Abstract: A new era in the treatment of systemic lupus erythematosus (SLE) may be dawning. Twelve years after the first approval of biologic therapy for patients with rheumatoid arthritis, the positive results of two large trials of a novel biologic therapy for SLE have raised hopes that a new approach to treatment may be at hand. This encouraging news follows several disappointments in trials of other biologic therapies and provides a timely moment to reflect on where we stand, what we have learned, and what may lie ahead.
Systemic lupus erythematosus (SLE) is a chronic, relapsing and remitting disease that is characterized by the production of antibodies to nuclear antigens and a broad array of clinical manifestations ranging from mild cutaneous and joint involvement to severe organ-threatening and life-threatening disease. Although genetic, environmental, and hormonal influences have all been implicated in disease pathogenesis, the cause of SLE remains unknown. Furthermore, the heterogeneous and unpredictable nature of SLE has complicated the design and execution of clinical trials. In part because of these issues, there has been no new drug approved for the treatment of SLE in over fifty years.
Against this discouraging background, the last five years have witnessed an upwelling of activity in the quest to discover new therapies for SLE. To begin with, advances in the understanding of disease pathogenesis have contributed to the development of novel therapeutic strategies designed to target distinct aspects of the immune system. In addition, the success of biologic therapies for rheumatoid arthritis has demonstrated that these kinds of therapies can be feasible, tolerable, and highly effective in altering the course of disease. Lastly, emphasis has been placed on improving clinical trial methodology and developing meaningful outcome measures that reliably reflect changes in disease activity. These advances now appear to pay off. Specifically, the past year has witnessed positive results in two large-scale clinical trials of the monoclonal antibody, belimumab (Benlysta), in patients with SLE. These results have raised the lupus community’s hopes that we might finally be on the verge of an FDA approval for a new lupus treatment.
Belimumab is a fully human monoclonal antibody targeting B-lymphocyte stimulator (BLyS), a cytokine that is critical for B cell survival and development after exit from the bone marrow. B cells are believed to be important in the pathogenesis of SLE via a variety of mechanisms including the production of autoantibodies, presentation of antigen, and secretion of cytokines. In the initial phase II, double-blind, placebo-controlled trial in patients with active SLE, belimumab failed to improve disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and did not decrease time to first SLE flare (Wallace et al., 2009). Despite these discouraging results, a series of post-hoc analyses suggested a path forward. Only 72% of patients in the phase II trial had been ANA (anti-nuclear antibody) positive at the time of study entry. When the analysis was restricted to these subjects, the physician’s global assessment (PGA) suggested an advantage for the treatment group relative to the control group. Encouraged by this observation, the study sponsor utilized data from the phase II trial to develop a novel SLE Responder Index (SRI). The SRI incorporated components of the SLEDAI, the British Isles Lupus Assessment Group (BILAG) disease activity instrument, and physician’s global assessment. This instrument was then utilized as the primary endpoint in two subsequent phase III trials (BLISS-52 and BLISS-76), each involving more than 800 subjects. Both were designed as randomized, double-blind, placebo controlled trials comparing belimumab (either 1mg/kg or 10mg/kg) plus standard of care therapy to placebo plus standard of care therapy in ANA and/or anti-dsDNA positive patients. Like the phase II trial, the phase III trials focused on patients with moderate disease activity while excluding patients with serious life-threatening organ involvement. They differed slightly from one another with respect to the regions of the world in which the studies were conducted and the frequency of background medications. The results of the BLISS-52 trial were presented in October 2009 at the annual scientific meeting of the American College of Rheumatology. 57.6% of the high dose belimumab group compared to 43.6% of the placebo group achieved the primary endpoint at week 52 (Navarra et al., 2009). Not only did this study achieve the primary SRI-based endpoint, but also there was a statistically significant difference between treatment and control with respect to each individual component of the SRI as well as many of the pre-defined secondary outcome measures, including mean corticosteroid dose.
Within two weeks after the presentation of the BLISS-52 data, the sponsor issued a press release announcing positive results in the BLISS-76 trial. In this trial, 43.2% of the high dose belimumab group compared to 33.8% of the placebo group achieved the primary endpoint at week 52 (clinical trial sponsor press release, 2009). The difference between the groups, although small in magnitude, was statistically significant. It would be premature to draw any firm conclusions from these top-line results available at this time solely through a press release. However, there can be no overstating the excitement that these favorable findings have created in the lupus community. As the full dataset becomes available and is subjected to thorough examination (perhaps before an FDA panel), we are sure to learn a lot more about belimumab and how it might be used in patients with SLE. Moreover, the success of these trials virtually guarantees that further investigations will be conducted to address the many important questions that initial successful clinical trials invariably raise but cannot answer. Among these questions, there is certain to be particular interest in determining where this therapy may best fit in the treatment of lupus (e.g., treatment of active disease versus maintenance of remission), and how well it might work in patients with the most severe manifestations of lupus, such as diffuse proliferative glomerulonephritis.
