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Upadacitinib as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs for psoriatic arthritis

Abstract Objective To assess the efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA. Methods Pooled data were analysed from patients with prior inadequate response or intolerance to one or more nbDMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) who received placebo, UPA 15 mg once daily (QD) or UPA 30 mg QD as monotherapy or in combination with two or fewer nbDMARDs for 24 weeks. Efficacy outcomes included achievement of ACR responses, Psoriasis Area and Severity Index responses, minimal disease activity and change from baseline and clinically meaningful improvement in the HAQ Disability Index. Adverse events (AEs) were summarized. Results A total of 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects for a 20% improvement in ACR criteria at week 12 were 33.7% (95% CI 24.4, 43.1) and 34.0% (95% CI 27.9, 40.1) for UPA 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (95% CI 36.9, 54.5) and 39.6% (95% CI 33.7, 45.5) for UPA 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for UPA monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy. Conclusion The efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of UPA with or without nbDMARDs in PsA. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov): SELECT-PsA 1 (NCT03104400), SELECT-PsA 2 (NCT03104374)


Introduction
Research advances have translated into diverse treatment options for PsA, including conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), with the potential to achieve low disease activity across various clinical domains [1][2][3]. However, questions remain regarding optimal treatment algorithms and treatment patterns and one key question for clinicians is whether comedication with csDMARDs is useful for patients with PsA [1][2][3].
The efficacy of csDMARDs such as MTX as concomitant therapy in PsA is not established, and several studies have demonstrated that MTX provides little additional benefit when combined with biologics or tsDMARDs [4][5][6][7]. For example, an analysis of two etanercept clinical trials found that etanercept was equally effective with or without MTX in patients with PsA [4]. Treatment guidelines for PsA differ on whether csDMARDs should be used as concomitant therapy; the EULAR guidelines [2] recommend combining biologics with csDMARDs (while acknowledging there is little evidence to support this), whereas the ACR guidelines [8] favour biologic monotherapy. In addition to a lack of clarity regarding the efficacy of combination therapy, many patients have contraindications to MTX or are unable to tolerate higher doses [5,9]. Agents with novel mechanisms of action that are effective as monotherapy would therefore be a useful treatment option for PsA. Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor designed to selectively target JAK1 over the other JAK family enzymes: JAK2, JAK3 or tyrosine kinase 2 [10]. UPA has been assessed for the treatment of PsA in two global phase 3 trials, SELECT-PsA 1 and SELECT-PsA 2 [11,12]. In both of these trials, UPA 15 mg and 30 mg once daily (QD) were significantly more effective than placebo in improving key clinical manifestations of PsA.
Here we report data from a pooled subgroup analysis of the two SELECT-PsA studies assessing efficacy and safety outcomes in patients who were treated with UPA as monotherapy or in combination with non-biologic DMARDs (nbDMARDs).

Patients
In SELECT-PsA 1 (NCT03104400) [11] and SELECT-PsA 2 (NCT03104374) [12], patients with active PsA (three or more swollen and three or more tender joints) and active or historical psoriasis were blindly randomized to UPA 15 mg QD, UPA 30 mg QD, placebo or adalimumab 40 mg every other week (SELECT-PsA 1 only) for 24 weeks. Patients in SELECT-PsA 1 had prior inadequate response (IR) or intolerance to one or more nbDMARD [11] and patients in SELECT-PsA 2 had prior IR or intolerance to one or more bDMARD [12]. Starting from week 16, patients who did not achieve !20% improvement in tender and swollen joint counts compared with baseline at both week 12 and week 16 were offered rescue therapy, which allowed patients to add or modify existing nbDMARDs, NSAIDs, acetaminophen, lowpotency opioid medications or corticosteroids in accordance with the protocol.
The two trials were conducted according to the International Conference on Harmonization Guidelines, the Declaration of Helsinki and applicable local country regulations. All study-related documents were approved by independent ethics committees and institutional review boards of the participating centres (Supplementary  Table S1, available at Rheumatology online). All patients provided written informed consent.

