183 A phase 1B/2A trial of tofacitinib, an oral janus kinase inhibitor, in systemic lupus erythematosus

作者：Sarfaraz Hasni, Sarthak Gupta, Michael A. Davis, Elaine Poncio, Yenealem Temesgen‐Oyelakin, Ann Biehl, Philip M. Carlucci, Xinghao Wang, Isabel Ochoa-Navas, Zerai Manna, Mohammad Naqi, Yinghui Shi, Donald E. Thomas, Jinguo Chen, Angélique Biancotto, Richard Apps, Foo Cheung, Yuri Kotiliarov, Ashley L. Babyak, Katie Stagliano, Wanxia Li Tsai, Laura Vian, Nathalia Gazaniga, Valentina Giudice, Martin P. Playford, Stephen R. Brooks, Rishi R. Goel, Meggan Mackay, Peter K. Gregersen, Betty Diamond, Xiaobai Li, Alan T. Remaley, Nehal N. Mehta, J.Conor O’Shea, Massimo Gadina, Mariana J. Kaplan · 发表于：Abstracts · 年份：2019 · DOI：10.1136/lupus-2019-lsm.183 · 被引用次数：13 · 研究领域：Systemic Lupus Erythematosus Research、Monoclonal and Polyclonal Antibodies Research、Chronic Lymphocytic Leukemia Research

Background A pharmacologic intervention that modulates JAK/STAT signaling pathways represents a novel approach for the treatment of Systemic Lupus Erythematosus (SLE). In animal models of SLE, tofacitinib improved clinical features, immune dysregulation and vascular dysfunction. The STAT4 risk allele is associated with higher risk of severe manifestations in SLE. We hypothesized that immune modulation in response to JAK/STAT inhibition would be more robust in SLE subjects that carry the STAT4 risk allele. Methods We conducted a phase 1b/2a randomized, double-blind, placebo-controlled clinical trial of oral tofacitinib, 5 mg twice daily, in 30 SLE subjects (2:1 drug to placebo ratio) with mild to moderate disease activity, stratified by the presence or absence of STAT4 risk allele. Study duration was 84 days (56 days of active treatment ; 28 days of off drug). In addition to recording adverse events (AEs), lipoprotein profile, non-invasive vascular function studies, immuno-phenotyping, and gene expression studies were performed. Results Tofacitinib was well tolerated with no worsening of SLE disease activity, and no severe AEs, opportunistic infections or liver function abnormalities. A total of 43 AEs (mostly mild respiratory infections) occurred in the treated group compared to 28 AEs in placebo. There was a significant increase in HDL-C and HDL particle size in tofacitinib-treated patients at day 56 (p=0.006) accompanied by significant improvements in plasma protein le...