Biotherapies in systemic lupus erythematosus: New targets

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Biotherapies in systemic lupus erythematosus: New targets Estibaliz Lazaro a,b,c , Marc Scherlinger a,b , Marie-Elise Truchetet a,b,c , Laurent Chiche d , Thierry Schaeverbeke a,b , Patrick Blanco a,b,c , Christophe Richez a,b,c,∗ a

Université de Bordeaux, 146, rue Léo-Saignat, 33076 Bordeaux, France FHU ACRONIM, centre hospitalier universitaire de Bordeaux, place Amélie-Raba-Léon, 33076 Bordeaux, France CNRS-UMR 5164 Immuno Concept, 146, rue Léo-Saignat, 33076 Bordeaux, France d Service de médecine interne, hôpital européen, 6, rue Désirée-Clary, 13003 Marseille, France b c

a r t i c l e

i n f o

Article history: Accepted 10 June 2016 Available online xxx Keywords: Biotherapies Systemic lupus erythematosus Interferon Glucocorticoids

a b s t r a c t Systemic lupus erythematosus (SLE) is an autoimmune disease with a polymorphic presentation. The variability in the clinical expression and severity of SLE makes new treatments both essential and challenging to develop. Several biotherapies targeting different pathophysiological pathways have been developed over the past 15 years. The results of Phase II trials were encouraging but rarely borne out by Phase III trials. Recent data, which are discussed in detail in this review, allowed belimumab – a monoclonal antibody against BLyS (B-lymphocyte stimulator) – to become the first biotherapy approved for use in SLE. Other molecules targeting B cells include the two anti-BLyS antibodies tabalumab and blisibimod; atacicept, which targets both BLyS and APRIL (a proliferation-inducing ligand); and the monoclonal antibody to CD22 epratuzumab. The rekindling of interest in the B-cell pathway has also driven new clinical research into rituximab, a monoclonal antibody targeting CD20 with evaluations of new strategies. A new and promising approach is the use of inhibitors of the type 1 interferon (IFN) pathway, of which the most promising is anifrolumab, a monoclonal antibody targeting the type 1 IFN receptor. In this review, we discuss study findings and their clinical relevance, present the most promising targets, and analyze possible explanations to negative results, such as inappropriate patient selection and treatment response criteria or the erratic use of high-dose glucocorticoid therapy. ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. © 2016 Societ

Many biotherapies have been developed for systemic lupus erythematosus (SLE) in recent years. Although drugs aimed at numerous targets have been assessed, few produced a significant difference in the primary outcome measure. Belimumab is one of these exceptions but is rarely prescribed, as its clinical effect is considered modest (albeit significant) and its cost high [1]. This article is a review of biotherapies developed for SLE. It is based mainly on the Phase II and Phase III studies indexed in PubMed, the abstracts of EULAR and ACR meetings, and ongoing trials registered on clinicaltrials.gov. The data retrieved by the literature search are recapitulated in , Table S1 (See the supplementary material associated with this article online). Fig. 1 provides an overview of the treatment targets.

∗ Corresponding author. CNRS-UMR 5164 Immuno Concept, Bordeaux University, bâtiment 1B, 146, rue Léo-Saignat, 33076 Bordeaux, France. E-mail address: [email protected] (C. Richez).

1. Bleak beginnings: a string of failures in the early 21st century 1.1. Is the B cell a wrong target? Rituximab was initially developed as a treatment for B-cell malignancies. Rituximab is a chimeric human monoclonal antibody that selectively targets CD20+ B cells and causes their depletion. Possible benefits in autoimmune disorders were rapidly suggested, and two double-blind randomized trials were performed, EXPLORER in patients with SLE but no active renal or neurological disease [2] and LUNAR in patients with lupus nephritis [3] (Table 1). EXPLORER included 257 patients, most of whom had skin and joint involvement, with high disease activity (British Isles Lupus Assessment Group Index [BILAG] A score in at least one domain) or moderate disease activity (BILAG B score in at least two domains). The primary outcome was a composite clinical response score based on the BILAG. Patients were randomized to receive rituximab or placebo in addition to their usual treatment and to high-dose prednisone for the first 10 weeks [2]. In LUNAR, 144

http://dx.doi.org/10.1016/j.jbspin.2016.07.004 ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. 1297-319X/© 2016 Societ

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Fig. 1. Pathogenesis of systemic lupus erythematosus and treatment targets that have been or are being evaluated.

