Despite these variables and the remaining hurdles in refining outcome measures and design issues, researchers remain optimistic about the future of clinical trials for lupus. It was noted that the first biologic drugs for RA entered clinical trials in the late 1980s, but the first approval did not come until 1999, after a series of false starts and failures. Moreover, even after an effective clinical trial strategy was identified in RA, many products failed to meet the designated outcome measures. And lupus biologic drugs only entered clinical trials in the mid-1990s.
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Explore This IssueAugust 2010
Andrea Peirce is editorial and communications director for the S.L.E. Lupus Foundation and Lupus Research Institute in New York. Dr. Lipsky is editor-in-chief of Nature Reviews Rheumatology. Dr. Schwartz is professor of clinical medicine at Washington University School of Medicine in St. Louis.
Background on Lupus Clinical Trials Discussed
Genentech’s EXPLORER trial enrolled 257 patients with moderately to severely active extrarenal lupus who displayed moderate to high activity breaking through background treatments. Because the FDA had suggested BILAG as the favored measure, the trial used BILAG v3. The trial used a graded responder endpoint (with a focus on major, partial, and non-response), rather than a binary “response/no response” measure. Patients were randomized to receive rituximab plus prednisone or placebo plus prednisone and were followed for 78 weeks. The EXPLORER trial failed to achieve primary or secondary endpoints but revealed no new major safety issues. The requirement for high activity made it difficult to recruit patients. EXPLORER also had a high (>25%) dropout rate (dropouts were counted as nonresponders, thereby increasing the nonresponse rate). Another potential confounder was the lack of a clear definition of flares—30% of patients met a stringent definition of response, but 70% did not.
This trial enrolled patients with biopsy-proven active lupus nephritis who were being treated with one background immunosuppressant (mycophenolate mofetil) and prednisone, which enabled researchers to leverage data from ongoing studies.
Success was defined by renal response at one year. The overall design was very similar to EXPLORER, other than differences in the patient population and the background therapy. The drug failed primary and secondary endpoints. No new safety issues emerged. The primary endpoint—a quantitative endpoint—was significantly easier to interpret than the EXPLORER BILAG endpoint.
HGS–Phase 2 Study
The trial enrolled 449 patients with active SLE in double-blind, extension, and long-term phases for a total of four years of follow-up. Patients, who were on the standard of care throughout the trial, had to have an SLE diagnosis with a history of measurable auto-antibodies. The study did not meet primary or secondary endpoints of percent reduction of SELENA-SLEDAI score at week 24 or time to first SLE flare over 52 weeks. The assumption of a 65–70% annual flare rate was too low in moderate to severe SLE. Permitting changes in prednisone and immunosuppressive medications also confounded SLE disease activity assessments. Researchers found the SELENA-SLEDAI was a better measure of sustained overall improvement than BILAG, and that BILAG B flares could be triggered easily. But researchers also found that BILAG was a better measure of organ-specific changes/worsening. Specifically, SELENA-SLEDAI tracks complete elimination, but not partial changes, of signs and symptoms, and BILAG tracks changes in disease activity for a defined time period.
The BLISS-52 study involved 90 study centers in 13 countries and enrolled 865 patients. The study was a 52-week, double-blind, placebo-controlled trial of belimumab (1 or 10 mg/kg) plus standard-of-care therapy or placebo plus standard of care. Efficacy analyses included the SELENA-SLEDAI, BILAG, and SELENA-SLEDAI Flare Index (SFI). The primary endpoint was the Week 52 SRI: improvement in SELENA-SLEDAI (≥4 point decrease), no new BILAG A or no new 2 B flares, and no >0.3 point worsening in Physician’s Global Assessment (PGA) versus baseline. At Week 52, there were 57.6% responders in the 10 mg/kg belimumab arm, 51.4% responders in the 1 mg/kg belimumab arm, and 43% responders in the control arm, with both doses of belimumab showing a statistically significant difference from placebo. Statistically significant differences from placebo were also seen in at least one belimumab dose group in the secondary endpoints. Belimumab was generally well tolerated and generally allowed reduction of steroid use.
This Bristol-Myers Squibb abatacept trial was a phase 2B, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of abatacept on a background of oral glucocorticosteroids to prevent lupus flares. Eligible subjects must have been diagnosed with SLE and must have been experiencing an active lupus flare that satisfied BILAG A or B event criteria within 14 days, and have been on a stable dose of prednisone (<30 mg) for at least one month. Patients were randomized to receive abatacept IV or placebo and were followed for one year. The study also included a fixed steroid taper for two months. The primary endpoint was new adjudicated BILAG A or B flares after the start of steroid taper. One hundred eighty patients received treatment: 121 received abatacept, and 59 received placebo. The incidence of a new flare (defined by adjudication of all BILAG A or B events) was 79.7% for the abatacept group compared with 82.5% for the placebo group, a nonstatistically significant difference.