Systemic lupus erythematosus
nature.com
James Wentworth1 & Clare Davies2
Systemic lupus erythematosus (SLE) is a complex, chronic, autoimmune disorder that involves multiple organ systems including the skin, joints, heart, lungs, blood, kidneys and, in the most severe cases, the brain. The disease mainly affects women from Afro-Caribbean, Asian or Hispanic descent; Caucasians are affected to a lesser extent. The diagnosis of SLE is a significant challenge, as symptoms can fluctuate and sometimes mimic those of other diseases. Furthermore, there is currently no test available that can diagnose SLE with certainty.
The difficulty in defining and diagnosing SLE, and the lack of appropriate epidemiological studies makes estimating the patient population problematic. The Lupus Foundation of America suggests that lupus may affect 1.5–2 million people in the US1. However, some, possibly more rigorous, epidemiology studies disagree with this number and estimate that SLE actually afflicts about 0.3 million people in this country2. We conservatively estimate that in 2008, there were 0.24 million patients with SLE in the US (Fig. 1), and 0.4 million in the seven major markets (France, Germany, Italy, Spain, UK, Japan and US).
There is a large unmet need in both the diagnosis and treatment of SLE. The US FDA has not approved a treatment for SLE in decades, even though current treatments lack specificity and can often cause considerable side effects. The heterogeneous and flaring nature of the disease makes assessment of drug efficacy in clinical trials difficult, and a lack of clarity from regulatory agencies has stifled SLE drug development in the past. However, recent insights into the biology of autoimmune diseases that extend to SLE, coupled with a better understanding of SLE pathogenesis, have renewed interest in this disease area. Product candidates are in development for different subcategories of SLE including lupus nephritis (LN), a kidney disorder associated with more severe SLE, and cutaneous lupus erythematosus, which affects the skin and has a broad spectrum of clinical manifestations.
Current treatment
The treatment of SLE is highly individualized and physicians (mainly rheumatologists) determine optimal therapy by assessing disease type and severity. Steroids, particularly prednisone, which is highly genericized, are often the key to controlling SLE. They are used as a rescue therapy and as maintenance for short periods, and effectively treat the symptoms of SLE. However, long-term steroid treatment can cause severe side effects and force physicians to use various drugs with other mechanisms of action.
Antimalarial drugs, such as hydroxychloroquine (Plaquenil; Sanofi–Aventis), are commonly prescribed for the treatment of SLE. An estimated 40% of patients with SLE plus multiple organ involvement receive products from this class (Table 1). Furthermore, although most immunosuppressants are restricted to off-label use in SLE, we estimate that at least half of all patients with lupus receive a drug from this class, especially those with LN or CNS involvement. Azathioprine, methotrexate and cyclophosphamide are commonly used immunosuppressants for SLE. Tacrolimus (Prograf; Astellas Pharma) shows particular benefit in LN, and the drug was approved for this indication in Japan in January 2007.
The transplant-rejection drug mycophenolate mofetil (CellCept; Aspreva/Roche) also showed some promise in SLE, particularly for LN. However, its development is on hold after a Phase III trial failed to show superiority over cyclophosphamide, another immunosuppressant commonly prescribed off-label in LN. Nevertheless, our data indicate that physicians prefer to prescribe mycophenolate mofetil over cyclophosphamide owing to safety concerns.
B-cells as the target of the future
The current focus for new SLE drugs is targeted therapies aimed at cytokines, and B and T cells. B cells are a particularly attractive target as autoantibodies often cause considerable pathology in SLE. There are now six products that specifically target B cells in the late-stage SLE pipeline (Table 2).
Rituximab (Rituxan/MabThera; Biogen Idec/Genentech/Roche), a chimeric anti-CD20 monoclonal antibody, was tipped to be the first therapy approved for SLE in decades, but it failed to meet the primary and secondary end points in the EXPLORER trial in SLE in April 2008 (Ref. 3). An ongoing LN study could still result in rituximab's approval for SLE with specific kidney involvement. Despite an FDA safety warning (December 2006) of progressive multifocal leukoencephalopathy in patients with SLE receiving rituximab, there is evidence for continued off-label use4.
Other B-cell therapies in Phase III trials that are competing with rituximab include the monoclonal antibodies belimumab (Human Genome Sciences/GlaxoSmithKline), targeted at the B-lymphocyte stimulator (BLyS), and epratuzumab (UCB), targeted at the B-cell specific surface receptor CD22. After rituximab's recent SLE trial failure, belimumab is the most advanced agent seeking SLE indication approval; enrolment and initial dosing in two Phase III trials was completed by August 2008. Belimumab has the potential to overtake rituximab as the first biologic to reach the market for SLE. Atacicept is a soluble fusion protein that inhibits B-cell activation and is being developed for both SLE and LN. Merck Serono recently acquired the exclusive development rights for atacicept from ZymoGenetics, which will provide a boost to its commercialization prospects. Genentech and Biogen Idec are key players in the autoimmune disease area and are looking to follow-on from rituximab with ocrelizumab, a humanized monoclonal antibody targeting CD20.
Outlook
From a stalled pipeline 10 years ago, there are now targeted products that have the potential to change the way that SLE is treated. The late-stage pipeline shows promise and the market is primed for growth over the next 10 years. However, the main stumbling block will continue to be the ability to prove efficacy to regulatory authorities, as the recent disappointments of rituximab in SLE and mycophenolate mofetil in LN have shown.
Datamonitor estimates that the lupus drug market in the seven major markets was worth at least US$330 million in 2007. Despite failing its Phase III trial in SLE, rituximab, which we believe generated lupus sales of $125 million in 2007, will continue to be prescribed off-label and sales will increase even further if it is approved for LN.
The key opportunities to drive future market growth will come from the approval of higher-priced targeted therapies. There are a number of companies pursuing targeted drug therapies for lupus indications (Table 2). Furthermore, greater patient potential exists in emerging markets because of racial differences in disease prevalence. Datamonitor estimates that the SLE patient population in China, India and Mexico is over 2.2 million. It is likely that only a small percentage of patients will be able to afford the expensive biologic therapies, but opportunity certainly exists for the cheaper small molecules.
References
1. Lupus Foundation of America (LFA). Introduction to Lupus. LFA web site [online], (2008).
2. Helmick, C. G. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 58, 15–25 (2008).
3. Genentech. Genentech and Biogen Idec Announce Top-Line Results From Phase II/III Clinical Study of Rituxan in Systemic Lupus Erythematosus. Genentech web site [online], (2008).
4. FDA. FDA Warns of Safety Concern Regarding Rituxan in New Patient Population. FDA web site [online], [online], (2006). |
