Biologicals for the treatment of systemic lupus erythematosus?

Abstract

The need for drug development in order to improve disease outcome and limit side-effects in severe lupus is an issue of major concern for both patients and clinicians dealing with lupus patients. For many years, results from randomized trials in systemic lupus erythematosus (SLE) have been very disappointing, with lack of efficacy for some drugs and development of severe side-effects such as infections for others. Fortunately, as more and more trials of biologics in the treatment of lupus are being performed, the first promising results have been achieved. Today, belimumab is expected to become the first approved drug for use in lupus in several decades, and preliminary reports showing beneficial results with epratuzumab have been presented. We may be at the threshold of a new era in SLE therapeutics.

Key words::

• Biologics
• systemic lupus erythematosus
• treatment

Key messages

• The need for new drug development for severe lupus is an issue of major concern.

• Earlier results from randomized trials in systemic lupus erythematosus (SLE) have been very disappointing, but in the last year more positive results have been achieved.

• Today, belimumab is expected to become the first approved biological drug for use in lupus, and results from other promising trials are awaited.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease characterized by dysregulation of the immune system. Hyperreactivity of both T and B lymphocytes is a prominent feature and plays a central role in the pathogenesis. The hyperreactive B cells lead to autoantibody formation against numerous autoantigens, causing immune complex formation and organ damage due to deposition in the tissue.

An increased morbidity and mortality is seen among lupus patients despite an improvement in therapeutic options during the past years. However, the therapies available today for treatment of lupus are mainly ‘borrowed’ from other specialities, and only a few drugs are today licensed for use in lupus. In fact, only acetylsalicylic acid, antimalarials, and prednisone have received Food and Drug Administration (FDA) approval for the treatment of lupus to date. The situation is similar in European countries, but some differences exist. For example, in Sweden, cyclophosphamide is approved for the treatment of lupus nephritis.

The therapy of lupus is based on the use of corticosteroids, alone or in combination with antimalarials and immunosuppressants including azathioprine, methotrexate, cyclosporin A, and mycophenolate. In severe or life-threatening disease, mainly in cases with lupus nephritis or CNS disease, the alkylating agent cyclophosphamide has been standard of care over the past decades.

The development of new biologic therapies has in recent years led to a substantial improvement in disease outcome in the treatment of rheumatological diseases such as rheumatoid arthritis (RA). Despite similar needs, less progress has been achieved in the field of biological agents in the treatment of lupus. In general, a challenge for SLE clinical trials is to allow some degree of flexibility in the use of background medications, due to the fluctuating and unpredictable course of the disease. Completely ‘fixed’ background medications, such as are customary for trials in RA and other arthritides, would not be feasible and also ethically questionable in trials of SLE. Although a number of noted failed trials have been reported or published, some recent clinical trials with more positive results suggest that biologics will begin to play an important role in the treatment of SLE as early as 2011. In this review we will summarize the development and results of biological therapies in lupus over the past decade. These include different targets to treat including anti-cytokine therapies, B cell depleting or modifying drugs, and therapies that interact with T cell activation.

Anti-cytokine therapies

IL-10

Interleukin (IL)-10 is a multifunctional cytokine that plays a role in growth and differentiation of B cells and autoantibody production. Serum IL-10 levels are significantly elevated in patients with active lupus and have been found to correlate with disease activity and anti-dsDNA levels (1), suggesting it could be a potential target for therapeutic interventions in SLE. The first report on the use of such a biologic therapy in lupus was published in 2000 by Llorente et al., describing the effects of monoclonal anti-IL-10 antibodies in a limited cohort of patients with active and steroid-dependent lupus (2). Although the treatment was effective regarding joint and cutaneous symptoms, all patients developed antibodies against the drug, and no further studies have been published to date on the use of anti-IL-10 in SLE.

Role of TNF-blocking therapies in lupus?