patients with class III or IV lupus nephritis were randomized to rituximab or placebo in addition to mycophenolate mofetil and prednisone. Complete or partial remission of the kidney disease was the primary outcome [3]. In neither trial was the primary outcome achieved. Another drug targeting CD20, ocrelizumab, was assessed during the same period. Ocrelizumab is a fully humanized monoclonal antibody. Encouraging findings from a Phase II trial (BEGIN) [4] prompted a Phase III trial (BELONG) in patients with lupus nephritis [5]. This trial was discontinued prematurely because of severe infectious side effects, and the development of ocrelizumab for SLE was stopped. 1.2. Co-stimulation pathways: unexpected adverse events Co-stimulation pathways contribute to activate autoreactive T cells. Among them, the CD40-CD40L and B7-CD28 pathways may hold promise as treatment targets in SLE. Two monoclonal antibodies to CD40L have been evaluated in SLE, ruplizumab and toralizumab. Ruplizumab [6] was evaluated in a Phase II study in patients with lupus nephritis. This drug reduced antidouble-stranded (anti-dsDNA), suggesting an immunomodulatory action. However, the study was stopped prematurely after 2 patients experienced myocardial infarction. Toralizumab was also

associated with thromboembolic events, and the development of both molecules was stopped [7]. Abatacept is a fusion protein composed of an IgG1 Fc fragment and CTLA4. Abatacept binds to B7 with high affinity, thus blocking the B7–B28 co-stimulation pathway. A controlled double-blinded Phase IIb trial included 118 patients with SLE, no renal or neurological involvement, and a score A or B on at least one BILAG domain [8]. The primary outcome was the proportion of patients with a new flare, defined as a BILAG A or B score on an additional domain, during the treatment year. Abatacept was not superior over standard treatment (Table 2). However, a subgroup analysis showed that abatacept was effective in patients with predominant joint manifestations (proportion of patients with new flares during the treatment year, 57.1% with abatacept and 84.4 % with standard treatment). Two trials evaluated abatacept in lupus nephritis. In the Phase II ACCESS trial, patients received abatacept induction therapy as an adjunct to glucocorticoid therapy and low-dose cyclophosphamide (EURO lupus regimen), followed by maintenance azathioprine therapy [9]. In the other trial, abatacept was combined with a glucocorticoid and mycophenolate mofetil [10]. In neither trial was abatacept superior over the control treatment in lupus nephritis (Table 2). The efficacy outcomes used should, however, be considered when interpreting these findings. Thus, post hoc analyses showed that abatacept was more effective than the control

Table 1 Efficacy of biotherapies targeting CD20 and CD22 in systemic lupus erythematosus. Name of the biotherapy

Treatment regimen Number (n) of patients per arm

Primary outcome

Rituximab (LUNAR) [3]

IV injection of 1000 mg on D1-D15-D168-D182 Placebo: n = 72 Rituximab: n = 72 IV injection of 1000 mg on D1-D15-D168-D182 Placebo: n = 88 Rituximab: n = 169 IV injection on D1 and D15, then W16, then every 16 weeks Placebo: n = 125 Ocrelizumab 400 mg: n = 126 Ocrelizumab 1000 mg: n = 127 12-week treatment cycles; 4 cycles Placebo: n = 266 600 mg on W0, W1, W2, and W3 of each cycle: n = 265 1200 mg on W0 and W2 of each cycle: n = 262 12-week treatment cycles; 4 cycles Placebo: n = 263 600 mg on W0, W1, W2, and W3 of each cycle: n = 266 1200 mg on W0 and W2 of each cycle: n = 262

No difference in complete or partial renal remission rate at W52 between the placebo arm and rituximab arm (45.8% versus 56.9%, respectively, for the global response; P = 0.18) No difference in clinical response rate assessed using the BILAG at W52 between the placebo (28.4%) and rituximab (29.6%) (P > 0.05)

Rituximab (EXPLORER) [2] Ocrelizumab (BELONG) [5]

Epratuzumab (EMBODY-1) [36]

Epratuzumab (EMBODY-2) [36]

No significant difference in global renal response at W48 between the placebo arm and the ocrelizumab 400 and 1000 mg arms (54.7, 66.7, and 67.1%, respectively) No difference in the BICLA response at W48 between the placebo (34.1%), epratuzumab 600 mg (37.5%), and epratuzumab 1200 mg (39.8%) (P > 0.05) No difference in the BICLA response at W48 between the placebo (33.5%), epratuzumab 600 mg (35.2%), and epratuzumab 1200 mg (34.1%) (P > 0.05)

IV: intravenous; SC: subcutaneous; D: day; W: week; BILAG: British Isles Lupus Assessment Group; SRI: Systemic lupus Responder Index; BICLA: BILAG-Based Composite Lupus Assessment.

