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06-05-2022 | Rheumatology | News | Article

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Adding BTK inhibitor to upadacitinib offers no benefit in RA

Author: Claire Barnard

medwireNews: Treatment with a fixed-dose combination of the novel Bruton’s tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib offers no additional benefit over upadacitinib alone for people with rheumatoid arthritis (RA), suggest phase 2 trial results.

Writing in The Lancet Rheumatology, Roy Fleischmann (University of Texas Southwestern Medical Center, Dallas, USA) and co-investigators explain that their proof-of-concept and dose-exploratory study was carried out following studies in animal models that demonstrated “potential disease-modifying effects” with elsubrutinib, leading them to hypothesize that “concurrent BTK and JAK inhibition could increase the treatment response compared with inhibiting either pathway alone.”

In all, 242 RA patients with an inadequate response to biologic agents were randomly assigned to receive once-daily oral treatment with upadacitinib 15 mg plus elsubrutinib 60 mg in a fixed-dose combination (ABBV-599), elsubrutinib at a dose of 5 mg, 20 mg, or 60 mg, upadacitinib 15 mg, or placebo. These agents were given alongside continued background treatment with conventional DMARDs, but all biologics were discontinued prior to study entry. The average DAS28-CRP score at baseline was approximately 6.0 points across the treatment groups.

The researchers found that patients treated with ABBV-599 experienced a least-squares (LS) mean decrease in DAS28-CRP from baseline to week 12 of 2.56 points, compared with a 1.12-point decrease for those given placebo, a significant difference.

The LS mean DAS28-CRP reduction in the ABBV-599 group was significantly greater than that observed for any dose of elsubrutinib given alone, but was comparable to the reduction seen in patients given upadacitinib alone, at 2.87 points. There was no significant difference among patients given elsubrutinib 5 mg, 20 mg, or 60 mg versus those given placebo (1.33, 1.32, and 1.52 vs 1.12 points, respectively).

These findings suggest that the reduction in disease activity with ABBV-599 “is achieved exclusively through JAK inhibition provided by upadacitinib, with no involvement of BTK inhibition,” say Fleischmann et al.

“[P]harmacokinetic results suggest that elsubrutinib achieved adequate target engagement with no exposure-dependent increases in efficacy response rates,” indicating that “the absence of clinical effects with elsubrutinib alone was likely not caused by inadequate exposure or BTK target engagement,” they add.

The investigators say that ABBV-599 was well tolerated overall, with treatment-emergent adverse events “generally balanced across treatment groups.”

They note that the combination therapy “has been discontinued from further clinical development for the treatment of rheumatoid arthritis,” but remains under investigation for systemic lupus erythematosus.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00092-3