BLISS-52 - The British Society for Rheumatology

Belimumab, a BLyS-Specific Inhibitor, 

Reduced Disease Activity, Flares and 

Prednisone Use in Patients with 

Active SLE: 

Efficacy and Safety Results from the 

Phase 3 BLISS-52 Study 

D. D’Cruz, C. Tanasescu, E. Nasonov, S. Navarra, R. Guzman, A. 

Gallacher, R.A. Levy, E.K. Li, M. Thomas, R. Jimenez, M. Leon, S. Hall, 

J.L. Lan, H.-Y. Kim, L. Pineda, Z.J. Zhong, W. Freimuth, 

and the BLISS-52 Study Group 

British Society of Rheumatology Meeting April 21, 2010

Disclosures 

This study was sponsored by Human Genome Sciences & GlaxoSmithKline 

David D’Cruz BLISS-76 Investigator Consulting fees – Aspreva, Roche, Bristol-Myers-Squibb 

Coman Tanasescu 

BLISS-52 Investigator 

Eugeny Nasonov BLISS-52 Investigator Speakers bureau – Roche, Schering-Plough, Wyeth 

Sandra Navarra BLISS-52 Investigator Research grants – Human Genome Sciences 

Renato Guzman 


Alberto Gallacher BLISS-52 Investigator Consulting fees – Human Genome Sciences 

Roger A Levy BLISS-52 Investigator Speakers bureau – Human Genome Sciences and GlaxoSmithKline 

Edmund Li 


Mathew Thomas BLISS-52 Investigator Other – Human Genome Sciences 

Renato Jimenez 

Gustavo Leon 

Stephen Hall 

Joung-Liang Lan 

Ho Youn Kim 

Lilia Pineda 

Z. John Zhong 

William Freimuth 






Stock – Human Genome Sciences 

Employment – Human Genome Sciences 

2

Belimumab Inhibits BLyS 

• Fully human IgG1λ 

monoclonal antibody 

• Selectively targets and 

inhibits the biological activity 

of soluble BLyS 

(B Lymphocyte Stimulator) 

Autoimmune Disease 

B-cell survival 

Belimumab Binds Soluble BLyS 

• Inhibition of BLyS 

results in apoptosis of 

autoreactive B-cells 

BLyS 

B-cell apoptosis 

TACI, BCMA or BAFF-R 

Belimumab 

Modified from Do RKG et al. J Exp Med. 2000;192:953-964; Ammana et al. J Immunol. 2003;170:4593-4600. 

3

BLISS-52: Study Design 

• Multicentre, randomized, double blind, placebo 

controlled trial 

• 90 centres/13 countries: Asia-Pacific, Latin America, 

and Eastern Europe 

• Dosing: d 0, 14, 28, then every 28 d through wk 48, 

with final evaluation at wk 52 

• Patients stratified at screening by: 

- SELENA-SLEDAI (6–9 vs ≥10), 

- Proteinuria (≤ vs >2 g/24 h) and 

- Race (African descent or indigenous American vs 

other) 

4

BLISS-52: Study Design 

•865 patients with active SLE 

• SELENA-SLEDAI ≥6 

•Seropositive (ANA ≥1:80 and/or 

anti-dsDNA ≥30 IU/mL) 

•Stable standard of care therapy >30 d 

•No active severe lupus nephritis or 

CNS lupus 

•Progressive restrictions on concurrent 

medications (wk 16, 24, and 44) 

