It was noted that, for business reasons, pharmaceutical companies often seek the broadest possible indication(s) for a new product. Companies may tend to avoid smaller, focused trials and favor trials with larger numbers of relatively heterogeneous patients. Of note, although some recent trials entered subjects with relatively uniform patient profiles, these trials had little success.
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Explore This IssueAugust 2010
The most successful trials were those of belimumab, which included large numbers of patients, permitted flexibility in background medication for a substantial portion of the trial, and employed a novel composite outcome that involved both measures of therapeutic success and the absence of deterioration. Whether this trial design or similar designs should become the paradigm for future lupus trials was discussed, but no consensus was reached.
Lessons Learned from Recent Trials
Rituximab: Genentech’s Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN/RPS Class III or IV Lupus Nephritis (LUNAR) and Rituximab in Patients with Severe SLE (EXPLORER) trials tested the anti-CD20 monoclonal antibody in two different patient populations: individuals with lupus nephritis and those with active nonrenal lupus. Both trials were unsuccessful in achieving their primary endpoint. Their failure may have stemmed at least partly from clinical trial design issues (including designated co-therapy for each of the treatment arms), inclusion criteria (i.e., the patient population studied), or ineffectiveness of the drug.
Because it has been claimed—either anecdotally or from data for early trials that were small or not randomized—that rituximab is effective in some lupus patients, some conference attendees speculated that rituximab may be effective for a subset of patients, possibly those with a CD20-positive B-cell driven pathogenesis, though this subset has not been identified. It was also noted that SLE patients with periodic flares may differ from those with chronically active lupus, SLE patients from different racial groups may exhibit different pathologies, and conditions within a single patient can vary over time.
Attendees discussed the validity or practicality of subclassifying SLE patients for highly targeted therapies, such as monoclonal antibodies, in future trials, and agreed that more targeted trials for these subgroups might be indicated if researchers can draw clear distinctions among these groups and if companies would be willing to narrow their potential drug markets, at least initially.
Belimumab: In Human Genome Sciences’ (HGS) Study of Belimumab in Subjects with SLE (BLISS-52) phase 3 trial, Benlysta (belimumab), a human monoclonal antibody that inhibits tumor necrosis factor SF13B or B-lymphocyte stimulator (BLyS), proved more effective than placebo in treating people with serologically active SLE.