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Table 2 Efficacy of biotherapies targeting the T cells in systemic lupus erythematosus. Name of the biotherapy

Treatment regimen Number (n) of patients per arm

Primary outcome

Abatacept [8]

IV injection on D1-D15-D29, then every 4 weeks until D337 Placebo: n = 58 Abatacept: n = 119 IV injection once a month for 24 months Placebo: n = 66 Abatacept: n = 68 IV injection Abatacept 30/10 30 mg/kg D1-D15-D29-D57, then 10 mg/kg once a month: n = 99 Abatacept 10/10 10 mg/kg once a month: n = 99 Placebo: n = 100 IV injection on D1, D15, D29, D57, D85, D113, D141 n = 28

No difference in the proportion of patients with new flares (BILAG A or B) by W52: placebo (82.5%), abatacept (79.5%) (P > 0.05 No difference in the proportion of patients with new flares (BILAG A or B) by W52: placebo (31%), abatacept (33%) (P > 0.05) No difference across the three arms in time to complete renal remission: placebo (20%), abatacept 30/10 (22.2%), abatacept 10/10 (27.3%) (P > 0.05)

Abatacept (ACCESS) [9] Abatacept [10]

Ruplizumab [6]

Premature discontinuation of the trial due to thromboembolic events In the 18 analyzed patients, the primary outcome was not achieved (≥ 50% decrease in proteinuria with no decline in kidney function at two consecutive visits between D57 and D141)

IV: intravenous; D: day; W: week; BILAG: British Isles Lupus Assessment Group.

intervention in lupus nephritis when the outcomes were those used in other trials such as LUNAR or Aspreva Lupus Management [11]. 1.3. Anti-cytokine treatments: disappointing results 1.3.1. TNF˛ antagonists The role for TNF␣ in the pathophysiology of SLE is controversial. TNF␣ levels are increased in serum and renal lesion samples from patients with active SLE [12]. Nevertheless, the increase in antinuclear antibody titers seen with TNF␣ antagonists limits the use of these drugs in SLE [13]. Pilot studies of infliximab in small numbers of patients have been published. Their results suggest that infliximab may hold promise for treating glomerulonephritis and refractory joint disease due to SLE [14,15]. However, no firm conclusions can be drawn regarding the possible interest for infliximab in SLE. At present, TNF␣ antagonists are not recommended as part of classic strategies for SLE. 1.3.2. Treatments targeting IL-6 IL-6 is a proinflammatory cytokine involved in the differentiation of B cells to plasma cells and of T cells to effector T cells. A Phase I dose–escalation study assessed tocilizumab, a monoclonal antibody to the IL-6 receptor. Significant improvements were documented in clinical parameters, particularly those assessing the joint involvement, and in anti-DNA titers [16]. Adverse events including neutropenia and infections occurred, however, hampering further development of tocilizumab in this indication. 2. The current situation: small advances but no breakthroughs 2.1. BLyS antagonists: some promise but persistent doubt B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL) are two cytokines that are pivotal in B-cell development, survival, and proliferation. They bind to two receptors at the B-cell surface, transmembrane activator and calcium-modulating ligand interactor (TACI) and B cell-maturation antigen (BCMA). BLyS also recognizes the receptor for the B-cell activating factor (BAFF-R) [17] (Fig. 1). In 2011, based on findings from the Phase III trials BLISS-52 [18] and BLISS-76 [19], belimumab became the first biotherapy to be approved for the treatment of SLE. Belimumab is an intravenously

