Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial

Abstract

Background: To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial.

Methods: Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years.

Results: Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses.

Conclusions: Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile.

Trial registration: NCT02706873.

Keywords: JAK inhibitor; Long-term extension; Methotrexate; Randomized controlled trial; Rheumatoid arthritis; SELECT-EARLY; Targeted synthetic DMARD; Upadacitinib.

Fig. 1

Disposition of Patients Through 5 Years in SELECT-EARLY. AE, adverse event; CDAI, Clinical Disease Activity Index; D/C, discontinued; L/C, logistical constraints; LoE, lack of efficacy; MTX, methotrexate; QD, once daily; UPA, upadacitinib; W, week. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit. ^bAt week 26, patients who did not achieve CDAI remission and at least 20% improvement from baseline in tender and swollen joint counts received rescue therapy (addition of MTX to insufficient responders in the UPA groups and addition of UPA 15/30 mg to insufficient responders in the MTX group)

Fig. 2

Proportions of Patients Achieving CDAI, DAS28(CRP) Disease Activity States and Boolean Remission Through 5 Years (AO). AO, as observed; CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; LDA, low disease activity; mono, monotherapy; MTX, methotrexate; QD, once daily; UPA, upadacitinib. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 dose mg per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit. Thresholds for CDAI were ≤ 2.8 for remission and ≤ 10 for LDA

Fig. 3

Proportions of Patients Achieving CDAI, DAS28(CRP) Disease Activity States and Boolean Remission Through 5 Years (NRI). CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; LDA, low disease activity; MTX, methotrexate; NRI, non-responder imputation; QD, once daily; UPA, upadacitinib. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit. Indicated assessments from period 1 (at weeks 4, 12, 24, 36, and 48) are summarized here along with all assessments from the long-term extension. Nominal ^***P < .001, ^**P < .01, and ^*P < .05 for upadacitinib 15 mg versus MTX. Nominal ^###P < .001, ^##P < .01, and ^#P < .05 for upadacitinib 30 mg versus MTX. Thresholds for CDAI were ≤ 2.8 for remission and ≤ 10 for LDA

Fig. 4

Proportions of Patients Achieving ACR Response Criteria Through 5 Years (AO). ACR20/50/70, ≥ 20%/50%/70% improvement in American College of Rheumatology response criteria; AO, as observed; mono, monotherapy; MTX, methotrexate; QD, once daily; UPA, upadacitinib. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit

Fig. 5

Proportions of Patients Achieving ACR Response Criteria Through 5 Years (NRI). ACR20/50/70, ≥ 20%/50%/70% improvement in American College of Rheumatology response criteria; mono, monotherapy; MTX, methotrexate; NRI, non-responder imputation; QD, once daily; UPA, upadacitinib. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit. Indicated assessments from period 1 (at weeks 4, 12, 24, 36, and 48) are summarized here along with all assessments from the long-term extension. Nominal ^***P < .001, ^**P < .01, and ^*P < .05 for upadacitinib 15 mg versus MTX. Nominal ^###P < .001, ^##P < .01, and ^#P < .05 for upadacitinib 30 mg versus MTX

Fig. 6

Radiographic Progression Through 5 Years (AO). AO, as observed; BL, baseline; mono, monotherapy; mTSS, modified Total Sharp Score; MTX, methotrexate; QD, once daily; UPA, upadacitinib. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. The switch occurred at different visits across the patient population, with the earliest switch occurring at the week 108 visit. Patients were required to have radiographic images at both week 192 and week 260 for inclusion in these analyses. Error bars represent the 95% confidence interval

Fig. 7

Exposure-Adjusted Event Rates for Adverse Events of Special Interest Through 5 Years. AE, adverse event; AESI, adverse event of special interest; CPK, creatine phosphokinase; DMARD, disease-modifying antirheumatic drug; GI, gastrointestinal; MACE, major adverse cardiovascular event; mono, monotherapy; MTX, methotrexate; NMSC, nonmelanoma skin cancer; PY, patient-years; QD, once daily; TB, tuberculosis; UPA, upadacitinib; VTE, venous thromboembolism. Treatment-emergent adverse event is defined as any adverse event with an onset date that is after the first dose of study drug, and no more than 30 days after the last dose of study drug. Data include patients receiving UPA or MTX monotherapy, censored at either time of rescue to UPA + MTX or with addition of background conventional synthetic DMARD. ^aPatients in the UPA 30 mg treatment group were later switched to the approved UPA 15 mg dose per protocol amendment. Upadacitinib 30 mg QD exposure was censored at the time of dose switch from 30 mg QD to 15 mg QD. ^bOpportunistic infections exclude herpes zoster and TB. ^cDefined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. ^dIncludes pulmonary embolism and deep vein thrombosis