Emerging biological therapies for systemic lupus erythematosus.

Review

Emerging biological therapies for systemic lupus erythematosus

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/11/14 For personal use only.

Chi Chiu Mok 1.

Background

Tuen Mun Hospital, Department of Medicine, Hong Kong, China

2.

Existing treatment and medical need

3.

Current research goals

4.

Scientific rationale

5.

Competitive environment

6.

Potential development issues

7.

Conclusion

8.

Expert opinion

Introduction: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unpredictable disease course, intermingled with periods of remission and exacerbation. Current therapies for SLE are not ideal in terms of efficacy and toxicity. Although the prognosis of the disease has improved in the past decades, further improvement is hindered by the occurrence of organ damage as a result of persistent disease activity and treatment-related complications. Novel biological therapies targeting at higher treatment efficacy and fewer adverse effects are being developed. Areas covered: This review summarizes recent data on novel biological therapies for SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. Expert opinion: The variable therapeutic response observed in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan of SLE patients should be individualized, with the target of quenching out disease activity, minimizing disease flares, and treatment related morbidities. Despite the disappointment of recent clinical trials, avenues are being opened for novel agents that intervene at different levels of the pathophysiological cascade of SLE. With the availability of a new treatment armamentarium, it is hoped that the survival rate and quality of life of SLE patients can continue to improve. Keywords: biologics, lupus, novel, targeted therapy, therapeutics, therapy Expert Opin. Emerging Drugs (2014) 19(2):303-322

1.

Background

Systemic lupus erythematosus (SLE) is a chronic multi-systemic autoimmune disease with unknown etiology [1,2]. The disease is characterized by a number of immunological abnormalities that include defective apoptosis and clearance of apoptotic materials such as nuclear autoantigens and nucleosomes and immune complexes by macrophages and the complement system [3], increased maturation of myeloid dendritic cells which drive the development of the pro-inflammatory Th17 cells [4], defective functions of the follicular and Qa-1 restricted CD8 regulatory T cells (Tregs) and the regulatory B cells [5,6]. The end result is activation of the T helper cells and autoreactive B cells, leading to overproduction of autoantibodies that mediate tissue inflammation and injury by immune complex deposition, complement activation, and antibody-mediated cytotoxicity. 2.

Existing treatment and medical need

SLE is a clinically and immunologically heterogeneous disease with variable and unpredictable disease course, intermingled with periods of flares and remission. The main stay of SLE therapies has been the nonsteroidal anti-inflammatory drugs, hydroxychloroquine, and the immunosuppressive agents [7]. Reduced life expectancy and quality of life of patients with SLE is caused by organ damage and the development of co-morbidities [8,9]. Management of refractory SLE manifestations 10.1517/14728214.2014.894018 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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Table 1. Novel biological therapies for systemic lupus erythematosus.

Current research goals

The current goal of development of novel therapeutics of SLE is to identify agents that are more effective than conventional therapies so as to reduce the risk of organ damage as a result of treatment refractoriness. To achieve this goal, large-scale randomized controlled clinical trials in multiple centers are needed to confirm the efficacy and safety of novel biological agents in comparison to conventional regimens. Whether these novel modalities are synergistic to conventional drugs, the optimal dosages, and duration of treatment have to be explored. Assessment tools have to be standardized and efficacy end points have to be appropriately defined. Postmarketing surveillance and registry data are also essential to evaluate the long-term safety, efficacy, and cost-effectiveness of these novel therapies (Table 1).

Targeting B cells Growth and survival factors Belimumab Atacicept Blisibimod Tabalumab Surface molecules Rituximab (chimeric anti-CD20) Ocrelizumab (fully humanized anti-CD20) Epratuzumab (fully humanized anti-CD22) Tolerization Abetimus sodium Proteasomes Bortezomib Targeting co-stimulatory molecules Abatacept (against CD80/86) AMG 557 (against B7RP-1, an inducible co-stimulator ligand) Targeting T cells Synthetic peptides Edratide Rigerimod Oral immunomodulator Laquinimod Targeting cytokines IL-6 Tocilizumab Sirukumab Type I interferons Sifalimumab Rontalizumab Targeting complements Eculizumab (anti-C5)

4.

remains a clinical and therapeutic challenge to most physicians. Despite the tremendous improvement in the prognosis of SLE in the past decades, further improvement is hindered by the occurrence of refractory disease and adverse effects related to conventional therapies such as glucocorticoids and the cytotoxic agents [10]. There is an unmet need for developing more efficacious treatment modalities with acceptable safety profile in SLE. A number of novel biological agents in the pipeline are being tested in SLE but so far only a few are promising. Belimumab is the only biological agent that is recently approved for the treatment of active SLE in addition to standard of care [11]. However, there are still uncertainties on the selection of the best patients for this agent and the optimal duration of therapy [12]. While pitfalls in study design, heterogeneity of the disease, and the limitations of the assessment tools for the efficacy end points may have contributed to the discouraging results of recent SLE trials, selection of appropriate SLE subsets, improvement in study design, and predefined criteria for meaningful clinical end points is prudent for future therapeutic trials of SLE [13]. 304

3.

Scientific rationale

The immunopathogenesis of SLE is complex. Multiple genetic, environmental, and hormonal factors are likely to contribute to the onset and exacerbation of the disease [2]. Excessive production of autoantibodies by B cells as a result of stimulation by autoreactive T cells or inadequate suppression by the natural killer cells and Tregs cells leads to immune complex formation and subsequent complementmediated damage. Moreover, dysregulation of the Th1, Th2, and Th17 pathways results in the elevation of the levels of a number of pro-inflammatory cytokines such as TNF-a, IL-6, IL-10, IL-15, IL-18 and IFN-a in patients with active SLE. Figure 1 shows the possible therapeutic interventions at different levels of the pathophysiological cascade of SLE. This review focuses on the biological agents that have been developed and studied since my last review on the same area [13].

5.

Competitive environment

The B cell remains the main target of therapy in SLE because it is central to the pathogenesis of SLE by producing autoantibodies. Biological agents have been developed to target the growth or survival factors, surface molecules, and receptors of B cells, leading to their apoptosis, depletion, or anergy. Inhibition of the co-stimulatory signals between B and T cells dampens T-cell activation and the subsequent B-cell hyperactivity. Synthetic peptides and small molecules work by restoring immune tolerance without significant immunosuppression. Finally, neutralization of excessive cytokines observed in SLE patients such as IL-10, TNF-a, IL-6, and the type I interferons and targeting complements are other approaches to control disease activity of SLE (Table 2).

Expert Opin. Emerging Drugs (2014) 19(2)


Rituximab Ocrelizumab

T cell tolerogen/modulation Edratide Rigerimod Laquinimod

Epratuzumab

Proteasome inhibitor Bortezomib

CD20 Anti-CD40L

CD22

CD40


B cell

CD40L

MHC II Ag

BCR

T cell inhibition Tacrolimus Sirolimus Syk inhibitor

TACI BAFF-R BCMA

B71/2

T cell

TCR

CD28/CTLA-4 CTLA4-Ig (Abatacept)

B cell tolerogen Abetimus sodium BLyS/BAFF APRIL

Belimumab Atacicept Blisibimod Tabalumab

Autoantibodies complement activation

Cytokines

Anti-IL-10 Anti-TNFα Anti-IL-6 (tocilizumab; sirukumab) Anti-IFNα (sifalimumab; rontalizumab; IFNα-kinoid)

Complement blockade: eculizumab

Figure 1. Targeted therapies for systemic lupus erythematosus. BAFF: B-cell-activating factor; BAFF-R: BAFF-receptor; BCMA: B-cell maturation antigen; BCR: B cell receptor; BLyS: B-lymphocyte stimulator; TACI: Transmembrane activator and calcium modulator ligand interactor.