administered human monoclonal IgG␭1 antibody against BLyS that blocks soluble BLyS but recognizes neither membrane-bound BLyS nor APRIL. Both trials included patients with seropositive SLE and a SELENA-SLEDAI ≥ 6 but no severe organ involvement (i.e., no severe renal or neurological manifestations). Table 3 reports the main results of the two trials. In post hoc analyses, features associated with a larger difference between belimumab and the placebo were high active disease (SELENA-SLEDAI ≥ 10), complement consumption, anti-dsDNA antibodies, and a prednisone dosage > 7.5 mg/day [20]. Furthermore, in the 267 patients with renal involvement according to the SELENA-SLEDAI but without severe active lupus nephritis, several renal parameters improved with belimumab therapy [21]. Circumspection is in order, however, when interpreting these renal findings, as most of the differences fell short of statistical significance. To date, safety data on belimumab are encouraging [22,23]. A more recent study evaluating the efficacy of subcutaneous belimumab was reported at the 2015 ACR meeting [24]. The inclusion criteria were slightly different, with a requirement for a SELENA-SLEDAI ≥ 8. As shown in Table 3, the results were similar to those obtained with intravenous administration. Studies are ongoing to assess the efficacy of belimumab in African-American patients (EMBRACE), lupus nephritis (BLISS-LN), and childhood-onset SLE (Table S1). Tabalumab is a human monoclonal IgG4 antibody that neutralizes both soluble and membrane BLyS. The result from ILLUMINATE 1 and 2 trials are disappointing (Table 3), although ILLUMINATE 2 demonstrated a significantly better response versus the placebo with 120 mg every 2 weeks [25,26]. ILLUMINATE 1 was indeed less encouraging but was not helped by the decision to consider patients who changed their dose of steroids to have failed the trial even if that change was a reduction in steroids [1]. Both trials used similar inclusion criteria to those in the BLISS trials. Tabalumab is no longer being developed. Blisibimod is composed of four high-affinity binding domains for BAFF fused with an IgG1 Fc fragment. This drug, which is still being developed, blocks both soluble and membrane BLyS. The primary outcome, i.e., an SRI-5 response at week 24, was not achieved in the Phase IIb trial [27]. Nevertheless, the highest dosage showed evidence of efficacy, particularly on the SRI-8 and in patients with very high disease activity at baseline, prompting further development of this drug. Thus, two Phase III trials are under way in patients with SELENA-SLEDAI values ≥ 10. Ataticept has a different mechanism of action. This recombinant fusion protein is composed of the extracellular portion of

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Table 3 Efficacy of biotherapies targeting the BLyS/APRIL system in systemic lupus erythematosus. Name of the biotherapy

Treatment regimen Number (n) of patients per arm

Primary outcome

Belimumab (BLISS-52) [18]

IV at W2 and W4, then every 4 weeks Placebo: n = 287 1 mg/kg: n = 288 10 mg/kg: n = 290 IV at W2 and W4, then every 4 weeks Placebo: n = 275 1 mg/kg: n = 271 10 mg/kg: n = 273 SC once a week Placebo: n = 280 200 mg: n = 556 Placebo: n = 378 120 mg SC every 2 weeks: n = 381 120 mg SC every 4 weeks: n = 378 Placebo: n = 376 120 mg SC every 2 weeks: n = 372 120 mg SC every 4 weeks: n = 376

SRI-4 response rate at W52 significantly higher than with placebo (44%) with 1 mg/kg (51%) or 10 mg/kg (58%): P = 0.0129 and P = 0.0006, respectively

Placebo: n = 269 100 mg SC once a week: n = 93 200 mg SC once a week: n = 92 200 mg SC every 4 weeks: n = 92 SC twice weekly for 4 weeks, then once a week until W52 Placebo: n = 157 75 mg: n = 159 150 mg: n = 145

SRI-5 response rate at W24 not better than pooled placebo (35.3%) with 100 mg SC/weeks (32.3%): P = 0.603 and a dose of 200 mg SC once weekly (43.5%; P = 0.154) or 200 mg SC every 4 weeks (35.9%; P = 0.925)

Belimumab (BLISS-76) [19]

Belimumab (BLISS-SC) [24] Tabalumab (ILLUMINATE -1) [25] Tabalumab (ILLUMINATE -2) [26]

Blisibimod (PEARL-SC) [27]

Atacicept (APRIL-SLE) [29]

SRI-4 response rate at W52 significantly higher than with placebo (33.5%) with 10 mg/kg (43.2%; P = 0.017) but no significant difference with 1 mg/kg (40.6%; P = 0.089) No significant difference at W76 SRI-4 response rate at W52 significantly higher than with placebo (48.7%) with 200 mg (61.4%; P = 0.0009) No difference for the SRI-5 response rate at W52 between the placebo (29.3%), 120 mg SC/2 weeks (31.8%) and a dose of 120 mg SC/4 weeks (35.2%): P > 0.05 SRI-5 response rate at W52 significantly higher than with placebo (27.7%) with 120 mg SC/2 weeks (38.4%; P = 0.002) but no significant difference with 120 mg SC/4 weeks (34.8%; P = 0.051)

Proportion of patients with a BILAG A or B flare by W52 similar with atacicept 75 mg and placebo (58 and 54%, respectively; P = 0.543).

