Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial

Summary

Background

Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

Methods

This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426.

Findings

Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58–70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60–73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29–42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42–55) patients receiving upadacitinib 15 mg and 105 (48%; 41–55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12–22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial.

Interpretation

Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms.

Funding

AbbVie Inc.

Introduction

According to the treat-to-target strategy, treatment of patients with rheumatoid arthritis should aim to achieve a state of low disease activity or remission at 6 months, and should be adjusted in the absence of improvement by 3 months.¹ Achievement of a good clinical response by 3 months can be indicative of long-term disease control;2, 3 conversely, insufficient early response indicates a lower likelihood of achieving disease control. In clinical practice, methotrexate is commonly used as a first-line treatment, with the addition of other conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or a biological DMARD (bDMARD) in patients who are intolerant of or have an insufficient response to csDMARDS (csDMARD-IR) by 3 months.4, 5, 6 Still, a substantial proportion of patients do not achieve the desired target of clinical remission or low disease activity because of a variety of factors, including intolerance, contraindication, or inadequate response to methotrexate or other csDMARDs, or development of immunogenicity leading to loss of efficacy with bDMARDs. Also, parenteral administration of bDMARDs can be a hurdle for some patients. A class of targeted synthetic DMARDs (tsDMARDs) has emerged that could be considered as an alternative treatment option for these patients. The Janus kinase (JAK) inhibitors are a class of orally administered tsDMARDs that have recently received regulatory approval, and are in clinical trials for the treatment of rheumatoid arthritis.7, 8, 9, 10

Upadacitinib, a JAK inhibitor, has been engineered for greater selectivity for JAK1 versus JAK2, JAK3, and Tyk2, and is being developed for the treatment of rheumatoid arthritis, either alone or in combination with methotrexate or other csDMARDs. Upadacitinib showed favourable efficacy in two phase 2, dose-ranging studies in patients with active rheumatoid arthritis, who had an inadequate response to previous treatment with anti-tumor necrosis factor (anti-TNF) therapy in BALANCE I,¹¹ or to methotrexate in BALANCE II.¹² In these studies, upadacitinib administered twice daily with an immediate-release formulation at doses ranging from 6 mg to 12 mg provided an optimal balance of efficacy and safety in patients with moderate-to-severe rheumatoid arthritis. An extended-release formulation, allowing once-daily dosing with upadacitinib (15 mg and 30 mg, which provide plasma exposures equivalent to immediate-release 6 mg twice daily and 12 mg twice daily, respectively), was developed for phase 3 studies in rheumatoid arthritis.¹³ We assessed the efficacy and safety of once-daily upadacitinib (15 mg and 30 mg) in combination with background csDMARDs in patients with rheumatoid arthritis who have inadequate response to one or more csDMARD(s).