Background: To compare the clinical efficacy, including inhibition of structural damage, and safety of upadacitinib (UPA), a JAK1-selective inhibitor, as monotherapy, vs methotrexate (MTX) monotherapy, in MTX-naïve patients with moderate to severely active rheumatoid arthritis (RA). Methods: In SELECT-EARLY, MTX-naïve patients with active RA who were positive for both RF and ACPA and/or had ⩾1 joint erosion were randomised 1:1:1 to once-daily (QD) UPA at 15mg or 30mg, or weekly MTX (titrated by week 8). Separate primary endpoints were ACR50 at week 12 (FDA), or the proportion of patients achieving DAS28CRP<2.6 at week 24 (EMA). Secondary endpoints included mean changes from baseline (Δ BL) in modified Total Sharp Score (mTSS) and proportion of patients with no radiographic progression (mTSS⩽0) at week 24. Results: Of 947 randomised patients, 945 received study drug; 840 (88.7%) completed week 24. ∼50% had an RA diagnosis of < 6 months and RA symptoms <2 years. Of the 945 patients, 874 (92.5%) had no prior MTX exposure; 706 (74.7%) had no prior csDMARD exposure. Both primary endpoints were met. Significantly more patients receiving UPA 15 and 30mg vs MTX achieved ACR50 responses at week 12 (52.1% and 56.4% vs 28.3%) and DAS28CRP<2.6 at week 24 (48.3% and 50.0% vs 18.5%). All ranked secondary endpoints were met: ACR50 at week 24, improvements in DAS28CRP, HAQ-DI, SF36-PCS, and the proportion of patients achieving DAS28CRP⩽3.2 at weeks 12 and 24. At week 24, mean ΔmTSS were 0.14 and 0.07 vs 0.67; significantly more patients had no radiographic progression on UPA 15 and 30mg vs MTX. LDA and remission by various criteria at weeks 12 and 24 were achieved in more patients on UPA vs MTX (nominal p<.001 for all). Up to week 24, treatment-emergent adverse events (AEs) and serious AEs were similar in the UPA 15mg and MTX arms, and slightly higher in the UPA 30mg arm. AEs leading to discontinuation were similar across arms. A numerically higher proportion of patients on UPA 30mg reported serious infections vs MTX and UPA 15mg, and there were more cases of herpes zoster in the UPA vs MTX arms. Four malignancies (MTX: 1 ovarian cancer; UPA 15: 1 metastatic malignant melanoma, 1 squamous cell carcinoma of the lung, 1 uterine carcinoma in situ), 4 major adverse cardiovascular events (MACE), and 6 deaths were reported (MTX: 1 sudden cardiovascular (CV) death; UPA 15mg: 1 CV death, 1 metastatic malignant melanoma; UPA 30mg: 1 CV death, 1 pneumonia and sepsis, 1 peritonitis). Two venous thromboembolic events were reported (1 pulmonary embolism on MTX, 1 deep vein thrombosis on UPA 30mg, none on UPA 15mg). Conclusion: In MTX-naïve patients, UPA 15 and 30mg QD demonstrated significant and clinically meaningful improvements in RA signs & symptoms vs MTX. Radiographic progression was significantly less with UPA vs MTX. Disclosures: R. Vollenhoven: Consultancies; AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex. Honoraria; AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex. Grants/research support; AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB; T. Takeuchi: Honoraria; Mitsubishi-Tanabe Pharma Corporation, Janssen Pharmaceutical KK, Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., AbbVie GK, Eisai Co., Ltd, Bristol-Myers Squibb Company, Daiichi Sankyo Company Ltd. Member of speakers’ bureau; ; Astellas Pharma Inc., AbbVie GK, Eisai Co., Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, UCB Japan Co., Ltd. Grants/research support; Chugai Pharmaceutical Co Ltd, Mitsubishi-Tanabe Pharma Corporation; Grants; Pfizer Japan Inc., Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd,. A.L. Pangan: Corporate appointments; AbbVie. Shareholder/stock ownership; AbbVie. A. Friedman: Corporate appointments; AbbVie. Shareholder/stock ownership; AbbVie. M.F. Mohamed: Corporate appointments; AbbVie. Shareholder/stock ownership; AbbVie. S. Chen: Corporate appointments; AbbVie. Shareholder/stock ownership; AbbVie. M. Rischmueller: Consultancies; Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB. R. Blanco: Consultancies; Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD. Member of speakers’ bureau; Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD. Grants/research support; Abbvie, MSD and Roche. R.M. Xavier: Consultancies; Abbvie, Pfizer, Novartis, Janssen, Lilly, Roche. V. Strand: Consultancies; AbbVie, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, Celltrion, CORRONA, Crescendo, EMD Serono, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kezar, Lilly, Merck, Novartis, Pfizer, Regeneron,
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Vollenhoven et al. (2019) studied this question.