Post on 05-Mar-2021
Effects of Belimumab on Renal Outcomes, Overall SLE Control, and Biomarkers:Findings from a Phase 3, Randomized, Placebo-controlled 104-week Study in Patients With Active Lupus Nephritis
Richard Furie1, Brad Rovin2, Frédéric Houssiau3, Gabriel Contreras4, Ana Malvar5,
Amit Saxena6, Xueqing Yu7, Y K Onno Teng8, Pieter van Paassen9, Ellen Ginzler10,
Diane L Kamen11, Mary Oldham12, Damon Bass13, Andre van Maurik12, Mary Beth
Welch13, Yulia Green14, Beulah Ji14, Christi Kleoudis15*, David A Roth13
1Northwell Health, Great Neck, NY, USA; 2The Ohio State University, Columbus, OH, USA; 3Cliniques Universitaires Saint-Luc, Brussels, Belgium;4University of Miami Miller School of Medicine, Miami, FL, USA; 5Organizacion Medica de Investigacion, Buenos Aires, Argentina; 6NYU School of Medicine,
New York, NY, USA; 7Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 8Leiden University Medical
Center, Leiden, the Netherlands; 9Maastricht University, Academisch Ziekenhuis Maastricht, Maastricht, the Netherlands; 10SUNY Downstate Health
Sciences University, Brooklyn, NY, USA; 11Medical University of South Carolina, Charleston, SC, USA; 12GlaxoSmithKline, Stevenage, Hertfordshire, UK; 13GlaxoSmithKline, Research Triangle Park, NC, USA; 14GlaxoSmithKline, Uxbridge, Middlesex, UK; 15Parexel, Durham, NC, USA
*At the time of study
Reprinted from the ACR Convergence held November 6-11, 2020. The American College of Rheumatology does not guarantee, warrant, or endorse any commercial products or services. Reprinted by GSK.
COI DISCLOSURE INFORMATION
RF has received advisory board fees and travel support from GSK, AbbVie, AstraZeneca (MedImmune), Biogen, Bristol-
Myers Squibb, Boehringer Ingelheim, Eli Lilly, EMD Serono, Equillium, Galápagos, Genentech, Glenmark
Pharmaceuticals, Novartis, Reistone Biopharma, Sanofi, Takeda, and Union Chimique Belge; consulting fees from
Alexion, Aurinia Pharmaceuticals, Daiichi Sankyo, Janssen Pharmaceutica, Kezar Life Sciences, and MorphoSys.
BR has received consulting fees from GSK.
FH has received grant/research support from UCB; consulting fees from GSK.
GC has received grant/research support and consulting fees from Genentech and Merck.
AM has received consulting fees from GSK and Roche.
AS has received consulting fees from GSK, Bristol-Myers Squibb and AstraZeneca.
XY has received grant/research support from National Natural Science Foundation of China, Baxter, Equipment Grant Program, Wanbang
Biopharmaceuticals, AstraZeneca and GSK; consulting fees from Baxter, Wanbang Biopharmaceuticals, Fresenius, and Fresenius Kabi; is
an officer or board member at Baxter, ARB, AstraZeneca, and GSK; royalties from Elsevier, CAN, People’s Medical Publishing House;
speaker/honoraria from Baxter, Fresenius and Fresenius Kabi, Wanbang Biopharmaceuticals, Kyowa Kirin.
YKOT has received grant/research support from GSK; consulting fees from GSK, Aurinia Pharmaceuticals and Novartis.
PVP has received consulting fees from Alexion.
EG has received grant/research support from GSK, Aurinia and Genentech; consulting fees from Ablynx and Janssen.
DLK has nothing to disclose.
MO, DB, AVM, MBW, YG, BJ, CK and DR are employees of GSK and hold stocks and shares in the company.
