Background/Purpose: In the SELECT-MONOTHERAPY trial, upadacitinib (UPA), an oral JAK inhibitor, demonstrated significantly greater efficacy compared to continuing methotrexate (MTX) when used as monotherapy over 14 weeks (wks) in patients (pts) with rheumatoid arthritis (RA) and prior inadequate response to MTX.¹ Here we describe the long-term safety and efficacy of UPA monotherapy in an ongoing long-term extension (LTE) of the SELECT-MONOTHERAPY trial.

Methods: Pts on stable MTX were randomized to either continue MTX (cMTX, given as blinded study drug) or switch to once-daily (QD) UPA 15 (UPA15) or 30 (UPA30) mg monotherapy for 14 wks. From Wk14, pts could enter a blinded LTE and continue to receive UPA15 or UPA30; pts randomized to cMTX were switched to UPA15 or UPA30 per pre-specified assignment at baseline. Treatment-emergent adverse events (TEAEs) per 100 pt yrs (PYs) of exposure are summarized up to a cut-off data of 5 February 2019, when all pts had reached Wk84. Efficacy outcomes through Wk84 are reported as observed and using non-responder imputation.

Results: Of 648 pts randomized, 598 (92%) completed 14 wks and entered the LTE on blinded UPA. By the cut-off date, 20% in total had discontinued due to the following: AE (6%), consent withdrawal (4%), lost to follow-up (2%), lack of efficacy (1%), or other reasons (7%). Cumulative exposures were 421.5 and 425.9 PYs for UPA15 and UPA30, respectively. The most frequently reported TEAEs were urinary tract infection, creatine phosphokinase (CPK) increase, upper respiratory tract infection, nasopharyngitis, worsening of RA, bronchitis, herpes zoster (HZ), and alanine aminotransferase increase; the most common serious AE was pneumonia. Events of HZ, hepatic disorder, and CPK elevations were higher among pts receiving UPA30, while rates of serious infection and malignancy appeared comparable between doses (Figure). Most HZ events involved 1-2 dermatomes, with a single disseminated cutaneous event (UPA30) and none with CNS involvement. Five patients experienced MACE, and there were 5 VTE events (UPA15: 4; UPA30: 1). All MACE and VTE events occurred in pts with underlying risk factors. Pts continuing to receive UPA15 and UPA30 achieved stringent endpoints at Week 84 (Table). Pts who switched from cMTX to UPA15 or UPA30 demonstrated comparable efficacy responses to those initially randomized to UPA.

Conclusion: The adverse event profile associated with long-term exposure to UPA15 or 30 as monotherapy was consistent with an integrated analysis of UPA safety across the entire phase 3 program, with no new safety signals identified. Further, UPA15 or 30 monotherapy resulted in continued and sustained improvements in RA signs and symptoms through 84 wks.

References:
               1. Smolen, et al. Lancet 2019;393:2303-11.
                   Original abs: Ann Rheum Dis. 2020; 79(S1):327.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/upadacitinib-as-monotherapy-in-patients-with-rheumatoid-arthritis-and-prior-inadequate-response-to-methotrexate-results-at-84-weeks/