Targeting B-cell growth and survival factors 5.1.1 Belimumab 5.1

B-lymphocyte stimulator (BLyS), or B-cell-activating factor (BAFF), belongs to the TNF ligand superfamily and is an essential factor for B-cell maturation, survival, proliferation, and immunoglobulin class switching [14]. BLyS binds to any of the three receptors on B cells, namely transmembrane activator and calcium modulator ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF-receptor (BAFF-R). In patients with SLE, levels of BLyS and BLyS mRNA are elevated [15,16], correlate with disease activity, and may predict lupus flares [15]. Belimumab is a fully humanized monoclonal antibody that specifically binds to soluble trimeric BLyS and prevents interaction of BLyS with its receptors. In clinical trials, belimumab treatment led to a reduction of peripheral CD20+ B cells [17], mainly caused by a decrease in number of naı¨ve B cells, transitional B cells, and activated B cells. Pre-switched memory B cells and plasmablasts decreased only after 18 months but Post-switched memory B cells and T cells were unaffected. There was a modest decrease in serum IgM level but there were no changes in the serum levels of IgG or IgG anti-DNA antibodies. Pre-existing anti-pneumococcal or anti-tetanus toxoid antibody levels were also unaffected by belimumab treatment [18,19].

Clinical trials of belimumab in SLE patients After a short-term Phase I dose escalation study established safety of belimumab [20], a Phase II placebo-controlled study of 449 patients with active SLE (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] score ‡ 4), who were randomly assigned to receive intravenous belimumab (1/4/10 mg/kg) or placebo, in addition to background immunosuppressive therapies was conducted [21]. At week 52, the efficacy of belimumab could not be demonstrated but post hoc analyses showed that autoantibodypositive patients (ANA ‡ 1:80 ± anti-dsDNA ‡ 30 IU/ml) had significantly better responses than placebo in terms of improvement in SELENA-SLEDAI, physicians’ global assessment (PGA), and the physical component scores of the SF-36. A SLE Responder Index (SRI), which is a composite clinical outcome defined by an improvement in SELENA-SLEDAI scores by ‡ 4, no British Isles Lupus Assessment Group (BILAG) worsening (new A or two B flares), and no worsening in PGA (increase by ‡ 0.3) compared to baseline, was subsequently worked out to evaluate the efficacy of treatment in future belimumab studies. In autoantibody positive patients recruited in this trial [21], belimumab treatment was associated with a significantly higher response rate than placebo (46 vs 29%) [22]. 5.1.1.1


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Table 2. Competitive environment table.


Compound

Company

Structure

Indication

Stage of development

Belimumab

GSK

Monoclonal antibody

Atacicept

Merck Serono

Fusion protein

Adult SLE patients with active disease despite standard treatment Nonrenal SLE patients

Blisibimod

Fusion protein

Nonrenal SLE

Tabalumab

Anthera Pharmaceuticals Eli Lily

Monoclonal antibody

Nonrenal SLE

Rituximab

Roche

Monoclonal antibody

Epratuzumab

UCB and Immunomedics

Monoclonal antibody

Nonrenal and renal SLE Nonrenal SLE

Abatacept

BMS

Fusion protein

Nonrenal and renal SLE

Phase III studies

Rigerimod Laquinimod

ImmuPharma Teva

Peptide Small molecule

Nonrenal SLE Renal SLE

Phase II studies Phase IIa study

Tocilizumab Sirukumab Sifalimumab

Roche Centocor MedImmune

Monoclonal antibody Monoclonal antibody Monoclonal antibody

Nonrenal SLE Cutaneous lupus Nonrenal SLE

Phase I study Phase I study Phase I study

Rontalizumab

Genentech

Monoclonal antibody

Nonrenal SLE

Phase II study

Eculizumab

Alexion Pharmaceuticals

Monoclonal antibody

Nonrenal SLE

Phase I study

Mechanism of action

Marketed

Inhibiting BAFF on B cells

Phase III studies

Blocking BAFF and APRIL on B cells Inhibiting BAFF on B cells Blocking both soluble and membrane-bound BAFF on B cells Depleting B cells

Phase III study in progress Phase III study in progress Phase III studies Phase III studies in progress

Modulating B cell signaling, cellular activation and survival Blocking costimulatory signals between T and B cells Tolerizing T cells Modulating T cell actions Blocking IL-6 receptor Blocking IL-6 Blocking type I interferon Blocking type I interferon Blocking complement C5

BAFF: B-cell-activating factor; SLE: Systemic lupus erythematosus.

Patients who completed this study were followed in a 24-week open-label extension (n = 345) [23]. During this phase, all belimumab and placebo treated patients were switched to receive 10 mg/kg of belimumab. Those who achieved a satisfactory response in this extension period were further followed longitudinally. At 7 years, 177 patients remained in the cohort [22]. The SRI response rates in autoantibody-positive patients were static (57% at year 2 and 65% at year 7). Severe flares occurred in 19% patients with placebo and 17% patients with belimumab treatment during the first year, with the annual rate declining to 2 -- 9% during years 2 -- 7. The most commonly reported AEs were arthralgia, upper respiratory tract infection, nausea, headache, and fatigue [23]. The annual rates of AEs and SAEs including infusion reactions, infections, malignancies, serious laboratory abnormalities were static during the 7 years’ treatment [22]. Phase III studies of belimumab in SLE The BLISS-52 was a 52-week double-blind randomized placebo-control study that included 865 patients from Asia, Eastern Europe, and Latin America [24]. The BLISS-76 was a 76-week study of the same design that involved 819 patients 5.1.1.2

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from North America and Europe [25]. The inclusion criteria were autoantibody-positive SLE patients with a SELENASLEDAI score of ‡ 6 and receiving stable SLE treatment regimens for ‡ 1 month. Participants were randomized to receive intravenous belimumab at 1 and 10 mg/kg or placebo on days 0, 14, 28 and then every 28 days on top of pre-existing therapies. In the BLISS-52 study [24], significantly higher SRI rates (primary efficacy end point) were noted with the belimumab 10 mg/kg dose group (58%) than with placebo (44%), with the difference being apparent at week 16. In the BLISS-76 study, the belimumab 10 mg/kg group also met the primary efficacy end point at week 52 (SRI rate 43.2 vs 33.5% in placebo; p = 0.02) [25]. In both studies, the cumulative risk of disease flares and time to first flare was in favor of the 10 mg/kg belimumab group [24,25]. Analyses of the pooled data from the BLISS-52 and BLISS-76 studies demonstrated that belimumab-treated (either dose) patients had a sustained and significantly higher decrease in IgG, improvement in complement levels and increase in sero-conversion of autoantibodies than the placebo group [18]. More patients in the belimumab than placebo




groups had improvement in the musculoskeletal and mucocutaneous BILAG domains at week 52 [26]. For patients with no organ domain involvement at baseline, significantly fewer patients treated with belimumab 10 mg/kg versus placebo had worsening in the SELENA-SLEDAI immunological and hematological domains at the end of study. The improvement in the physical component score and vitality domain of the SF-36, and the FACIT-Fatigue scores was significantly greater in the belimumab-treated patients [27]. In the BLISS-52 trial [24], significantly more patients in the 10 mg/kg belimumab group could have prednisone dose reduced by ‡ 50% from week 24 to 52 when compared to placebo (28 vs 18%, p = 0.01). However, in the BLISS-76 study [25], this corticosteroid sparing effect could not be demonstrated. 5.1.1.3 Subsets of SLE patients with better response to belimumab

Post hoc analyses of the two BLISS studies showed that patients with SELENA-SLEDAI ‡ 10, low complement, anti-dsDNA positivity or corticosteroid use at baseline had greater differences in the week 52 SLE SRI rates than placebo as compared to those without these characteristics, indicating a greater magnitude of therapeutic benefit in these subgroups of patients [28]. Secondary end points such as severe disease flares, corticosteroid sparing effect, improvement in fatigue, and health-related quality of life also showed greater effects in the low complement/anti-dsDNA positive subgroup of belimumab-treated patients. Patients with renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 at baseline had increased risk of disease flare over 1 year [29]. Safety of belimumab in SLE Overall, AEs and SAEs, including malignancy and mortality, were similar between the belimumab and placebo groups of patients in the BLISS studies [24,25]. Depression was numerically more common with belimumab treatment and there were two suicides. Although hypersensitivity and infusion reaction (mostly mild) occurred at a similar frequency between belimumab and placebo, serious infusion/hypersensitivity reaction, which could be delayed for several hours after completion of infusion, was more commonly reported in belimumab-treated patients [30]. Safety data pooled from the Phase II [20] and two Phase III studies [24,25] showed that the rates of any SAE were 16.6 and 18.0% with placebo and belimumab (10 mg/kg), respectively [31]. The corresponding rates of serious infusion reactions and serious infections were 0.4 and 0.9%, and 5.5 and 5.3%, respectively. Malignancy rates (excluding nonmelanoma skin cancer) were similar between all belimumab doses and placebo (0.29 vs 0.20 per 100 patient-years). 5.1.1.4

