OVERVIEW

Phase III trials were randomized, double-blind, and placebo-controlled, and assessed intravenous and subcutaneous methods of administration1-4

BLISS-SC

Patients enrolled: N=836
Treatments: BENLYSTA SC 200 mg + standard therapy vs placebo + standard therapy
Duration: 52 weeks
Regions: 177 centers throughout North America, South America, Europe, and Asia

BLISS-52

Patients enrolled: N=865
Treatments: BENLYSTA IV 1 mg/kg*, BENLYSTA IV 10 mg/kg, or placebo, each in addition to standard therapy
Duration: 52 weeks
Regions: 90 centers throughout South America, Asia, Eastern Europe, and Australia

BLISS-76

Patients enrolled: N=819
Treatments: BENLYSTA IV 1 mg/kg*, BENLYSTA IV 10 mg/kg, or placebo, each in addition to standard therapy
Duration: 76 weeks with primary endpoint at 52 weeks
Regions: 136 centers throughout North America
and Europe
*The 1-mg/kg dose is not recommended.

A Phase II trial (N=449) did not meet the co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and time to first flare over 52 weeks (28% of the population was autoantibody negative at baseline). This led to the selection of a targeted autoantibody-positive population in Phase III trials.1,5

ENTRY CRITERIA

Phase III trial entry criteria

Patients met the following2-4,6

  • Patient is 18 years of age or older and has been diagnosed with SLE according to the American College of Rheumatology criteria
  • Patient meets at least 1 of the following:
  • Antinuclear antibody (ANA) titer ≥1:80
  • Anti-dsDNA autoantibodies ≥30 IU/mL
  • Patient currently receiving any of the following types of standard therapy, alone or in combination, for ≥30 days:
  • Antimalarial
  • Immunosuppressive
  • Corticosteroid
  • NSAID
  • Patient has active disease*
  • SELENA-SLEDAI score ≥8 for BLISS-SC
  • SELENA-SLEDAI score ≥6 for BLISS-52 and BLISS-76

*Can include both clinical and serological manifestations of SLE.
eg, arthritis, rash, hair loss.
eg, decreased complement and anti-dsDNA.

 

Patients were excluded if they had1,6

  • Severe active lupus nephritis
  • Proteinuria >6 g over 24 hours or equivalent using spot urine protein to creatinine ratio
  • Serum creatinine >2.5 mg/dL
  • Required hemodialysis within 90 days of study entry
  • Required high-dose prednisone (>100 mg/day) within 90 days of study entry
  • Severe active CNS lupus
  • Patient required therapeutic intervention for any of the following CNS lupus symptoms within 60 days of study entry: seizures, psychosis, organic brain syndrome, cerebrovascular accident (CVA), cerebritis, or CNS vasculitis

Use of other biologics or IV cyclophosphamide was not permitted.

Use of BENLYSTA is not recommended in these situations.

BENLYSTA can be used in patients with renal involvement excluding patients with severe active lupus nephritis.

STANDARD THERAPIES PERMITTED

Permitted changes to standard therapy2-4,6

Corticosteroids*

52 weeks  
44 No increases; decreases allowed
24 Maintained within 25% or 5 mg over baseline dose, whichever was higher
0 No maximum dose limitations; can add new
 

Antimalarials

52 weeks  
16 No further dose increases permitted; decreases allowed. No new medication permitted
0 Dose increases/decreases permitted; can add new
 

Immunosuppressants

52 weeks  
16 No further dose increases permitted; decreases allowed. No new medication permitted
0 Dose increases/decreases permitted; no new
  • No new NSAID was permitted after Week 44, unless the duration of treatment was <1 week
  • Patients dropping out of the trial early, or requiring changes in standard therapy that were not permitted, were considered non-responders
  • In the trial, a higher proportion of patients on placebo + standard therapy were considered failures for these reasons compared with the BENLYSTA group

SRI-4 PRIMARY ENDPOINT

Primary endpoint

Patients had to successfully meet all 3 components of the SRI-4 at Week 52 to be considered a responder2-4,7§

  • ≥4-point reduction in SELENA-SLEDAI score
  • Requires complete elimination of ≥1 disease manifestations
  • No marked worsening in any organ systems
  • No new flare requiring disease-modifying treatment|| (BILAG A), AND
  • ≤1 flare requiring symptomatic therapy (BILAG B)
  • No worsening of overall condition
  • <0.3-point increase in PGA

*Prednisone or prednisone equivalent.
Within 8 weeks before Week 52, daily corticosteroid dose could not be increased beyond the dose at Week 44 or at baseline, whichever was higher.
At Week 24, daily corticosteroid dose (defined as sum of all corticosteroid doses over any 7 consecutive days divided by 7).
§The primary efficacy endpoint was a composite index (SLE Responder Index-4 or SRI-4) that comprised the following criteria at Week 52 vs baseline: ≥4-point reduction in SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index) score and no new BILAG (British Isles Lupus Assessment Group) A organ domain score or 2 new BILAG B organ domain scores and no worsening (<0.30-point increase) in PGA (Physician’s Global Assessment) score.
||glucocorticoid >20 mg/day or immunosuppressants.
eg, antimalarial drugs, NSAIDs, or glucocorticoids <20 mg/day.

REFERENCES:

  1. BENLYSTA [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2017.
  2. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two–week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017;69(5):1016-1027.
  3. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731.
  4. 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.
  5. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178.
  6. Data on file, Human Genome Sciences, Inc.
  7. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61(9):1143-1151.

ORGAN INVOLVEMENT

Trial patients exhibited multiple disease manifestations, including renal involvement, prior to receiving BENLYSTA1,2

Organ involvement at baseline (% of patients)

Organ Domain* BLISS-SC3
(N=836)
  BLISS-524
(N=865)
  BLISS-765
(N=819)
Mucocutaneous 88   82   82
Immunology 76   85   74
Musculoskeletal 79   59   73
Renal 12   20   11
CV and respiratory 6   4   9
CNS 1   2   3
Vascular 8   7   6
Hematological and fever 8   7   12

15% of patients in the three Phase III clinical trials had renal involvement1,2

*As defined by SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index).

Studies were designed to evaluate efficacy in overall disease activity and were not powered to evaluate efficacy in specific organ domains.

Reduction in disease activity was primarily related to improvements in the mucocutaneous, musculoskeletal, and immunologic organ domains.

STANDARD THERAPIES

Patients were receiving one or more standard therapies at baseline

53% of patients treated with BENLYSTA in three trials were not receiving immunosuppressants3-5

Use of standard therapy at baseline2,6

BLISS-SC % of patients receiving BENLYSTA (n=556)
BLISS-SC % of patients receiving placebo (n=280)
Pooled BLISS-52 and BLISS-76 % of patients receiving BENLYSTA (n=416)
Pooled BLISS-52 and BLISS-76 % of patients receiving placebo (n=418)
Approximately 25% of patients were on one therapy only.2,6

REFERENCES:

  1. BENLYSTA [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2017.
  2. Data on file, Human Genome Sciences, Inc.
  3. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two–week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017;69(5):1016-1027.
  4. Navarra S, Guzmán R, Gallacher A, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731.
  5. 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.
  6. Schwarting A, Dooley MA, Roth DA, Edwards L, Thompson A, Wilson B. Impact of concomitant medication use on belimumab efficacy and safety in patients with systemic lupus erythematosus. Lupus. 2016;25(14):1587-1596.

831315R0 February 2018

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