BACKGROUND AND OBJECTIVES
• LN is the most common serious complication of SLE and
a major risk factor for morbidity and mortality in patients
with SLE1
• Belimumab is approved for the treatment of active,
antibody-positive SLE2
• A post hoc analysis of belimumab trials showed
improvements in renal parameters in patients with SLE3
1. Hanly JG, et al. Rheumatol 2016;55:252-62; 2. Benlysta Prescribing Information GlaxoSmithKline; 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125370s016lbl.pdf [Accessed September 2020];
3. Dooley MA, et al. Lupus 2013;22:63–72
IV, intravenous; LN, lupus nephritis; SLE, systemic lupus erythematosus
• The objective of the Phase 3, randomized, double-blind,
placebo-controlled, 104-week BLISS-LN study was to
assess the efficacy and safety of IV belimumab plus
standard therapy in adult patients with SLE and active LN
Patients with
active LN
Day -60 Day 0Start of standard therapy
induction
Belimumab 10 mg/kg IV + standard therapy
Placebo IV + standard therapy
Belimumab 10 mg/kg IV
+ standard therapy
28-week
open label
104-week double-blind treatment
Week 104
Primary endpoint:
• PERR
Key secondary endpoints:
• CRR
• Time to renal-related event or death
• ORR
Week 52
Key secondary
endpoint:
• PERR
Week 24
Steroids must be
≤10 mg/day to be
considered a responder
W24 W52 W104
HDCS + MMF
followed by
MMF
HDCS + CYC
followed by
AZA
or
Randomization (1:1)
Stratified by race and
induction/maintenance regimen:
STUDY DESIGNBLISS-LN: Phase 3, randomized, double-blind, placebo-controlled study
Key eligibility criteria:
• Age ≥18 years
• Screening uPCR ≥1
• Recent renal biopsy LN (Class III, IV, V or III+V or IV+V)
• Time to first severe SFI flare
• SLEDAI-S2K score <4 at Week 104
• Prednisone dose ≤7.5 mg/day at Week 104
• Prednisone dose ≤5 mg/day at Week 104
• Change from baseline in biomarkers (anti-dsDNA, anti-C1q, C3, C4)
• Safety
Other endpoints:
“Induction” “Maintenance”
Anti-ds-DNA, anti-double-stranded DNA; AZA, azathioprine; C3/C4, complement 3/4; CRR, complete renal response; CYC, cyclophosphamide; HDCS, high-dose corticosteroids; MMF, mycophenolate mofetil;
ORR, ordinal renal response; PERR, primary efficacy renal response; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index; SFI, SELENA-SLEDAI Flare Index
uPCR, urinary protein:creatinine ratio; W, week
RESULTS
• 448 patients were randomized and received ≥1 dose of study treatment (safety population)
– 446 patients comprised the mITT population* (223 patients in each group)
CharacteristicsPlacebo
n=223
Belimumab 10 mg/kg IV
n=223
Age (years), mean (SD) 33.1 (10.6) 33.7 (10.7)
Female, n (%) 196 (87.9) 197 (88.3)
LN disease duration (years), median (IQR) 0.2 (0.1, 3.4) 0.2 (0.1, 3.3)
Renal biopsy class, n (%)
Class III or IV 132 (59.2) 126 (56.5)
Class III and V or Class IV and V 55 (24.7) 61 (27.4)
Class V 36 (16.1) 36 (16.1)
SLEDAI-S2K† score, mean (SD) 12.2 (4.8) 12.5 (5.3)
Biomarkers, n (%)
Anti-dsDNA positive (≥30 IU/ml) 169 (75.8) 173 (77.6)
Anti-C1q positive (≥22.2 IU/ml) 172 (77.8) 181 (81.2)
Low C3 (<90 mg/dl) 133 (59.6) 134 (60.1)
Low C4 (<10 mg/dl) 58 (26.0) 65 (29.1)
*Defined as all randomized patients who received ≥1 dose of investigational treatment, excluding 2 patients due to issues with source documentation or Good Clinical Practice
