Clinical evidence of the role of belimumab in the treatment of systemic lupus erythematosus

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1 Cliical evidece of the role of belimumab i the treatmet of systemic lupus erythematosus Cli. Ivest. (2011) 1(11), Belimumab is a huma moocloal atibody that bids soluble B lymphocyte stimulator, thus prevetig the bidig to its receptors o B cells. B lymphocyte stimulator has prove to be a key factor i the selectio ad survival of these cells. Two Phase III trials have demostrated that belimumab, i combiatio with stadard therapy, was geerally well tolerated ad sigificatly reduced disease activity ad flare rates i patiets with active systemic lupus erythematosus (SLE), thus allowig its approval by the Europea ad America regulatory agecies as the first biological therapy for SLE. The aim of this article is to review the evidece-based cliical effectiveess of belimumab i the treatmet of SLE patiets. Ricard Cervera 1 & Gerard Espiosa1 Departmet of Autoimmue Diseases, Hospital Clíic, Villarroel 170, 08036, Barceloa, Cataloia, Spai Author for correspodece: Tel.: Fax: rcervera@cliic.ub.es 1 Keywords: B-lymphocyte stimulator belimumab biological therapy systemic lupus erythematosus Systemic lupus erythematosus (SLE) is the most represetative of the autoimmue diseases. Oe of its mai pathogeic mechaisms is the productio of autoatibodies leadig to the geeratio of immue complexes that, fially, produce orga damage [1]. B cells play a cetral role i the pathogeesis of SLE through atibody-depedet ad atibody-idepedet fuctios [2]. Therefore, B cell-targeted therapies may represet a valuable treatmet of patiets with SLE. The primary ratioale of these therapies would be the elimiatio of autoatibodies. Oe of the mai strategies for B-cell targetig is represeted by the ihibitio of factors ivolved i the survival or differetiatio of B cells. B lymphocyte stimulator (BLyS), also kow as B cell activatig factor, has prove to be a key factor i the selectio ad survival of aive autoreactive B cells [3]. BLyS is a type II trasmembrae protei of the TNF family that exists i both membrae-boud ad soluble forms ad is expressed by a wide variety of cell types such as moocytes, macrophages, ad moocyte-derived dedritic cells. Its gee expressio ad secretio are regulated by iflammatory cytokies, i particular iterfero-g ad, to a lesser extet, IL-10 ad IL-2. BLyS ca bid to three receptors: BLyS receptor 3 (BR3 or B cell-activatig factor-r), trasmembrae activator-1 ad calcium modulator ad cyclophili ligad-iteractor, ad B-cell maturatio atige. Via BR3, BLyS atagoizes apoptosis of trasitioal immature B cells, thus allowig differetiatio ad etrace of cells ito the mature, preimmue B-cell populatios [4]. Therefore, if this biologic process is impaired, it could allow the survival of aive autoreactive B cells istead of their elimiatio by apoptosis. Belimumab is a huma moocloal atibody (IgG1) that bids soluble BLyS ad ihibits its bidig to trasmembrae activator-1 ad calcium modulator ad cyclophili ligad-iteractor, B-cell maturatio atige, ad BR3. The i vitro ad i vivo pharmacological properties of belimumab suggest that it bids soluble BLyS ad ihibits stimulatio of B-cell proliferatio ad atibody secretio iduced by BLyS [5]. Coversely, belimumab does ot affect IgG plasma cells; therefore, there is ot much effect o autoatibodies. The aim of this review article is to aalyze /CLI Future Sciece Ltd ISSN

2 Cervera & Espiosa the evidece-based iformatio about its cliical usefuless i the treatmet of patiets with SLE. BLyS i SLE patiets Several authors have studied the role of BLyS i SLE patiets [6 10]. Cheema et al. aalyzed the relatioship betwee serum levels of BLyS ad serum levels of immuoglobulis ad/or autoatibody titers i 185 patiets with various systemic autoimmue diseases (95 with SLE ad 67 with rheumatoid arthritis) [6]. Serum BLyS levels were elevated i 21% of patiets ad correlated sigificatly with serum IgG levels. I additio, they correlated positively with ati-dsdna atibody titers i SLE patiets ad i those with rheumatoid artritis with rheumatoid factor titers. Collis et al. studied 60 patiets with SLE, 30 patiets with rheumatoid arthritis ad 30 healthy idividuals. BLyS protei, full-legth BLyS mrna, ad DBLyS mrna levels were greater i SLE patiets tha i rheumatoid arthritis patiets or ormal cotrol idividuals [7]. Full-legth BLyS ad DBLyS mrna levels correlated sigificatly with BLyS protei levels i the SLE cohort. Furthermore, BLyS mrna levels were more closely associated with serum immuoglobuli levels ad SLE Disease Activity Idex (SLEDAI) scores tha were BLyS protei levels. Moreover, chages i SLEDAI scores were more closely associated with chages i BLyS mrna levels tha with chages i BLyS protei levels amog the 37 SLE patiets from whom repeat blood samples were obtaied. Hog et al. studied 56 patiets with pediatric SLE over a 6 moth iterval. I this cohort, plasma BLyS protei ad blood leukocyte BLyS mrna levels were each sigificatly elevated, ad plasma BLyS protei levels, but ot blood leukocyte BLyS mrna levels, were correlated with disease activity [8]. The BLyS expressio profiles remaied stable at 6 moths. Stohl et al. aalyzed 68 patiets with SLE i a logitudial study for a media of 369 days ad disclosed that serum levels of BLyS correlated with disease activity [9]. I total, 50 ad 61% of SLE patiets preseted with persistetly or itermittetly elevated serum BLyS ad blood BLyS mrna pheotypes, respectively. I additio, surface BLyS expressio by SLE peripheral blood moouclear cells was also ofte icreased. Iterestigly, treatmet of patiets who had elevated serum BLyS levels with itesive courses of high-dose corticosteroids resulted i marked reductios i serum BLyS levels, ad taperig of the corticosteroid dosage ofte resulted i icreases i serum BLyS levels. Of ote, serum BLyS levels geerally correlated with ati-dsdna titers. Petri et al. desiged aother logitudial study with a larger umber of patiets followed-up durig a loger period of time [10]. These ivestigators tried to correlate plasma BLyS levels, immuosuppressive therapy ad other cliical parameters with disease activity i 245 patiets with SLE evaluated prospectively over a 2-year period. Disease activity was evaluated with the Safety of Estroges i Lupus Erythematosus Natioal Assessmet (SELENA) versio of SLEDAI. Plasma BLyS levels were associated with ati-dsdna titers ad SELENA-SLEDAI scores. This correlatio was edorsed i multivariate aa lysis i that a greater icrease i the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit ad with a greater icrease i the BLyS level from the previous visit. Belimumab i aimal models Precliical data demostrated that belimumab ihibited BLyS-iduced proliferatio of B cells i vitro [11]. Later o, i studies o cyomolgus mokeys treated with belimumab, reductios as great as 75% were observed i the umber of lymphoid tissue ad peripheral blood CD20 + B cells ad CD21+ plasmacytoid cells that recovered to ormal levels withi 3 5 moths after belimumab discotiuatio. I this study, itraveous doses of up to 50 mg/kg delivered every 2 weeks over 6 moths were well tolerated by the mokeys [12]. Belimumab i SLE patiets The evidece of the cliical effectiveess ad safety of belimumab i huma SLE patiets comes from four cliical studies [13 19]. Belimumab i a Phase I study I a Phase I dose-escalatio study performed i 70 patiets with SLE, belimumab did ot show related serious adverse evets [13]. This study radomized patiets with mild-to-moderate SLE to receive placebo ( = 13) or belimumab ( = 57) at four differet doses (1, 4, 10 ad 20 mg/kg) as a sigle ifusio ( = 34) or two ifusios ( = 36), 21 days apart. Patiets were followed for days to assess adverse evets, peripheral blood B cell couts, serology ad SLE disease activity. There were o differeces i the icideces of adverse evets ad laboratory abormalities betwee belimumab ad placebo groups. Overall, adverse evets were reported i 12 (92%) patiets treated with placebo ad 55 (97%) patiets treated with belimumab. Of ote, there was o icrease i the icidece of ifectios i the belimumab groups (37% for all patiets treated with active aget vs 62% for placebo). The most commo adverse evet i patiets treated with belimumab were arthralgia (26%) followed by headache (21%), rash (21%), diarrhea (18%) ad ausea (18%). The frequecy of adverse evets did ot

