BLISS : LN TRIAL

PRESENTER – DR NEELAM DEVI MARAVI

MODERATOR – DR RAMMOHAN S. BHAT
 INTRODUCTION

• Lupus Nephritis usually occurs within 6 months of

the diagnosis of SLE.

• Clinically, LN is diagnosed from the presence of

proteinuria, active urinary sediments , or
decreased GFR.

• Diagnosis from a kidney biopsy remains the gold

standard of diagnosis and provides useful
prognostic and therapeutic information.
• Approximately 10–30% of patients with LN ultimately
progress to end-stage kidney disease (ESKD)

• Moreover, up to 60% of patients with lupus nephritis

never attain complete remission , and these patients
experience poor long-term outcomes.
 BELIMUMAB

• Belimumab is a recombinant human IgG1-λ

monoclonal antibody that inhibits the soluble
form of BAFF, preventing activation of BAFF
receptors, thus inhibiting B-cell survival and
maturation.
 BACKGROUND OF STUDY

• To know the efficacy and safety of intravenous

belimumab as compared with placebo, when
added to standard therapy (mycophenolate
mofetil or cyclophosphamide–azathioprine), In
adults with active lupus nephritis.

• Two-Year, Randomized, Controlled Trial of

Belimumab in Lupus Nephritis.

• Published in The new england journal o f medicine

september 2020.
 THE STUDY
• Methods
– This is a phase 3, multinational, multicenter, randomized, double-
blind, placebo-controlled, trial conducted at 107 sites in 21
countries.
• Inclusion criteria
– Age of more than 18 years
– Autoantibody-positive (antinuclear antibody titers ≥1:80, anti-
double-stranded DNA antibodies, or both).
– Clinical diagnosis of SLE by American College of Rheumatology
(ACR) criteria 1987.
– Urinary protein to creatinine ratio of ≥1 (corresponding to ~
1g/day proteinuria)
– Biopsy-proven lupus nephritis. ISN-RPS class III (focal), IV
(diffuse), or V (membranous) within 6 months of screening.
• Exclusion criteria
– On dialysis within the past 1 year.
– eGFR <30 ml /min/ 1.73 m2 BSA.
– Treatment with belimumab within the past year.
– Receipt of any B cell-targeted therapy (for example,
rituximab), an investigational biological agent within
the past year.
– Previous failures of both cyclophosphamide (CYC) and
mycophenolate mofetil (MMF) induction.
– Receipt of cyclophosphamide induction therapy within
3 months before the trial.
– Pregnancy or breastfeeding.
 INTERVENTION

• Participants were randomly assigned in a 1:1 ratio to

receive intravenous belimumab (at a dose of 10
mg/kg) or matching placebo, on a background of
standard therapy.
• Randomization was stratified according to the
induction regimen (CYC/MMF) and race group (Black
or non-Black).
• In addition to standard therapy, patients received
intravenous belimumab or placebo on days 1
(baseline), 15, and 29 and every 28 days thereafter to
week 100, with final assessments at week 104.
 STANDARD TREATMENT
• Induction therapy was chosen by the investigators and
initiated within 60 days before receiving study drug. Either
intravenous CYC or oral MMF.
• Patients receiving CYC (given as 500 mg every 2 weeks for 6
infusions) were then given oral azathioprine (AZA) until the
trial ended.
• Patients started on MMF continued it until the end of the
trial.
• Based on the investigator’s discretion, high-dose
glucocorticoids (1 to 3 daily doses of 500-1,000 mg of IV
methylprednisolone) were administered during induction,
followed by oral prednisone.
• ACE inhibitors or ARBs as well as hydroxychloroquine was
encouraged for all patients.
 Conclusion

• The trial favored belimumab in enhancing renal

responses in addition to standard therapy in LN
management; the risk of a renal-related event - mostly
proteinuria though, with little effect on clinically
relevant outcomes, was almost 50% lower in patients
receiving belimumab than among those who received
standard therapy alone.
• Autoreactive B cells have a key role in the
pathogenesis of LN, thus BAFF antagonists are a
central matter of interest and it appears as they have
now have a place in the future exploration of
management of LN.
• Partial Renal Response(PRR):
- Estimated GFR no more than 10% below the baseline
value or within normal range AND

- ≥ 50% decrease in the urine PCR with one of the following:

– a urine PCR of < 1.0, if the baseline ratio was ≤3.0 OR
– a urine PCR of < 3.0, if the baseline ratio was >3.0

- No receipt of rescue therapy resulting in treatment failure

• No Renal Response(NRR): Not meeting criteria for either

CRR or PRR
 Treatment Failure –

• If they violated the glucocorticoid rules ( i.e to taper

glucocorticoids to 10 mg or less per day by week 24
and to not exceed this dose through week 104), or
received additional immunosuppressive agents
beyond the induction and maintenance regimens.

