The improvements in rheumatoid arthritis (RA) disease activity observed with the combination drug ABBV-599 are attributable to its Janus kinase (JAK) inhibitor, upadacitinib, and not its Bruton’s tyrosine kinase (BTK) inhibitor, elsubrutinib, according to study results published in The Lancet Rheumatology.

This multicenter, double-blind, randomized controlled phase 2 trial took place at 75 community sites across 8 North American and European countries. A total of 242 patients with RA (mean age at baseline, 58.0±11.3 years; 84% women; 81% White) who had an inadequate or adverse response to biological disease-modifying antirheumatic drugs (bDMARDs) were included in the study. Patients were assigned to receive either ABBV-599 (ie, upadacitinib 15 mg + elsubrutinib 60 mg; n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or  placebo (n=19). The study completion rate was 89% (n=215). The researchers used the number of previous bDMARDs to stratify randomization. The study’s primary endpoint was the change from baseline to week 12 in Disease Activity Score of 28 Joints with C-Reactive Protein (DAS28-CRP). Safety and pharmacokinetics were also examined.

Compared with placebo, the following were the DAS28-CRP 12-week least squares mean changes from baseline:


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  • ABBV-599: –1.44 (90% CI, –2.03 to –0.85; P <.0001)
  • Elsubrutinib 60 mg: –0.40 (90% CI, –1.03 to 0.23; P =.29)
  • Elsubrutinib 20 mg: –0.20 (90% CI, –0.85 to 0.44; P =.61)
  • Elsubrutinib 5 mg: –0.21 (90% CI, –0.84 to 0.41; P =.57)
  • Upadacitinib: –1.75 (90% CI, –2.38 to –1.13; P <.0001)

Elsubrutinib alone did not show any significant difference in efficacy compared with placebo. All groups experienced similar rates of treatment-emergent adverse events, which occurred in 47% (n=113) of participants.

Limitations of this study included small sample sizes, a short study period, a lack of long-term results, the potential that the study population did not accurately represent the general population with RA, and the borrowing of historical placebo data in sensitivity analyses.

The study authors concluded, “[T]he combination of this BTK inhibitor with a JAK inhibitor does not offer any advantage in clinical control of rheumatoid arthritis disease activity, and, as a result, ABBV-599 has been discontinued from further clinical development for the treatment of rheumatoid arthritis.”

Disclosure: This clinical trial was supported by AbbVie. Please see the original reference for a full list of authors’ disclosures.

Reference

Fleischmann R, Friedman A, Drescher E, et al. Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial. Published online April 27, 2022. Lancet Rheum. doi:10.1016/S2665-9913(22)00092-3