3 Cliical evidece of the role of belimumab i the treatmet of SLE chage with icreasig doses of belimumab. Six patiets (oe placebo ad five belimumab) developed eight serious adverse evets, oe of which were cosidered related to the study aget. Sigificat reductios i media percetages of CD20 + B cells were observed i patiets treated with a sigle dose of belimumab versus placebo (day 42: p = ad day 84: p = ) ad i patiets treated with two doses of belimumab versus placebo (day 105: p = ). I the same sese, reductio of ati-dsdna atibody titers was demostrated. Specifically, a subset aa lysis of 31 belimumab-treated patiets with ati-dsdna atibody levels 10 IU/ml or greater at baselie revealed sigificat chages from 28 to 56 days after the last dose across all cohorts (p < 0.05). However, SLE disease activity did ot chage after oe or two doses of belimumab. Overall, there was a tred toward reduced scores of SELENA-SLEDAI i both belimumab ad placebo groups but it should be oted that a Phase I study is ot powered to detect cliical efficacy. Belimumab i a Phase II study A subsequet Phase II dose-ragig trial was performed i 449 SLE patiets [14]. I this study, patiets were radomized to receive 1, 4 or 10 mg/kg of belimumab or placebo o days 0, 14, 28, ad the every 28 days for 52 weeks. Belimumab or placebo was added to stadard therapy. Active disease was defied by a SELENASLEDAI score of >4 at screeig. I additio, patiets had to receive a stable regime of treatmet icludig predisoe, atimalarials ad immuosuppressive agets for at least 60 days before the first dose. Patiets with active lupus ephritis or C ivolvemet were excluded. Belimumab was well tolerated, but the study failed to meet its primary ed poits, the chage i the SELENA-SLEDAI score from baselie to weeks 24 ad 52 ad the time to first mild/moderate or severe flare as defied by the SLE flare idex (SFI) durig 21 weeks. I this sese, the authors did ot observe dose-depedet chages i the SELENA-SLEDAI score. The percetage of patiets who experieced a SLE flare was similar i all groups (icludig placebo). However, i a subgroup aa lysis of patiets with serologically active disease at baselie, defied by atiuclear atibody (ANA) titer >1:80 ad/or ati-dsdna >30 IU/ml (72% of the total group of radomized patiets), belimumab did lead to a sigificatly better respose over placebo at week 52. Specifically, whe compared with placebo group, they had sigificatly reductios i SELENA-SLEDAI scores from baselie (-28.8% vs -14.2%; p = ), improvemets i physicia s global assessmet (PGA) (-32.7 vs -10.7%; p = ) ad i Short Form 36 Physical Compoet Summary (SF-36 PCS; 3.0-poit icrease vs 1.2-poit icrease; p = 0.041). Regardig the biologic activity of belimumab, the authors foud a sigificat reductio of aive (-70.8%), activated (-70.4%) ad plasmacytoid B cells (-62.5%) at week 52. Coversely, the media value of memory B cells was icreased by 88% by day 28 ad gradually retured to baselie at week 52. Belimumab treatmet led to a sigificat reductio i immuoglobuli levels (10% for IgG, 14% for IgA, 29% for IgM ad 34% for IgE) at week 52. Reductios were detected at week 8 i all immuoglobuli types. The reductio of IgG ati-dsdna atibody levels was more proouced i the belimumab group (29.4 vs 8.6%; p = ). Complemet levels rose i patiets with baselie low levels of complemet. The rates of adverse evets ad serious adverse evets were similar i the belimumab ad placebo groups. Oly urticaria was more frequet i patiets treated with belimumab (4 vs 0%). The icidece of ifectios ad severe ifectios was similar amog two groups. The preservatio of log-lived plasma cells ad memory B cells could have cotributed to this low rate of ifectios. This Phase II trial was later cotiued as a opelabel extesio study of which 4 year safety ad efficacy data for 237 patiets have bee reported [17]. I this study, at week 56, patiets who had bee treated with placebo were switched to belimumab 10 mg/kg ad those patiets treated with belimumab could remai o their curret dose or receive 10 mg/kg. At week 80, all patiets received belimumab 10 mg/kg i a cotiuatio trial over 4 years. The results of this study were aalyzed with a ew disease activity idex: the SLE respoder idex (SRI) [18]. This idex was developed accordig to the recommedatios of the US FDA, the Outcome Measures i Rheumatology Cliical Trials (OMERACT) ad the Europea League Agaist Rheumatism (EULAR) for the developmet of drugs for the treatmet of SLE that covered the use of disease activity idex, flares ad orga-specific outcomes. Specifcally, SRI was defied by a >4-poit reductio i SELENA-SLEDAI score, o ew British Isles Lupus Assessmet Group (BILAG) A or o more tha 1 ew BILAG B domai score, ad o deterioratio from baselie i the PGA assessmet by >0.3 poits. The icidece rate of adverse evets i the extesio study decreased (194 per 100 patiet/years to 173 per 100 patiet/years) over 4 years. I the subset of serologically active SLE patiets, at week 52, SRI rate was 46% i those treated with belimumab versus 29% i those treated with placebo (p < ). SRI rate icreased to 55% by week 76 ad was maitaied Cli. Ivest. (2011) 1(11) 1557