IV: intravenous; SC: subcutaneous; D: day; W: week; BILAG: British Isles Lupus Assessment Group; SRI: Systemic lupus Responder Index.

the TACI receptor bound to a human IgG1 Fc fragment. It blocks both APRIL and BLyS [17]. A Phase II/III trial in lupus nephritis was stopped after the inclusion of only 6 patients due to the development of severe infections with an IgG decrease to less than 3 g/L in 3 of the 4 patients given the active drug [28]. At baseline, the patients were taking high-dose glucocorticoid therapy and mycophenolate mofetil 3 g/d. These concomitant treatments may explain the vulnerability to infections. A Phase II/III trial (APRILSLE) was conducted in patients with SLE but no severe active renal or neurological disease and no history of treatment with cyclophosphamide or mycophenolate mofetil [29]. The primary objective was to evaluate the efficacy of two atacicept dosages (75 and 150 mg) in preventing the occurrence of flares. Enrollment in the 150 mg arm was stopped prematurely because 2 patients experienced fatal infections (pneumococcal pneumonia and leptospirosis). No significant difference was found between the 75 mg dosage and the placebo. In contrast, evidence of efficacy was demonstrated in the study completers who took 150 mg/day. The ongoing Phase IIb trial ADDRESS II evaluates the number of SRI-4 responders at week 24 with the same two dosages versus a placebo in patients with SLE. The results may provide further information on the risk–benefit ratio of atacicept.

performed in the UK by Lightstone et al. has rekindled interest in rituximab. In one study by this group, 50 patients with lupus nephritis were treated without oral glucocorticoids: their regimen consisted of 2 doses of rituximab (1 g) and methylprednisolone (500 mg) 2 weeks apart; and mycophenolate mofetil, 1–3 g/day [34]. After 1 year, 52% of patients had achieved a complete renal remission, with no worrisome adverse events. These results are far superior over those obtained in the LUNAR trial [3]. Of note, 22 patients had class V disease without concomitant class III/IV lesions. To further evaluate the usefulness of this therapeutic regimen and the validity of treating lupus nephritis without oral glucocorticoids, the same investigators have started a randomized controlled trial, RITUXILUP, in which the comparator is the same regimen without rituximab but with 0.5 mg/kg/day prednisone at treatment initiation. Another ongoing randomized controlled trial, RING, is evaluating the efficacy of rituximab in patients with lupus nephritis and persistent proteinuria (≥ 1 g/d), despite standard immunosuppressive therapy for 6 months. The proportion of patients with a complete renal remission will be compared between the rituximab arm and the standard treatment arm (azathioprine or mycophenolate mofetil). Patients will take less than 10 mg/d of prednisolone. 2.3. But another fiasco

2.2. Rituximab: a new hope Despite the failure of the EXPLORER and LUNAR trials, rituximab continues to be viewed as potentially beneficial in SLE. In both trials, rituximab exerted robust effects on B-cell counts and anti-dsDNA titers. Furthermore, a post hoc analysis of data from EXPLORER suggests that rituximab may prevent the occurrence of severe SLE flares [30]. Finally, several observational studies, although uncontrolled, support the efficacy and safety of rituximab in SLE [31,32]. In the latest recommendations on the management of lupus nephritis issued by the EULAR and ERA-EDTA [33], rituximab is considered useful in patients with class V nephritis, as an alternative to mycophenolate mofetil, and above all in patients with lupus nephritis who fail to respond to standard treatment. Work

Epratuzumab is a humanized monoclonal antibody targeting CD22 on the B-cell surface. This drug modulates signaling pathways within B cells without substantially diminishing the circulating B-cell counts. In the Phase IIb trial EMBLEM, epratuzumab in a cumulative dosage of 2400 mg/month yielded promising results in moderate-to-severe SLE [35]. The results of two Phase III trials, EMBODY-1 and -2, were reported at the 2015 ACR meeting [36]. These trials included patients with active SLE defined as at least one BILAG A score or at least two BILAG B scores, in the dermatological, musculoskeletal, or cardiopulmonary domains. Exclusion criteria were anti-phospholipid syndrome and a BILAG A score for renal or central neurological involvement. Table 1 lists the main findings. Neither the primary outcome nor any of the secondary outcomes

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Table 4 Efficacy of biotherapies targeting type 1 interferons in systemic lupus erythematosus. Name of the biotherapy

Treatment regimen Number (n) of patients per arm

Primary outcome

Rontalizumab (ROSE) [39]

