B cell Inhibition with Epratuzumab Fails in Two Phase III Lupus Trials Save
Targeting B cells in systemic lupus erythematosus, the prototypic autoimmune disorder, has long been an attractive target for researchers. Despite negative trials with rituximab and the limited success of belimumab, efforts to inhibit B cell activity have continued.
However, the humoral approach to lupus control suffered another disappointement as UCB has issued a press release stating their lupus clinical trials with epratuzumab, an anti-CD22 monoclonal antibody, failed to meet their primary endpoints in two large phase III clinical trials, called EMBODY 1 and EMBODY 2.
The EMBODY 1 (n= 786) and EMBODY 2 (n=788) trials compared placebo to treatment with 2400 mg of epratuzumab, given as either 600 mg weekly for 4 weeks or 1,200 mg every 2 weeks for four weeks. After 48 weeks the primary endpoint was not achieved, as measured by the percentage of patients achieving a combined response index, the BILAG-based Combined Lupus Assessment (BICLA).
No new safety concerns arose from the safety data in these studies. Common adverse events included upper respiratory tract infections, urinary tract infections, headache and nausea in both trials.
The challenges of lupus management have been trumped by the frustrations of novel lupus drug development. Numerous agents (e.g., rituximab, belimumab, sifalimumab, atacicept and now epratuzumab) targeting B cells have stuggled and many have failed to yield clinical results that could be described as encouraging. Hence, clinicians now have to wonder whether B cell inhibition was the wrong target all along or are we doing the clinical trials wrong?
The latter is quite possible as the BILAG, BICLA and SLEDAI are hardly tools that approximate what is done in daily practice. The outcome measures in lupus are flawed with high placebo responses and narrow treatment effects. Lastly, the problem may be these trials are trying to treat "lupus" in general, instead of the problematic components of active lupus - namely the nephritis or acute and chronic lupus skin disease or problematic cytopenias, etc. With more problem-focused lupus trials, the outcomes can be more easily defined and measured and the interpretations of such results would easily translate to daily practice.
Dr. Ted Pincus once said that "clinical trials that use measures that are not aligned with that done in clinical practice are inherently flawed". He said this to an audience of rheumatoid researchers. I wish others had heard and learned from his experience.