Tofacitinib Monotherapy in Rheumatoid Arthritis: Clinical Trials and Real-World

iebpharma

To evaluate the characteristics, efficacy, and retention of tofacitinib monotherapy in patients with rheumatoid arthritis using data from randomized controlled trials (RCTs) and real-world data (RWD).

Patients and Methods: Three patient groups receiving tofacitinib 5 mg twice daily (BID) monotherapy were defined for post hoc RCT/long-term extension (LTE) analyses: (1) disease-modifying antirheumatic drug (DMARD)-inadequate responder patients from phase 3/3b/4 RCTs; (2) methotrexate-naïve patients from a phase 3 RCT; and (3) index study patients continuing in an LTE study. Outcomes included low disease activity (LDA)/remission rates defined by Clinical Disease Activity Index (CDAI); Disease Activity Score in 28 joints (DAS28-4), erythrocyte sedimentation rate; DAS28-4, C-reactive protein (DAS28-4[CRP]); and rates of/time to discontinuation due to lack of efficacy/adverse events. RWD were identified by non-systematic literature searches of PubMed, Embase, and American College of Rheumatology/European Alliance of Associations for Rheumatology congress abstracts (2012– 2022).

Results: RCT/LTE analyses included 1000/498 patients receiving Tofacitinib 5 mg (Tofacent) BID monotherapy. Baseline disease activity was high; patients tended to receive concomitant glucocorticoids; most were biologic DMARD-naïve. CDAI LDA rates were 32.2– 62.2% for Groups 1/2 (months 3– 12) and 64.0– 70.7% for Group 3 (months 12– 72). In Groups 1, 2, and 3, 4.0%, 15.6%, and 27.7% of patients, respectively, discontinued tofacitinib monotherapy due to lack of efficacy/adverse events. From 11 RWD publications, 16.6– 66.1% received tofacitinib monotherapy. Consistent with clinical data, tofacitinib monotherapy effectiveness (month 6 CDAI LDA, 30.2%; month 3 DAS28-4[CRP] remission, 53.4%) and persistence were observed in RWD, with retention comparable to tofacitinib combination therapy.

Conclusion: Tofacitinib monotherapy demonstrated clinically significant responses/persistence in RCT/LTE analyses, with effectiveness observed and persistence comparable to combination therapy in RWD.

Trial Registration: NCT00814307, NCT02187055, NCT01039688, NCT00413699, NCT00661661 (ClinicalTrials.gov).

Keywords: autoimmune, JAK inhibitor, clinical practice, long-term, efficacy, retention

Introduction
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects approximately 0.10–0.38% of people in regions across the world and is a significant contributor to global disability.1,2 Current treatment guidelines from the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) recommend that patients with RA initiate treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) with the addition of a biologic (b)DMARD, such as a tumor necrosis factor inhibitor (TNFi), or targeted synthetic DMARD, such as a Janus kinase (JAK) inhibitor, in case of therapeutic failure.3,4

Tofacitinib is an oral JAK inhibitor for the treatment of RA that can be used in combination with csDMARDs, such as methotrexate (MTX), or as monotherapy in patients who may be intolerant to csDMARDs.3,4 Tofacitinib has been shown to be efficacious as monotherapy in phase 3 and 3b/4 randomized controlled trials (RCTs), reducing the signs and symptoms of RA in MTX-naïve patients receiving tofacitinib as a first-line therapy5 and in patients with an inadequate response to csDMARDs or bDMARDs.6,7

While RCTs have long been considered the gold standard for evaluating the efficacy of interventions, with well-defined patient groups and specific inclusion/exclusion criteria, data from these trials can be complemented with real-world data (RWD) from settings more representative of clinical practice.8,9 Therefore, in this analysis, we used RWD to contextualize the findings from RCTs and long-term extension (LTE) studies of patients with RA receiving tofacitinib 5 mg twice daily (BID) as monotherapy. Patient characteristics, tofacitinib efficacy, and treatment retention were evaluated to further inform clinical decision-making.

