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)