Study designs for lupus nephritis

BENLYSTA is the first and only FDA-approved biologic for active lupus nephritis studied with both MMF and CYC.

CYC = cyclophosphamide; MMF = mycophenolate mofetil.

BLISS-LN: the largest and longest trial of a biologic in lupus nephritis1

Study design

BLISS-LN was a Phase III study of 448 adult patients with active lupus nephritis* who were randomized to:

  • BENLYSTA + ST
    OR
  • Placebo + ST

BENLYSTA 10 mg/kg or placebo was administered by IV infusion on Days 0, 14, and 28 and at 4-week intervals thereafter through Week 104.

Standard therapy (ST) was defined as:

  • MMF + high-dose steroids followed by MMF + low-dose steroids
    OR
  • CYC + high-dose steroids followed by AZA + low-dose steroids

View efficacy for lupus nephritis

  • * Confirmed biopsy-proven Class III, IV, V, or V in combination with III or IV.
  • AZA = azathioprine; BLISS-LN = Belimumab International Study in Lupus Nephritis; IV = intravenous.

BLISS-LN primary and secondary endpoints

Analysis of the primary and secondary endpoints was performed in a hierarchical manner—if, at any point, statistical significance was not met, subsequent endpoints could not be considered significant.2

Primary endpoint2

Renal response (RR) at Week 104*

  • eGFR ≥60 mL/min/1.73 m2 or eGFR no worse than 20% below the preflare value; and uPCR ≤0.7; and not a treatment failure†

Renal response was determined by reproducible changes in proteinuria and renal function at Weeks 100 and 104.

Patients who discontinued BENLYSTA or placebo, had treatment failure, or withdrew from the trial were counted as not having had a response.2

Secondary endpoints2

Complete renal response (renal remission) at Week 104

eGFR ≥90 mL/min/1.73 m2 or eGFR no worse than 10% below the preflare value; and uPCR <0.5; and not a treatment failure.†

Renal response (RR) at Week 52

eGFR ≥60 mL/min/1.73 m2 or eGFR no worse than 20% below the preflare value; and uPCR ≤0.7; and not a treatment failure.†

Time to renal-related event or death

First instance of ESKD, doubling of serum creatinine, renal worsening (increased proteinuria and/or impaired renal function), renal disease–related treatment failure, or death.‡

Other endpoint

Steroid use1

  • Daily steroid use was converted to a prednisone-equivalent dose

* RR is equivalent to PERR (primary efficacy renal response).

† Treatment failures were defined as patients who received prohibited medications. For these endpoints, in order to be considered a responder, steroid dose had to be reduced to ≤10 mg/day from Week 24.

‡ Treatment failures were defined as patients who received prohibited therapy due to inadequate lupus nephritis control or renal flare management.

  • eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; uPCR = urine protein:creatinine ratio.

View efficacy for lupus nephritis

Key inclusion and exclusion criteria

INCLUSION CRITERIA1:

  • Adult ≥18 years old
  • SLE clinically diagnosed by ACR criteria
  • Autoantibody test: ANA+ and/or positive anti-dsDNA
  • Active lupus nephritis: biopsy confirmed in the past 6 months (Class III, IV, and/or V)
  • Clinically active renal disease at screening requiring induction therapy with CYC + high-dose steroids or MMF + high-dose steroids

EXCLUSION CRITERIA1:

  • On dialysis within the past year or eGFR <30 mL/min/1.73 m2 at screening
  • Previous failures of both CYC and MMF induction
  • Received induction therapy with CYC within 3 months prior to induction therapy for BLISS-LN
  • Received B-cell–targeted therapy (eg, rituximab) 1 year before randomization
  • Severe active CNS lupus requiring intervention within 60 days of baseline
  • Required management of acute or chronic infections within 60 days of baseline
  • ACR = American College of Rheumatology; ANA = antinuclear antibodies; anti-dsDNA = anti-double-stranded DNA; CNS = central nervous system; SLE = systemic lupus erythematosus.

View efficacy for lupus nephritis

Add BENLYSTA as part of initial and maintenance therapy for your patients with lupus nephritis

Indication & Safety Info

Indication

Important Safety Information

Indication

BENLYSTA is indicated for patients aged ≥5 with active systemic lupus erythematosus (SLE) or active lupus nephritis who are receiving standard therapy. BENLYSTA is not recommended in patients with severe active central nervous system lupus.

Important Safety Information

CONTRAINDICATION

Previous anaphylaxis with BENLYSTA.

WARNINGS AND PRECAUTIONS

Serious Infections: Serious and sometimes fatal infections have been reported and occurred more frequently with BENLYSTA. Use caution in patients with severe or chronic infections, and consider interrupting therapy in patients with a new infection.

 

Progressive Multifocal Leukoencephalopathy (PML): Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported. If PML is suspected, immunosuppressant therapy, including BENLYSTA, must be suspended until PML is excluded. If confirmed, stop immunosuppressant therapy, including BENLYSTA.

 

Hypersensitivity Reactions (Including Anaphylaxis): Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported. Generally, reactions occurred within hours of the infusion but may occur later, including in patients who have previously tolerated BENLYSTA. Non-acute hypersensitivity reactions (eg, rash, nausea, fatigue, myalgia, headache, and facial edema) typically occurred up to a week after infusion. Monitor patients during and after treatment and be prepared to manage anaphylaxis and infusion-related reactions. Be aware of the risk of hypersensitivity reactions, which may present as infusion-related reactions. Discontinue immediately in the event of a serious reaction. With intravenous administration, if an infusion reaction develops, slow or interrupt the infusion.

 

Depression and Suicidality: Depression and suicidality were reported in patients receiving BENLYSTA. Before adding BENLYSTA, assess patients’ risk of depression and suicide and monitor them during treatment. Instruct patients/caregivers to contact their HCP if they experience new/worsening depression, suicidal thoughts/behavior, or other mood changes.

 

Malignancy: There is an increased risk of malignancies with the use of immunosuppressants. The impact of BENLYSTA on the development of malignancies is unknown.

 

Immunization: Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established.

 

Use With Biologic Therapies: Available data do not support the safety and efficacy of concomitant use of BENLYSTA with rituximab in patients with SLE. An increased incidence of serious infections and post-injection systemic reactions in patients receiving BENLYSTA concomitantly with rituximab compared to patients receiving BENLYSTA alone has been observed. The safety and efficacy of BENLYSTA concomitantly with other biologic therapies, including B-cell-targeted therapies, have not been established. Caution should be exercised if BENLYSTA is administered in combination with other biologic therapies.

 

ADVERSE REACTIONS

The most common serious adverse reactions in adult SLE clinical trials were serious infections; some were fatal. The most common adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous injection).

 

Adverse reactions reported in clinical trials with SLE pediatric patients (≥5 years) and adult patients with lupus nephritis were consistent with those observed in adult SLE trials.

 

USE IN SPECIFIC POPULATIONS

Pregnancy: There are insufficient data in pregnant women to establish whether there is drug-associated risk for major birth defects or miscarriage. After a risk/benefit assessment, if prevention is warranted, women of childbearing potential should use contraception during treatment and for ≥4 months after the final treatment.

 

Pregnancy Registry: HCPs are encouraged to refer patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/benlysta-belimumab/.

 

Please see full Prescribing Information and Medication Guide for BENLYSTA.

To report SUSPECTED ADVERSE REACTIONS, contact GSK at gsk.public.reportum.com or 1-888-825-5249, or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References

  1. Data on file, GSK.

  2. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117-1128.