R 

A 

N 

D 

O 

M 

I 

Z 

E 

Randomized 

Placebo 

+ Standard of Care 

Belimumab 1 mg/kg 


Belimumab 10 mg/kg 


5

BLISS-52: Completion Status 

Placebo 

N=287 

Belimumab 

1 mg/kg 

N=288 

Belimumab 

10 mg/kg 

N=290 

Completed 78.7% 83.3% 83.1% 

Withdrawn 21.3% 16.7% 16.9% 

Adverse Event 6.6% 5.6% 5.2% 

Lack of Efficacy 5.6% 4.2% 4.1% 

Subject Request 2.4% 2.1% 1.0% 

Pregnancy 1.4% 1.0% 2.8% 

Lost to Follow-up 1.4% 2.1% 1.0% 

Protocol Violation 2.4% 0.7% 1.0% 

Investigator Decision 1.0% 0.7% 1.0% 

Lack of Compliance 0.3% 0.3% 0.3% 

Other 0 0 0.3% 

6

BLISS-52: Baseline Characteristics 

Region, % 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

Latin America 50.5 49.7 48.3 

Asia 35.9 36.8 39.7 

Eastern Europe 11.5 11.8 10.7 

Australia 2.1 1.7 1.4 

Mean age ± SD 36.2 ± 11.8 35.0 ± 10.6 35.4 ± 10.8 

Sex, % 

Female 94.1 94.1 96.6 

Male 5.9 5.9 3.4 

Race, % 

Asian 36.6 36.8 40.0 

Indigenous American 31.0 34.0 31.7 

White/Caucasian 28.6 26.4 24.5 

Black/African-American 3.8 2.8 3.8 

7

BLISS-52: Baseline SLE Characteristics* 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

SLE duration, years 5.9 ± 6.2 5.0 ± 4.6 5.0 ± 5.1 

SELENA-SLEDAI score 9.7 ± 3.6 9.5 ± 3.8 9.9 ± 3.9 

PGA (scale 0–3) 1.4 ± 0.5 1.4 ± 0.5 1.4 ± 0.4 

BILAG 1A or 2B, % 57.8 56.9 59.3 

Proteinuria, g/24 h 0.6 ± 1.1 0.6 ± 1.1 0.5 ± 0.9 

ANA ≥1:80, % 92.7 95.1 95.5 

Anti-dsDNA ≥30 IU/mL, % 71.4 76.7 75.2 

Low C3 (

Baseline BILAG Organ Domains: A or B 

BILAG Organ Domain 

A 

BLISS-52 

N=865 

B 

MUCOCUTANEOUS 31 (3.6%) 482 (55.7%) 

MUSCULOSKELETAL 91 (10.5%) 366 (42.3%) 

HEMATOLOGY 6 (0.7%) 155 (17.9%) 

RENAL 8 (0.9%) 107 (12.4%) 

VASCULITIS 30 (3.5%) 50 (5.8%) 

GENERAL 6 (0.7%) 71 (8.2%) 

CV & RESPIRATORY 6 (1.0%) 18 (2.1%) 

NEUROLOGICAL 0 1 (0.1%) 

9

BLISS-52: Primary Efficacy Endpoint 

(Patient Response Rate) 

SLE Responder Index at Week 52 

≥4-point improvement in SELENA SLEDAI score 

AND 

No new BILAG 1A/2B flares 

AND 

No worsening in PGA (

BLISS-52: Primary Endpoint and 

Components of SLE Responder Index 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

Primary endpoint 

SRI at wk 52, % 43.6 

Components of SRI 

51.4 

p =.01 

57.6 

p

BLISS-52 Response Rate Over 52 Weeks 

12

BLISS-52: Secondary Efficacy Endpoints 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n= 88) 

Belimumab 

10 mg/kg 

(n=290) 

Prednisone Sparing: % patients reduced 

from >7.5 mg/d by ≥ 25% to ≤7.5 mg/d during 

wk 40–52† 

Prednisone Use: % patients increased from 

≤7.5 mg/d at baseline to >7.5 mg/d at wk 52†* 

(n=192) 

12.0 

(n=95) 

35.8 

(n=204) 

20.6 

P=.025 

(n=84) 

29.8 

P=.56 

(n=204) 

18.6 

P=.05 

(n=86) 

19.8 

P=.02 

PGA: mean absolute Δ at wk 24 ± SE -0.39 ± 0.03 

SF-36 PCS: mean absolute Δ at wk 24 ± SE 3.6 ± 0.4 

SF-36 PCS: mean absolute Δ at wk 52 ± SE* 3.0 ± 0.5 

-0.44 ± 0.03 

P=.27 

3.7 ± 0.4 

P=.81 

4.2 ± 0.5 

P=.03 

-0.54 ± 0.03 

P

BLISS-52: More Belimumab Than Placebo 

Patients Reduced Steroids By ≥50% 

14

BLISS-52: Belimumab Improved PGA 

Over 52 Weeks 

PGA, physician’s global assessment. 

