A New Era in Lupus Therapy
A New Era in Lupus Therapy
Staring with the approval of the first anti-tumor necrosis factor agents in 1998-1999, biologics have revolutionized the treatment of rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathies and have had a similar impact in various disease areas outside of rheumatology, such as inflammatory bowel disease, psoriasis, and multiple sclerosis. In contrast, the impact of biologics on the treatment of systemic lupus erythematosus (SLE) has been less decisive, with multiple failed trials and a long period of uncertainty. Nevertheless, with the recent approval of belimumab (Benlysta®; GlaxoSmithKline) -- a biologic specifically developed for the treatment of SLE and the first-ever biologic to receive regulatory approval for this indication -- and with some encouraging results from clinical trials of other biologics, it may be said that the treatment of SLE has entered the biologic age.
Here, I will review some of the earlier, disappointing clinical trials, pointing out some lessons that could be learned; this includes data on rituximab, the most widely used off-label biologic for SLE. I will then discuss the data from the successful belimumab clinical trials that supported its regulatory approval and which can guide clinicians today in optimally using this medication. And I will end with some recent data on newer biologics that may become therapeutics for SLE in the future.
At a time when it seemed that all rheumatoid arthritis trials were successful, a string of negative clinical trial results instilled profound skepticism in the SLE community on the feasibility of even doing such trials. Some of these trials involved conventional pharmaceutical agents, and not all were truly negative. For instance, the 2 trials of dehydroepiandrosterone (DHEA; prasterone) done in the late 1990s missed clinical significance for their primary endpoints by a very small margin while having many significant secondary endpoints; such a result would normally be interpreted as suggesting an effective drug in an underpowered trial, so that the trial could be redone on a larger scale with positive results. This teaches us the important lesson of correctly sizing clinical trials.
Trials of abetimus, a specific downregulator of anti-DNA-producing B-cells, failed in part on account of the dramatically lower rate of renal flares observed in the control arm of the trial compared with expectations -- although in the end, the true effect may have been quite weak as well. And the ALMS trial of mycophenolate mofetil (MMF) in lupus nephritis failed only in the sense that it did not achieve the endpoint required by regulatory authorities; it did, in fact, show that MMF was at least equivalent to cyclophosphamide, which any sensible person would recognize as a very positive result. When it comes to use of biologics in SLE, there were failures in early-stage trials of 2 different anti-CD40 ligand biologics as well as of some others in very early stages of development.
But in terms of impact, the 2 randomized trials of rituximab stand out. This anti-CD20 agent was approved for the treatment of rheumatoid arthritis early in the millennium, and soon reports started emerging of apparently successful off-label treatment in patients with lupus. At the Karolinska University Hospital, we treated a large cohort of patients with rituximab and observed striking clinical improvements that we felt were not consistent with the natural course of the disease or the other medications the patients had received, particularly in lupus nephritis. These results were sufficiently encouraging that the manufacturer of rituximab, Genentech (now Roche), initiated 2 randomized, placebo-controlled clinical trials in order to demonstrate efficacy and achieve regulatory approval.
Contrary to prevailing expectations, both of these trials were negative. The EXPLORER trial, done in patients with nonrenal SLE, showed no differences between rituximab and placebo for most of the clinical endpoints; in the LUNAR trial, in patients with lupus nephritis, there were numerical differences that did not achieve statistical significance.
Discussions about how to interpret these trials have been ongoing ever since. In my view, the EXPLORER trial should be considered a conclusive trial in terms of the role of rituximab in treating patients with the more common nonrenal manifestations of mild or moderate lupus: rashes and arthritis. In such patients, rituximab is not effective. The EXPLORER trial cannot tell us much about patients with severe disease or with uncommon nonrenal lupus manifestations, such as central nervous system disease or severe hematologic disease, because these patients were represented in only small numbers.
The interpretation of the LUNAR trial should, in my mind, be a different one. In this case, a difference was seen, but it failed to achieve significance; this could be due to the trial being of a modest size. In addition, the study population consisted of patients with newly diagnosed, untreated nephritis (or a new flare), and rituximab was added to standard therapy with MMF. This was quite different from off-label experiences, where rituximab was usually used after standard therapy had failed. I conclude that for the latter group of patients, rituximab may still be an appropriate treatment, but additional clinical trials would be very desirable.