Tumour necrosis factor (TNF) is a proinflammatory and regulatory cytokine and has been shown to be elevated in SLE serum. TNF-inhibitors are used widely in rheumatology and have during the past decade in a dramatic way altered the disease course and prognosis for large groups of patients with RA and other arthritides. Because some animal experimental studies suggested that treatment with recombinant TNF-α was beneficial in inducing a delay in nephritis development in at least one animal model of SLE (3), anti-TNF agents in patients with SLE have never come to general use. Although serum TNF levels are increased in lupus patients, the use of TNF-blocking agents in SLE has been felt to be contraindicated, also due to observations on the development of SLE-related autoantibodies (anti-nuclear antibodies (ANA), anti-dsDNA antibodies, anti-cardiolipin antibodies) (4), and even the development of a drug-induced lupus-like syndrome in some patients with RA who were treated with anti-TNF agents. Thus, experiences with anti-TNF have only been described for a very limited number of patients. Aringer et al. first described the use of infliximab in a small cohort of SLE patients with nephritis or arthritis, showing long-standing effects in the nephritis subpopulation but with a concomitant increase in the titres of several autoantibodies. The arthritis in these patients improved temporarily but required repeated infusion to maintain effect, just as is generally the case in RA patients (5). Follow-up data from 13 infliximab-treated patients demonstrated an increase in life-threatening infusion-related events including fatal complications after repeated administration of the drug (6), and two randomized controlled trials using TNF inhibitors (infliximab and etanercept) for use in active lupus nephritis have been terminated because of recruitment difficulties (www.clinicaltrials.gov). Based on the available data, the use of TNF-blockers in SLE is controversial and today not recommended in SLE.

Anti-interferon-alpha

SLE patients have elevated serum levels of interferon-alpha (IFN-α), and studies have reported that serum IFN-α levels correlate with disease activity and severity (7). A subset of SLE patients have been shown to have an elevated expression of type I interferon-regulated genes, an ‘IFN signature’. Therapies using monoclonal antibodies directed against IFN-α are currently undergoing clinical trial including rontalizumab and sifalimumab as well as an anti- IFN-α-inducing ‘kinoid’, a novel approach where the cytokine itself is modified and used as a vaccine to induce blocking antibodies in the host. In a phase I dose-escalating study with a single injection of sifalimumab, a dose-dependent inhibition of type I interferon-regulated genes was shown both in the circulation and in skin biopsies (8). Furthermore, an improvement of disease activity was shown, and the treatment was associated with down-regulation of proinflammatory cytokines. A dose-dependent reduction in the IFN-regulating pathway has also been shown in initial reports in a phase I study with rontalizumab (9).

Thus, inhibition of IFN-α is an intensively investigated approach to SLE. Laboratory and animal data support this approach, and initial studies have supported sufficient safety to continue and demonstrated a biological effect. Most likely, the key issue with this approach will be the safety of such treatments. IFN-α plays key roles in protection from viral infections including influenza and may have an important role in cancer surveillance. The results from phase II trials are awaited, and larger trials will be needed to assess the long-term benefit/risk for this therapeutic direction.

Anti-IL-6

IL-6 is a cytokine that plays a major role in regulating acute-phase responses of inflammation. In lupus, IL-6 has been suggested to play a role in B cell hyperreactivity and may have a role in mediating tissue damage. Serum IL-6 levels have been reported to be elevated in active lupus patients and to correlate with disease activity (1,10). IL-6 receptor blockade with tocilizumab (Actemra^®, RoActemra^®, Roche, Switzerland) has recently been approved for the treatment of RA and is under trial also for other rheumatological diseases.

In a phase I dose-escalating short-term study with tocilizumab in mild-to-moderate SLE, patients improved in disease activity as well as serologically with a decrease in anti-dsDNA antibodies and circulating plasma cells. Treatment led to a dose-related decrease in absolute neutrophil count and a higher than expected rate of infections (11). The results of the study do not, at this time point, support the use of this biologic in SLE, and it is unclear if further randomized clinical trials will be undertaken.

B cell-depleting therapies

Rituximab

B lymphocytes play a central role in SLE by production of autoantibodies, antigen presentation, cytokine production, and regulation of T cell function. During the past decade, an increasing number of case reports, case series, and observational studies have described the clinical effects of B cell-targeting therapies (primarily anti-CD20, rituximab, Rituxan, MabThera^®, Roche, Switzerland) in patients with SLE (12–19). These reports have led to an increasing off-label use of rituximab, mainly in severe and therapy-resistant lupus.

Despite the promising results from non-controlled studies, two recent randomized placebo-controlled phase II/III trials—EXPLORER (The Exploratory Phase II/III SLE Evaluation of Rituximab) and LUNAR (LUpus Nephritis Assessment with Rituximab)—both failed to attain either their primary or secondary end-points.

In the EXPLORER study (20), patients with moderate to severe non-renal lupus on background immunosuppressant drugs and corticosteroids were randomized to rituximab or placebo and followed for 52 weeks. Although no difference in either primary or secondary outcome measures was observed at study end, the rituximab-treated group had significantly better serological outcomes regarding anti-dsDNA and complement measurements.