Role of belimumab in the treatment of SLE In March 2011, belimumab was approved by the US FDA for the treatment of autoantibody positive adult patients with 5.1.1.5

active SLE despite standard therapies at the dosage of 10 mg/kg to be given intravenously at 2-week intervals for the first 3 doses, followed by 4-week intervals [11]. This is the first drug to be approved for the treatment of SLE in over 50 years. However, there is a lack of consensus among physicians on the selection of the most appropriate SLE subsets to receive belimumab. What constitutes ‘standard therapies’ depends much on clinical judgment because of the heterogeneity of patients recruited in the belimumab trials [12]. As there are no head-to-head comparative data on the efficacy of belimumab with the conventional agents such as methotrexate, azathioprine (AZA), mycophenolate mofetil (MMF), cyclophosphamide (CYC), tacrolimus and even rituximab, the use of belimumab before an adequate trial of these alternative modalities remains anecdotal. For patients who are reluctant to receive or intolerant to conventional drugs because of toxicities, including those dependent on high-dose corticosteroids with unacceptable side effects, belimumab may be considered. Subsets of SLE patients who may benefit more from belimumab are those with more active disease (SELENA-SLEDAI ‡ 10), particularly musculoskeletal and mucocutaneous manifestations, and greater serological activity (high anti-dsDNA and low complement levels) [26,28]. Belimumab is not studied and not indicated in patients with severe active neuropsychiatric lupus and lupus nephritis (proteinuria ‡ 6 g/day; serum creatinine ‡ 2.5 mg/dl; recent hemodialysis). In fact, only 5.9% of those SLE patients in the two belimumab Phase III trials had proteinuria of ‡ 2 g/day. In a post hoc analysis of 267 (16%) patients with renal disease recruited in the two BLISS trials, numerically more patients treated with belimumab had improvement in proteinuria and renal remission as compared to placebo, in particular those receiving MMF or with serological activity [32]. However, interpretation of the results is confounded by the small number of patients. A new study of belimumab in lupus nephritis is in progress (BLISS-LN) (NCT01639339). Belimumab is not recommended to be used in combination with CYC or other biological agents. The magnitude of clinical benefit of belimumab is modest and its cost-effectiveness in SLE management has to be further explored. Finally, although the rates of lupus flares were shown to be static over 7 years in users of belimumab as maintenance [22], the figures did not take into account patients who discontinued therapy and a reference figure from a control group was unavailable. Based on the current information, belimumab should be used for at least 16 weeks to expect a clinical response. If a response is not achieved in 6 months, treatment discontinuation should be considered [12]. The optimal duration of belimumab therapy in SLE patients is unclear and the decision should be individualized. Atacicept APRIL (a proliferation-inducing ligand), a homolog of BAFF, is also a member of the TNF family that is important for the 5.1.2


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survival and activation of B cells [33]. BAFF binds to three receptors (BAFF-R, TACI, and BCMA) on B cells. While BAFF-R is the only receptor that receives signals uniquely from BAFF, APRIL binds to TACI and BCMA receptors with a higher affinity than BAFF. Atacicept (TACI-Ig) is a fully human recombinant fusion protein that blocks the activity of both BAFF and APRIL [34]. Unlike belimumab which neutralizes only the soluble BAFF, atacicept also inhibits membrane-bound BAFF. A Phase Ib dose-escalating placebo-controlled study in SLE (n = 49) demonstrated biologic activity of atacicept in reducing peripheral mature B cells and Ig level in a dose-dependent manner [35]. Mild injection site reaction was more common with atacicept than with placebo but the frequency of SAEs was not higher. In two Phase II studies of rheumatoid arthritis [36,37], atacicept has been shown to reduce the levels of IgG, IgM and IgA, as well as the number of mature B and plasma cells. However, serious hypogammaglobulinemia and increase in the rate of serious infection was not reported. Unlike the experience with rheumatoid arthritis, atacicept may lead to profound hypogammaglobulinemia in patients with active lupus nephritis and nephrotic range of proteinuria [38]. A Phase II/III randomized, double-blind, placebo-controlled, 52-week study of atacicept (150 mg subcutaneously twice weekly for 4 weeks, then weekly) in patients with active lupus nephritis who received background high-dose corticosteroid (0.8 mg/kg/day or 60 mg/day prednisone) and MMF (3 g/day) was terminated after recruiting 6 patients (4 received atacicept) because of an unexpected and serious decline in serum IgG levels (n = 3) and the occurrence of serious infections (pneumonia; n = 2) [38]. Another 52-week Phase II/III trial of atacicept in 461 patients with SLE was recently reported [39]. Patients with active SLE (‡ 1 BILAG A and/or B) who were treated with a corticosteroid taper for 10 weeks and achieved BILAG C/D were randomized 1:1:1 to receive placebo, atacicept 75 or 150 mg twice weekly for 4 weeks, then weekly for 48 weeks. The primary outcome, defined as the proportion of patients who experienced a new BILAG A or B flare, was not met in the atacicept 75 mg arm (flare rate 57.9 vs 54.1% in controls; p = 0.54). Treatment was discontinued in the 150 mg arm after enrollment of 145 subjects due to two fatal pulmonary infections (flare rate 36.6 vs 54.1% in controls; p = 0.002). Total SAEs and AEs related to infections were, however, similar across the treatment and placebo groups of patients. These findings suggested efficacy of atacicept in SLE but further studies are needed to clarify its risk-to-benefit ratio. Blisibimod Blisibimod (A-623) is a fusion protein consisting of four BAFF-binding domains fused to the N-terminus of the fragment crystallizable region (Fc) of a human antibody. It is a potent BAFF inhibitor that is administered by subcutaneous 5.1.3

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injection [40]. A Phase IIb randomized controlled trial was conducted in serologically active SLE patients (n = 547) with a SELENA-SLEDAI score ‡ 6 at baseline [41]. Patients were randomized to receive 3 dosage regimens of blisibimod or placebo in matching dosing regimens. At week 24, it was demonstrated that blisibimod (200 mg weekly dose) treatment was associated with a significantly higher rate of SRI-5 response (SRI with ‡ 5-point improvement in SELENA-SLEDAI) than the placebo group. The drug was well tolerated at all doses with no increase in the incidence of infections and SAEs. A Phase III clinical trial is in progress (CHABLIS-SC1-NCT01395745). Tabalumab Tabalumab (LY2127399) is a fully humanized monoclonal antibody against both soluble and membrane bound BAFF [42]. A Phase II randomized controlled trial has shown efficacy of tabalumab in patients with active rheumatoid arthritis with an inadequate response to methotrexate but naı¨ve to biological therapy [43]. However, another Phase II study did not demonstrate benefit of tabalumab in active rheumatoid arthritis patients with an inadequate response to the TNF inhibitors [44]. Phase III studies of tabalumab in active SLE without serious renal and neuropsychiatric manifestations are ongoing (NCT01205438 and NCT01196091). 5.1.4

