Tregalizumab lacks clinical efficacy in RA
medwireNews: Tregalizumab has failed to show clinical efficacy in a phase IIb study of patients with active rheumatoid arthritis (RA) who have had an inadequate response to methotrexate.
Among 321 patients randomly assigned to receive tregalizumab, at a weekly dose of 25 mg, 100 mg, or 200 mg, or placebo in addition to methotrexate, there was no significant difference in the proportion who achieved at least a 20% improvement in the American College of Rheumatology Criteria (ACR20).
This primary outcome was achieved by 42.3% of the 71 patients taking tregalizumab 25 mg, 47.0% of 66 receiving 100 mg and 44.3% of 70 receiving 200 mg, compared with 35.2% of 71 patients given placebo.
The number of patients in remission or with low disease activity according to Disease Activity Score at 28 joints (<2.6 and <3.2 points, respectively) was low in all groups and not significantly different, and while decreases in Simplified Disease Activity Index, Clinical Disease Activity Index, tender joint count, and swollen joint count scores were evident, tregalizumab treatment was not superior to placebo.
Despite no clinical efficacy being demonstrated with tregalizumab, the researchers note that treatment had the expected biological effect for an anti-CD4 immunoglobulin G antibody, decreasing CD4 expression in a dose-dependent way compared with no change in expression levels with placebo.
The team, led by Ronald van Vollenhoven (Amsterdam Rheumatology and Immunology Center, the Netherlands), say the findings suggest that regulatory T cells (Tregs) may have a “less important role” in RA than previously thought.
Tregalizumab “binds a specific epitope on the CD4 molecule, leading to the selective activation of Tregs,” they explain.
But the researchers add that it is possible that tregalizumab may be more effective with long-term use. After 12 weeks, patients who responded to tregalizumab could continue treatment while non-responders were escalated to the next higher dose and placebo-treated patients to active treatment for up to 48 weeks, during which time the number of patients who achieved ACR20, 50, and 70 responses continued to increase.
“Thus, it is possible that a convincing therapeutic effect would have emerged after a longer treatment period,” the researchers suggest in the Annals of the Rheumatic Diseases. “A delayed time to clinical response might be related to the unique mechanism of activating Tregs.”
They also propose that the efficacy of tregalizumab may be limited to specific subgroups of patients or be disease specific. The team explains that patients with RA tend to have high thioredoxin-1 levels, which may diminish tregalizumab binding and signaling, but that the agent “may be effective in other immune conditions such as allergic asthma or transplantation.”
By Lucy Piper
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