Outcomes
Efficacy endpoints included the proportion of patients achieving 20%, 50% and 70% improvement in ACR criteria (ACR20, ACR50 and ACR70, respectively) at weeks 12 and 24; a Static Investigator Global Assessment of Psoriasis score of 0 or 1 (sIGA 0/1) and at least a 2 point improvement from baseline at week 16; 75%, 90% and 100% improvement in Psoriasis Area Severity Index (PASI 75, PASI 90 and PASI 100, respectively) responses at week 16; resolution of enthesitis at week 24; resolution of dactylitis at week 24; minimal disease activity (MDA) at week 24 and clinically meaningful improvement in the HAQ Disability Index (HAQ-DI; improvement of !0.35 vs baseline [13]) at week 12. Changes from baseline in pain and HAQ-DI at week 12 were also assessed. Safety outcomes were summarized by the frequency of adverse events (AEs) and laboratory abnormalities over 24 weeks.

Statistical analysis
All patients who had received at least one dose of study drug were pooled and included in the efficacy analyses. Patients receiving adalimumab in SELECT-PsA 1 were excluded from this analysis. The clinical trials were designed a priori for this analysis and patients were stratified by current use of one or more nbDMARD at randomization.
Demographic and clinical characteristics are presented using descriptive statistics. For binary efficacy endpoints, frequencies and percentages are reported, with non-responder imputation used for missing data; point estimates and 95% CIs for placebo-subtracted differences were calculated based on Cochran-Mantel-Haenszel analysis adjusting for study. For continuous endpoints, within-group least squares (LS) means (95% CI) and between-group LS means (95% CI) are presented and were calculated based on the mixed-effects model repeated measures analysis with unstructured variance-covariance matrix. The model included treatment, visit, treatment-visit interaction and study as fixed factors and the continuous fixed covariate of baseline measurement. Safety data in patients who received at least one dose of study drug are presented descriptively. Laboratory abnormalities were graded according to the Common Toxicity Criteria developed by the National Cancer Institute (version 4.03). Baseline demographic and disease characteristics were generally balanced across the treatment arms and between patients receiving monotherapy and combination therapy, either with MTX only or with any nbDMARD (Table 1). Across all the groups, slightly more than half of patients were female and the mean age was 51-52 years. The mean duration since PsA diagnosis was longer in the monotherapy group compared with the combination therapy groups. The mean PASI score in patients with a body surface area >3% at baseline ranged from 10.2 to 12.7 in the monotherapy subgroup and from 8.8 to 11.5 in the combination therapy subgroups. At baseline, around one-quarter of patients had dactylitis and more than half of patients had enthesitis.

Efficacy outcomes
The proportion of patients achieving efficacy outcomes ( Table 2) and the corresponding placebo-subtracted treatment effects (Fig. 1) were consistent between UPA as monotherapy, UPA in combination with MTX and UPA in combination with any nbDMARD, with associated 95% CIs overlapping between the subgroups for each dose (Fig. 1). In addition, comparable treatment effects were mostly observed between the UPA 15 mg and 30 mg doses ( Table 2 and Fig. 1).
Other skin endpoints such as achievement of PASI 90/ 100 and sIGA 0/1 with at least a 2 point improvement at week 16 demonstrated consistent placebo-subtracted treatment effects with overlapping CIs between monotherapy and combination therapy for both doses ( Fig. 1). Change from baseline in pain and HAQ-DI scores at week 12 in the monotherapy and combination therapy groups also showed comparable results ( Fig. 1 and Table 2). ACR20/50/70 responses at week 24 (Supplementary Table S2, available at Rheumatology online) were consistent with results at week 12.
Study-specific results for the SELECT-PsA 1 (nbDMARD-IR) and SELECT-PsA 2 (bDMARD-IR) studies reflect those of the integrated analysis, with generally comparable proportions of patients in the monotherapy and combination therapy subgroups of each study achieving ACR20/50/70 responses, MDA and sIGA 0/1 and at least a 2 point improvement across all treatment subgroups (Supplementary Table S3, available at Rheumatology online).