Targeting surface molecules of B cells 5.2.1 Rituximab 5.2

Rituximab is a chimeric monoclonal antibody that is specifically directed against the CD20 molecule on the surface of B cells. Mature B cells and B-cell precursors from pre-B-cell to memory B-cell stage are depleted by this compound, with the sparing of stem cells pro-B cells and terminally differentiated plasma cells that do not express CD20. The Fc portion of rituximab is responsible for antibody-dependent and complement-mediated cytotoxicity, as well as apoptosis of the CD20+ B cells [45]. Re-population of B cells, which normally occurs at 6 -- 9 months after rituximab treatment, predominantly involves a subset of naı¨ve or antigenically inexperienced transitional B cells similar to that after bone marrow transplantation [46]. Although rituximab does not deplete mature plasma cells, repeated courses may lead to hypogammaglobulinemia [47]. Initial experience with rituximab demonstrated its efficacy in refractory SLE manifestations, including renal disease, in both adult and pediatric patients [48-52]. In one earlier study with 10 patients with proliferative lupus nephritis, rituximab and oral prednisolone resulted in good clinical response in 8 patients, coupled with a reduction of T-cell activation markers [51]. Another study of 7 patients with cyclophosphamide-refractory proliferative lupus nephritis showed that the addition of rituximab resulted in reduction of anti-dsDNA and anti-C1q titers, as well as improvement of histology on repeat renal biopsy at 6 months [52]. More recent open-labeled studies have confirmed efficacy of rituximab, used in conjunction with corticosteroids




and other immunosuppressive agents, in refractory, relapsed, or new onset lupus manifestations that include nephritis and neuropsychiatric disease [53-57]. A multicenter study of 116 patients with severe refractory SLE revealed a clinical response (complete or partial) to rituximab in 63% of patients at 6 months [58]. On further follow-up of 20 months, 78% patients responded. SLE flares occurred in 38% of patients after the first infusion. Ramos-Casals et al. [59] reviewed 188 patients with refractory SLE treated with rituximab in the literature. Clinical efficacy was demonstrated in 91% of patients. The commonest indication was lupus nephritis, followed by articular, mucocutaneous, and hematological disease. In all patients, rituximab was used in combination with corticosteroid and 22% of patients were treated with a protocol consisting of intravenous pulse methylprednisolone and CYC. The weekly regimen (375 mg/m2 4 doses) was used in 39% cases and the fortnight regimen (1 g fixed dose 2 doses) was used in 22% of the reports. Weidenbusch et al. [60] summarized 26 reports (300 patients) in the literature regarding the efficacy of rituximab in refractory lupus nephritis. The weekly regimen (375 mg/m2 4) and the fortnight regimen (1 g 2 doses) was used in 49 and 37% of patients, respectively. After 60 weeks, complete or partial renal response was seen in 87% of patients with class III, 76% of patients with class IV and 67% patients with class V lupus nephritis, respectively. A pooled analysis of 164 patients with lupus nephritis treated with rituximab in different European centers was recently reported [61]. Rituximab was administered in combination with corticosteroids (99%) and CYC (35%) or MMF (34%). At 12-months, complete response and partial response was observed in 30 and 37% of the patients, respectively. A higher response rate (complete or partial) was found in patients with class III or mixed types of lupus nephritis in comparison with class IV or pure class V lupus nephritis. Finally, data of 136 SLE patients from a French rituximab registry [62] reported an overall response rate of 71% by improvement in the SELENA-SLEDAI score. Efficacy was similar between patients receiving rituximab monotherapy and those receiving concomitant immunosuppressive agents. Articular, cutaneous, renal, and hematologic improvement was noted in 72, 70, 74 and 88% of patients, respectively. Among responders, 41% experienced a disease flare, which responded to rituximab re-treatment in the majority of cases (91%). Factors affecting response to rituximab in SLE Vital et al. studied 39 SLE patients treated with rituximab (1 g 2 doses) and corticosteroids [63]. After one course of rituximab, the time to relapse was highly variable, with half of the patients having this in 6 -- 18 months. B cell depletion and repopulation were also variable. Persistence of B cells after rituximab is associated with a greater likelihood of not having a clinical response, and a faster repopulation of memory B cells and plasmablasts was associated with earlier relapse of SLE. Other factors that have been reported to influence 5.2.1.1

the clinical efficacy of rituximab in SLE include the FcgammaRIIIa genotype [64], higher absolute CD19+ B-cell counts at baseline [65], failure of early B-cell depletion in the first month of treatment [66], the African race and patients with an expanded autoantibody profile (Ro, nRNP/Sm) and raised BLyS levels at baseline [66]. In addition, up to one-third of SLE patients develop neutralizing antibodies to rituximab [65,67], which may also reduce the efficacy of the drug in depleting B cells. A recent extended follow-up (up to 41 months) of 15 rituximab-treated SLE patients revealed that delayed reconstitution of peripheral blood CD27+ memory B cells was associated with prolonged clinical response and sero-conversion of the autoantibodies [68]. Rituximab regimen without oral corticosteroids The optimal dosage regimen of rituximab, frequency of re-treatment, and combination with other immunosuppressive agents, such as CYC and MMF in the treatment of SLE, has yet to be determined. Despite these uncertainties, efficacy of a rituximab regimen without long-term corticosteroids has recently been proposed [69]. Condon et al. followed 50 patients with lupus nephritis treated with 2 doses of rituximab (1000 mg 14 days apart) and intravenous methylprednisolone (500 mg on days 1 and 15) together with maintenance treatment of MMF (1 g/day titrating to a maximum dose of 3 g/day to a 12 h trough mycophenolic acid level of 1.2 -- 2.4 mg/l). At 52 weeks, complete response and partial response was achieved in 52 and 34% of the patients, respectively. Patients with class III, IV, and V lupus nephritis responded similarly. Relapses occurred in 11 patients, at a median time of 65 weeks from remission. Adverse events were infrequent, with hospital admission in 18% patients and infection occurring in 10% of patients. This regimen, known as RITUXILUP, is different from the conventional use of rituximab in that combination with oral corticosteroid is not required. However, the dosage of concomitant MMF has to be titrated to a target serum level to allow for its optimal effect. The very impressive clinical efficacy of this rituximab regimen without maintenance corticosteroid in lupus nephritis has to be reproduced and compared with conventional treatment regimens for lupus nephritis. 5.2.1.2

Randomized controlled trials of rituximab in SLE As the anecdotal success of rituximab in SLE in open case series may result from publication bias, two randomized controlled trials were recently carried out to evaluate the efficacy of Bcell depletion in extrarenal and renal SLE. The EXPLORER study is a multicenter randomized placebo-controlled trial of rituximab in 257 patients with moderate to severe extrarenal lupus (defined as one or more domain with a BILAG A or two or more domains with BILAG B) despite treatment with one immunosuppressive drug (AZA, MMF, or methotrexate) [70]. Participants were randomized in a 2:1 ratio to receive either rituximab (1000 mg 2 doses 14 days apart) for two 5.2.1.3


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courses administered at baseline and week 26. At week 52, clinical responses (major and partial), AUC of total disease activity and analysis of the BILAG index results showed no statistically significant differences between the rituxumab- and placebotreated patients. A subgroup analysis revealed that rituximabtreated African and Hispanic patients had a better clinical improvement. The frequency of AEs and SAEs were also similar between the two treatment arms. A further analysis of disease flares in those who responded to treatment again did not show significant difference between the two groups in the prevention of moderate or severe flares. However, rituximab treatment was associated with a lower rate of annualized BILAG A flares, and a trend toward prolonging the time to A flares. Using a similar treatment protocol, a Phase III randomized, double-blind, placebo-controlled multicenter study (LUNAR) was performed in patients with active proliferative lupus nephritis [71]. Patients with ISN/RPS class III or IV lupus nephritis and urine protein to creatinine (UP/Cr) ratio > 1.0 were randomized to receive rituximab (1000 mg) or placebo infusion on days 1, 15, 168 (week 24) and 182 (week 26), in addition to corticosteroid and MMF (> 2 g/day). Seventytwo patients were recruited in each treatment arm and twothirds of patients had class IV lupus nephritis. At week 52, no statistically significant differences in the primary and secondary end points were observed between the rituximab- and placebo-treated patients, although there were numerically more responders in the rituximab group (57 vs 46% in the placebo group). However, improvement in anti-dsDNA and complement levels was more marked in rituximab users. Africans treated with rituximab tended to have better response compared to the Caucasians. Adverse effects of rituximab in SLE In the EXPLORER study [70], the rates of SAEs and AEs were similar between the rituximab and placebo groups of patients. Infusion reactions (starting from third infusion) and neutropenia were numerically more common in rituximab users. The rates of serious infections did not seem to be higher in rituximab- than placebo-treated patients. In the LUNAR study [71], although the rates of SAEs and AEs were similar between the rituximab and placebo groups, neutropenia, leukopenia, hypotension, infusion-related reactions, herpes zoster, and opportunistic infections were numerically more common in rituximab-treated patients. Data from the French rituximab registry [62] revealed that 13% of SLE patients developed infusion-related reactions to the drug -- serious in 12% and delayed onset in 29% of patients. Serum sickness like-reactions occurred in 4% of patients. Serious infections occurred at a rate of 6.6/100 patient-years of follow-up. Progressive multifocal leukoencephalopathy (PML) is a rare, progressive, and typically fatal demyelinating disease of the central nervous system caused by the JC virus [72]. After the US FDA MedWatch reported two fatal cases of PML in SLE patients treated with rituximab in 2006 [73], a literature 5.2.1.4

