At a teleconference in February sponsored by the Lupus Research Institute (LRI), researchers expressed cautious optimism about developing drugs for systemic lupus erythematosus (SLE) because basic research is uncovering new details underlying the complexity of the disease. Clinical development success, however, continues to evade companies.
Conference participants noted that at least until very recently lupus was handled like an orphan disease, with the pharmaceutical industry largely ignoring it because of its perceived rarity and the fear of not recouping drug development costs. More Americans are diagnosed with lupus, they said, than with cerebral palsy, multiple sclerosis, sickle cell anemia, cystic fibrosis, or AIDS; about 1.5 million individuals in the U.S. have the disease.
But as recent history continues to demonstrate, pharma’s reluctance to dive into the murky development waters of antilupus drugs remains well-founded despite the market opportunity. The odds against successful development of a therapy for lupus remain high, with only Human Genome Sciences and GlaxoSmithKline’s (GSK) Benlysta showing Phase III success.
Current treatments for lupus vary depending on the extent of the disease and may change over time. Some medications used to ease symptoms include nonsteroidal anti-inflammatory drugs, antimalarials, corticosteroids, and immunosuppressive medications. “Today, we do have therapies that work,” remarked Lee Simon, M.D., an associate clinical professor of medicine at Harvard Medical School. “In the 1950s, 95 percent of people were dead within five years of diagnosis. Today, 95 percent of patients survive five years out. But the treatments we have carry a heavy toxic burden. So, we need new drugs that work as well, if not better, with less harsh side effects.”
Predicted Successes that Failed
In a 2006 report, Decision Resources said that Roche and Aspreva's CellCept and Biogen Idec and Genentech’s Rituxan would emerge as “the leading therapies for the treatment of SLE, driving the market to more than quadruple from $300 million in 2005 to $1.3 billion in 2015.” The report further said that “Although corticosteroids and antimalarials will continue to be used as mainstay treatments for the disease, their major market sales will be dwarfed by the increased use and resulting sales of novel agents including CellCept and high-priced biologics including Rituxan and Human Genome Science/GlaxoSmithKline's LymphoStat-B.” LymphoStat-B is now known as Benlysta.
These predictions haven’t exactly panned out. Roche and Aspreva discontinued CellCept development in 2007, because the drug was unable to demonstrate superiority to intravenous cyclophosphamide. About a year later, Genentech, now part of Roche, and Biogen Idec reported that Rituxan failed to meet its primary and secondary endpoints in SLE. In 2009, the companies announced that Rituxan also did not significantly reduce disease activity in patients with lupus nephritis, which is an inflammation of the kidney and a complication of SLE. This March also saw a lupus trial failure from Roche and Biogen Idec’s Ocrelizumab, another anti-CD20 mAb like Rituxan.
Nearest Shot on Goal
The only remaining SLE contender cited in the 2006 Decision Resources report is Benlysta. This mAb, which belongs to a new class of drugs called BLyS-specific inhibitors, recognizes and blocks the biological activity of B-lymphocyte stimulator, or BLyS, a naturally occurring protein that was discovered by Human Genome Sciences. Elevated levels of BLyS prolong the survival of B cells, which can contribute to the production of autoantibodies like anti-dsDNA antibodies that target the body’s own tissues.
Benlysta successfully met its primary endpoint in two Phase III trials in patients with abnormal levels of anti-dsDNA antibodies at the time of trial enrollment. If approved, Benlysta will become the first new therapeutic approved for SLE in about 50 years. According to Lazard Capital Markets analyst Terence Flynn, global sales could reach $3 billion by 2014.
Basic Research on B Cells in Lupus
Future clinical successes in SLE may be related to the development of more drugs aimed at treating molecular characteristics that are more specifically related to the disease. “I think one of the reasons that there is a measure of excitement in lupus and in other complex diseases that we've been confronted with for a long time is the advent of a whole series of new molecular tools that allow us to address basic issues,” commented Salk Institute neurobiology professor Greg E. Lemke, Ph.D.
For example, Petar Lenert, M.D., Ph.D., and colleagues, authors of a 2009 paper published in Arthritis Research and Therapy, said that more selective approaches to weeding out B cells that promote lupus may be better than nonselective B-cell depletion. Autoreactive B cells produce the autoantibodies characteristic of lupus but also contribute to disease pathogenesis by presenting autoantigens to T cells and secreting proinflammatory cytokines.
Dr. Lenert and other scientists have shown that intracellular nucleic acid sensing receptors that function in innate immunity, like toll-like receptor (TLR) 7 and TLR9, may play an important role in SLE. Dual engagement of rheumatoid factor-specific AM14 B cells through the B-cell receptor and TLR7/9 results in proliferation of autoimmune B cells. Therefore, Dr. Lenert explained, strategies that preferentially block innate immune activation through TLRs in autoimmune B cells may be preferred over nonselective B-cell depletion.
Dr. Lenert’s group found that a certain type of double-stranded DNA-like molecule that carries autoimmune-inhibitory sequences could selectively reduce the activity of autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage. The authors concluded that use of this specific class of nucleotides could result in a new approach to autoimmune disease therapeutics. Dr. Lenert was more circumspect in a conversation with GEN about the role of TLRs in autoimmunity. “It’s an area that requires much more research,” he said.
The search for and development of a lupus drug that induced tolerance in B cells directed against double-stranded DNA by cross-linking surface antibodies, however, proved to be La Jolla Pharmaceuticals’ undoing. The firm had to discontinue development of Riquent in February 2009 after it failed in lupus nephritis. La Jolla was delisted from NASDAQ this March, and Adamis Pharmaceuticals terminated its proposed merger with the firm; Riquent was La Jolla's only clinical-stage drug.
Dr. Lenert’s concerns that the field requires further research remains the defining characteristic of current drug development efforts for SLE. Perhaps the Phase III success of Benlysta will encourage companies to keep on trying against tough odds.