4 Cervera & Espiosa through week 208 (i origial belimumab patiets). Takig ito accout placebo ad belimumab patiets after 1 year, the frequecy of ew BILAG A or 2B flares declied to 5% at 4 years ad the frequecy of flares by SFI declied to 16% at 4 years. This cotiuatio trial demostrated that belimumab added to stadard therapy was geerally well tolerated over 4 years ad, iterestigly, serologically active SLE patiets treated with belimumab showed sustaied improvemet i disease activity ad declie i BILAG ad SFI flares over time. However, it should be oted that cohort studies such as this extesio trial have some limitatios: for istace, those patiets who do badly are likely to be icluded amog the dropouts ad they would ot be i the study at the ed of this time, so data are biased towards those who stay i cohort, as these are likely to be the best respoders. It is uclear whether patiets are doig better over time or whether those doig better all alog are the oes still stayig i the study. The importat fidig, however, could be that those who do cotiue to be treated seem to do quite well. Belimumab i two Phase III studies Fially, belimumab has bee evaluated i two large radomized, double-blid, placebo-cotrolled, multiceter Phase III trials, BLISS-52 [15] ad BLISS-76 [16], that icluded 867 ad 819 seropositive (ANA- ad/or ati-dsdna atibodies) patiets, respectively. All patiets had active disease defied as SELENA-SLEDAI score 6 ad were o stable therapy for at least 30 days before the first dose. Patiets with active lupus ephritis or C ivolvemet were also excluded i these two trials. The desig of the 2 trials was the same, but BLISS-52 was a 52 week study that erolled patiets from Cetral ad Easter Europe, Lati America ad Asia-Pacific regio, while BLISS76 was a 76 week study that erolled patiets from North America ad Wester ad Cetral Europe. Icluded patiets were radomized to receive 1 mg/ kg belimumab, 10 mg/kg belimumab, or placebo. Belimumab or placebo was admiistered itraveously o days 0, 14, 28, ad the every 28 days thereafter for the 48 weeks (BLISS-52) ad 72 weeks (BLISS-76), respectively. All patiets received stadard therapy (as prescribed by their physicias i charge accordig to their experiece) i additio to the study medicatio. The primary efficacy ed poit of the two trials was the SRI at week 52 ad other efficacy aalyses icluded the SELENA-SLEDAI, BILAG ad SFI scores. Regardig results of the BLISS-52 study, SRI respose rates were higher i the 1 mg/kg (51.4%; p = 0.013) ad i the 10 mg/kg belimumab dose group (57.6%; p = ) tha i those patiets treated with placebo (43.6%) (Table 1). I additio, sigificat improvemet was foud i at least oe of the belimumab treatmet groups for the other measures of efficacy (SELENASLEDAI 4-poit reductio, improvemet or o >0.3 poit worseig i PGA, reductio i predisoe use, ad reductio i flare rates by SFI ad ew BILAG 1A or 2B ad icrease i time to first flare). Besides, the authors evaluated the impact of belimumab o physical fuctioig, fatigue ad other health-related quality of life measures of SLE patiets. I this sese, Table 1. Mai cliical results of the radomized, multiceter Phase III trial BLISS-52. Parameter Placebo ( = 287) Belimumab 1 mg/kg ( = 288) Belimumab p-value 10 mg/kg ( = 290) 125 (44%) 148 (51%) 167 (58%) (46%) 153 (53%) 169 (58%) Primary ed poit SRI at week 52 Secodary ed poits SS 4-poit reductio No PGA >0.3 poit worseig 199 (69%) 227 (79%) 231 (80%) No ew BILAG 1A or 2B scores 210 (73%) 226 (78%) 236 (81%) (13%) 47 (16%) 41 (14%) Adverse evets Serious adverse evets Ifectios 183 (64%) 197 (68%) 194 (67%) Serious ifectios 17 (6%) 22 (8%) 13 (4%) Ifusio reactios 49 (17%) 47 (16%) 48 (17%) p-values refer to differece betwee placebo ad belimumab 10 mg/day treatmet groups. There was o statistical differece betwee the two arms of belimumab treatmet. BILAG: British Isles Lupus Assessmet Group; PGA: Physicia s global assessmet; SRI: SLE respoder INDEX; SS: SELENA-SLEDAI. Data take from [15]