Safety outcomes
Generally, the frequency of AEs and serious AEs was comparable in patients receiving UPA 15 mg and 30 mg when administered as monotherapy and in combination with MTX or any nbDMARD through week 24 ( Table 3). The frequency of discontinuation of study drug, patients lost to follow-up and discontinuation due to a lack of efficacy in patients receiving UPA 15 mg were higher in the monotherapy group compared with the combination therapy groups ( Table 4). The higher frequency of discontinuation of study drug was attributed to a relatively smaller sample size in the monotherapy subgroup, and the occurrence of three cases of malignancy other than non-melanoma skin cancer with UPA 15 mg monotherapy (compared with no cases in the UPA 15 mg combination therapy group) for which discontinuation was required per the protocol.
The frequency of serious infections and herpes zoster was similar for placebo and UPA 15 mg QD as           Patients who discontinued study drug are counted under each reason given for discontinuation, therefore the sum of the counts given for the reasons may be greater than the overall number of discontinuations. PBO: placebo. monotherapy or combination therapy but higher in the UPA 30 mg QD monotherapy and combination therapy subgroups (Table 3). All herpes zoster events were mild or moderate in severity except for one severe, nonserious event involving two dermatomes in a patient receiving UPA 30 mg QD with MTX. There were no major adverse cardiovascular events or venous thromboembolic events reported with UPA monotherapy. One non-fatal myocardial infarction was reported in a patient receiving UPA 15 mg QD with MTX, one pulmonary embolism was reported in a patient receiving UPA 15 mg QD with SSZ and one pulmonary embolism was reported in a patient receiving UPA 30 mg QD with MTX. In addition, one deep vein thrombosis was reported in a patient receiving placebo in the monotherapy group and one non-fatal myocardial infarction was reported in a patient receiving placebo in combination with MTX. AEs of hepatic disorder (which were mostly nonserious transaminase elevation) and creatine phosphokinase (CPK) elevation were more common in the combination therapy groups than the monotherapy group, and more common with UPA 30 mg vs UPA 15 mg ( Table 3). AEs of anaemia, neutropenia and lymphopenia were generally consistent across the monotherapy and combination therapy groups (Table  3). Grade 3 or 4 changes in laboratory values were infrequent (Table 5).

