Upadacitinib in patients from China, Brazil, and South Korea with rheumatoid arthritis and an inadequate response to conventional therapy

Abstract Aim This study assessed the efficacy and safety of upadacitinib (UPA), in combination with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs), in Chinese, Brazilian, and South Korean patients with active rheumatoid arthritis (RA) and an inadequate response (IR) to csDMARDs. Methods Patients on stable csDMARDs were randomized (1:1) to once‐daily UPA 15 mg or matching placebo (PBO) for a 12‐week, double‐blind period. The primary endpoint was the proportion of patients achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Results In total, 338 patients were randomized and treated, of whom 310 (91.7%) completed the double‐blind phase. The study met the primary endpoint of ACR20 at week 12 for UPA 15 mg vs PBO (71.6% vs 31.4%, P < .001), with a treatment difference observed as early as week 1. All ranked and other key secondary endpoints, including more stringent responses such as ACR50, ACR70 (≥50%/70% improvement in ACR criteria), and Disease Activity Score in 28 joints using C‐reactive protein <2.6, were met for UPA 15 mg vs PBO. The incidence of serious infections (2.4% vs 0.6%) and herpes zoster (HZ: 1.8% vs 0.6%) was higher with UPA 15 mg vs PBO. There was one case of venous thromboembolism reported in the UPA group. Conclusion UPA 15 mg in combination with csDMARDs demonstrated clinical and functional improvement and an acceptable safety profile over 12 weeks among patients from China, Brazil, and South Korea who had moderately to severely active RA and an IR to csDMARDs.


| INTRODUC TI ON
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that, if left untreated or inadequately treated, could lead to progressive functional impairment, significant disability, reduced quality of life, and increased mortality. 1,2 Methotrexate (MTX; a conventional synthetic disease-modifying antirheumatic drug [csDMARD]) is generally the recommended first-line therapy in the treatment of RA, with addition of other csDMARDs, biologic DMARDs (bDMARDs), or targeted synthetic DMARDs (tsDMARDs) in patients with an inadequate response (IR) after 3 months. [3][4][5] There remains a large unmet medical need in the treatment of RA despite major progress over the last 30 years and development of therapies such as anti-tumor necrosis factor, anti-interleukin-6, CTLA4-Ig, and anti-CD20 agents, among others. [6][7][8][9] The percentage of patients with RA who reach and maintain a status of low disease activity (LDA) or clinical remission (CR) remains unsatisfactory and, over time, many patients discontinue treatment due to adverse events (AEs) or loss of efficacy. 10,11 To address this, novel therapies are required to complement the available RA armamentarium. [10][11][12] The Janus kinase (JAK) family of signaling molecules (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) mediates intracellular signaling downstream of multiple cytokines and growth factors. 13 JAK pathway activation initiates the expression of survival factors and other molecules that facilitate leukocyte cell trafficking and proliferation, and thereby contributes to the pathogenesis of inflammatory and autoimmune disorders including RA. 13,14 Inhibition of JAK signaling is an established approach for the treatment of RA, [14][15][16][17] and JAK inhibitors form the tsDMARD class of treatments. 5 Upadacitinib (UPA) is a JAK inhibitor engineered to have greater selectivity for JAK1 over JAK2, JAK3, and TYK2, and is approved by the United States Food and Drug Administration, the European Medicines Agency, the Pharmaceuticals and Medical Devices Agency, and several other regulatory agencies (including in South Korea and Brazil) for the treatment of patients with moderately to severely active RA and an IR to MTX. [18][19][20][21] UPA has a favorable benefit-risk profile based on several global phase III trials in a variety of patient populations. [22][23][24][25][26] The objective of this study was to assess the efficacy and safety of UPA 15 mg in combination with csDMARDs over 12 weeks in patients from China, Brazil, and South Korea who had moderately to severely active RA and an IR to csDMARDs.

| Study design and participants
This is a phase III, multicenter study that includes 2 periods. This report describes the results from period 1, which was the 12-week, randomized, double-blind, placebo (PBO)-controlled period of the study conducted at 37 sites in China, Brazil, and South Korea. Period 2 is the open-label, 52-week extension in patients who completed period 1 and which is ongoing and therefore not discussed in this report ( Figure S1).

| Randomization and masking
Patients who met the eligibility criteria were randomized 1:1 to receive either a once-daily extended-release formulation of UPA 15 mg or matching PBO, administered orally for 12 weeks, along with background csDMARD treatment. Randomization was stratified by country; patients from China were expected to comprise up to 80% of the total study population. Patients were randomized using an interactive response technology with a randomization schedule generated by the Data and Statistical Sciences Department of the study sponsor. Patients, investigators, and the sponsor were masked to this allocation. UPA 15 mg extended-release tablets and PBO tablets were identical in appearance in order to maintain blinding.

