A Phase 1b/2a Trial of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus

Sarfaraz Hasni¹, Sarthak Gupta ², Michael Davis ³, Elaine Poncio ⁴, Yenealem Temesgen-Oyelakin ⁴, Phillip Carlucci ⁴, Xinghao Wang ⁴, Mohammad Naqi ⁴, Martin Playford ⁵, Rishi Goel ⁴, Xiaobai Li ⁶, Ann Biehl ⁴, Isabel Ochoa-Navas ⁴, Zerai Manna ⁴, Yinghui Shi ⁷, Don Thomas ⁸, Jinguo Chen ⁹, Angélique Biancotto ⁹, Richard Apps ⁹, Foo Cheung ⁹, Yuri Kotliarov ⁹, Ashley Babyak ⁶, Katie Stagliano ⁹, John Tsang ⁹, Wanxia Tsai ¹⁰, Laura Vian ¹⁰, Nathalia Gazaniga ⁴, Valentina Giudice ⁴, Stephen Brooks ¹¹, Meggan Mackay ¹², Peter Gregersen ¹³, Betty Diamond ¹⁴, Nehal Mehta ¹⁵, Alan Remaley ⁵, John O'Shea ¹⁶, Massimo Gadina ¹⁰ and Mariana Kaplan ¹⁶, ¹National Institute of Arthritis, Musculoskeletal, and Skin diseases/ National Institutes of Health, Bethesda, MD, ²Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, ³NIAMS/NIH, Bethesda, MD, ⁴NIAMS/NIH, Bethesda, ⁵NHLBI/NIH, Bethesda, ⁶Clinical Center/NIH, Bethesda, ⁷Office of Clinical Director, NIAMS, NIH, Bethesda, MD, ⁸Walter Reed National Military Medical Center, Bethesda, MD, ⁹NIAID/NIH, Bethesda, ¹⁰Translational Immunology Section, NIAMS, NIH, Bethesda, MD, ¹¹Biomining and Discovery Section/NIAMS/NIH, Bethesda, MD, ¹²Feinstein Institute for Medical Research, New York, ¹³Feinstein Institutes for Medical Research, Manhasset, NY, ¹⁴Feinstein Institutes of Medical Research, Manhasset, NY, ¹⁵National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA, Bethesda, MD, ¹⁶National Institute of Arthritis, Musculoskeletal, and Skin diseases/ National Institutes of Health, Bethesda

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: clinical trials and lipids, Systemic lupus erythematosus (SLE), Tofacitinib

Session Information

Date: Sunday, November 10, 2019

Session Title: 3S110: SLE – Clinical III: Clinical Trials II (939–944)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: 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 differ between SLE subjects that carry or not 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, with 56 days of active treatment followed by 28 days of off drug period. In addition to recording adverse events (AEs), lipoprotein profile, non-invasive vascular function studies, immuno-phenotyping, and gene expression studies were performed at various time points.

Results: Tofacitinib was well tolerated with no worsening of SLE disease activity, and no severe AEs, opportunistic infections or liver function abnormalities. No thromboembolic events were observed in this short duration trial. 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 accompanied by significant improvements in plasma protein lecithin: cholesterol acyltransferase (LCAT) concentration and cholesterol efflux capacity. Arterial stiffness decreased in the tofacitinib-treated group but not in the placebo-treated group. The type I Interferon gene signature, circulating levels of low- density granulocytes and neutrophil extracellular traps significantly decreased in the tofacitinib treated group compared to the placebo group by the end of treatment, accompanied by significant decreases in pSTAT phosphorylation of different immune cells. Various T cell activation and checkpoint markers significantly decreased in tofacitinib treated individuals and this was modulated by presence or absence of STAT4 risk allele.

Conclusion: In a short-term trial, tofacitinib was well tolerated in SLE subjects with mild-moderate disease activity. Use of tofacitinib resulted in improvements in innate and adaptive immune dysregulation and lipoprotein phenotype and function. This study also points to the potential utility of including genetic data in clinical trials to advance precision medicine. Long-term studies are needed to determine the efficacy of tofacitinib in the various manifestations of SLE including cardiovascular risk.

Demographics Table

Adverse Events

Significant Increase-p=0.0006- in HDLc Number and Particle Size in Treatment group at Day 56

Disclosure: S. Hasni, None; S. Gupta, None; M. Davis, None; E. Poncio, None; Y. Temesgen-Oyelakin, None; P. Carlucci, None; X. Wang, None; M. Naqi, None; M. Playford, None; R. Goel, None; X. Li, None; A. Biehl, None; I. Ochoa-Navas, None; Z. Manna, None; Y. Shi, None; D. Thomas, None; J. Chen, None; A. Biancotto, None; R. Apps, None; F. Cheung, None; Y. Kotliarov, None; A. Babyak, None; K. Stagliano, None; J. Tsang, None; W. Tsai, None; L. Vian, None; N. Gazaniga, None; V. Giudice, None; S. Brooks, None; M. Mackay, None; P. Gregersen, None; B. Diamond, None; N. Mehta, AbbVie, 2, Abbvie, 2, Celgene, 2, Jannsen, 2, Janssen, 2, Novartis, 2, 5, US government, 3; A. Remaley, None; J. O'Shea, Pfizer Inc., 7; M. Gadina, None; M. Kaplan, None.

To cite this abstract in AMA style:

Hasni S, Gupta S, Davis M, Poncio E, Temesgen-Oyelakin Y, Carlucci P, Wang X, Naqi M, Playford M, Goel R, Li X, Biehl A, Ochoa-Navas I, Manna Z, Shi Y, Thomas D, Chen J, Biancotto A, Apps R, Cheung F, Kotliarov Y, Babyak A, Stagliano K, Tsang J, Tsai W, Vian L, Gazaniga N, Giudice V, Brooks S, Mackay M, Gregersen P, Diamond B, Mehta N, Remaley A, O'Shea J, Gadina M, Kaplan M. A Phase 1b/2a Trial of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-phase-1b-2a-trial-of-tofacitinib-an-oral-janus-kinase-inhibitor-in-systemic-lupus-erythematosus/. Accessed December 1, 2020.

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