Belimumab was found to have no effect on time to flare or SLE Disease Activity Index in a randomized trial involving 449 patients with mild to moderate active SLE. In response, sponsor Human Genome Sciences Inc. created a novel combined end point, applied it retroactively, and declared the study a success. The new combined primary end point is being used in two ongoing phase III trials of the anti-BlyS agent, each double the size of the earlier one.
The new end point consists of at least a 4-point improvement on the SLE Disease Activity Index, no new 1A/2B British Isles Lupus Assessment Group domain scores, and no worsening in Physician Global Assessment.
While Dr. Wofsy said the company's persistence is laudable, he was highly critical of the new combined end point, as well as the fact that the earlier negative trial has never been published, although it was first presented in 2005.
“This trial has been subjected to spin unlike any other trial I've ever seen,” he said. “I think this novel end point is a disservice to the community. It doesn't translate into anything meaningful to anybody who takes care of lupus patients.” He added that if the phase III trials prove positive, “that may be a business triumph but it won't be a scientific breakthrough.”
“In the end, if you can't make lupus nephritis better with these risky immunosuppressive drugs, you probably don't have a drug,” Dr. Wofsy asserted.
Like belimumab, atacicept blocks the BlyS pathway. But atacicept also blocks the APRIL (a proliferation-inducing ligand) pathway, thereby more effectively blocking signals to B cells. B-cell levels in treated patients fall by about 50%, as with belimumab, but atacicept-treated patients also show a 50% reduction in IgM and 20% decrease in IgG.
“But if atacicept is more effective, it may also be more toxic. Only time and more studies will tell. There's an array of B-cell therapies out there that are under investigation, and no one can tell you which one is going to be best,” Dr. Wofsy said.
Both atacicept and belimumab are agents that are more likely to sustain a remission than induce it, in his view.
Other potential biologic therapies in lupus include anti-CD3, -4, or -22, anti-B7, anti-C5, anti-interleukin-10, and agents directed at the interleukin-6 receptor. Stem cell transplantation is also under investigation.
Dr. Wofsy serves as a consultant to Serono and ZymoGenetics and is organizing the phase II-III clinical trials of atacicept for SLE. He is also a consultant to Bristol-Myers Squibb regarding abatacept, and to Genentech/Biogen Idec/Roche regarding rituximab and ocrelizumab.
'If atacicept is more effective, it may also be more toxic. Only time and more studies will tell.' DR. WOFSY