• Initiated the use of ACE inhibitors, ARBs , or

antimalarial drugs after week 24.

• If the standard therapy (CYC–AZA or MMF) exceeded

permitted doses.
 RESULTS

• The mean age was 33.4±10.6 years

• Median duration of lupus nephritis was 2.4 months.
• Only 14% patients were Black.
• Almost 90% were females.
• 58% of the cohort had kidney-biopsy specimens
suggestive of class III or IV lupus nephritis, 26% had
class III or IV with class V, and 16% had isolated class V.
• The GFR was well preserved (100±40), and the mean
proteinuria was 3.4 g/g Cr.
• About two-thirds were on ACEi/ARBs
• Hydroxychloroquine usage was not reported however.
Primary and Major Secondary Efficacy
Endpoints
• At week 104, primary efficacy renal response
was significantly higher in patients in the
belimumab group than in the placebo
• More patients in the belimumab group had a
primary efficacy renal response at an earlier
time point (week 52) than in the placebo
group and the primary efficacy renal response
was sustained through week 104.
• Significantly more patients had a complete renal
response including a decrease in the ratio of
urinary protein to creatinine to less than 0.5 and
no treatment failure at week 104 in the
belimumab group than placebo group.

• Patients who received belimumab had a

significantly lower risk of a renal related event or
death than placebo.
 SUBGROUP ANALYSES

• In both the MMF and CYC– AZA subgroups, more patients

who received belimumab had a primary efficacy renal
response than patients in the placebo group with the
overall response driven by the results in the larger MMF
subgroup.

• In the CYC–AZA subgroup, there was no benefit in CRR with

belimumab and the benefit was mostly seen in the MMF
group.
• Black patients who received belimumab appeared more
likely to have a primary efficacy renal response and a
complete renal response at week 104 than those who
received placebo.
 OTHER EFFICACY ENDPOINTS (POST HOC
ANALYSIS)

• More patients who received belimumab had a

decrease in UPCR (from ≥0.5 to <0.5) at week 104
than placebo.
•
• The mean observed eGFR values initially increased
from baseline in both trial groups; however, from
week 52, eGFR values declined in the placebo
group, whereas the eGFR remained stable through
week 104 in the belimumab group.
 BIOMARKER ENDPOINTS

• Patients in the belimumab group had greater

reductions in ds DNA and C1q ab and greater
increases in complement C3 and C4 levels and
more conversions to normal levels than
patients who received placebo.
 SAFETY

• Adverse events, including infections, occurred

with similar frequency in the two groups.

• Anti-belimumab antibodies were not detected.

• Infection-associated deaths were balanced

between the two groups.

• No deaths were directly attributed to lupus

nephritis by the investigators.
 LIMITATIONS

• The original endpoints categorized responses as

complete, partial, or no response according to the
level of proteinuria, eGFR from 24-hr urine
collections, and microscopic examination of
urinary sediment, although favored belimumab,
were not significantly different between the
belimumab and placebo groups.

• Whether this change in the endpoint by the

investigators was independent of any data
collected before the change is questionable.
• The investigators permitted only 2 induction and
maintenance regimens, although additional
therapies for lupus nephritis, such as calcineurin
inhibitors, are currently used in practice.

• The induction regimen was selected by the

treating physician and was not randomly assigned,
making it open for unknown biases.

• In addition, patient-reported outcomes were not

included in the trial.
 UNCERTAINTIES

• Whether the belimumab has a role in managing

patients in whom induction therapy fails or those
with relapse?

• Would the addition of belimumab be helpful in

facilitating glucocorticoid tapering?

• And could belimumab decrease the progression

to ESKD and subsequent flares in patients with
severe LN?
THANK YOU