{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:49:34Z","timestamp":1785401374171,"version":"3.56.0"},"reference-count":39,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin\u20101 receptor\u2013associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C\u2010reactive protein (DAS28\u2010CRP) at week 12. Treatment\u2010emergent adverse events (TEAEs) were monitored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, 460 patients were randomized. At week 12, zimlovisertib + tofacitinib demonstrated a greater magnitude of mean CFB in DAS28\u2010CRP (\u22122.65; 90% confidence interval [CI], \u22122.84 to \u22122.46) versus tofacitinib (\u22122.30; 90% CI, \u22122.49 to \u22122.11; <jats:italic>P<\/jats:italic> = 0.032); mean CFB with zimlovisertib + ritlecitinib (\u22122.35; 90% CI, \u22122.54 to \u22122.15) was similar to tofacitinib. TEAEs were reported in 246 patients (53.5%), with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by 9 patients (2.0%) and 10 patients reported serious AEs. One patient receiving tofacitinib died because of severe COVID\u201019 infection. Safety profiles were similar across all treatment groups, with no evidence of additive\/synergistic issues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Zimlovisertib + tofacitinib was more effective than tofacitinib for the primary endpoint, whereas the efficacy of zimlovisertib + ritlecitinib did not achieve statistical significance versus tofacitinib. All treatments were well tolerated.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43184","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T04:59:46Z","timestamp":1744606786000},"page":"1337-1348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Efficacy and Safety of Zimlovisertib, Ritlecitinib, and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate"],"prefix":"10.1002","volume":"77","author":[{"given":"Spencer I.","family":"Danto","sequence":"first","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Salganik","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindita","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Hrycaj","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Ko\u015bcian Municipal Hospital  Ko\u015bcian Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Jashi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Institute of Clinical Cardiology  Tbilisi Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negin","family":"Shojaee","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi Shankar P.","family":"Singh","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Page","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Peeva","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean S.","family":"Beebe","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-018-0016-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00211-4"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key054"},{"key":"e_1_2_8_5_1","article-title":"APLAR RA SIG group. Clinical remission of rheumatoid arthritis in a multicenter real\u2010world study in Asia\u2010Pacific region","volume":"15","author":"Sun X","year":"2021","journal-title":"Lancet Reg Health West Pac"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24596"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223356"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216655"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/rap\/rkac057"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40744-021-00357-1"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41032"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2008250"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-9255-7-41"},{"key":"e_1_2_8_14_1","article-title":"Prescribing information","author":"Xeljanz","year":"2018","journal-title":"Pfizer"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-2008-6"},{"issue":"10","key":"e_1_2_8_16_1","article-title":"Efficacy and safety of the selective interleukin\u20101 receptor associated kinase 4 inhibitor, PF\u201006650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate. Arthritis","volume":"71","author":"Danto SI","year":"2019","journal-title":"Rheumatol"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00188"},{"key":"e_1_2_8_18_1","article-title":"Prescribing information","author":"LITFULO","year":"2023","journal-title":"Pfizer"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41316"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380602"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780350502"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119513469"},{"key":"e_1_2_8_24_1","volume-title":"Analyzing Longitudinal Clinical Trial Data: A Practical Guide","author":"Mallinckrodt C","year":"2017"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1983.10477938"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.2307\/3314658"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.1999.01202.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41953"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206028"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.13380"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.093690"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-014-2546-x"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0213219"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2021-001673"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2022.12.029"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-024-00846-3"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.130683"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xjidi.2022.100156"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.20494"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.103948"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.43184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T01:02:03Z","timestamp":1759194123000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.43184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,25]]},"references-count":39,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/art.43184"],"URL":"https:\/\/doi.org\/10.1002\/art.43184","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,25]]},"assertion":[{"value":"2024-07-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}