5 Cliical evidece of the role of belimumab i the treatmet of SLE Table 2. Mai cliical results of the radomized, multiceter Phase III trial BLISS-76. Parameter Placebo ( = 275) Belimumab 1 mg/ Belimumab 10 mg/kg p-value kg ( = 271) ( = 273) 92 (33%) 110 (41%) 118 (43%) < (35%) 116 (43%) 127 (46%) <0.01 Primary ed poit SRI at week 52 Secodary ed poits SS 4-poit reductio No PGA >0.3 poit worseig 173 (63%) 197 (73%) 190 (70%) No ew BILAG 1A or 2B scores 180 (65%) 203 (75%) 189 (69%) 54 (20%) 63 (23%) 61 (22%) Adverse evets Serious adverse evets Ifectios 190 (69%) 202 (74%) 202 (74%) Serious ifectios 16 (6%) 19 (7%) 20 (7%) Ifusio reactios 27 (10%) 42 (15%) 37 (14%) p-values refer to differece betwee placebo ad belimumab 10 mg/day treatmet groups. There was o statistical differece betwee the two arms of belimumab treatmet. BILAG: British Isles Lupus Assessmet Group; PGA: Physicia s global assessmet; SRI: SLE respoder idex; SS: SELENA-SLEDAI. Data take from [16]. mea improvemets from baselie i SF-36 physical fuctioig, bodily pai ad Physical Summary Scores were sigificatly greater with belimumab (1 ad 10 mg/kg) versus placebo at week 52. Patiets i the 10 mg/kg belimumab treatmet group demostrated greater mea improvemet i Fuctioal Assessmet of Chroic Illess Therapy (FACIT) fatigue versus placebo patiets by week 8 (3.9 ± 0.5 poits vs 1.8 ± 0.5; p = ), ad further improved, with sigificat differeces observed at week 36 (4.4 ± 0.6 vs 2.7 ± 0.6; p < 0.05) ad week 52 (4.8 ± 0.6 vs 2.1 ± 0.6; p < 0.05) [19]. I BLISS-76, SRI respose rates at week 52 were 34% o placebo, 41% o 1 mg/kg (p = 0.104) ad 43% o 10 mg/kg belimumab (p = 0.021) (Table 2). However, there were o differeces i SRI respose rates betwee the three groups at week 76 (32.4% for patiets o placebo vs 39.1% for those o belimumab 1 mg/kg [p = 0.11] ad 38.5% for those o belimumab 10 mg/kg [p = 0.13]). Furthermore, multiple ladmark SRI aa lysis also did ot show statistically sigificat differece earlier i the trial. I additio, BLISS-76 showed o beefit for belimumab i North America patiets ad suggested the possibility of poorer performace of belimumab amog patiets of Africa acestry. Iterestigly, belimumab improved respose rates usig higher thresholds for SELENA-SLEDAI improvemet (SRI 5 7 defied as improvemet of SELENASLEDAI score >5 7 poits) at week 52 ad 76, with eve greater differetiatio from placebo, reduced SELENA-SLEDAI scores at week 52 ad week 76, ad reduced risk of severe flare (26.5, 18.5 ad 20.5% for placebo patiets, belimumab 1 mg/kg, ad belimumab 10 mg/kg, respectively; hazard ratio for belimumab 1 mg/kg 0.66, p = 0.023). I additio, patiets treated with belimumab had sigificat reductios i immuoglobulis (IgG, IgM, IgA), IgG ati-dsdna IgG, ad sigificatly greater icreases i C3 ad C4 levels ad a higher percetage of ormalizatio of low C3 ad C4 compared with placebo patiets at week 52. Coversely, statistically sigificat PGA improvemet ad steroid dose reductio were ot detected with belimumab treatmet. The icidece of all adverse evets, icludig serious ifectios was comparable betwee belimumab treatmet groups ad placebo i both studies. Whereas o maligacies were reported i BLISS-52, six maligacies occurred i BLISS-76 (oe o placebo, three o 1 mg/kg, two o 10 mg/kg). Overall, i these two Phase III trials belimumab sigificatly reduced SLE disease activity ad SLE flare rates i patiets with active SLE. I additio, it was geerally well tolerated i combiatio with stadard therapy. It must be emphasized that both Phase III trials did meet their prespecified primary ed poits despite the less robust results of the BLISS-76. Future perspective I the light of the results of these trials, the FDA ad the Europea Medicies Agecy have approved this moocloal atibody as the first biological therapy for SLE. However, three questios should be aswered. First, it will be very importat to idetify which SLE patiets will beefit from this treatmet. A iterestig Cli. Ivest. (2011) 1(11) 1559