In the LUNAR study (21), patients with proliferative (class III/IV) lupus nephritis had rituximab or placebo added on to standard of care treatment combined with high-dose corticosteroids and were followed for 52 weeks. As in the EXPLORER study, the serological improvement was statistically better in the rituximab group, but no difference was demonstrated in either primary or secondary outcome measures. In both the EXPLORER and LUNAR trials, rituximab was added to standard but powerful background therapies including immunosuppressives such as azathioprine and mycophenolate. It could be argued that such background therapy would have made it harder to detect a real effect of rituximab, although the modest response rates in all groups in these two trials also proves that these conventional therapies are not particularly effective.

Despite failure of the two recent controlled trials, there has been and is a worldwide off-label use of rituximab in the treatment of severe and refractory cases of lupus. Enthusiasm for rituximab was, however, also dampened by reports on the development of progressive multifocal leucoencephalopathy (PML) following rituximab therapy in two SLE cases. PML is caused by reactivation of JC virus and is a highly fatal condition which is generally seen only in severely immunosuppressed individuals.

These first alarming reports of PML have not been confirmed in larger series of patients or in the controlled trials, and additional studies have shown that PML may also occur in SLE patients with minimal immunosuppressive treatment (22), suggesting the risk is mediated as much by the disease as by the treatment. Nevertheless, continued vigilance is recommended, and treatment with rituximab should preferably be administered only in severe and therapy-resistant cases.

Ocrelizumab

Ocrelizumab is a humanized anti-CD20 antibody used in two phase III studies for active non-renal SLE and in lupus nephritis. In the latter trial, nicknamed BELONG, ocrelizumab was administered as add-on therapy to standard of care treatment (either cyclophosphamide or mycophenolate) combined with high-dose corticosteroids and with a follow-up of 2 years. Both trials were prematurely discontinued, and the reasons given for this include reference to serious infectious complications in trials of ocrelizumab for RA but may also reflect more prosaic business considerations. Publication of the study results is awaited (www.clinicaltrials.org; Table I).

Table I. Biologic therapies in SLE — summary of trials.

Target	Therapeutic agent	Stage clinical trial	Outcome	Future perspective	Reference
Anti-cytokine therapies
IL-10	Monoclonal IL-10	Pilot study	+ Clinical improvement 5/6 pts at 6 months– Development of antibodies against study drug	No current on-going studies	(2)
TNF	Infliximab (Remicade^®, Johnson & Johnson, USA)	Pilot, uncontrolled	+ Arthritis pts temporary improvement; nephritis pts reduction of proteinuria– Development of SAE 2/11 pts after long-term administration	Completed	(6)
TNF	Etanercept (Enbrel^®, Amgen, USA)	Phase II; renal lupus		Terminated due to recruitment problems	www.clinicatrials.gov NCT00447265
TNF	Infliximab (Remicade^®, Johnson & Johnson, USA)	Phase II–III; renal lupus		Terminated due to recruitment problems	www.clinicatrials.gov NCT00368264
IFN-alpha	Sifalimumab MEDI-545	Phase I–II	+ Inhibition of over-expression of type I interferon-inducible genes in skin and circulation	Completed, on-going phase II	(8)
IFN-alpha	Rontalizumab; rhuMab; ‘ROSE’	Phase I–II		Phase II on-going	(9) www.clincaltrials.gov NCT00962832
IL-6	Tocilizumab (Actemra^®, RoActemra^®, Roche, Switzerland)	Phase I	+ Improvement in disease activity and serology– Decrease in neutrophils, infections	Unclear if future trials are planned (side-effects)	(11)
B cell-targeting therapies
Anti-CD20	Rituximab (MabThera^®, Roche, Switzerland); ‘EXPLORER’	Phase II–III; active non-renal lupus	+ Serological improvement– Primary and secondary end-point not met	Completed	(20)
Anti-CD20	Rituximab (MabThera^®, Bristol-Myers-Squibb, USA); ‘LUNAR’	Phase II–III; renal lupus	+ Serological improvement– Primary and secondary end-point not met	Completed	(21)
Anti-CD20	Ocrelizumab; ‘BEGIN’	Phase III; active non-renal		Prematurely terminated	www.clinicaltrials.gov NCT00539838
Anti-CD20	Ocrelizumab; ‘BELONG’	Phase III; renal lupus		Prematurely terminated	www.clinicaltrials.gov NCT00626197
Anti-CD22	Epratuzumab	Pilot study	+ Improvement in disease activity	Completed	(23)
Anti-CD22	Epratuzumab; ‘EMBLEM’	Phase II b	+ Improvement in disease activity	Final results awaited	(24)
Anti-BAFF	Belimumab (Benlysta^®, Human Genome Science, USA)	Phase I–III	+ Improvement in disease activity at 52 weeks	Completed	(27)
TACI-Ig	Atacicept	Phase I b	+ Reduction of immunoglobulins and B cell number	Completed	(29)
TACI-Ig	Atacicept	Phase II; renal lupus	– Infections	Prematurely terminated	www.clinicaltrials.gov NCT00573157
TACI-Ig	Atacicept	Phase II–III; active non-renal		On-going	www.clinicaltrials.gov NCT00624338
B cell tolergen (LJP 394, Riquent)	Abetimus sodium	Phase III; renal lupus (delay in flare)	+ Reduction of anti-dsDNA– Primary end-point not met	Completed	(31)
T cell-targeting therapies
Anti-CD40:CD40L	Anti-154 IDEC-131	Phase II	+ Improvement in disease activity– Placebo group same improvement	Completed	(33)
Anti-CD40:CD40L	BG9588	Phase II	– Development of thromboembolic events	Prematurely discontinued due to side-effects	(34)
CTLA4-Ig	Abatacept (Orencia^®, Bristol-Myers-Squibb, USA)	Phase II; non-renal lupus	+ Improvement in patient-reported outcomes– Primary end-point not met	Completed	(35)
CTLA4-Ig	Abatacept (Orencia^®)	Phase I–II; renal lupus		Completed	www.clinicaltrials.gov NCT00094380
CTLA4-Ig	Abatacept (Orencia^®); ‘ACCESS’	Phase II; renal lupus		On-going	www.clinicaltrials.gov NCT00774852