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search revealed 50 cases of PML in rheumatic diseases [74], of which SLE was over-represented (64% of all cases). In 41% of SLE patients, minimal immunosuppressive therapy (low-dose prednisone with or without an antimalarial agent only or no immunosuppressive agents) was given 6 months prior to onset of PML. These observations showed that PML in SLE appeared to be disproportional to the degree of iatrogenic immunosuppression, highlighting the role of host factors in its predisposition to this viral infection. Although the overall incidence of PML in autoimmune diseases is still low, the increased risk of SLE patients should be noted. Physicians should consider PML in any SLE patient who presents with new onset neurologic manifestations, particularly those that worsen with immunosuppressive therapies. Ocrelizumab Ocrelizumab is a fully humanized anti-CD20 monoclonal antibody with a similar action to rituximab. Compared to rituximab, ocrelizumab may have less immunogenicity and complement activation which, theoretically, may reduce the development of drug neutralizing antibodies and infusion reactions. Two international multicenter Phase III double-blind randomized placebo-controlled trials of ocrelizumab in nonrenal (BEGIN) and renal (BELONG) SLE have been conducted [75]. Ocrelizumab was given at either 400 or 1000 mg intravenously on day 1 and day 15, with repeat single dosing every 4 months. The BEGIN study was discontinued early. The BELONG study recruited patients with proliferative lupus nephritis (class III/IV), who were randomized to receive ocrelizumab at 2 doses or placebo on top of high-dose glucocorticoids and either MMF or CYC (according to the Euro-lupus protocol, i.e., 500 mg intravenous 2-weekly for 6 doses, followed by AZA). A total of 381 patients were recruited before the trial was terminated early because of an imbalance of the rate of serious infections in patients receiving ocrelizumab compared to placebo. In 223 patients who had passed the 32-week treatment point, the overall renal response of the combined ocrelizumab groups (67%) was nonsignificantly higher than that of placebo (55%) [76]. However, there was a greater difference in the treatment effect between ocrelizumab and placebo in those who received the CYC as compared with the MMF regimen. The increase in serious infections with ocrelizumab occurred with background MMF but not with the CYC regimen. Infusion reactions occurred more frequently with ocrelizumab than placebo infusion (12 vs 9%) and these developed most commonly during the first infusion of the first course. Neutropenia occurred exclusively in around 2% of the ocrelizumab users. 5.2.2

Epratuzumab Epratuzumab is a humanized monoclonal IgG antibody that specifically targets the CD22 antigen on mature B cells, which is a B-cell-specific surface antigen involved in the modulation 5.2.3




of B cell receptor signaling, cellular activation, and survival [77]. Compared to rituximab, epratuzumab exhibits less cytotoxic but more modulatory effects on B cells [78]. In vitro study shows that epratuzumab promptly induces a prominent reduction of CD22, CD19, CD21, and CD79b on surface of B cells derived from patients with SLE [77]. Although some Fc-independent loss of CD22 is expected from internalization by epratuzumab, the concurrent reduction of CD19, CD21, and CD79b is Fc-dependent and results from their transfer from epratuzumab-opsonized B cells to FcgR-expressing monocytes, natural killer cells, and granulocytes via trogocytosis. As epratuzumab does not induce complementdependent cellular cytotoxicity, infusion reaction is not reported in patients recruited in clinical studies. In a pilot trial, administration of epratuzumab leads to a modest 35 -- 40% reduction in peripheral B cells (mainly CD27-) without significant effects on T cells, autoantibody titers or immunoglobulin levels [79,80]. Two earlier randomized placebo-controlled trials of epratuzumab (ALLEVIATE-1 and 2) in addition to standard of care in SLE patients with moderate to severe activity were terminated because of the disruption of drug supply [78]. Analyses of the available data (n = 90) showed some short-term efficacy of epratuzumab in terms of clinical response and quality of life, and confirmed its safety [81,82]. A more recent Phase IIb randomized controlled trial (ENBLEM) in 227 SLE patients with moderate to severe disease activity (excluding severe neuropsychiatric and renal disease) showed that the overall responder rate at week 12 was nonsignificantly higher in all epratuzumab groups than placebo [83]. Post hoc analyses showed that patients who received a cumulative dose of 2400 mg of epratuzumab showed a significantly better improvement than placebo. The frequencies of AEs and SAEs, including infusion reactions, were comparable across all groups of patients. Epratuzumab led to a moderate reduction in the absolute B-cell counts without affecting the serum immunoglobulin levels. Although this study was not powered to detect a difference in clinical efficacy across treatment arms, it indeed shows that epratuzumab may be an effective option for SLE in addition to standard therapies. Phase III studies are ongoing (EMBODY 1 and EMBODY 2 -- NCT01262365 and NCT01261793). 5.3

B-cell tolerization Abetimus sodium (LJP394)

another multicenter Phase II/III trial of 230 patients with lupus nephritis, which demonstrated that in a subgroup of patients with high-affinity serum IgG fraction for the DNA epitope of abetimus, weekly infusion of abetimus sodium (100 mg) significantly reduced the number of renal flares and prolonged the time to renal flare at 76 weeks compared with placebo [85]. However, in a subsequent Phase III trial of 317 SLE patients with a history of renal flare and anti-dsDNA titer of ‡ 15 IU/ml, abetimus (100 mg/week) did not significantly prolong the time to renal flare, the need for rescue immunosuppressive therapy, or the time to major SLE flares as compared to placebo after up to 22 months in an intentto-treat population based on the presence of high-affinity antibodies to abetimus at baseline [86]. As a higher dose of abetimus may suppress anti-dsDNA antibodies more profoundly without undue adverse effects, a clinical trial (ASPEN) using a much higher dose of abetimus (900 mg/week) was initiated [87]. This event-driven randomized placebo-controlled international Phase III trial recruited 943 SLE patients with a history of renal disease. However, the study was terminated when interim efficacy analysis indicated that it would be futile to continue. Targeting proteasomes In patients with SLE, the long-lived plasma cells, which represent a major fraction of autoantibody-producing B cells, are generally resistant to immunosuppressive therapies, including the B-cell depleting agents described earlier [88]. The retention of these cells may be responsible for perpetuation of disease activity or disease flares. Bortezomib, an inhibitor of the 26S proteasome that enhances killing of the myeloma plasma cells [89], has been used with success in several murine models of lupus [90-92]. Proteasome inhibition leads to a preferential reduction of autoantibody producing plasma cells and abrogates in vitro and in vivo IFN-a production from toll-like receptor activated plasmacytoid dendritic cells, mediated by the inhibition of both the survival and functions of these cells [90]. Successful treatment of human SLE with bortezomib has been reported [93,94] and linked to the killing of the long-lived and short-lived plasma cells. However, the high incidence of neurological, gastrointestinal, and hematological side effects is the major limiting factor for the further study of this drug in SLE. Other proteasome inhibitors with a better safety profile have to be explored. 5.4

5.3.1

Abetimus sodium consists of four dsDNA epitopes conjugated to a non-immunogenic polyethylene glycol platform. It tolerizes B cells by cross-linking anti-dsDNA immunoglobulin receptors on their cell surfaces and triggering the signal transduction pathways that lead to B-cell anergy or apoptosis [84]. An initial placebo-controlled study demonstrated a significant and persistent reduction of anti-dsDNA titers in patients receiving the highest dose of abetimus without an increase in the frequency of adverse events [84]. This was followed by

