Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Aug;10(4):901-915.
doi: 10.1007/s40744-023-00557-x. Epub 2023 May 18.

Long-Term Efficacy and Safety of Upadacitinib in Patients with Rheumatoid Arthritis: Final Results from the BALANCE-EXTEND Open-Label Extension Study

Alan Kivitz  1 , Alvin F Wells  2 , Juan I Vargas  3 , Herbert S B Baraf  4   5 , Maureen Rischmueller  6   7 , Justin Klaff  8 , Nasser Khan  8 , Yihan Li  8 , Kyle Carter  8 , Alan Friedman  8 , Patrick Durez  9
Affiliations

Long-Term Efficacy and Safety of Upadacitinib in Patients with Rheumatoid Arthritis: Final Results from the BALANCE-EXTEND Open-Label Extension Study

Alan Kivitz et al. Rheumatol Ther. 2023 Aug.

Abstract

Introduction: Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6 years of treatment.

Methods: Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6 mg twice daily (BID). Dose increases to 12 mg BID were required for patients with < 20% improvement in swollen or tender joint counts at weeks 6 or 12 and permitted for those not achieving Clinical Disease Activity Index (CDAI) low disease activity (LDA; CDAI 2.8 to ≤ 10). Dose reduction to UPA 6 mg BID was permitted only for safety or tolerability reasons. After January 2017, the 6/12 mg BID doses were replaced by 15/30 mg once-daily extended-release equivalents. Efficacy and safety were monitored up to 6 years of UPA treatment; outcomes included rates of achievement of LDA or remission. Data were analyzed for patients who received the lower UPA dose throughout; titrated up to the higher UPA dose from weeks 6 or 12; or titrated to the higher UPA dose and back down.

Results: Overall, 493 patients entered BALANCE-EXTEND ('Never titrated', n = 306; 'Titrated up', n = 149; 'Titrated up and down', n = 38), and 223 patients (45%) completed the 6-year study. Total cumulative exposure was 1863 patient-years. Rates of LDA and remission were maintained through 6 years. Overall, 87%/70%/73% of patients in the 'Never titrated'/'Titrated up'/'Titrated up and down' groups achieved CDAI LDA at week 312, while the respective rates of Disease Activity Score 28 with C-reactive protein meeting LDA and remission criteria were 85%/69%/70% and 72%/46%/63%. Improvements in patient-reported outcomes were similar among the three groups. No new safety signals were identified.

Conclusions: In this open-label extension of two phase 2 studies, UPA demonstrated sustained efficacy and an acceptable safety profile through 6 years of treatment in patients who completed the study. These data support a favorable long-term benefit-risk profile of UPA in patients with RA.

Trial registration: Trial registration number: NCT02049138.

Keywords: Extension; Janus kinase inhibitor; Phase 3; Rheumatoid arthritis; Treatment; Upadacitinib.

PubMed Disclaimer

Conflict of interest statement

Alan Kivitz has received consulting fees and/or honoraria from AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, EcoR1 Capital, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Grünenthal, Horizon, Janssen, Lilly, Merck, Novartis, Orion, Pfizer, Regeneron Pharmaceuticals, SUN Pharma Advanced Research, and UCB; owns stocks or options in Amgen, Gilead, GlaxoSmithKline, Novartis, Pfizer, and Sanofi; has received fees from AbbVie for his role as a Principal Investigator in the study; and is a board and/or advisory board member for AbbVie, Bendcare LLC, Boehringer Ingelheim, ChemoCentryx, Flexion, Gilead, Grünenthal, Horizon, Janssen, Lilly, Novartis, Pfizer, Regeneron, and UCB. Alvin F. Wells has received consulting fees and research support from AbbVie. Juan I. Vargas has received honoraria and fees from AbbVie as a Principal Investigator in the study. Herbert S. B. Baraf has received grant/research support from AbbVie, Genentech, Gilead, Janssen, and Lilly; has acted as a consultant for Gilead and Janssen; and has received honoraria and fees from AbbVie as a Principal Investigator in the study. He has retired from the Center for Rheumatology and Bone Research since the completion of the study. Maureen Rischmueller has received grant/research support from AbbVie, Amgen, BMS, Janssen Global Services, Lilly, Novartis, Pfizer, Sanofi Pasteur Biologics, and UCB Biosciences; and has acted as a consultant for AbbVie, BMS, CSL Behring, Gilead, Janssen Global Services, Lilly, Pfizer, Sanofi US Services, and UCB Biosciences. Justin Klaff, Nasser Khan, Yihan Li, Kyle Carter, and Alan Friedman are employees of AbbVie and may own stocks or options. Patrick Durez has received speaker fees from AbbVie, Galapagos, Lilly, Nordimed, and Thermo Fisher Scientific Inc.

Figures

Fig. 1
Fig. 1
Patient disposition. Never titrated: patients who received upadacitinib 6 mg BID/15 mg QD for the duration of BALANCE-EXTEND. Titrated up: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD because of lack of efficacy and remained on that dose thereafter. Titrated up and down: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD and were later titrated back down to 6 mg BID/15 mg QD because of intolerance. BID twice daily, QD once daily
Fig. 2
Fig. 2
DAS28-CRP ≤ 3.2/ < 2.6, CDAI LDA/remission, and SDAI LDA/remission rates in BALANCE-EXTEND at week 312 (as-observed data). Never titrated: patients who received upadacitinib 6 mg BID/15 mg QD for the duration of BALANCE-EXTEND. Titrated up: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD because of lack of efficacy and remained on that dose thereafter. Titrated up and down: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD and were later titrated back down to 6 mg BID/15 mg QD because of intolerance. BID twice daily, CDAI Clinical Disease Activity Index, DAS28-CRP Disease Activity Score 28 with C-reactive protein, LDA low disease activity, QD once daily, SDAI Simplified Disease Activity Index
Fig. 3
Fig. 3
ACR response rates in BALANCE-EXTEND at week 312 (as-observed data). Never titrated: patients who received upadacitinib 6 mg BID/15 mg QD for the duration of BALANCE-EXTEND. Titrated up: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD because of lack of efficacy and remained on that dose thereafter. Titrated up and down: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD and were later titrated back down to 6 mg BID/15 mg QD because of intolerance. ACR American College of Rheumatology, ACR20/50/70 20%/50%/70% improvement in ACR response criteria, BID twice daily, QD once daily
Fig. 4
Fig. 4
Change from baseline in HAQ-DI (a), PtGA (b), FACIT-F (c), and patient’s assessment of pain (d) in BALANCE-EXTEND at week 312 (as-observed data). Never titrated: patients who received upadacitinib 6 mg BID/15 mg QD for the duration of BALANCE-EXTEND. Titrated up: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD because of lack of efficacy and remained on that dose thereafter. Titrated up and down: patients who were titrated up from 6 mg BID/15 mg QD to 12 mg BID/30 mg QD and were later titrated back down to 6 mg BID/15 mg QD because of intolerance. BID twice daily, FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, PtGA Patient’s Global Assessment of disease activity, QD once daily
See this image and copyright information in PMC

References

    1. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685–699. doi: 10.1136/annrheumdis-2019-216655. - DOI - PubMed
    1. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924–939. doi: 10.1002/acr.24596. - DOI - PMC - PubMed
    1. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:FC fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253–259. doi: 10.1056/NEJM199901283400401. - DOI - PubMed
    1. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35–45. doi: 10.1002/art.10697. - DOI - PubMed
    1. Rendas-Baum R, Wallenstein GV, Koncz T, et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther. 2011;13(1):R25. doi: 10.1186/ar3249. - DOI - PMC - PubMed

Associated data