6 Cervera & Espiosa exploratory coclusio of Phase II trial was that belimumab was effective i serologically positive patiets defied as ANA titer >1:80 or positive ati-dsdna, as tested at baselie by a cetral laboratory [14] (ot to be cofused with a history of such or a geerally cosistet test from place to place). I this sese, BLyS levels above the limit of quatitatio at baselie were detected i 54% of serologically active patiets compared with oly 24% of those seroegative. However, it should be take ito cosideratio that autoatibody testig is ot always cosistet from laboratory to laboratory, so that it could be that some people labelled seroegative by a test might be seropositive at a differet laboratory; this might mea that usig autoatibodies as a surrogate marker for BLyS levels may be fudametally flawed. Takig ito accout these data, patiets icluded i Phase III trials had ANA 1:80 ad/or ati-dsdna atibodies 30 IU/ml together with SELENA-SLEDAI score 6. Therefore, the patiets who seem more likely to beefit from this drug are those with high SELENA-SLEDAI scores ad more serological activity (high ati-dsdna ad low complemet levels). The secod importat questio to be aswered is the effect of belimumab i daily cliical practice. I the previous trials, the chages i disease activity measures, such as SRI, SELENA-SLEDAI, PGA ad BILAG from baselie to 52 weeks betwee patiets treated with placebo ad those treated with belimumab has bee less tha 15%. We do ot kow, however, which be the cliical effect i real life maagemet of SLE patiets. Fially, the third importat questio is to kow which will be the effect i the most severe cases of SLE, ad hece the oes that are i eed for ew targeted therapies, such as those with lupus ephritis ad C ivolvemet, that were excluded from all these trials. Therefore, future studies o the effect of belimumab are expected, icludig real life registries (with more emphasis i some populatios such as North Americas ad those of Africa descet) as well as specific trials o patiets with lupus ephritis or C ivolvemet. Fiacial & competig iterests disclosure Ricard Cervera received cosultig fees from Huma Geome Sciece ad GlaxoSmithKlie. The authors have o other relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript apart from those disclosed. No writig assistace was utilized i the productio of this mauscript. Executive summary Belimumab is a huma moocloal atibody that bids soluble B lymphocyte stimulator (BLyS), also kow as B cell-activatig factor, thus prevetig the bidig to its receptors o B cells. BLyS atagoizes apoptosis of trasitioal immature B cells, thus allowig differetiatio ad etrace of cells ito the mature, pre-immue B cell populatios. Therefore, if this biologic process is impaired, it could allow the survival of aive autoreactive B cells istead of their elimiatio by apoptosis. Evidece from aimal ad huma studies has demostrated overexpressio of BLyS i systemic lupus erythematosus (SLE). A Phase II trial demostrated that belimumab, added to stadard therapy for the disease, was well tolerated ad improved may disease activity idexes such as Safety of Estroges i Lupus Erythematosus Natioal Assessmet SLE Disease Activity Idex (SELENA-SLEDAI) score, Physicia Global Assessmet, ad Short Form 36 Physical Compoet Summary (SF-36 PCS) i a subset of serologically active SLE patiets. I two Phase III trials, belimumab sigificatly reduced SLE disease activity ad SLE flare rates i patiets with active SLE. I additio, it was geerally well tolerated i combiatio with stadard therapy. The US FDA ad the Europea Medicies Agecy have approved this moocloal atibody as the first biological therapy for SLE. 3 O Neill S, Cervera R. Systemic lupus erythematosus. Best Pract. Res. Cli. Rheumatol. 24, (2011). Scheider P, MacKay F, Steier V et al. BAFF, a ovel ligad of the tumor ecrosis factor family, stimulates B cell growth. J. Exp. Med. 189, (1999). 4 State of the art o the epidemiology of systemic lupus erythematosus. Bosse C, Scheider P. BAFF, APRIL ad their receptors: structure, fuctio ad sigalig. Semi. Immuol. 18, (2006). 5 Bibliography Papers of special ote have bee highlighted as: of cosiderable iterest 1 2 Saz I, Lee FE. B cells as therapeutic targets i SLE. Nat. Rev. Rheumatol. 6, (2010) Dig C. Belimumab, a ati-blys huma moocloal atibody for potetial treatmet of iflammatory autoimmue diseases. Expert Opi. Biol. Ther. 8, (2008). 6 Cheema GS, Roschke V, Hilbert DM et al. Elevated serum B lymphocyte stimulator levels i patiets with systemic immue-based rheumatic diseases. Arthritis Rheum. 44, (2001). 7 Collis CE, Gavi AL, Migoe TS et al. B lymphocyte stimulator isoforms i systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mrna levels tha with plasma BLyS protei levels. Arthritis Res. Ther. 8(1), R6 (2006).