IV/4 weeks 750 mg: n = 81 Placebo: n = 41 SC/2 weeks 300 mg: n = 78 Placebo: n = 38 IV/4 weeks 1200 mg: n = 107 600 mg: n = 108 200 mg: n = 108 Placebo: n = 108 IV/4 weeks 300 mg: n = 99 1000 mg: n = 104 Placebo: n = 102

Proportion of patients with a BILAG score improvement, no new BILAG A, and no more than 1 new BILAG B 41.8% with placebo 45.5% with rontalizumab P = 0.60

Sifalimumab (MEDI-545) [40]

Anifrolumab (MEDI-546) [41]

SRI-4 response at W52 significantly better than placebo (45.4%) with 1200 mg (59.8%; P = 0.031)

SRI-4 response on D169 + prednisone < 10 mg/d and ≤ baseline dose, maintained between D85 and D169: significantly higher proportion vs. the placebo (17.6%) with 300 mg (34.3%; P = 0.014)

IV: intravenous; SC: subcutaneous; D: day; W: week; BILAG: British Isles Lupus Assessment Group; SRI: Systemic lupus Responder Index.

were achieved in these trials and epratuzumab is, therefore, no longer being developed for SLE. 3. The future of biotherapies for SLE: encouraging prospects 3.1. Drugs targeting type 1 interferons (IFNs) Type 1 interferons (IFNs), i.e., chiefly IFN-␣ and IFN-␤, are key cytokines in the pathophysiology of SLE, such as TNF-␣ in rheumatoid arthritis [37]. Several strategies designed to block these cytokines have been developed [38]. Rontalizumab [39] and sifalimumab [40] are monoclonal antibodies against IFN-␣ and do not block the other type 1 IFNs, such as IFN-␤. In addition, recognition

by these monoclonal antibodies varies across IFN-␣ subtypes. Anifrolumab [41] is a monoclonal antibody that binds to the type 1 IFN receptor (IFNAR), preventing it from being engaged by any of the type 1 IFNs. Table 4 reports the findings from trials evaluating the clinical efficacy of biotherapies targeting type 1 IFNs. The patients included in these trials had active SLE defined as at least one BILAG A score or two BILAG B scores; additional requirements were an SLEDAI-2 K value ≥ 6 and a physician-assessed visual analog scale score ≥ 1 for sifalimumab and anifrolumab. Exclusion criteria were severe renal or neurological involvement and profound cytopenia. Concomitant treatments varied across trials; immunosuppressive drugs were usually continued in stable dosages but were stopped in the study of rontalizumab. Variable dosages of glucocorticoids were used (Tables 4 and 5).

Table 5 Glucocorticoid therapy regimens in published studies of biotherapies in systemic lupus erythematosus. Name of drug

Dosage in prednisone-equivalents at baseline

Start of taper

Target dosage in prednisone-equivalents

Methylprednisolone bolus

0.5 to 1 mg/kg

D16

Rituximab (LUNAR) [3]

0.75 mg/kg (≤ 60 mg/d)

D16

W10: ≤ 10 mg/d W52: ≤ 5 mg/d W16: ≤ 10 mg/d

Ocrelizumab (BELONG) [5]

0.5 to 0.75 mg/kg (≤ 60 mg/d)

D0

W10: ≤ 10 mg/d

Belimumab (BLISS-52) [18]

No restriction

W24

Belimumab (BLISS-76) [19]

Between D -30 and D0: ≤ 40 mg/d

W24

Tabalumab (ILLUMINATE 1/2) [25,26]

≤ 40 mg/d

D0

Dosage decreased by 25% or 5 mg between W24 and W44 and between W52 and W68 Dosage decreased by 25% or 5 mg between W24 and W44 and between W52 and W68 W24: dosage ≤ baseline, with a target of ≤ 7.5 mg/d for at least 3 months between W24 and W52

100 mg before each rituximab infusion 1000 mg from D1 to D3, then 100 mg before each rituximab infusion Before each ocrelizumab infusion and bolus allowed until D15 Allowed until W24

Biotherapies targeting B cells Rituximab (EXPLORER) [2]

Biotherapies targeting T cells Abatacept (ACCESS) [9] Abatacept [8]

60 mg/d ≤ 30 mg/d (≤ 20 mg/d at screening ≤ 30 mg/d at randomization) 0.5 to 0.8 mg/kg/d Abatacept [10] (≤ 60 mg/d) Biotherapies targeting type 1 interferons 0.25 to 0.5 mg/kg/d Rontalizumab (ROSE) [39] Sifalimumab (MEDI-545) No restriction [40]

Allowed until W24

Allowed until W24

W2 D29 or D57 depending on disease activity

W10: ≤ 10 mg/d No target dosage

Allowed Allowed between D29 and D57

D29

W13: ≤ 5 mg/d

Three 500 mg boluses allowed at inclusion

D0 Between D85 and D113, then between D169 and D281

W6: ≤ 10 mg/d No target dosage

Not allowed IV boluses not allowed IM injections of 80 mg or 160 mg allowed

IV: intravenous; SC: subcutaneous; IM: intramuscular; D: day; W: week.