Materials and Methods
Post Hoc Analysis of Clinical Trial Data
Three groups of patients with RA receiving tofacitinib 5 mg BID monotherapy in RCTs and LTE studies were analyzed. Only patients treated with tofacitinib 5 mg BID were included in this analysis, as this is the recommended tofacitinib dosage for RA in line with product labeling and was the dosage for most patients treated in real-world settings. In line with the recommended use in the tofacitinib product label,10,11 Group 1 consisted of patients with moderate to severe RA and an inadequate response to DMARDs from one phase 3 and one phase 3b/4 RCT: ORAL Solo (NCT00814307; phase 3),6 which included patients with an inadequate response to ≥1 cs/bDMARD, and ORAL Strategy (NCT02187055; phase 3b/4),7 which included MTX-inadequate responder patients. Group 2 comprised MTX-naïve patients with RA from the phase 3 RCT ORAL Start study (NCT01039688);5 this group was analyzed separately and included for context. Group 3 included patients who received tofacitinib 5 mg BID monotherapy throughout the global LTE study ORAL Sequel (NCT00413699)12 or the Japanese LTE study (NCT00661661).13 Patients in Group 3 could have enrolled from any index study (ie not limited to ORAL Solo, ORAL Strategy, or ORAL Start) and therefore could have received index dosages other than 5 mg BID. In addition, patients in Group 3 may not have received tofacitinib as a monotherapy in their index studies. Full details of the study designs and inclusion/exclusion criteria are outlined in Supplementary Table 1.

All studies included in this post hoc analysis were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Council for Harmonisation and were approved by the institutional review board and/or independent ethics committee at each participating center (Supplementary Material- List of Investigators and Corresponding Ethics Committees or Institutional Review Boards). As all patients provided written informed consent, all of the data included in this analysis were covered by the original ethical/approval process. Consequently, no additional ethical review/approval was required for this post hoc analysis.

Assessments
Efficacy outcomes included the proportion of patients achieving Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission (scores ≤10 and ≤2.8, respectively), Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR])-defined LDA and remission (scores ≤3.2 and <2.6, respectively), and DAS28-4, C-reactive protein (DAS28-4[CRP]) ≤3.2 and <2.6 (DAS28-4[CRP] scores have not been validated for LDA and remission but are commonly used in rheumatology). The rates of study discontinuation and time to study discontinuation due to lack of efficacy or adverse events (AEs) were analyzed.

Statistical Analyses
Rates for LDA, remission, and discontinuation due to lack of efficacy or AEs were summarized by treatment (tofacitinib 5 mg BID monotherapy) in each group of patients. Kaplan–Meier curves and survival estimates were generated for discontinuation due to lack of efficacy or AEs in each group.

Literature Search of Real-World Data
A non-systematic literature search was performed to identify publications that reported RWD for patients treated with tofacitinib monotherapy. PubMed, Embase, and ACR/EULAR congress abstracts were searched for publications between November 2012 (when tofacitinib was approved for the treatment of RA by the US Food and Drug Administration) and January 2022 using the following search terms: (“tofacitinib” OR “Xeljanz”) AND (“rheumatoid arthritis” OR “arthritis, rheumatoid”) AND (“monotherapy” OR “mono”) AND (“RWD” OR “RWE” OR “real world” OR “real life” OR “cohort” OR “registry”). The authors also drew on their expert knowledge of the wider literature to provide articles of interest for additional context. Across outcomes, available RWD were presented to contextualize the clinical trial data.

Results
Patients
The RCT analysis included 1000 patients treated with tofacitinib 5 mg BID monotherapy (Group 1, n = 627; Group 2, n = 373); the LTE analysis (Group 3) included 498 patients. Generally, baseline disease activity (based on CDAI) was high, and most patients were bDMARD-naïve. Across groups, concomitant glucocorticoid use ranged from 46.9–57.1%. Patients in Group 2 had a shorter disease duration compared with Groups 1 and 3, and a higher proportion of patients in Group 3 was of an Asian background compared with Groups 1 and 2, owing to the fact this group included patients from the Japanese LTE study (Table 1).


Table 1 Demographics and Baseline Disease Characteristics for Patients Receiving Tofacitinib Monotherapy in Clinical Trials and Available RWD Sources

In the literature search, 12 publications were found to contain relevant RWD for patients with RA receiving tofacitinib monotherapy, and these are summarized in Supplementary Table 2. The proportions of patients receiving tofacitinib monotherapy ranged from 16.6–66.1%.14–24 Where data were available, patients in these RWD analyses tended to be older and have lower baseline disease activity compared with patients in the clinical trials (Table 1). Patients had lower tender and swollen joint counts and were less likely to be bDMARD-naïve in the RWD analyses compared with the RCT and LTE studies (Table 1).