5.5

Targeting co-stimulatory molecules Abatacept

5.5.1

The interaction of CD80 or CD86 molecule on B cells and CD28 on T cells provides an important second co-stimulatory signal for T-cell activation, which is important for the subsequent antibody production by B cells. Abatacept (CTLA4-Ig) is a recombinant fusion protein consisting of the extracellular domain of CTLA4 and a modified fragment of Fc domain of human IgG1 that binds CD80 or CD86 with


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a higher affinity than CD28, and thus inhibits this costimulatory pathway and subsequent full T-cell activation [95]. Administration of CTLA4-Ig has been shown to delay onset of autoimmunity and mortality in different murine SLE models [96-98] through reduction of autoreactive B cells, inhibition of immunoglobulin switching and production of autoantibodies, and ameliorating histological glomerular inflammation. Combining CYC and CTLA4-Ig was more effective than either agent alone in reducing renal disease severity and mortality in the NZB/W lupus mice [99]. A 12-month Phase IIb exploratory double-blind, placebocontrolled trial was carried out to evaluate the safety and efficacy of abatacept in nonrenal SLE [100]. Patients (n = 175) with predominantly active lupus arthritis (54%), discoid skin lesions (34%) or serositis (11%) were randomized in a 2:1 ratio to receive intravenous infusion of abatacept (10 mg/kg) or placebo on days 1, 15, 29, and then every 4 weeks. Prednisone (30 mg/day or equivalent) was given for 1 month and tapered per protocol. At 12 months, the proportion of patients with the primary end point (new BILAG A or B flare) following corticosteroid taper was nearly identical between the abatacept and placebo groups of patients (79.7 vs 82.5%). Secondary efficacy end points (new SLE flare within the initial 6 months, total number of SLE flares per patient, time to a SLE flare, and proportion of patients with no SLE flares while receiving low-dose prednisone (£ 7.5 mg/day) for any 2 consecutive months) were also not met. Post hoc analyses revealed that severe SLE flares (BILAG A) were less frequent in abatacept- than placebo-treated patients (40.7 vs 54.4%) over 12 months. The treatment difference was greatest in patients who had polyarthritis as the primary manifestation. Improvement in patient-reported outcomes, such as quality of life, fatigue, and sleep problems score was greater in abatacept- than placebo-treated patients. However, SAEs were numerically more frequent in abatacept- than placebo-treated patients (19.8 vs 6.8%). In a 12-month Phase II/III multicenter randomized controlled trial, 289 patients with active ISN/RPS class III or IV proliferative lupus nephritis [101] were randomized to receive abatacept (30 mg/kg loading for 3 months, followed by 10 mg/kg), abatacept (10 mg/kg), or placebo infusion on top of corticosteroids and MMF. The initial dosage of prednisone (or equivalent) was 30 -- 60 mg/day with taper to 10 mg/day at week 12, and the target dosage of MMF was 2 g/day for Caucasians or Asians, and 3 g/day for Africans at day 57. Complete response was defined as a UP/Cr of < 30 mg/mmol, inactive urinary sediment and an estimated glomerular filtration rate of no more 10% of the baseline value. After 52 weeks, no significant difference in the time to reach a complete response (predefined primary end point) was observed among the treatment and placebo groups of patients. The proportion of patients who achieved complete response and renal improvement criteria was also similar in the three groups. However, exploratory post hoc analyses 312

indicated that when other definitions of renal response (e.g., those used in the LUNAR study) were used, a positive effect of abatacept could be observed [102]. The incidence of SAEs was nonsignificantly higher in the abatacept groups. Based on the success in the murine models of SLE, the role of abatacept--CYC combination for treating SLE was explored. A Phase II randomized placebo-controlled trial testing the efficacy of abatacept (500 -- 1000 mg based on body weight) in addition to high-dose oral prednisone and low-dose intravenous CYC (500 mg 2-weekly for six doses, followed by up to 2 mg/kg of AZA, i.e., the Euro Lupus regimen) in proliferative (class III/IV) lupus nephritis (ACCESS) was started. Interim analysis showed that at week 24, abatacept-treated patients did not achieve a significantly higher renal response rate than the placebo group [103]. Subgroup analysis of different ethnic groups also did not show any difference between abatacept and control groups of patients. Treatment is still unblinded and repeat analysis will be performed after a longer period of observation. Targeting T cells Synthetic peptides developed to target inappropriate inflammatory responses have been tested in various autoimmune diseases [104]. The advantage of such a strategy is restoration of immune tolerance without suppressing the immune system. 5.6

Edratide Edratide (hCDR1) is a synthetic peptide based on the sequence of the first complementarity-determining (CDR1) region of a pathogenic human anti-DNA monoclonal antibody (16/6 idiotype). Edratide ameliorated the clinical manifestations of murine and human lupus by downregulating pathogenic cytokines and apoptosis, IFN-a gene expression, and upregulates immunosuppressive molecules and Tregs cells in peripheral blood mononuclear cells of patients with SLE [105-107]. However, a 24-week Phase II dose-escalating study of 340 SLE patients with mild to moderate disease activity was halted because the primary end point of a reduction in SLEDAI-2K scores was not achieved [108]. 5.6.1

Rigerimod (Lupuzor) The P140 peptide (Rigerimod) is a 21-mer linear peptide that is issued from the small nuclear ribonucleoprotein U1-70K and phosphorylated at the Ser140 position. It is a promiscuous MHC class II binder that is recognized by the T cell receptor of CD4+ T cells [104]. Through unknown mechanisms, this peptide blocks inappropriate T-cell reactivity to MHC-presented self-peptides, thus restoring immune tolerance. In the MRL/lpr lupus mice, P140 inhibited antidsDNA production, dampened proteinuria and improved their survival [109,110]. An early Phase IIa study of 20 patients with active SLE showed that three 2-weekly subcutaneous injection of rigerimod (200 µg) was safe and led to improvement of disease activity and reduction in anti-dsDNA 5.6.2




titers [111]. Another Phase IIb randomized placebo-controlled trial of 136 SLE patients with SLEDAI-2K ‡ 6 but without BILAG A score confirmed that subcutaneous injection of rigerimod (200 µg) 4-weekly in addition to standard therapy achieved a significantly higher SRI than placebo at week 12 (62 vs 39%), and was well tolerated [112]. The most common adverse event was a mild injection-site erythema. A new Phase III study of rigerimod in lupus has been approved by the FDA. Laquinimod Laquinimod is an oral medication that has been shown to be effective in the treatment of relapsing-remitting multiple sclerosis [113]. Laquinimod exerts immunomodulating effects on antigen presenting cells that direct T cells toward an antiinflammatory phenotype characterized by downregulation of the pro-inflammatory cytokines, such as IL-6, IL-12, IL-17, IL-23, and TNF-a, but increasing production of IL-10. A Phase IIa randomized placebo-controlled study was performed in 46 patients with active lupus nephritis in addition to high-dose corticosteroids and MMF [114]. Preliminary results showed that combination of laquinimod (0.5 mg and 1.0 mg/day) to MMF and corticosteroid had an additive effect in improving renal function and proteinuria. AEs and SAEs were not significantly increased in the treatment groups. A larger study is being planned.

Another anti-IL-6 monoclonal antibody (sirukumab) was tested in a Phase I placebo-controlled study in 46 patients with either SLE or cutaneous lupus [120]. Sirukumab led to dose-independent reduction in total while cell, absolute neutrophil and platelet counts and minor elevation in total cholesterol levels. AEs and minor infections were numerically more common in sirukumab than placebo groups of patients. Treatment was generally well tolerated and further clinical trials are in progress.