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The response to these treatments varied according to whether the patients had a type 1 IFN signature at baseline. This finding may constitute a breakthrough in the development of personalized treatments for SLE. The safety profile was acceptable in all four trials reported to date. Nevertheless, this strategy may increase the risk of infections due to viruses such as the varicella-zoster virus. No new trials of rontalizumab and sifalimumab in SLE are registered on ClinicalTrials.gov. Anifrolumab is being evaluated in two Phase III trials in extrarenal SLE and in one Phase II trial in lupus nephritis.

BLyS levels has been reported in patients with SLE and rituximabinduced B-cell depletion [47]. Maintenance belimumab therapy given after rituximab may prevent the rise in BLyS. This strategy is being investigated in lupus nephritis in a Phase II trial of rituximab combined with cyclophosphamide and followed by belimumab [47].

3.2. IFN-˛ kinoid

One explanation for the failure of most biotherapies in clinical trials is the heterogeneity of SLE. The variations in the clinical presentation, disease activity, and severity are a major obstacle to developing a clinical protocol in a uniform patient population. Except those focusing on lupus nephritis, trials have included patients with fairly mild disease to minimize the risk of permanent impairments due to disease progression in the control group and, if the tested drug lacked efficacy, in the intervention group. Improvements are more difficult to detect against a background of mild instead of severe abnormalities. The data suggest a need for selecting patients with evidence of severe disease such as anti-dsDNA antibodies, complement consumption, a higher level of disease activity with an SLEDAI value ≥ 10 at baseline, and glucocorticoid dependency [48,49]. Another criticism is that hydroxychloroquine was not used consistently. In one trial, for instance, the proportion of patients taking hydroxychloroquine was 55.1% in the subcutaneous rontalizumab arm and 79% in the placebo arm [39]. Furthermore, nearly half the clinical trial reports fail to indicate the number of patients taking hydroxychloroquine, although the therapeutic benefits of synthetic antimalarials in SLE are well established. Consequently, when developing the randomization scheme and choosing the primary outcome, one should consider the number of previous treatment lines and the clinical pattern (i.e., renal, neurological, hematological, cutaneous, or articular). Nevertheless, recruiting a sufficient number of patients may prove difficult with this approach. The variability in the assessment tools used and creation of a different composite evaluation criterion appear unfortunate and may have influenced the trial results. Among the many tools available for assessing the activity of SLE, the BILAG and SLEDAI are the most widely used. These two instruments supposedly measure the same thing but were developed using different methodological approaches that explain the limitations of each. In contrast to the BILAG, the SLEDAI does not allow an accurate assessment of each organ system. The SLEDAI is less sensitive than the BILAG for detecting changes in activity for individual organ systems (items are present or absent, whereas the BILAG may show new or worsened items). On the other side, BILAG is not a global score. Furthermore, the BILAG is complex and was developed for an intent-to-treat approach whose validity is theoretically limited over time, as progress occurs in the therapeutic management of SLE. The BILAG performs less well than the SLEDAI for detecting improvements, particularly partial improvements. These limitations have prompted the recent development of composite scores that combined the advantages of the BILAG and SLEDAI. For instance, the SLE Responder Index was developed based on the results of the Phase II trial of belimumab [50], then used as the primary outcome for the two Phase III trials of this drug [18,19]. The validity and clinical relevance of this tool remain to be demonstrated. In trials of biotherapies, the control groups received the standard treatment for SLE. An important issue is whether the glucocorticoid dosages used in several trials (Table 5) were in adequation with the most recent recommendation, given the reports of numerous adverse effects of glucocorticoid therapy in SLE [51–53]. In the most

