LB0003 Tofacitinib with and without methotrexate versus adalimumab with methotrexate for the treatment of rheumatoid arthritis: results from oral strategy, a phase 3b/4 randomised trial

Abstract

BackgroundTofacitinib is an oral JAK inhibitor for the treatment of RA. There is no direct comparison of tofacitinib monotherapy vs tofacitinib +MTX in MTX inadequate responders (IR) and limited data comparing tofacitinib (±MTX) vs adalimumab (ADA) +MTX in patients (pts) with RA.ObjectivesTo compare efficacy and safety of tofacitinib monotherapy, tofacitinib+MTX, and ADA+MTX in a head-to-head, non-inferiority trial in MTX-IR pts.MethodsIn this randomised, triple-dummy, active-controlled, 1-year, Phase 3b/4 trial (ORAL Strategy; NCT02187055), pts had active RA (≥4 tender/painful joints on motion and ≥4 swollen joints [28-joint count] at baseline [BL]) inadequately controlled with MTX. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (5 mg mono BID), tofacitinib 5 mg BID +MTX (5 mg BID+MTX) or subcutaneous ADA 40 mg every other week +MTX (ADA+MTX); MTX dose: 15–25 mg/wk. The primary endpoint was ACR50 at Month (Mo) 6. Non-inferiority between treatments was declared if the lower bound of 98.34% two-sided confidence intervals of the difference of ACR50 response at Mo 6 was larger than -13% (based on meta analysis of ADA trials1), and superiority if it was larger than 0%. Other endpoints included: ACR20/50/70 and least-squares mean changes from BL in SDAI, DAS28-4(ESR) and HAQ-DI at Mos 6 and 12. Safety was assessed throughout the trial.Results1146 pts were randomised and treated (5 mg mono BID: n=384; 5 mg BID+MTX: n=376; ADA+MTX: n=386). Demographics and BL disease characteristics were similar across groups. Most pts were female (82.7–83.1%), white (75.9–77.1%), with a mean age of 49.7–50.7 years, median disease duration of 5.4–6.1 years and mean HAQ-DI score of 1.6. Across groups, 80.2–81.6% of pts completed the study. ACR50 response rate at Mo 6 was 38.3% for 5 mg mono BID, 46.0% for 5 mg BID+MTX and 43.8% for ADA+MTX. Non-inferiority was demonstrated for 5 mg BID+MTX vs ADA+MTX (P<0.0001) but not for 5 mg mono BID vs ADA+MTX (P=0.0512) or 5 mg mono BID vs 5 mg BID+MTX (P=0.2101) which, although numerically different, were not statistically different (Figure). Tofacitinib monotherapy achieved the efficacy expected of an effective immunomodulator in this pt population. Secondary efficacy analyses were generally consistent with the primary analysis (Table). Adverse event (AE), serious AE and discontinuation due to AE rates were generally clinically similar across groups, though numerically fewer pts had increased alanine aminotransferase with 5 mg mono BID vs 5 mg BID+MTX or ADA+MTX.ConclusionsTofacitinib 5 mg BID+MTX was as effective as ADA+MTX in MTX-IR pts with RA. However, clinical outcomes of all 3 regimens, including tofacitinib 5 mg BID monotherapy, were comparable. There were no new or unexpected safety issues.References Machado et al. Rev Bras Reumatol 2013;53:419–430. AcknowledgementsThis study was funded by Pfizer Inc. Editorial support provided by D Binks of CMC.Disclosure of InterestR. Fleischmann Grant/research support from: Abbott, Amgen, Astellas, Bristol-Myers Squibb, Boehringer Inge...

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future

“…Compared to their biologic counterparts, JAKi differ in the route of administration, safety and efficacy profile and costs of manufacturing. Given the evidence of superiority or non-inferiority of JAKi vs. adalimumab emerging from RCTs [ 125 , 156 , 190 ], the 2020 updated EULAR therapeutic guidelines [ 113 ] recommended the use of JAKi as an alternative to biologics in RA patients refractory to cDMARDs and having poor prognostic factors, as well as in those failing a previous biologic or synthetic line [ 24 ]. A preference for biologics or JAKi should be accorded based on contraindications, monotherapy need or cost issues.…”

“…Physical function (HAQ-DI score and other PROs) improved from baseline to a generally similar extent in patients receiving tofacitinib plus MTX, adalimumab plus MTX or tofacitinib monotherapy [ 156 ].…”

Real-world effectiveness of biological therapy in patients with rheumatoid arthritis: Systematic review and meta-analysis

“…The ADACT and AMPLE trials compared the efficacy of tocilizumab versus adalimumab and abatacept versus adalimumab, respectively, and indicated greater effectiveness of non-TNFi over the TNFi analyzed (Gabay et al, 2013;Weinblatt et al, 2013). Regarding JAKi, RCT findings are controversial, pointing to the greater effectiveness of baricitinib over adalimumab (Keystone et al, 2017;Taylor et al, 2017) and lower effectiveness of tofacitinib than of adalimumab (Fleischmann et al, 2017).…”

Cost-effectiveness of janus kinase inhibitors for rheumatoid arthritis: A systematic review and meta-analysis of cost-utility studies

“…According to clinical effectiveness data, JAK-i is not inferior to TNF-a-i in RA patients who have failed csDMARDs. (van Vollenhoven et al, 2012;Strand et al, 2016;Fleischmann et al, 2017;Taylor et al, 2017;Ren et al, 2018;Uttley et al, 2018) Based on National institute for health and care excellence (NICE)'s report, both TOFA and BARI are equally effective as other bDMARDs at treating moderate to severe RA, when used alone or in combination with MTX. (Baricitinib for moderate to severe, 2017; Tofacitinib for moderate to severe, Ren et al, 2018;Uttley et al, 2018) However, they are considered to be costeffective options only for csDMARD IR severe RA patients and not for moderate RA.…”

“…Given that JAK-i [Tofacitinib (TOFA), Baricitinib (BARI), Upadacitinib (UPA), Filgotinib (FILG)] are as clinically effective as bDMARDs (Strand et al, 2016;Fleischmann et al, 2017;Taylor et al, 2017;Grimm et al, 2021), clinicians and policymakers would consider the cost-effectiveness of these drugs when determining the treatment for RA patients. (Russell et al, 1996) Cost-effectiveness analyses (CEA) collate evidence from multiple sources to comparatively analyse considering both the costs and benefits of the treatment.…”