7 Cliical evidece of the role of belimumab i the treatmet of SLE Hog SD, Reiff A, Yag HT et al. B lymphocyte stimulator expressio i pediatric systemic lupus erythematosus ad juveile idiopathic arthritis patiets. Arthritis Rheum. 60, (2009). i cyomolgus mokeys: pharmacokietic, pharmacodyamic ad toxicologic effects. Toxicol. Sci. 91, (2006). 13 Stohl W, Metyas S, Ta SM et al. B lymphocyte stimulator overexpressio i patiets with systemic lupus erythematosus: logitudial observatios. Arthritis Rheum. 48, (2003). Petri M, Stohl W, Chatham W et al. Associatio of plasma B lymphocyte stimulator levels ad disease activity i systemic lupus erythematosus. Arthritis Rheum. 58, (2008). Baker KP, Edwards BM, Mai SH et al. Geeratio ad characterizatio of LymphoStat-B, a huma moocloal atibody that atagoizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, (2003). Halper WG, Lappi P, Zaardi T et al. Chroic admiistratio of belimumab, a BLyS atagoist, decreases tissue ad peripheral blood B-lymphocyte populatios Furie R, Stohl W, Gizler EM et al. Biologic activity ad safety of belimumab, a eutralizig ati-b-lymphocyte stimulator (BLyS) moocloal atibody: a Phase I trial i patiets with systemic lupus erythematosus. Arthritis Res. Ther. 10, R109 (2008). Wallace DJ, Stohl W, Furie RA et al. A Phase II, radomized, double-blid, placebo-cotrolled, dose-ragig study of belimumab i patiets with active systemic lupus erythematosus. Arthritis Rheum. 61, (2009). Navarra SV, Guzma RM, Gallacher AE et al. Efficacy ad safety of belimumab i patiets with active systemic lupus erythematosus: a radomised, placebocotrolled, Phase III trial. Lacet 377, (2011). Origial article that reports the results of the belimumab Phase III trial BLISS-52. Cli. Ivest. (2011) 1(11) 16 Furie R, Petri M, Zamai O et al. A Phase III, radomized, placebo-cotrolled study of belimumab, a moocloal atibody that ihibits BLyS, i patiets with systemic lupus erythematosus. Arthritis Rheum. DOI: / art (Epub ahead of prit) (2011). Origial article that reports the results of the belimumab Phase III trial BLISS Petri MA, Furie R, Merrill JT et al. Four year experiece of belimumab, a BlyS specific ihibitor, i systemic lupus erythematosus (SLE). Am. Col. Rheumat. Nat. Meetig Abstract 2069 (2009). 18 Furie RA, Petri MA, Wallace DJ et al. Novel evidece-based systemic lupus erythematosus respoder idex. Arthritis Rheum. 61, (2009). 19 Taasescu C, Gallacher A, Garcia M et al. Belimumab, a BLyS-specific ihibitor, sigificatly improved physical fuctioig, fatigue, ad other health-related quality of life (HRQoL) measures i patiets with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. A. Rheum. Dis. 69(Suppl. 3), 556 (2010). 1561

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