compliance; †defined as SELENA-SLEDAI with proteinuria scoring as per SLEDAI-2000 rules
IQR, interquartile range; mITT, modified intention-to-treat; SD, standard deviation
Patient baseline characteristics
RESULTSPrimary and key secondary endpoints
Endpoint, n (%)Placebo
n=223
Belimumab
10 mg/kg IV
n=223
Treatment
difference (%)
OR/HR
(95% CI) vs placebop-value
Primary endpoint:
PERR at Week 104*† 72 (32.3) 96 (43.0) 10.8 OR 1.6 (1.0, 2.3) 0.0311
Secondary endpoints:
CRR at Week 104*† 44 (19.7) 67 (30.0) 10.3 OR 1.7 (1.1, 2.7) 0.0167
PERR at Week 52*† 79 (35.4) 104 (46.6) 11.2 OR 1.6 (1.1, 2.4) 0.0245
Time to renal-related
event or death‡ 63 (28.3)║ 35 (15.7)║ − HR 0.5 (0.3, 0.8) 0.0014
ORR at Week 104§†
Complete response 44 (19.7) 67 (30.0) 10.3
0.0096Partial response 38 (17.0) 39 (17.5) 0.4
Non-responders 141 (63.2) 117 (52.5) −10.8
*OR (95% CI) and p-value are from regression model comparing belimumab and placebo with covariates for treatment group, induction regimen (CYC vs MMF), race (Black
African Ancestry vs other), baseline uPCR, and baseline eGFR; †study WD, TF, and IPD were imputed as non-responders; ‡HR and p-value are from Cox proportional hazards
model adjusted for induction regimen (CYC vs MMF), race (Black African Ancestry vs other), baseline uPCR, and baseline eGFR; §p-value is from rank ANCOVA model comparing
belimumab and placebo with covariates for treatment group, induction regimen (CYC vs MMF), race (Black African Ancestry vs other), baseline uPCR, and baseline eGFR; ║number/proportion of patients reporting the event
ANCOVA, analysis of covariance; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IPD, investigational product discontinuation; OR, odds
ratio; TF, treatment failure; WD, withdrawal
RESULTSPERR and CRR by visit
PERR is defined as uPCR ≤0.7, and eGFR no worse than 20% below pre-flare value or ≥60 ml/min/1.73 m2, and not a treatment failure; CRR is defined as uPCR
<0.5, and eGFR no worse than 10% below pre-flare value or ≥90 ml/min/1.73 m2, and not a treatment failure
SE, standard error
RESULTS PERR at Week 104 by treatment regimen, LN class, and race
*Defined as uPCR ≤0.7, and eGFR no worse than 20% below pre-flare value or ≥60 ml/min/1.73 m2, and not a treatment failure
BEL, belimumab; PBO, placebo
RESULTS CRR at Week 104 by treatment regimen, LN class, and race
*Defined as uPCR <0.5, and eGFR no worse than 10% below pre-flare value or ≥90 ml/min/1.73 m2, and not a treatment failure
RESULTSTime to renal-related event or death and renal flares
(post hoc*)
*Except analysis for time to renal-related event or death by treatment regimen, which were pre-specified†Some patients were no longer on treatment by Week 24
RESULTS
Time to first severe SFI flare is defined as (event date – treatment start date) + 1
Other efficacy endpoints
31.4
18.8
0
10
20
30
40
50
60
70
80
90
100
Pati
ents
(%)
Time to first severe
SFI flare
(patients with an event)
18.4
29.6 27.827.8
40.836.8
0
10
20
30
40
50
60
70
80
90
100
SLEDAI-S2K score<4at Week 104
Prednisone dose ≤7.5 mg/day at Week 104
Prednisone dose ≤5 mg/day at Week 104
Pati
ents
(%)
OR (95% CI) vs placebo
1.8 (1.1, 2.8)
p=0.0164
OR (95% CI) vs placebo
1.6 (1.1, 2.4)