5.6.3

5.7

Targeting cytokines and complements IL-6 inhibition

5.7.1

IL-6 is mainly secreted by activated macrophages and T cells and is induced by other cytokines such as TNF and IFN-g. IL-6 may act synergistically with the type I interferons to activate B cells and enhance autoantibody production that includes anti-dsDNA. Administration of an anti-mouse antiIL-6 or anti-IL-6 receptor monoclonal antibody prevented increase in anti-dsDNA, progression of proteinuria, and reduced mortality in the lupus prone mice [115,116]. IL-6 is elevated in patients with active SLE and correlated with disease activity and anti-dsDNA levels [117]. An open-label Phase I study of tocilizumab in 16 SLE patients with mild to moderate activity were given 2-weekly infusion of the drug for 12 weeks (2, 4, or 8 mg/kg) [118]. SLEDAI score improved by > 4 points in more than half of the patients, which was coupled with a reduction in anti-dsDNA levels. Arthritis improved in all patients who had this manifestation at baseline. Laboratory analysis revealed that activated T and B cells, plasmablasts, and post-switched memory B cells were decreased with tocilizumab treatment [119]. On the contrary, antigen-inexperienced IgD+CD27- B cells and mature naı¨ve B cells increased significantly. However, tocilizumab led to a dose-related decrease in neutrophil count [118]. Infections occurred in 69% of patients but none were associated with neutropenia. It was concluded that although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, further studies are warranted.

Type I IFNs The type I IFNs, in particular IFN-a, have been implicated in the pathogenesis of SLE [121]. Immune complexes consisting of DNA- or RNA-containing autoantigens induce production of type I IFNs by immature plasmacytoid dendritic cells through FcgR-dependent internalization of these complexes and activation of the TLR7 and 9 receptors [122]. Elevated levels of IFN-a, IFN-driven chemokines, and expression of IFN-regulated genes were demonstrated in patients with SLE, and correlated with disease activity, anti-dsDNA, complements, and serum IL-10 levels [123-129]. Polymorphisms of several components of the IFN signaling pathway have been associated with increased susceptibility to SLE [130,131]. Sifalimumab (MEDI-545) is a fully humanized anti-IFN-a monoclonal antibody that binds specifically to most IFN-a subtypes and prevents signaling through the type I IFN receptor. A Phase Ia placebo-controlled study in patients with moderate disease activity established safety of the drug and its efficacy in inhibiting type I IFN-induced mRNAs (type I IFN signature) in whole blood and corresponding changes in related proteins in affected skin [132]. Another Phase I randomized placebo-controlled dose-escalating study in 161 SLE patients with moderate-to-severe disease activity showed sustained inhibition of IFN gene signature after sifalimumab treatment [133]. Although clinical activity between treatment and placebo groups of patients did not differ significantly, this study confirmed safety of the study drug and supported its further development. Rontalizumab, another human IgG1 monoclonal antibody that neutralizes all known isoforms of human IFN-a, has also been tested in SLE. A Phase I double-blind placebo-controlled trial of rontalizumab in 60 SLE patients again established safety of this agent and its efficacy in reducing the expression of IFN-regulated genes [134]. One hundred and fifty-nine SLE patients with moderate to severe extrarenal SLE were randomized to receive rontalizumab (intravenous or subcutaneous) or placebo in a Phase II study [135]. Immunosuppression was discontinued at study entry and prednisone was tapered to £ 10 mg by week 8. At week 24, the overall response rates by BILAG or SRI were similar between the treatment and placebo groups. Post hoc analysis of a subgroup with low expression of the IFN genes showed a significantly higher rate of SRI and lower rate of flares in the intravenous rontalizumab than placebo arm of patients. However, there were more 5.7.2


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SAEs in the treatment than placebo group of patients, particularly in patients with high IFN gene expression at baseline. More recently, immunization with the IFN-a-kinoid (IFN-K) has been shown to be safe and efficacious in inducing polyclonal antibodies that neutralize all 13 subtypes of human IFN-a in 28 women with mild to moderate SLE [136]. IFN-K led to decrease in the expression of IFN-induced genes and improvement in complement C3 levels, which correlated with the anti-IFN-a antibody titers. Complements Early complements are important in the clearance of immune complexes and apoptotic bodies in patients with SLE. Complements are also important in the regulation of T-cell and B-cell functions [137]. Activation of terminal complement is associated with disease flares and damage to tissues and organs, particularly in lupus nephritis. Monoclonal antibodies that specifically inhibit terminal complement activation while preserving the critical functions of the early complement cascade are now available. A monoclonal antibody targeting the C5 complement protein and blocks its cleavage (eculizumab) has shown promise in the lupus prone mice by delaying the onset of proteinuria, ameliorating the course of nephritis and improving survival [138]. A Phase I single dose study in SLE patients demonstrated that eculizumab was safe and well tolerated [137,139]. 5.7.3

6.

Potential development issues

Conventional therapies for SLE are not ideal in terms of efficacy and safety profile. Biological agents are being developed in order to enhance the therapeutic efficacy, prevent disease flares and reduce treatment related toxicities. The failure of recent major clinical trials of B-cell modulation and blockers of the co-stimulatory pathway has added uncertainties to this development but also provided insights for future trial designs. Inclusion criteria and treatment protocol design, assessment tools for SLE activity, and end points for efficacy might all influence the performance of randomized controlled studies. 7.

Conclusion

Despite the futility of recent clinical trials of several biological agents, the encouraging preliminary results of ongoing studies such as epratuzumab and blisibimod, and the approval of belimumab confirm that B-cell modulation remains a promising approach in the treatment of SLE. The synthetic peptides and the oral immunomodulator may also prove to be effective treatments for SLE. The variability of clinical response among SLE patients may reflect the clinical heterogeneity of the disease and the failure of treatment to eliminate the pathological memory B-cell clones and long-lived plasma cells. Ironically, depletion of these cells may increase the risk of serious infections and hence lower the benefit-to-risk ratio of the targeted 314

therapies. Improvement in study design and the definitions of efficacy end points is needed in future clinical trials of biologics in SLE. Enhancing the treatment efficacy of more serious or refractory SLE manifestations remains an unmet need as these are the major determinants for mortality and morbidity of the disease. The long-term safety and cost-effectiveness of the novel biologics in SLE has to be explored. 8.

Expert opinion

Study design and treatment protocol of clinical trials

8.1

The clinical and immunological heterogeneity of SLE makes it difficult to design clinical trials. Manifestations with different pathogenic mechanisms are often grouped together for the evaluation of the effect of a novel treatment modality (e.g., the belimumab, abatacept trials). Even if a regimen is shown to be effective, candidates who are most likely to benefit are uncertain as the results are derived from a heterogeneous population. Sample size of subgroups may not be large enough to make any solid conclusions. Perhaps inclusion of specific SLE subsets with a narrow range of manifestations such as those with biopsy proven nephritis or arthritis may help improve the homogeneity of the population studied. However, this requires a bigger sample size. The problem is further escalated by the inter-ethnic difference in the response to treatment and tolerability. An example is lupus nephritis in which the Africans may respond better to MMF and the Asians cannot tolerate higher doses of MMF (beyond 2 g/day) [140]. In the LUNAR study [71], the overall sample size may not be large enough to detect a difference between the treatment and placebo groups of patients. Despite the fact that a more favorable response was observed in the Africans, the study was not powered to evaluate this subgroup further. Moreover, as lupus nephritis may take > 52 weeks to respond to a treatment regimen, the superiority of rituximab to placebo may not be apparent in such a short-term study. Biomarkers may act as surrogate indicators for the pharmacologic response to novel therapeutic agents and supporting a hypothesized mechanism of action. They may also help to identify subsets of patients who benefit more from the new therapies. Although there are still no known biomarkers that have been validated in SLE, they can be combined with the primary clinical end point in future clinical trials to enhance the understanding of the efficacy of new biological agents in SLE. Refractory versus non-refractory lupus manifestations

