NEW YORK, NY – The number of new agents for the management of systemic lupus erythematosus (SLE), from mycophenolate mofetil and abatacept to rituximab and belimumab, suggests a robust therapeutic pipeline for SLE, a heterogeneous disease for which there have been few therapeutic advances in the last 40 years, according to experts speaking here Saturday at "Lupus Now: State-of-the-Art Approaches from the Experts."
"I hazard to guess that most people would not feel that they could take care of lupus patients with the drugs that are FDA-approved to treat lupus today," says Joan T. Merrill, MD, head of the clinical pharmacology research program at the Oklahoma Medical Research Foundation in Oklahoma City and medical director of the Lupus Foundation of America, which sponsored the program. "We have to beg, borrow, and steal drugs from other diseases, [but] there is robust drug development in lupus today."
Dr. Merrill notes that although doctors understand the causes of lupus a lot better and have a better idea of how to approach immunomodulation than they did 10 years ago, "a lot of barriers to drug development still exist," namely the heterogeneity of SLE, she says.
Current SLE drugs in the pipeline include the following:
- Mycophenolate Mofetil (MMF) This agent, which inhibits lymphoid/myeloid cells, is being used to treat lupus although it has not yet been specifically approved by the US Food and Drug Administration for this indication. Currently approved for use in treating allograft rejection, MMF may one day be approved to treat lupus nephritis. Several studies in Type III/IV nephritis are now underway, Dr. Merrill says. In one study comparing MMF to cyclophosphamide, patients talking MMF had a higher completion and remission rate than their counterparts taking the gold standard. MMF-treated patients also had fewer early withdrawals, no serious deep infections, and possibly less adverse reproductive effects than patients in the cyclophosphamide arm, according to Dr. Merrill, who notes that the next step is to determine whether remission can be maintained.
- Dehydroepiandrosterone (DHEA; prasterone) This weak male steroid reverses steroid deficiency. "The data are well known," Dr. Merrill says, noting that DHEA looked promising for mild lupus and could be steroid-sparing, and there was early evidence that it showed a nice improvement in bone density. While it failed an FDA-required bone density study, Dr. Merrill says, "It is not dead yet."
- LJP 394 (Riquent®) Preliminary studies showed that this B-cell tolerogen decreased nephritis in patients with high avidity anti-DNA. Phase III trials showed improvements in quality of life, but no effect on disease activity. "This is an intriguing agent for lupus that is structured in such a way that it acts like double-stranded DNA and sucks up antibodies," Dr. Merrill says, adding that while there were a number of multicenter trials, "they were not dosed optimally enough," resulting in a failure to meet primary endpoints. "This drug is likely to be studied [further] and we may have a chance to at least get dosage optimized so we can determine whether it will work or not," she says.
- Abatacept (Orencia®) This agent, which blocks a costimulatory pathway required for optimum activation of T cells, has been shown to prolong survival in models of murine lupus. According to Dr. Merrill, phase II trials are looking at this agent for lupus.
- Rituximab (Rituxan®) Already approved for the treatment of lymphoma, rituximab, a genetically derived chimeric murine/human monoclonal antibody directed against the CD20 antigen found on B lymphocytes, is currently being studied in lupus. "There is great anecdotal evidence for its use in lupus," Dr. Merrill says, pointing out that one open-label study showed clinical improvements over 6 months with some associated serologic changes.
- Belimumab (Anti-BlyS) A fully human monoclonal antibody, BlyS is an essential survival factor for B cells, and a blockade of BlyS reduces the number and function of B cells. A phase I lupus study showed good safety, with one patient developing neutralizing antibodies to the drugs. According to Dr. Merrill, BlyS uniformly reduced CD20+ B cells, but effects on immunoglobulin levels were more variable. Phase II trials are underway, and three companies are currently developing antagonists of this monoclonal antibody.
In the largest-ever placebo-controlled phase II trial for lupus, Human Genome Sciences, Inc, recently announced that LymphoStat-Bâ„¢ (belimumab) failed to meet the overall primary efficacy endpoints of reducing the signs and symptoms of SLE at week 24 or increasing the time to first lupus flare over a 52-week treatment period.
Reference
- Merrill JT. Lupus Now: State-of-the-Art Approaches from the Experts; October 29, 2005; New York, NY.