Biologics for SLE: Introduction
Staring with the approval of the first anti-tumor necrosis factor agents in 1998-1999, biologics have revolutionized the treatment of rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathies and have had a similar impact in various disease areas outside of rheumatology, such as inflammatory bowel disease, psoriasis, and multiple sclerosis. In contrast, the impact of biologics on the treatment of systemic lupus erythematosus (SLE) has been less decisive, with multiple failed trials and a long period of uncertainty. Nevertheless, with the recent approval of belimumab (Benlysta®; GlaxoSmithKline) -- a biologic specifically developed for the treatment of SLE and the first-ever biologic to receive regulatory approval for this indication -- and with some encouraging results from clinical trials of other biologics, it may be said that the treatment of SLE has entered the biologic age.
Here, I will review some of the earlier, disappointing clinical trials, pointing out some lessons that could be learned; this includes data on rituximab, the most widely used off-label biologic for SLE. I will then discuss the data from the successful belimumab clinical trials that supported its regulatory approval and which can guide clinicians today in optimally using this medication. And I will end with some recent data on newer biologics that may become therapeutics for SLE in the future.
Learning From Failed Trials
At a time when it seemed that all rheumatoid arthritis trials were successful, a string of negative clinical trial results instilled profound skepticism in the SLE community on the feasibility of even doing such trials. Some of these trials involved conventional pharmaceutical agents, and not all were truly negative. For instance, the 2 trials of dehydroepiandrosterone (DHEA; prasterone) done in the late 1990s missed clinical significance for their primary endpoints by a very small margin while having many significant secondary endpoints; such a result would normally be interpreted as suggesting an effective drug in an underpowered trial, so that the trial could be redone on a larger scale with positive results. This teaches us the important lesson of correctly sizing clinical trials.
Trials of abetimus, a specific downregulator of anti-DNA-producing B-cells, failed in part on account of the dramatically lower rate of renal flares observed in the control arm of the trial compared with expectations -- although in the end, the true effect may have been quite weak as well. And the ALMS trial of mycophenolate mofetil (MMF) in lupus nephritis failed only in the sense that it did not achieve the endpoint required by regulatory authorities; it did, in fact, show that MMF was at least equivalent to cyclophosphamide, which any sensible person would recognize as a very positive result. When it comes to use of biologics in SLE, there were failures in early-stage trials of 2 different anti-CD40 ligand biologics as well as of some others in very early stages of development.
But in terms of impact, the 2 randomized trials of rituximab stand out. This anti-CD20 agent was approved for the treatment of rheumatoid arthritis early in the millennium, and soon reports started emerging of apparently successful off-label treatment in patients with lupus. At the Karolinska University Hospital, we treated a large cohort of patients with rituximab and observed striking clinical improvements that we felt were not consistent with the natural course of the disease or the other medications the patients had received, particularly in lupus nephritis. These results were sufficiently encouraging that the manufacturer of rituximab, Genentech (now Roche), initiated 2 randomized, placebo-controlled clinical trials in order to demonstrate efficacy and achieve regulatory approval.
Contrary to prevailing expectations, both of these trials were negative. The EXPLORER trial, done in patients with nonrenal SLE, showed no differences between rituximab and placebo for most of the clinical endpoints; in the LUNAR trial, in patients with lupus nephritis, there were numerical differences that did not achieve statistical significance.
Discussions about how to interpret these trials have been ongoing ever since. In my view, the EXPLORER trial should be considered a conclusive trial in terms of the role of rituximab in treating patients with the more common nonrenal manifestations of mild or moderate lupus: rashes and arthritis. In such patients, rituximab is not effective. The EXPLORER trial cannot tell us much about patients with severe disease or with uncommon nonrenal lupus manifestations, such as central nervous system disease or severe hematologic disease, because these patients were represented in only small numbers.
The interpretation of the LUNAR trial should, in my mind, be a different one. In this case, a difference was seen, but it failed to achieve significance; this could be due to the trial being of a modest size. In addition, the study population consisted of patients with newly diagnosed, untreated nephritis (or a new flare), and rituximab was added to standard therapy with MMF. This was quite different from off-label experiences, where rituximab was usually used after standard therapy had failed. I conclude that for the latter group of patients, rituximab may still be an appropriate treatment, but additional clinical trials would be very desirable.