SAE = serious adverse event; SLE = systemic lupus erythematosus.

Epratuzumab

Epratuzumab is a humanized monoclonal antibody directed against CD22, a B lymphocyte-specific surface antigen with importance for regulation of signalling. In contrast to anti-CD20 agents, it modulates B cell function without complete peripheral B cell depletion. In a pilot study anti-CD22 was shown to reduce disease activity and was well tolerated (23). Recently the preliminary results from a phase II trial (EMBLEM) demonstrated significant improvements in disease activity and quality of life and reduction of corticosteroid usage compared to placebo in moderate-to-severe SLE (24). In that study, epratuzumab was administered as four weekly infusions given in various dosages, and the results were evaluated after 12 weeks using the BILAG scoring system. The rate of adverse events was comparable to placebo. The results suggest that epratuzumab is a promising new biologic therapy in lupus.

Belimumab

B lymphocyte stimulator/B cell-activating factor (BLyS/BAFF) levels are elevated in SLE and have been shown to correlate with disease activity. Both BAFF and APRIL (A PRoliferation-Inducing Ligand) promote B cell survival and differentiation and have become new targets for inhibition in recent trials in lupus. Belimumab (Benlysta^®, Human Genome Science, USA) is a human monoclonal antibody against BAFF. In a large dose-escalating double-blind placebo-controlled phase II trial with patients with moderate disease activity, the primary end-point at 52 weeks’ follow-up was not attained (25). However, in a post-hoc analysis excluding patients who lacked both ANA and anti-dsDNA antibodies, a modest but statistically significant improvement in disease activity was noted in the belimumab-treated group. Moreover, in a long-term open-label extension of the study a drop in flare rate has been observed in the belimumab-treated patients, suggesting that there may be a beneficial effect over longer periods of time (26).

The lessons learned from this first phase II trial were used to design follow-up phase III studies, the BLISS-52 and BLISS-76 trials, now requiring patients to have either ANA or anti-dsDNA, to have higher disease activity at entry, and to pre-specify a compound SLE responder index (SRI) as the primary outcome of these trials. The SRI integrated information from the SLEDAI, BILAG, SLE flare index, and physician's global assessment to arrive at a final dichotomous outcome. In the large BLISS-52 study, comparing low and high doses of intravenous belimumab versus placebo in lupus patient with moderate-to-severe non-renal lupus, the SRI was achieved by statistically significantly more patients in both treatment arms when compared to placebo (27). Being the first positive phase III trial in SLE, the study represents a landmark in future development of biologics in lupus.

The second phase III study with belimumab, BLISS-76, with a similar design to the previous study and with its primary end-point at 52 weeks, again showed a significant favourable effect, but in the high-dose group (10 mg/kg) only. Clearly, while both these trials achieved a statistically significant difference in the response rates, many patients failed to achieve the response criterion even in the active treatment group at week 52 (42% not reaching SRI in BLISS-52 and 57% in BLISS-76), underscoring the need for further developments of therapies and therapy strategies. These two trials were very similar in their design, the only difference being a longer treatment period of 76 weeks in the latter (28). However, the trials were performed in different regions of the world: US and Western Europe for BLISS-76, South America, Asia, and Eastern Europe for BLISS-52. When reviewing the base-line characteristics of patients in these two trials, it is clear that the patients in BLISS-52 had, on average, higher disease activity at base-line, which was shown in subsequent analyses to be a predictor of therapeutic efficacy for belimumab and providing a plausible explanation for the numeric differences in outcomes between the trials.

In both phase III trials with belimumab, background medications, including glucocorticoids, antimalarials, and some immunosuppressives, were allowed with considerable freedom for the clinician to adjust dosages as clinically needed during certain portions of the trial. This may have impacted the results in various ways, for example by contributing to a relatively high background response rate in the placebo group, but also by allowing glucocorticoid dosage to be used as a secondary outcome.

With two large positive phase III trials demonstrating efficacy in moderate-to-severe predominantly non-renal lupus, belimumab may be the first drug approved for lupus in many decades. Marketing authorization applications have been submitted to the FDA and EMA for belimumab (Benlysta), and a FDA advisory panel recently voted 13–2 to approve Benlysta. The panel also noted some concerns, including an apparent lack of effectiveness in a subset analysis of African-American patients. The FDA cited this concern when requesting an extension of their decision deadline until March 2011. It should be noted that this concern is based on one of many subset analyses, and that a similar analysis of a phase II trial with belimumab suggested very good efficacy in the same subset of patients.

Atacicept

The membrane molecule named, none too succinctly, ‘Transmembrane Activator and calcium modulator and Cyclophilin ligand Interactor’ (TACI) binds to both BAFF and APRIL. Atacicept is a molecule with the extracellular domain of TACI combined with IgG1 (IgG-TACI) and has been shown to have effects on plasma cells. In a phase I study in lupus patients, subcutaneous atacicept was well tolerated (29), but a phase II study on lupus nephritis patients of atacicept combined with mycophenolate has been discontinued due to infections (www.clinicaltrials.gov). Currently, there is an on-going phase II/III study in non-renal lupus patients, here combined with less powerful concomitant immunosuppressant drugs (www.clinicaltrials.gov).

Abetimus sodium

Abetimus sodium (formerly LJP 394; Riquent), is a B cell tolerogenic DNA-oligomeric construct with ability to reduce circulating anti-dsDNA antibody levels (30). Following initial promising study results, the drug has been investigated in several clinical trials for lupus. In a final international double-blind placebo-controlled phase III trial, the drug was administered in patients with a history of lupus nephritis with the aim to evaluate if the drug could delay development of renal flares. Although the drug was shown to reduce anti-dsDNA antibodies significantly, no effect in time to renal flare was observed (31), and further studies have not been conducted.

T cell targets

CD40:CD40 ligand

The CD40 ligand is over-expressed on CD4+ and CD8+ T cells in SLE. Data from murine studies on lupus-prone mice have previously shown a decrease in disease severity and improved survival compared to control mice after treatment with an anti-CD40L antibody (32). Two clinical trials using anti-CD40 in human SLE have been carried out. In a phase II study with anti-154 (IDEC-131), improvements in the actively treated group were no better than in placebo-treated patients (33). The other study, BG9588, was terminated prematurely due to thromboembolic events (34), and further studies have not been performed.

Co-stimulation blockade

CTLA4-Ig

Abatacept (Orencia^®, CTLA4-Ig, Bristol-Myers-Squibb, USA) is an approved drug for RA and modulates T cell co-stimulation by binding to the B7 (CD80/86) molecule on the surface of antigen-presenting cells and B lymphocytes, thereby preventing the mediation of the ‘second signal’ needed for T cell activation. In a randomized 1-year placebo-controlled phase II study on active non-renal SLE, no improvement was found as compared to placebo (35). An improvement was, however, seen regarding fatigue, sleep, and quality of life. Two randomized studies on renal lupus are on-going. A recent press release, however, has indicated that one of these two trials failed to achieve its primary end-point. The result from the remaining study is awaited.

Summary and future perspectives

In summary, the development of biological therapeutic agents for SLE over the past decade has been characterized by high expectations but also by significant disappointments. Perhaps the challenges inherent in developing medications for this uncommon, heterogeneous disease were not always appreciated, and some of the biologics that were tested did not have the efficacy needed to be successful. Nonetheless, valuable lessons have been learned over these years, and encouragingly a number of successful phase II and III clinical trials have now been reported. The first biologic for SLE may be approved during the current year, and several more are likely to follow. In the near future, biologics are likely to become important tools for clinicians who treat patients with SLE.

Declaration of interest: Ronald F. van Vollenhoven has received research support and/or honoraria from GlaxoSmithKline, Human Genome Science, Merck Serono, Roche, and UCB Pharma. Iva Gunnarsson declares no conflicts of interest.