15

BLISS-52: Belimumab Reduced 

FACIT-Fatigue* Over 52 Weeks 

*figure shows reverse scoring, so that lower values represent less fatigue 

16

BLISS-52: Belimumab Significantly 

Reduced SLE Flares (SFI) 

1 mg/kg 

P=0.0022 

10 mg/kg 

P=0.0034 

Flare Rate: 

10 mg/kg: 70.7% 

1 mg/kg: 70.5% 

Placebo: 80.1% 

Median Time to Flare 

10 mg/kg: 119 days 

1 mg/kg: 126 days 

Placebo: 84 days 

Hazard Ratio: 

10 mg/kg: 0.76 

1 mg/kg: 0.75 

P values were from proportional hazard model adjusted for baseline stratification factors. 

17


Reduced Severe SLE Flares (SFI) 

Flare Rate: 

10 mg/kg: 13.8% 

1 mg/kg: 17.7% 


Hazard Ratio: 

10 mg/kg: 0.57 

1 mg/kg: 0.76 


18


Reduced BILAG 1A/2B SLE Flares 

1 mg/kg 

P=0.4804 

10 mg/kg 

P=0.0016 

Flare Rate: 

10 mg/kg: 18.6% 

1 mg/kg: 26.0% 


Hazard Ratio: 

10 mg/kg: 0.58 

1 mg/kg: 0.87 


19

BLISS-52: Summary of Adverse Events 

Event, % 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

All AEs 91.6 91.7 91.7 

Serious AEs 12.5 16.3 14.1 

Severe AEs 11.8 12.5 11.4 

Serious and/or severe AEs 16.7 19.8 17.2 

Dose interruptions 4.9 8.0 6.2 

Discontinuations 6.6 5.6 5.2 

Deaths 1.0 0.7 1.4 

20

BLISS-52: 

Most Frequent Adverse Events (≥10%) 

Adverse Event, % 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

Headache 26.5 20.1 22.8 

Upper respiratory tract infection 16.4 14.2 12.4 

Arthralgia 11.8 7.3 11.4 

Urinary tract infection 8.7 10.4 9.0 

Influenza 8.7 7.6 11.4 

Diarrhea 7.0 9.7 10.3 

Nasopharyngitis 8.0 10.4 6.9 

Hypertension 10.5 8.7 5.9 

Nausea 10.8 5.6 7.9 

21

BLISS-52: Protocol-Specified 

Adverse Events of Special Interest 

Placebo 

(n=287) 

Belimumab 

1 mg/kg 

(n=288) 

Belimumab 

10 mg/kg 

(n=290) 

All infections, % 63.8 68.4 66.9 

Serious Infections 5.9 7.6 4.5 

Severe Infections 3.1 3.5 2.4 

Discontinuation 0.7 0.3 1.0 

Infusion reaction, % 17.1 16.3 16.6 

Hypersensitivity 0.3 1.4 0.7 

Malignancy 0 0 0 

22

• Belimumab: 

BLISS-52: Summary 

BLISS-52 Trial Met its Primary Efficacy Endpoint 

– Reduced SLE disease activity 

– Reduced overall and severe SLE flare rates 

• Delayed time-to-first SLE flare 

– Demonstrated steroid-sparing effect 

– Improved PGA by week 4 

– Reduced fatigue as early as wk 8 

– Improved HRQoL as measured by SF-36 PCS at wk 52 

– Was generally well tolerated in combination with standard of 

care SLE therapy 

– Overall rates of AEs, serious AEs, and infections were 

comparable to placebo (standard of care alone) 

23

Acknowledgments 

Thanks to the patients and their families for participating in this trial. 