Discussion
In this analysis, UPA used as a monotherapy or in combination with nbDMARDs (including MTX alone or any nbDMARD) was similarly well tolerated and effective in treating the major clinical manifestations of PsA, including musculoskeletal symptoms (peripheral arthritis, enthesitis and dactylitis), psoriasis, physical function and pain.
The finding that UPA combination therapy in PsA does not provide significant improvements in efficacy over monotherapy is consistent with observations investigating the efficacy of other PsA therapies used in combination with MTX or other nbDMARDs. A propensity scorematched analysis of a large registry of patients with PsA (n ¼ 497) treated either with a combination of a TNF inhibitor (TNFi) and an nbDMARD or TNFi monotherapy demonstrated no difference between groups in time to remission, defined as achieving a 28-joint DAS using CRP (DAS28-CRP) <2.6 [6]. Similarly, a pooled analysis of two 24 week, placebo-controlled trials of subcutaneous etanercept (25 mg twice weekly or 50 mg once weekly) with (n ¼ 322) or without MTX (n ¼ 152) in patients with PsA showed a similar proportion of patients across the two groups achieving ACR20 [4]. Furthermore, in the Study of Etanercept and MTX in Subjects with PsA (SEAM-PsA), both etanercept monotherapy and MTX combination therapy showed greater efficacy than MTX monotherapy in patients with PsA, according to ACR20 and MDA response rates and the extent of radiographic progression at follow-up [7]. Similarly, a post hoc analysis of 455 patients in the SPIRIT-P1 (NCT01695239) and SPIRIT-P2 (NCT02349295) trials found that treatment with once-monthly or once-fortnightly ixekizumab improved the signs and symptoms of PsA either alone or in combination with MTX [14]. More recently, a metaanalysis of randomized controlled trials found that the addition of MTX to biologics led to no clinical improvements vs biologic monotherapy in patients with PsA [15]. Within the same drug class, a study of tofacitinib found that withdrawal of MTX in patients receiving stable combination therapy did not result in clinically meaningful changes in disease activity or safety [16]. Interestingly, these data contrast with observations in RA, where combining bDMARDs with MTX results in increased efficacy [17,18]. This is thought to be due to the reduction of anti-drug antibodies by MTX, resulting in increased drug survival [19]. However, this effect is not relevant to UPA since it does not induce immunogenicity in patients.
The data from our analysis also suggest that UPA was well tolerated when used as a monotherapy and when administered in combination with MTX alone or any nbDMARD, with the majority of AEs seen at comparable frequencies across the monotherapy and combination therapy groups. Hepatic disorders were more frequent with UPA as combination therapy compared with UPA as monotherapy, which is not surprising given the wellknown effects of nbDMARDs such as MTX on liver function [20,21]. CPK elevation also appeared to be higher in the combination therapy vs monotherapy groups, particularly in patients receiving UPA 30 mg. However, grade 3 or 4 changes in transaminases, CPK and other laboratory parameters were infrequent. Given that the efficacy of UPA monotherapy appeared to be comparable to that of UPA combination therapy, a reduction in the risk of mild laboratory abnormalities could be a benefit of treatment with UPA monotherapy, while also reducing the burden of medication use.
There appeared to be a higher rate of placebo response in the combination therapy groups compared with the monotherapy group. This may reflect the fact that the combination therapy groups had a higher proportion of patients from SELECT-PsA 1, which demonstrated higher placebo responses compared with SELECT-PsA 2 (Supplementary Table S3, available at Rheumatology online). In addition, patients in SELECT-PsA 1 and 2 were permitted to receive up to two concomitant nbDMARDs, which may have further increased the placebo response. The relatively high placebo response in SELECT-PsA 1 may be due to the fact that patients in this trial were less treatment refractory than those in SELECT-PsA 2 (nbDMARD-IR vs bDMARD-IR) [11,12]. However, the placebo response in SELECT-PsA 1 was generally comparable to similar studies of JAK inhibitors in patients with PsA, such as the OPAL Broaden study (NCT01877668) of tofacitinib [22].
A primary strength of the current analysis is that it is based on a pooled analysis of data from two large, phase 3 clinical trials. Although the comparison of UPA as monotherapy vs combination therapy was not a primary objective of the studies, this analysis was planned prior to trial conduct and patients were stratified by current use of one or more nbDMARD at randomization. One limitation of the study is that the majority of patients taking a concomitant nbDMARD were receiving MTX, and thus it was not possible to individually assess UPA in combination with other nbDMARDs such as SSZ or LEF. In addition, although it was permitted, relatively few patients were receiving UPA in combination with two nbDMARDs, so the safety and efficacy of this treatment regimen could not be assessed. It should also be noted that all patients who were taking a nbDMARD at study entry met inclusion criteria related to active disease. Thus these data permit assessment of the safety and efficacy of treatment with UPA added to stable background therapy and are not able to inform the benefit or risk of starting both drugs simultaneously or adding a nbDMARD to existing UPA therapy. Finally, this analysis focussed on 24 week data; long-term efficacy and safety for UPA monotherapy and combination therapy, including any long-term benefits (such as exploring late-stage drug survival with or without combination therapy), will be assessed in the ongoing SELECT-PsA 1 and SELECT-PsA 2 studies.
In conclusion, the results of this analysis show that the efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs. This supports the use of UPA with or without nbDMARDs in PsA and suggests that UPA monotherapy may be a useful treatment option in patients with contraindications to MTX or those who are unable to tolerate higher doses.