001)

Anti-dsDNA positive to negative (vs. placebo 6%)

belimumab 1 mg/kg (13%, p<0.0145)

belimumab 10 mg/kg (17%, p<0.0008)

Adverse Events

• Generally well tolerated
• Similar adverse events rates across the groups given belimumab 1mg/kg, 10mg/kg and placebo:
  • Serious infection: 22 (8%), 13 (4%), and 17 (6%)
  • Severe or serious hypersensitivity infusion reactions: 2 (<1%), 2 (<1%), and 0
  • Deaths: 2 (<1%), 4 (1%), and 3 (1%)
  • No malignant diseases reported

Criticisms

• Exclusion of patients with severe lupus nephritis and CNS lupus
• Included few African American patients
• Only composite disease activity outcome reported, individual disease domain response not captured
• More research is needed to clarify the optimal primary endpoint selection, as different endpoints (composite disease activity response score), depending on the composition and calculation, can lead to different conclusions being drawn regarding the drug efficacy

Funding

Human Genome Sciences and GlaxoSmithKline

Further Reading

• BILSS-76 extension trial: Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. doi:10.1002/art.30613.