p=0.0139
OR (95% CI) vs placebo
1.5 (1.0, 2.3)
p=0.0444
HR (95% CI) vs placebo
0.6 (0.4, 0.8)
p=0.0042
n=41 n=62 n=66 n=91 n=62 n=82n=70 n=42
*In patients with positive autoantibody at baseline (anti-dsDNA ≥30 IU/ml or aC1q ≥22.2 IU/ml)†In patients with low complement (C3 <90 mg/dl or C4 <10 mg/dl) at baseline‡p-values are for comparison between treatment groups. Rank ANCOVA model or ANCOVA model comparing belimumab and placebo with covariates for treatment group, baseline autoantibody value, induction
regimen (CYC vs MMF), and race (Black African Ancestry vs other)
RESULTSOther endpoints: percentage change from baseline
in biomarkers at Week 104
AE, adverse event; SAE, serious adverse event
Safety eventPlacebo
(n=224)
Belimumab
10 mg/kg IV
(n=224)
≥1 AE, n (%) 211 (94.2) 214 (95.5)
≥1 treatment-related AE, n (%) 119 (53.1) 123 (54.9)
≥1 SAE, n (%) 67 (29.9) 58 (25.9)
≥1 treatment-related SAE, n (%) 25 (11.2) 23 (10.3)
AE resulting in study drug discontinuation, n (%) 29 (12.9) 29 (12.9)
All fatal SAEs, n (%) 5 (2.2) 6 (2.7)
On-treatment, n (%) 3 (1.3) 4 (1.8)
Post-treatment, n (%) 2 (0.9) 2 (0.9)
RESULTSOther endpoints: Safety
CONCLUSIONS
In BLISS-LN, the largest LN study to date,
belimumab plus standard therapy
compared with standard therapy alone,
improved renal outcomes, overall SLE
disease activity, biomarker levels, and
reduced steroid use, while maintaining
an acceptable safety profile
Acknowledgments
The authors would like to thank the
patients and their families, the
investigators and their research staff,
and GSK staff who were involved in
these studies
The NEW ENGLAND JOURNAL of MEDICINE
ORIGINAL ARTICLE
Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis
Richard Furie, M.D., Brad H. Rovin, M.D., Frederic Houssiau, M.D., Ph.D.,
Ana Malvar, M.D., Y.K. Onno Teng, M.D., Ph.D., Gabriel Contreras, M.D., M.P.H.,
Zahir Amoura, M.D., Xueqing Yu, M.D., Chi-Chiu Mok, M.D., Mittermayer B. Santiago, M.D., Amit Saxena, M.D.,
Yulia Green, M.D., Beulah Ji, M.D., Christi Kleoudis, M.P.H., Susan W. Burriss, M.S.,
Carly Barnett, M.P.H., and David A. Roth, M.D.
New England Journal of Medicine. 2020;383(12):1117-28. doi:10.1056/NEJMoa2001180
This study (GSK Study BEL114054; NCT01639339) was funded by GSK.
Editorial support for oral presentation development was provided by
Olga Conn, PhD, of Fishawack Indicia Ltd, UK, and was funded by GSK.
RESULTS
Placebo
n=223
Belimumab
10 mg/kg IV
n=223
SLEDAI-S2K at Week 104
n 128 138
Mean (SD) −6.4 (5.5) −7.9 (5.1)
Median (IQR) −6.0 (−9.5, −2.0) −6.5 (−12.0, −4.0)
Treatment difference vs
placebo−1.5
95% CI −2.4, −0.6
p-value 0.0009
Renal vs Non-Renal SLEDAI-S2K at Week 104
Placebo
n=223
Belimumab
10 mg/kg IV
n=223
SLEDAI-S2K excluding renal items at Week 104
n 128 138
Mean (SD) −2.1 (3.3) −2.3 (3.2)
Median (IQR) −2.0 (−4.0, 0.0) −2.0 (−4.0, 0.0)
Treatment difference vs
placebo−0.4
95% CI −0.8, −0.0
p-value 0.0436
Data presented are on-treatment and therefore approximately 60% of patients are included in these analyses
The SLEDAI-S2K treatment differences are adjusted estimates from an ANCOVA model with covariates of baseline SLEDAI-S2K score (excluding renal items where appropriate),
induction regimen (CYC vs MMF), and race (Black African Ancestry vs other)