The success of BLISS-52 may have resulted from a new design based on a post-hoc analysis of data from a disappointing phase 2 trial. In this analysis, HGS researchers identified a subpopulation of patients who had improved with treatment. The patients in this subpopulation had detectable anti-DNA antibodies and shared other characteristics as well: they were, on average, younger, were more likely to be African American, and had higher disease activity, more detectable serum BLyS levels, and higher serum immunoglobin G. The post-hoc analysis and identification of this subpopulation became the basis for a promising strategy that allowed the drug to demonstrate its efficacy.
In BLISS-52, HGS focused specifically on this seropositive subpopulation, and the conference group agreed that this focus likely contributed to the success of the trial. It was also noted that, in order to retain patients in the trial, HGS allowed participants wide latitude in using other medications and did not mandate a particular steroid dosing schedule. Several attendees noted that this approach may have handicapped belimumab, because some of belimumab’s efficacy might have been masked by the presence of these other medications in both the belimumab and “placebo” arms of the study. Despite this handicap, the trial met its primary outcome measure.
Importantly, the flexible criteria helped in the recruitment and retention of 865 patients in the study, providing a power of more than 90% for the study to achieve a statistically significant difference in its primary outcome measure between the belimumab and control groups. Because BLISS-52 recruited so many patients, the trial was able to show statistical significance despite relatively modest findings: 57.6% of the belimumab-treated patients met the primary composite outcome compared with 43% of the controls.
The successful HGS trial demonstrated that application of these particular trial design strategies can result in a statistically significant difference between a new agent and placebo on background standard-of-care treatment. The adoption of similar strategies as a general model for other lupus clinical trials was discussed, but no consensus was reached.
TABLE 1: The BILAG-2004 Index
This comprehensive computerized index measures changes in clinical disease activity over time and is based on the principle of the physicians’ intention to treat. It updates the Classic BILAG assessment and consists of questions on patient history, examination findings, and laboratory results. Separate alphabetic scores are assigned to each of nine organ-based systems:
- Constitutional
- Mucocutaneous
- Neuropsychiatric
- Musculoskeletal
- Cardiorespiratory
- Gastrointestinal
- Ophthalmic
- Renal
- Hematologic
Source: Isenberg DA, Rahman A, Allen E, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford). 2005;44(7):902-906.