BLISS-52 Study Group 

Acevedo, Eduardo 

Alamo, Jorge 

Amante, Eric Jason 

Anaya, Juan 

Antigua, Joseph 

Bae, Sang Cheol 

Bichile, Lata 

Bojinca, Mihai 

Bolosiu, Horatiu 

Branco Pinto Duarte, Angela 

Cabello, Eduardo 

Cappuccio, Ana 

Capraru, Monica 

Chahade, William 

Chalem, Philippe 

Chen, Ying-Chou 

Cho, Chui-Soo 

Chung, Won Tae 

Das, Siddharth 

Duhau, Javier 

Ershova, Olga 

Gallacher, Alberto 

Garcia, Mercedes 

Guzman, Renato 

Hall, Stephen 

Hofman, Julio 

Huang, Chung-Ming 

Ilivanova, Elena 

Ionescu, Ruxandra 

Jaller, Juan 

Jan Wu, Yeong-Jian 

Jimenez, Renato 

Kang, Young Mo 

Keiserman, Mauro 

Kim, Ho-Youn 

Kim, Hyoun Ah 

Kim, Sung-Il 

Lai, Ning-Sheng 

Lan, Joung-Liang 

Latorre, Luis 

Lavras Costallat, Lilian 

Lee, Ka-Wing 

Leon, Manuel 

Levy, Roger 

Li, Kwok-Ming, Edumund 

Lichauco, Juan Javier 

Littlejohn, Geoff 

Lu, Ling-Ying 

Luo, Shue-Fen 

Machado, Daniel 

Massardo, Maria 

Matsievskaya, Galina 

Mazurov, Vadim 

Mok, Chi-Chiu 

Molina, Jose 

Munoz, Yezid 

Nasonov, Eugeny 

Navarra, Sandra 

Otero, William 

Pal, Sarvajeet 

Park, Won 

Pastor, Cesar 

Perez, Emmanuel 

Radominski, Sebastiao 

Radrigan, Francisco 

Rajasekhar, Liza 

Ramiterre, Edgar 

Rillo, Oscar 

Roimicher, Luis 

Saaibi, Diego 

Santiago, Mittermayer 

Sarano, Judith 

Scali, Juan 

Scheinberg, Morton 

Scoton, Antonio 

Shilkina, Nataliya 

Shim, Seung Cheol 

Smith, Malcolm 

Song, Yeong-Wook 

Spindler, Alberto 

Tanasescu, Coman 

Tarey, Subhash 

Tate, Guillermo 

Taylor, Andrew 

Thomas, Matthew 

Tsai, Shih Tzu 

Tsai, Wen-Chan 

Veeravalli, Sarath 

Velez, Patricia 

Wei, Cheng-Chung 

Ximenes, Antonio 

Yu, Chia-Li 

24

Deaths 

Placebo 

1 mg/kg 

10 mg/kg 

N=287 

N=288 

N=290 

3 (1.0%) 2 (0.7%) 4 (1.4%) 

CL002-001, 44/F, Myocardial 

infarction, 

PR, Day 328 

CO001-016, 24/F, Cardiac 

arrest, Gastroenteritis 

bacterial, Vasculitis 

gastrointestinal, Dehydration, 

Preceded by sepsis 

PNR, Day 70 

IN005-015, 18/F, Death 

(unknown), 

NR, Day 225 

AR005-006, 32/F, Sepsis, 

Cellulitis, Arterial 

hypotension 

PNR, Day 13 

RU005-010, 58/F, Ischemic 

stroke, Osteochondrosis, 

NR, Day 345 

CL001-024, 52/F, Bacterial 

sepsis, Herpes zoster, 

Hemolytic anemia 

PR, Day 331 

IN004-002, 19/F, Diarrhea 

infectious, Cutaneous 

vasculitis, Hypochromic 

anemia, 

PR, Day 336 

KR008-001, 22/F, Completed 

suicide, 

NR, Day 272 

PE002-001, 33/F, Respiratory 

failure, 

PNR, Day 128 

CL001-007 (1 mg/kg) withdrew due to AE after Day 112 visit and died at Day 216 

(respiratory arrest/nephrotic syndrome/renal failure) 

25 

CONFIDENTIAL July 2009

BLISS-52 - The British Society for Rheumatology

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