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
Background: ABBV-599 is really a novel fixed-dose mixture of the Bruton’s tyrosine kinase (BTK) inhibitor elsubrutinib and also the Janus kinase (JAK) inhibitor upadacitinib under analysis to treat autoimmune illnesses. We aimed to find out whether ABBV-599 could boost the treatment response for patients with active rheumatoid arthritis symptoms in contrast to inhibiting either path alone, while keeping a suitable safety profile.
Methods: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight europe and The United States. We enrolled patients who have been 18 years or older with rheumatoid arthritis symptoms and insufficient response or your inability to tolerate biological disease-modifying antirheumatic drugs. Qualified patients were at random assigned (3:2:2:2:2:1) via interactive response technology to get daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the amount of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked through the study. The main endpoint was vary from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for those patients who received research drug. Pharmacokinetics and safety were also assessed. This research is registered with ClinicalTrials.gov, number NCT03682705.
Findings: Between March 8, 2018, and March 26, 2020, 242 patients were at random allotted to receive ABBV-599 (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). From the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White-colored the mean age at baseline was 58·0 years (SD 11·3). In contrast to placebo, minimal squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85 p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23 p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44 p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41 p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13 p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups. Interpretation: Significant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib.