Results of the phase 2b trial "suggest that this combination could be developed as a therapeutic strategy," the study team said in Annals of Internal Medicine.
"The development of new treatments for lupus has been frustratingly slow with only a few positive clinical trials for this debilitating disease over the last decade," Dr. Michael Ehrenstein, consultant rheumatologist at University College London Hospitals, London, UK, told Reuters Health by email.
"Thanks to the dedication of the lupus teams at participating hospitals we are delighted to not only have completed recruitment, but also to provide preliminary evidence for a clinical benefit of the combination of rituximab and belimumab, compared to patients treated with rituximab alone. These results will need to confirmed in a larger clinical trial," Dr. Ehrenstein said.
For some lupus patients, repeated cycles of rituximab lead to increasing serum anti-dsDNA antibody levels, which are associated with disease flares and elevated serum B-cell-activating factor (BAFF) levels. Belimumab is a BAFF-neutralizing monoclonal antibody.
The BEAT-LUPUS trial enrolled 52 patients with SLE refractory to conventional treatment and who were recommended for rituximab therapy.
All participants received two infusions of rituximab administered two weeks apart. Half were then randomly allocated to belimumab and half to placebo, administered intravenously at randomization and at two and four weeks and then monthly through 52 weeks.
At 52 weeks, compared with placebo, belimumab reduced IgG anti-dsDNA antibody levels (the primary outcome) by 70% and also reduced severe lupus flares by three-fold, with 10 severe flares occurring in the placebo group versus three in the belimumab group (hazard ratio, 0.27).
Belimumab significantly suppressed B-cell repopulation compared with placebo, with no increase in the incidence of serious adverse events.
Serious adverse events were reported in six (23%) patients in each group; serious infections were seen in three (12%) patients taking belimumab and four (15%) taking placebo.
"The frequency of adverse effects was as expected for patients with active SLE, and there was no difference between those receiving belimumab compared with placebo after rituximab," the study team reports.
They caution that the sample size was small because there were no published safety data on using belimumab with rituximab when the trial began. Therefore, the trial was powered on anti-dsDNA antibody levels as a surrogate endpoint.
Despite these caveats, the data provide preliminary evidence to support use of belimumab after rituximab and "are consistent with the hypothesis that a surge in BAFF levels after rituximab can trigger SLE exacerbations."
"These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE, at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages," they say.
The authors of an editorial say this study sheds light on the potential synergy between rituximab and belimumab in SLE patients.
"B-cell depleting therapy may not benefit all SLE patients. However, for a subset of SLE patients, the combination of rituximab and belimumab may be highly effective with a reasonable safety profile," write Dr. Medha Barbhaiya with Weill Cornell Medicine in New York and Dr. Katherine Liao with Brigham and Women's Hospital in Boston.
"Future studies are needed to determine the optimal sequence of treatments, clinical responses, characterization of patients likely to respond, and adverse event profiles in larger populations to help us better care for our patients with SLE," the editorial writers say.
The BEAT-LUPUS trial was supported by Versus Arthritis and the University College London Hospitals Biomedical Research Center, which is funded through a grant from the National Institute of Health Research. GlaxoSmithKline provided belimumab free of charge, as well as additional funding.
SOURCE: https://bit.ly/3b5XSSi and https://bit.ly/3b6pabp Annals of Internal Medicine, online October 25, 2021.
By Megan Brooks
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