8.2

The development of novel therapies for patients with more serious or refractory lupus manifestations remains an unmet need. While controlled studies of belimumab, rituximab, and abatacept studies have excluded patients with severe or




refractory lupus renal and neuropsychiatric diseases, these manifestations are often reported to respond to B-cell depletion, in particular rituximab, in uncontrolled studies [48-62]. Thus, the negative results of these controlled studies do not necessarily imply that these agents are not effective in refractory or severe SLE manifestations. Randomized controlled trials of the novel biological agents in refractory lupus manifestations are needed to resolve this issue. In the ACCESS trial, patients were not suffering from refractory renal disease [103]. The negative result cannot rule out the efficacy of the CYC--abatacept combination regimen for refractory lupus nephritis. The positive post hoc results of the two abatacept and SLE studies [100,101] also suggest that abatacept can be considered as an off-label treatment for refractory arthritis or nephritis related to active SLE. However, whether abatacept should better be combined with MMF or CYC for serious lupus manifestations is unclear. Background immunosuppressive treatment In the EXPLORER and LUNAR studies, the background immunosuppressive treatment (such as moderate to high dose corticosteroids) in the protocol may have been effective for the majority of cases, leading to a higher than expected response rates in the placebo arm [70,71]. This may have led to a false negative result because a much bigger sample size is required to show the difference in efficacy between rituximab and placebo. Similarly, in the abatacept nonrenal lupus trial [100], the background immunosuppression (moderate dose of prednisone) itself is highly effective for the manifestations studied. This may have masked the efficacy of abatacept. Tapering or minimization of immunosuppressive therapies before entry into a study of novel agent should be considered in future trials. 8.3

Treatment regimen Furthermore, while most positive reports of rituximab in severe or refractory SLE involved a combination of rituximab (weekly dose of 375 mg/m2 4 doses) with CYC instead of MMF, it remains to be seen if the lower efficacy of the regimen in the rituximab controlled studies is due to the lower rituximab dosage (1000 mg 2 doses in total) and with MMF combination. In the ocrelizumab study, it appears that the synergism between B-cell depletion and CYC is greater than that of MMF [76], suggesting that the CYC combination should be further studied in more serious or refractory lupus manifestations. 8.4

Toxicities of therapies Some of the novel biological agents have indeed shown efficacy in the treatment of SLE. However, further development is halted because of adverse safety signals. In the ocrelizumab study [76], a synergistic effect was observed between the drug and low-dose CYC in the treatment of lupus nephritis. Atacicept was also effective at higher dose, but this was associated with increased risk of serious infection [39]. In the 8.5

abatacept SLE studies [100,101], there were numerically higher incidence of SAEs with abatacept than with placebo treatment. Interestingly, the observed increase in serious infections in the ocrelizumab studies occurred mainly in the group with concomitant high-dose corticosteroid and MMF treatment [76]. Similarly, in the atacicept studies, hypogammaglobulinemia and serious infections also occurred in combination with corticosteroids and MMF [38,39]. Whether the combination with MMF is the culprit for more profound immunological effects of the biological agents warrants further study. Nevertheless, the observation suggests that B-cell modulation remains a promising approach for the treatment of SLE but the risk-to-benefit ratio has to be considered in the development of future therapeutics. In view of the limited treatment and follow-up duration of randomized controlled trials, rare adverse events like uncommon opportunistic infections and long-term complications of therapies such as malignancies and mortality cannot be evaluated. Data from national registries of biologics are needed for the real-life assessment of long-term safety and efficacy of novel therapeutic agents in patients with SLE. An initiative was commenced in the United Kingdom with the establishment of the BILAG Biologics Registry for SLE.

Assessment tools and predefined efficacy end points

8.6

The SLEDAI [141] and its modifications SLEDAI-2000 [142] and SELENA-SLEDAI [143] are global indices that include 24 weighted clinical and laboratory items with a scoring range from 0 to 105. The indices have the advantages of measuring lupus activity quantitatively and objectively in the past 10 days. They are simple and easy to use in clinical practice. Definitions for mild or moderate and severe disease flares are available in the SELENA instrument. However, a key problem of these global indices is that the change of activity in individual systems cannot be reflected. Moreover, partial improvement or deterioration to treatment cannot be captured. The BILAG scoring system [144] captures improvement and deterioration of disease activity in eight organ system domains in the past 1 month, mainly based on the need to change therapies. It is the only organ-specific index that scores lupus manifestations as new, the same, worse, improving or never present in each item. Each organ system is scored for disease activity with A (most active), B (moderate active), C (mild activity), D (stable), or E (never involved). The total score ranges from 0 to 81. As the BILAG consists of 86 items, it is obviously time consuming to complete. Moreover, the decision to change treatment by physicians may not necessarily correlate with the presence of residual disease activity and may be limited by other clinical circumstances. Training is needed for investigators for BILAG scoring. The PGA [145] is a visual analog scale using three benchmarks for assessing disease activity in the past 2 weeks. The score ranges from 0 to 3 and an increase of ‡ 0.3 points


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from baseline or last visit is considered to indicate significant worsening of disease activity. Although the scale is simple to use and sensitive to reflect the change in the overall status of patients, it is subjective, semi-quantitative, and subject to variability among different doctors. In the belimumab trials, a composite index (SRI) was designed to define clinical response. This SRI incorporates the strengths of different activity indices by quantifying the improvement in disease activity (SELENA-SLEDAI), and ensuring no worsening in the overall status of the patients (PGA) and in previously unaffected organ systems (BILAG). Although the SRI has not been thoroughly validated, it is being used in ongoing studies of biological therapies in SLE patients. Because of the involvement of three indices, the SRI is fairly tedious and may not be applicable in daily clinical practice. As the weighted score is different in different organ systems in the SELENA-SLEDAI, the cut-off of improvement by 4 or more points may not be sensitive enough to capture improvement in certain systems. In other words, patients who do not meet the SRI criteria for a response may not necessarily be nonresponders to treatment from the clinical point of view. The FDA guidance document on how to conduct clinical trials in SLE [146] states the primary end point for clinical improvement in SLE activity be determined by a disease activity index has documented validity, reliability, and sensitivity to change in the targeted clinical trial setting. The BILAG is the preferred index but other disease activity indices can be used in clinical trials if the instrument measurement properties are adequate for the specific clinical trial setting. Evaluation of SLE flares in clinical trials can either be a reduction in the frequency of flares or an increase in the time to flare for a new agent compared to the control group. If time to flare is evaluated as the primary end point, the trial duration should be at least 1 year. Acceptable flare indices for clinical trials include the BILAG and SELENA-SLEDAI flare instrument. More recently, a SLEDAI-2K Responder Index 50 was developed to capture partial improvement in disease activity in different domains of the index [147]. This responder index has been validated to be sensitive in identifying clinical

316

response in longitudinal studies of SLE [148] and may prove useful in future clinical trials of novel therapeutic agents in SLE. An analysis of the Phase IIb epratuzumab trial showed a discrepancy of the response rates based on different composite outcome measures [149]. This was attributed by the inconsistent scoring of the individual items on SLEDAI-2K and BILAG. In the abatacept nonrenal SLE trial [99], there was also discordance between flares defined by the BILAG criteria and the treating physicians’ opinion in this study (lower rate of flares as assessed by physicians). Thus, the inclusion of both severe (BILAG A) and moderate (BILAG B) SLE flares for the definition of the primary efficacy outcome may have underestimated the true incidence of disease flares. In fact, when more serious BILAG A flares were considered, a greater difference was observed between the treatment and placebo groups of patients. This illustrates that the inconsistency of reporting by the investigators may lead to unexpected results in clinical SLE trials. Thus, appropriate training should be given to all members of the study teams and regular monitoring for the consistency of the SLEDAI and BILAG should be performed. Finally, defining an appropriate primary efficacy end point in the evaluation of a new treatment modality for SLE is of paramount importance. For instance, in the abatacept lupus nephritis trial [101], the predefined primary efficacy end point appeared to be too stringent in terms of the change in glomerular filtration rate and the target proteinuria level. Post hoc analyses of the data using different definitions for renal response in fact demonstrated efficacy of abatacept [102]. Medical advancement has led to the emergence of novel targeted therapies for SLE. With the improvement in study design and identification of the most suitable patient subsets, it is expected that new treatments with a high benefit-to-risk ratio will soon be available and the survival and quality of life of patients with SLE can continue to improve.

Declaration of interest CC Mok received one-off honoraria from Pfizer and GlaxoSmithKline for delivering lectures in the past 12 months.



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Affiliation Chi Chiu Mok MD FRCP Tuen Mun Hospital, Department of Medicine, Tsing Chung Koon Road, New Territories, Hong Kong, SAR, China Tel: +852 2468 5386; Fax: +852 2456 9100; E-mail: [email protected]

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