Upadacitinib is an oral selective JAK-1 inhibitor that is being clinically investigated for the treatment of patients with moderate-to-severe rheumatoid arthritis (RA). This is a report of the double-blind, placebo-controlled period 1 of the randomized phase 3 study that evaluated upadacitinib in patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs).
During the double-blind, placebo-controlled period 1 of the SELECT-NEXT study, patients were randomized 1:1:1 to receive the once-daily, extended-release formulation of upadacitinib at 15 mg or 30 mg, or placebo for 12 weeks. Period 2 of the study (a blinded extension for 5 years) was not included in this analysis. The 2 parallel primary efficacy end points were the proportion of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) response and Disease Activity Score 28‒C-reactive protein (DAS28-CRP) low disease activity (LDA; ≤3.2) at week 12; secondary outcomes included ACR20 at week 1, 50% improvement in ACR criteria (ACR50), 70% improvement in ACR criteria (ACR70), DAS28-CRP <2.6 , Clinical Disease Activity Index (CDAI)-LDA (≤10), change from baseline in HAQ-DI, Short Form (SF)-36, morning stiffness duration, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).
Of the 661 randomized patients who received the study drug, 618 (93.5%) completed period 1 of the study and were included in this analysis (upadacitinib 15 mg, 221; upadacitinib 30 mg, 219; placebo, 221). Baseline patient and disease characteristics were similar across the treatment arms. In terms of the 2 primary end points, a significantly higher proportion of patients treated with upadacitinib 15 mg and 30 mg once daily achieved an ACR20 response at week 12 (64% and 66% vs 36%; P <.001) and DAS28-CRP LDA (48% and 48% vs 17%; P <.001) compared with placebo. Notably, a significantly higher proportion of upadacitinib-treated patients achieved ACR50 (upadacitinib 15 mg, 38%; upadacitinib 30 mg, 43%; placebo, 15%) and ACR70 responses (upadacitinib 15 mg, 21%; upadacitinib 30 mg, 27%; placebo, 6%) in the 15-mg and 30-mg once-daily arms (43.4% and 26.5%) compared with placebo. Moreover, a significantly higher proportion of upadacitinib-treated patients achieved clinical remission at week 12, as assessed by DAS28-CRP <2.6 (15 mg, 31%; 30 mg, 28%; placebo, 10%; P <.001) and CDAI-LDA (15 mg, 40.3%; 30 mg, 42%; placebo, 19%; P <.001) versus placebo. Notably, significant improvements were observed by week 1 of treatment. Patients treated with upadacitinib at both doses also experienced significantly greater improvements in DAS28-CRP, HAQ-DI, SF-36, pain, Patient Global Assessment, morning stiffness, and FACIT-F versus placebo (P <.001).
Safety analysis showed a numerically higher incidence of adverse events (AEs; upadacitinib 15 mg, 56.6%; upadacitinib 30 mg, 53.9%; placebo, 48.9%) and serious AEs (upadacitinib 15 mg, 4.1%; upadacitinib 30 mg, 2.7%; placebo, 2.3%) with upadacitinib versus placebo. The most frequently reported AEs (>3%) included nasopharyngitis, upper respiratory infection, headache, cough, nausea, and diarrhea. Although the overall incidence of infection was higher in the upadacitinib 15-mg (29.0%) and 30-mg (31.5%) cohorts versus placebo (21.3%), incidence of serious infections was low (0.5% and 1.4%, respectively). Three cases of herpes zoster/varicella zoster virus infection were reported in the active arm (2 in the 30-mg cohort, 1 in the placebo cohort). In the upadacitinib cohorts, 2 malignancies, including nonmelanoma skin cancer, and 3 adjudicated cardiovascular events were reported. No deaths or cases of tuberculosis or gastrointestinal perforations were reported, and incidence of hematologic toxicities was low.
In conclusion, the study met all primary and key secondary end points to demonstrate that upadacitinib 15 mg and 30 mg once daily with background conventional synthetic DMARDs was associated with significant improvement in disease activity and functional outcomes in this patient population with RA and inadequate response to conventional synthetic DMARDs compared with placebo.
Burmester GR, et al. ACR 2017. Abstract 1904.