The success of the belimumab trials provides a reference point against which to reconsider the interpretation of recent trials of other potential biologic therapies for lupus that did not meet their primary endpoints. Prior to the recent belimumab reports, rituximab (Rituxan) had received the greatest attention for its apparent promise in SLE. Rituximab is a chimeric mouse/human monoclonal antibody that binds to the CD20 antigen that is expressed on the surface of B cells from the pre-B cell through memory B cell stages. Importantly, CD20 is not expressed on B cell precursors or plasma cells. Treatment with rituximab results in rapid depletion of B cells. Rituximab was initially approved in 1997 for the treatment of CD20 positive non-Hodgkin’s lymphoma and then in 2006 for the treatment of rheumatoid arthritis. Because of the putative role of B cells in the pathogenesis of SLE, rituximab was viewed as an appealing treatment option for lupus. This belief was reinforced in recent years by several uncontrolled studies suggesting that rituximab might be beneficial across a broad range of manifestations of lupus, including lupus nephritis. Thus, the recent negative results of two large phase II/III trials of rituximab were particularly surprising and disappointing. The EXPLORER trial was a randomized, double-blind, placebo-controlled trial of rituximab added to standard of care therapy for moderate-severe non-renal SLE. In addition, patients were treated initially with a course of high dose steroids. The steroids were then tapered according to a pre-defined regimen over a period of 10 weeks to <10mg/d. All patients remained on their baseline immunosuppressive medications. The primary outcome measure was clinical response as defined by the BILAG. The rates of major and partial clinical response at week 52 were similar in the rituximab and placebo groups. In addition, there were no differences between the groups in any of the secondary endpoints (Merrill et al., 2008).
The LUNAR trial was a randomized, double-blind, placebo-controlled trial of rituximab plus mycophenolate mofetil (MMF) versus MMF alone in 144 patients with active proliferative lupus nephritis. As in the EXPLORER trial, both groups initially received concomitant high dose steroids. After 52 weeks, there was no statistically significant difference in the rate of complete or partial renal response between the rituximab and placebo groups (Furie et al., 2009). It may be noteworthy, however, that the response rates in this trial (57% in the rituximab group vs. 46% for the control group) closely mirror the response rates in the BLISS-52 trial (58% vs. 44%) and approximate the magnitude of the effect size in the BLISS-76 trial (43% vs. 34%). Thus, at this point, it is difficult to be certain whether the failure of the LUNAR trial to meet its objective reflects an unequivocal failure of the drug or an underpowered study. It may also be important to note that in the prior encouraging uncontrolled experiences with rituximab in lupus nephritis, rituximab was typically administered in combination with cyclophosphamide. Thus, if rituximab and cyclophosphamide have synergistic effects, this benefit would have been missed in the LUNAR trial in which the active comparator was MMF. Given the negative results of the EXPLORER and LUNAR trials, it remains to be seen whether these issues will ever be resolved.
Unlike rituximab and belimumab which target the B cell arm of the immune system, abatacept (CTLA4-Ig, Orencia) inhibits T cell costimulation. Abatacept is a soluble fusion protein composed of the extracellular domain of CTLA4 and the modified CH2 and CH3 domains of IgG1. CTLA4-Ig binds to B7-1 and B7-2 on antigen presenting cells and downregulates T cell activation by disrupting the CD28-B7 costimulatory interaction.
Abatacept was compared to placebo in a randomized, placebo controlled, phase II trial of patients with active SLE characterized by arthritis, serositis, or rash. There was no difference in the percentage of patients who experienced the primary endpoint of SLE flare, as defined by BILAG, over the course of 52 weeks (Merrill et al., 2008). However, like the initial negative phase II belimumab trial, this trial contained hints of possible activity. Specifically, at each visit throughout the course of the trial, investigators were asked to declare whether, in their judgment, the patient wasexperiencing a disease flare. Interestingly, by this measure, the investigators discerned a difference in flare rates between the abatacept group (64%) and placebo group (83%). This difference was especially pronounced in the subgroup of patients with arthritis. Whether this difference can be reproduced in a prospective study, as was the case for belimumab, remains to be determined. In the meantime, abatacept is being studied in two ongoing trials for the treatment of lupus nephritis, in conjunction with MMF in one trial and in conjunction with cyclophosphamide in the other.