| Outcomes
The primary endpoint was the proportion of patients achieving ≥20% improvement in ACR criteria (ACR20 response) at week 12. Ranked key secondary endpoints at week 12 were change from baseline in Disease Activity Score in 28 joints using CRP  Table S1). Other key secondary endpoints were the proportion of patients achieving an ACR50/70 response (≥50%/70% improvement in ACR criteria) at week 12 and an ACR20 response at week 1 (see Table S1). Additional endpoints included change from baseline in pain using a visual analog scale, remission based on CDAI ≤2. 8

| Statistical analysis
A sample size of 322 was planned to provide ≥90% power for a 21.7% difference in ACR20 response rate at week 12 (assuming a PBO ACR20 response rate of 36.7%), at a 2-sided significance level of 0.05 and accounting for a 10% dropout rate. This sample size was also planned to provide ≥90% power for most of the key secondary endpoints, including change from baseline in DAS28-CRP, ACR50 response rate, LDA and CR based on DAS28-CRP, and SF-36 Physical Component Summary (PCS), at a 2-sided significance level of 0.05 and accounting for a 10% dropout rate.
All efficacy analyses were carried out using the Full Analysis Set (FAS), which included all randomized patients who received ≥1 dose of study drug. For binary endpoints, frequencies and percentages were reported for each treatment group and comparison between UPA 15 mg and PBO was conducted using the Cochran-Mantel-Haenszel test adjusting for the stratification factor (country). Nonresponder imputation was used to handle missing data for binary endpoints. Patients who discontinued the study drug prematurely were considered as non-responders for all subsequent visits after discontinuation, and patients with missing values at a specific visit were considered as non-responders for that visit. For the continuous endpoints of change from baseline in DAS28-CRP and HAQ-DI, missing data were handled by multiple imputation (MI) and statistical inference was conducted using analysis of covariance (ANCOVA), with treatment group as the fixed factor and the corresponding baseline value and country as covariates. For other continuous endpoints, statistical inference was conducted using the mixed-model repeated measures (MMRM) method, which included the fixed effects of treatment, visit, treatment by visit interaction, and country, and the fixed covariate of baseline value in the model, using an unstructured variance-covariance matrix. From both the ANCOVA (coupled with MI) and MMRM analyses, the least squares (LS) mean and 95% confidence interval (CI) were reported for each treatment group, and LS mean treatment differences and associated 95% CI and P values were reported comparing UPA 15 mg with PBO. A sequential testing method was used to control the overall type I error rate of primary and ranked key secondary endpoints.
Safety analyses were carried out using the Safety Analysis Set, which included all patients who received ≥1 dose of study drug.
Patients with treatment-emergent AEs (TEAEs) were tabulated by preferred term as in the Medical Dictionary for Regulatory Activities, system organ class, severity, and relationship to study drug as assessed by the investigator.
This trial was registered with ClinicalTrials.gov, identifier: NCT02955212.  Table 1). The concomitant csD-MARDs the patients were receiving are detailed in Table S2.

| Efficacy
At week 12, ACR20 (primary endpoint) was achieved by a signifi-

| Safety
Through week 12, rates of TEAEs were numerically higher in the UPA 15 mg group compared with the PBO group (   (Table S5). One patient in the PBO group experienced an event of drug-induced liver injury and met Hy's law criteria. The patient was taking isoniazid as a prophylactic treatment for latent tuberculosis identified at screening, and the event resolved on day 45 after both isoniazid and study drug (PBO) were permanently discontinued.

| Pharmacokinetics
Within 24 hours of dosing, UPA mean plasma concentrations ranged from 58.7 ng/mL (around the peak time) to 6.1 ng/mL (close to the trough time) in patients in the UPA 15 mg group. These concentrations were consistent with the predicted concentrations based on prior pharmacokinetic evaluations of UPA. 28,29

| D ISCUSS I ON
This study was the first to assess the efficacy and safety of UPA

ACK N OWLED G M ENTS
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.

DATA AVA I L A B I L I T Y S TAT E M E N T
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial level data (analysis datasets), as well as other information (eg protocols and Clinical Study Reports), provided the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit https://www.abbvie.com/ our-scien ce/clini cal-trial s/clini cal-trial s-data-and-infor matio n-shari ng/ data-and-infor matio n-shari ng-with-quali fied-resea rchers.html.