Promise for belimumab, rituximab combination in patients with primary Sjögren's syndrome
medwireNews: Subcutaneous belimumab combined with intravenous rituximab is well tolerated by patients with primary Sjögren's syndrome and shows positive signs of efficacy, suggest phase 2 study results.
The rationale for combining belimumab and rituximab is to enhance B-cell depletion by rituximab, explained Xavier Mariette (Université Paris-Saclay, France) at the EULAR 2021 Virtual Congress.
Belimumab targets BLyS, a potent promoter of B-cell hyperactivity. Increased levels of this cytokine have been observed following rituximab treatment and are thought to contribute to autoreactive B-cell repopulation thereby limiting the efficacy of the drug, he added.
In all, 86 patients were enrolled in the study and randomly assigned to receive subcutaneous belimumab 200 mg weekly for 24 weeks in combination with intravenous rituximab 1000 mg at weeks 8 and 10 followed by placebo for the remainder of the 52 weeks, belimumab as monotherapy for 52 weeks, rituximab monotherapy at weeks 8 and 10, or placebo for 52 weeks. A total of 60 (70%) patients completed treatment and attended follow-up to the 68-week visit.
The study’s primary endpoint of safety and tolerability was met and there were “no new safety issues” reported for the combination arm, the presenter said.
Adverse events were the most common reason for study withdrawal or treatment discontinuation and this occurred more frequently in the active treatment arms than the placebo group, at rates of 21% in the combination group, 13% and 20% in the belimumab and rituximab monotherapy groups, respectively, and 8% in the placebo group.
Nevertheless, “the proportions of patients experiencing at least one adverse event were similar across the four treatment groups,” Xavier reported, and events “were in line with the known safety profiles of belimumab and rituximab.”
Serious adverse events were observed in 13% of the combination arm, 8% and 16% of the belimumab and rituximab monotherapy arms, respectively, and none of the placebo group; there was one death from food asphyxiation in the combination treatment that was not considered treatment related.
Serious adverse events of special interest were low, with one serious acute delayed reaction and one case of suicide ideation, both of which occurred in the rituximab monotherapy group.
Mariette highlighted that there was “near complete” depletion of CD20-positive B-cells in salivary gland biopsies at 24 weeks in patients receiving combined treatment, from a median 88 cells/mm2 at baseline to 0 cells/mm2. This was not seen in any of the other three groups, Mariette noted, with numbers for these patients ranging from 61 to 158 cells/mm2 at 24 weeks.
He also noted positive findings for the other secondary efficacy endpoints, including a trend toward improvement in total scores on the EULAR Sjögren's syndrome disease activity index (ESSSDAI) over time for patients in all the active treatment groups relative to placebo, but particularly for those receiving combination treatment, who had an average 3.99-point greater decrease from baseline than patients taking placebo.
There was a numerically higher percentage of ESSDAI responders in the combination treatment group at week 52 that was maintained to week 68. And stimulated salivary flow showed a trend for numerically greater increases in the combination treatment group at weeks 36, 52, and 68, compared with placebo, whereas flow rates in the monotherapy treatment groups were similar to those of placebo.
However, patient-reported symptoms of oral dryness did not notably improve with combined belimumab and rituximab or with monotherapy treatment.
Mariette concluded: “Overall, the results of this phase 2 study merit further investigation of the combination treatment and belimumab monotherapy in patients with primary Sjögren's syndrome.”
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