IFN-␣ kinoid is composed of IFN-␣, coupled to the immunogenic protein keyhole limpet hemocyanin. It was designed to induce the production of natural polyclonal antibodies targeting all IFN␣ isotypes. IFN-␣ kinoid is a vaccine rather than a biotherapy. The concept developed from work on TNF-␣ [42]. A Phase I/II randomized placebo-controlled trial in 28 women with moderate-to-severe SLE (SLEDAI-2 K between 4 and 10 with no BILAG scores of A) established that IFN-␣ kinoid was immunogenic [43]. In patients who exhibited the IFN signature at baseline, this signature became less marked after treatment. A Phase IIb trial in patients with the IFN signature is ongoing. 3.3. New treatments targeting co-stimulation pathways 3.3.1. The ICOS/ICOS ligand pathway This pathway is involved in T-cell activation, synergistically with the CD28/B7 pathway. Phase I trials of molecules that target ICOS (MEDI-570) and ICOS ligand (AMG 557) are ongoing in patients who have lupus without renal involvement. 3.3.2. The CD40/CD40 ligand pathway The occurrence of thromboembolic complications during treatment with ruplizumab or toralizumab prompted the production of a new monoclonal antibody directed at the CD40 ligand, CDP7657. The original feature of this antibody is its PEGylated monovalent structure, with no Fc fragment and, therefore, no ability to bind to the platelet receptor Fc␥RIIa, which limits the risk of increased platelet aggregation. No thromboembolic events were recorded during the Phase I trial of CDP7657 in 28 healthy volunteers and 17 patients with SLE [44]. Dapirolizumab, a PEGylated antibody to CD40L, is also being evaluated in a Phase I trial in lupus, which has shown a good safety profile [45]. 3.3.3. The TWEAK/Fn14 pathway This pathway involves TWEAK (TNF-like weak inducer of apoptosis) and its receptor Fn14 (FGF-inducible 14). It is overexpressed in autoreactive T cells. The TWEAK pathway has been shown to play a role in a murine model of lupus nephritis. A Phase II trial (ATLAS) assessed a monoclonal antibody to TWEAK in lupus nephritis. The data are being analyzed. No further trials in SLE have been registered. 3.4. Obinutuzumab: the last-generation antibody targeting CD20 Obinutuzumab is a fully humanized anti-CD20 monoclonal antibody characterized by stronger antibody-dependent cytotoxicity compared to rituximab. A Phase II trial (NOBILITY) of obinutuzumab in class III/IV lupus nephritis is ongoing. 3.5. Combining biotherapies: rituximab followed by belimumab Similar to observations in vasculitis associated with antineutrophil cytoplasmic autoantibodies [46], a sharp rise in circulating

4. Why the repeated failures?

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recent studies, one of the objectives is to taper glucocorticoid below 10 mg/d, whereas it was not mandatory in previous studies. Achieving disease control with a single biotherapy targeting a single pathway and used in a single dosage is probably an unrealistic goal. Patient subgroups should therefore be identified, based not only on conventional clinical and laboratory parameters, but also on molecular criteria that should not be limited to the IFN signature. Uniform patient subgroups could thus be obtained, permitting the development of tailored therapeutic strategies [54]. Disclosure of interest E.L., P.B., L.C., and M.S. declare that they have no competing interest. C.R. has received honoraria from GSK, Astra-Zeneca, UCB, Roche, and BMS. C.R. has received a research grant from Roche. M.E.T. has sat on a board about rituximab for Roche. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jbspin. 2016.07.004. References [1] Isenberg D. Further thoughts about the ILLUMINATE studies of tabalumab in SLE. Ann Rheum Dis 2016;75:e11. [2] Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222–33. [3] Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64:1215–26. [4] Genovese MC, Kaine JL, Lowenstein MB, et al. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum 2008;58:2652–61. [5] Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum 2013;65:2368–79. [6] Boumpas DT, Furie R, Manzi S, et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003;48:719–27. [7] Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 2004;13:391–7. [8] Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:3077–87. [9] Group AT. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study. Arthritis Rheumatol 2014;66:3096–104. [10] Furie R, Nicholls K, Cheng TT, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 2014;66:379–89. [11] Wofsy D, Hillson JL, Diamond B. Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials. Arthritis Rheum 2013;65:1586–91. [12] Maury CP, Teppo AM. Tumor necrosis factor in the serum of patients with systemic lupus erythematosus. Arthritis Rheum 1989;32:146–50. [13] Richez C, Schaeverbeke T, Dumoulin C, et al. Myeloid dendritic cells correlate with clinical response whereas plasmacytoid dendritic cells impact autoantibody development in rheumatoid arthritis patients treated with infliximab. Arthritis Res Ther 2009;11:R100. [14] Aringer M, Graninger WB, Steiner G, et al. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum 2004;50:3161–9. [15] Uppal SS, Hayat SJ, Raghupathy R. Efficacy and safety of infliximab in active SLE: a pilot study. Lupus 2009;18:690–7. [16] Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010;62:542–52.

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