|Table 1. Recent Controlled Clinical Trials in Systemic lupus erythematosus (SLE)|
|Study Drug||Number of Patients||SLE Manifestation||Primary Result|
|Belimumab||449||Active non-renal SLE||No difference between belimumab and placebo groups in disease activity at 24 weeks or time to flare at 52 weeks, as assessed by SLEDAI|
|Belimumab||865||Active non-renal SLE||At 52 weeks, 58% of the belimumab (10mg/kg) group vs. 44% of the placebo group achieved a clinical response, as assessed by SRI|
|Belimumab||819||Active non-renal SLE||At 52 weeks, 43% of the belimumab (10mg/kg) group vs. 34% of the placebo group achieved a clinical response, as assessed by the SRI|
|Rituximab||257||Active non-renal SLE||No difference in response rate at 52 weeks between the rituximab and placebo groups, as assessed by BILAG|
|Rituximab||144||Active lupus nephritis||No difference in renal response rate at 52 weeks between the rituximab plus MMF group vs. the MMF group alone|
|Abatacept||175||Active non-renal SLE (arthritis, serositis, or rash)||No difference in new flare rate at 52 weeks between the abatacept and placebo groups, as assessed by BILAG|
|SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SRI, SLE Responder Index; BILAG, British Isles Lupus Assessment Group.|
We are currently experiencing a critical and exciting time for drug development in SLE. The novel therapies described above are farthest along in the development at the moment, but they represent the tip of an iceberg. Many other biologic agents with diverse mechanisms of action are, or soon will be, entering into clinical trials in SLE. These include other B-cell directed therapies, such as epratuzumab (anti-CD22) and atacicept (TACI-Ig), as well as therapies directed against cytokines, toll-like receptors, and components of the complement system. We are still a long way from knowing which of these approaches will be most effective, or whether different agents may prove best for different manifestations and/or stages of disease.
In closing, a review article on this topic requires clear disclosures from the authors. Both of us have been, and continue to be, involved in trials of atacicept, a B cell therapy that may become a competitor to the B cell therapies described in this article. One of us (MD) participated in therituximab trials, and the other (DW) has a close family member who is employed by the company that manufactures rituximab. Both of us are currently involved in a trial of abatacept in lupus nephritis. Even if we have been able to maintain our objectivity in this brief review, our knowledge of the facts is undoubtedly influenced by the relationships we have. Despite these reservations, we feel that a discussion of potential biologic therapies for lupus is important and timely. We hope to learn from the successes and failures of the completed SLE trials in a way that will benefit the design, and objective outcome, of future trials.
Furie R, Looney RJ, Rovin B, Latinis KM, Appel G, Sanchez-Guerrero J, Fervenza FC, Maciuca R, Brunetta P, Zhang D, et al. Efficacy and safety of rituximab in subjects with active proliferative lupus nephritis (LN): results from the randomized, double-blind phase III LUNAR study. American College of Rheumatology 2009 Annual Scientific Meeting: Philadelphia, PA, USA, October 17-21, 2009.
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg D, Hsieh HJ, et al. Efficacy and safety of rituximab in patients with moderately to severely active systemic lupus erythematosus (SLE): results from the randomized, double-blind phase II/III study (EXPLORER). American College of Rheumatology 2008 Annual Scientific Meeting: San Francisco, CA, USA, October 24-29, 2008.
Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace D, Bae S, Sigal L, Becker J, Kelly S, et al. The efficacy and safety of abatacept in SLE: results of a 12-month exploratory study. American College of Rheumatology 2008 Annual Scientific Meeting: San Francisco, CA, USA, October 24-29, 2008.
Navarra S, Guzman R, Gallacher A, Levy RA, Li EK, Thomas M, Jimenez R, Leon M, Hall S, Lan JL, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares, and prednisone use in patients with active SLE: efficacy and safety results from the phase 3 BLISS-52 study. American College of Rheumatology 2009 Annual Scientific Meeting: Philadelphia, PA, USA, October 17-21, 2009.
Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, Petri MA, Ginzler EM, Chatham WW, McCune WJ, et al. A phase II randomized, double-blind, placebo-controlled, dose-ranging study of belimumab of patients with active systemic lupus erythematosus. Arthritis Rheum 61(9):1168-78, 2009.
[Discovery Medicine, 9(44):20-23, January 2010.]