Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results through 3 years from the SELECT-COMPARE study

Abstract

Objectives: To assess the long-term safety and efficacy of the Janus kinase inhibitor upadacitinib versus adalimumab over 3 years in the ongoing long-term extension (LTE) of SELECT-COMPARE, a randomised controlled phase 3 trial of patients with active rheumatoid arthritis and inadequate response to methotrexate (MTX).

Methods: Patients on stable background MTX were randomised 2:2:1 to upadacitinib 15 mg, placebo or adalimumab 40 mg. Patients with an insufficient response were switched by week 26 from placebo to upadacitinib, upadacitinib to adalimumab or adalimumab to upadacitinib. Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years. Safety and efficacy results were analysed here through 3 years. Treatment-emergent adverse events (AEs) were summarised based on exposure to upadacitinib and adalimumab. Efficacy was analysed by original randomised groups (non-responder imputation), as well as separately by treatment sequence (as observed).

Results: Rates of several AEs were generally comparable between upadacitinib and adalimumab, including AEs leading to discontinuation, serious infections and serious AEs, malignancies, major adverse cardiac events, venous thromboembolism and deaths. Consistent with earlier results, herpes zoster, lymphopaenia, hepatic disorder and CPK elevation were reported at higher rates with upadacitinib versus adalimumab. In terms of efficacy, upadacitinib continued to show numerically better clinical responses than adalimumab over 3 years across all endpoints, including low disease activity and remission.

Conclusion: The safety profile of UPA 15 mg was consistent with previous study-specific and integrated safety reports. Higher levels of clinical response continued to be observed with upadacitinib versus adalimumab through 3 years of treatment.

Keywords: adalimumab; arthritis; cardiovascular diseases; rheumatoid; therapeutics; tumor necrosis factor inhibitors.

Figure 1

Disposition of patients through week 156. Numbers of patients on study drug, with primary reason for discontinuation summarised during long-term extension through week 156. *Rescue occurred only before or at week 26; no rescue was allowed after week 26. †All placebo patients not previously rescued (at weeks 14, 18 or 22) were switched to upadacitinib at week 26. ADA, adalimumab; AE, adverse event; D/C, discontinued; EOW, every other week; f/u, follow-up; l/c, logistical restrictions; LOE, lack of efficacy; MTX, methotrexate; PBO, placebo; QD, once daily; UPA, upadacitinib; Wk, week.

Figure 2

Treatment-emergent adverse event summary through 156 weeks (E/100 PY (95% CI)). Data through 156 weeks include all patients receiving upadacitinib or adalimumab, including rescue groups, with assignment based on drug exposure at the time of event. The last week-156 visit was on 6 August 2020. Exposure-adjusted event rates (EAERs) are reported for all events. *Exposure-adjusted incidence rates (EAIRs) were the same as EAERs for malignancies, MACE and VTE. All events were considered AESIs except any AE, serious AEs, AE leading to discontinuation of study drug and deaths. †Opportunistic infections exclude herpes zoster, tuberculosis and oral candidiasis. Event rates for oral candidiasis and active tuberculosis were similar on upadacitinib and adalimumab (0.2 and 0.1 E/100 PY vs 0.3 and 0.2 E/100 PY, respectively). ‡Includes non-treatment emergent deaths. ADA, adalimumab; AE, adverse event; AESI, adverse event of special interest; CPK, creatine phosphokinase; EOW, every other week; MACE, major adverse cardiovascular event; MTX, methotrexate; NMSC, non-melanoma skin cancer; PY, patient-years; QD, once daily; UPA, upadacitinib; VTE, venous thromboembolism.

Figure 3

Proportions of patients achieving CDAI LDA/remission and DAS28(CRP) ≤3.2/<2.6 through 156 Weeks (NRI). Treatment groups are by initial randomisation. #P<0.05, ##p<0.01, ###p<0.001 for upadacitinib plus MTX versus adalimumab plus MTX. All p values are nominal. NRI was used for patients who were rescued or prematurely discontinued study drug, as well as for missing data. Data points plotted here are shown in online supplemental table 6. ADA, adalimumab; CDAI, clinical disease activity index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; EOW, every other week; MTX, methotrexate; NRI, non-responder imputation; PBO, placebo; QD, once daily; UPA, upadacitinib.

Figure 4

Proportions of patients attaining disease activity states over 156 weeks (AO). Groups are by treatment sequence AO, without imputation for missing data. All patients in the placebo group who were not previously rescued were switched to upadacitinib at week 26. ADA, adalimumab; AO, as observed; CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; EOW, every other week; MTX, methotrexate; QD, once daily; UPA, upadacitinib.

Figure 5

Mean change from baseline in HAQ-DI and pain at week 156 (LOCF). Nominal ^##p<0.01, ^###p<0.001 for upadacitinib plus MTX versus adalimumab plus MTX. Treatment groups are by initial randomisation. Observations after rescue were replaced with the last observation prior to rescue, and analysis was based on ANCOVA model with treatment and prior bDMARD use as fixed factors and bL value as covariate. HAQ-DI is rated on a 0–3 scale; patient’s assessment of pain is scored on a 0–100 mm scale. ADA, adalimumab; bDMARD, biological disease modifying antirheumatic drug; bL, baseline; EOW, every other week; HAQ-DI, Health Assessment Questionnaire-Disability Index; LOCF, last observation carried forward; LS, least squares; MTX, methotrexate; QD, once daily; UPA, upadacitinib.

Figure 6

Radiographic outcomes at 6 months, 1 year and 2 years (AO). *Per study design, all patients in the placebo group who were not previously rescued were switched to upadacitinib at week 26. Data are reported AO. (A) Determination of no radiographic progression was assessed by a change from baseline in mTSS ≤0. (B) Least-squares mean change from baseline in mTSS. ADA, adalimumab; AO, as observed; bL, baseline; EOW, every other week; LS, least squares; MTX, methotrexate; PBO, placebo; QD, once daily; mTSS, modified Total Sharp Score; UPA, upadacitinib.