Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double‐Blind, Randomized Controlled Trial

Abstract

Objective To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1‐selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). Methods In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. Results At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28‐CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28‐CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib‐treated patients than placebo‐treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). Conclusion Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates ...

Exposure–Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit–Risk Assessment in Rheumatoid Arthritis

“…Details of the study designs for the two phase IIb and the five phase III studies have been previously described. [2][3][4][5]19 These studies represent all controlled upadacitinib phase IIb and III studies in subjects with rheumatoid arthritis with results available to date, which encompassed different populations (csDMARD-IR, MTX-IR, Biologics-IR and MTX-naïve patients) and treatment modalities (on background of MTX/csDMARDs or monotherapy). Data from the phase III SELECT-EARLY 2 were not included in the exposure-response efficacy analyses due to the lack of placebo control arm to inform the placebo response (therefore the net treatment effect in this early disease population).…”

“…17,18 Upadacitinib demonstrated robust efficacy and acceptable safety in two phase II and in five phase III studies in subjects with moderate to severe RA. [2][3][4][5][6]19 Upadacitinib pharmacokinetics were thoroughly characterized following the administration of the immediate-release and extended-release formulations through noncompartmental analyses in phase I studies 20,21 as well as through population pharmacokinetic analyses across phase I to III studies. 21,22 Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A4 isozyme (CYP3A); ~30% of upadacitinib dose is recovered in urine and feces as metabolites.…”

“…6 The exposure-response analyses reported herein were conducted using the combined data from two phase IIb and five subsequently conducted phase III studies in patients with RA to (i) characterize the relationships between upadacitinib plasma exposure and efficacy and select safety parameters using the totality of the data in subjects with RA; (ii) identify any potential influence of subject-specific covariates on the exposure response relationships of efficacy and safety variables; and (iii) predict changes in upadacitinib efficacy response or safety variables under certain scenarios of increased upadacitinib exposures to support overall benefit-risk and dose recommendation in moderate to severe RA. 3,685 subjects with moderate to severe RA from the phase IIb studies BALANCE I and II 6 and four of the five phase III studies-SELECT-NEXT, 3 SELECT-BEYOND, 4 SELECT-COMPARE, 19 and SELECT-MONOTHERAPY 5 -were included in the exposure-response efficacy analyses. Data from the phase III SELECT-EARLY 2 were not included in the exposureresponse efficacy analyses due to the lack of placebo control arm to inform the placebo response (therefore the net treatment effect in this early disease population).…”

Upadacitinib for the treatment of rheumatoid arthritis

“…A similar difference in response rates for low disease activity after 14 weeks was evident in patients switched to upadacitinib compared with continuing methotrexate, and at 12 weeks when combined with a cDMARD and compared with placebo . In patients for whom methotrexate alone was inadequate, adding upadacitinib, adalimumab or placebo achieved remission in 29%, 18% and 6% respectively after 12 weeks . Over 48 weeks of treatment, upadacitinib was associated with superior clinical responses, including low disease activity and remission, compared with adalimumab (see Figure ) …”

“…It was compared with methotrexate as monotherapy in patients with moderate to severe active RA not previously treated with methotrexate (and mostly no other cDMARDs either) (SELECT‐EARLY, n=631) or when methotrexate achieved an inadequate response (SELECT‐MONOTHERAPY, n=433) . It was compared with placebo as add‐on therapy after a cDMARD was unsatisfactory (SELECT‐NEXT, n=442); compared with adalimumab in combination with methotrexate (SELECT‐COMPARE, n=1629); and with placebo in combination with a cDMARD after failure of a bDMARD (SELECT‐BEYOND, n=333) . These figures exclude patients randomised to treatment with a 30mg dose of upadacitinib (which offered only marginally greater efficacy and was not subsequently licensed).…”