OP0280 THE SELECTIVE JAK1 INHIBITOR INCB054707 AMELIORATES CUTANEOUS LESIONS IN A SPONTANEOUS MURINE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS. (June 2019)

• Record Type: Journal Article
• Authors: Fay, Brittany; He, Xin; Margulis, Alexander; Yang, Yan-Ou; LI, Yu; Yao, Wenqing; Huarte, Eduardo; Smith, Paul; Scuron, Monika
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 221
• Page End: 222
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.4967
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple organs, including the skin, joints and kidneys. The disease is characterized by the development of skin lesions, autoantibody production and inflammation-induced glomerulonephritis. The skin is involved in up to 85% of SLE cases 1 . In the MRL/lpr spontaneous mouse model of SLE, disease symptoms also include lymphocyte hyper-proliferation, resulting in lymphadenopathy and splenomegaly. The evolutionary conserved Janus kinase-signal transducer of activators of transcription (JAK-STAT) pathway constitutes a rapid membrane to nucleus signaling modality that affects key biological aspects of the mammalian immune system 2 . Janus kinase 1 (JAK1) is involved in the downstream signaling pathway of type I interferons (IFNs), and high levels of type I IFNs are associated with SLE 3 . INCB054707 is an oral small molecule JAK1 selective inhibitor currently being evaluated in clinical trials for the dermatological disease hidradenitis suppurativa (NCT03569371 & NCT03607487 ). We hypothesized that INCB054707 should reduce IFN signaling and ameliorate cutaneous lesions in SLE. Objectives: To determine the effectiveness of INCB054707, a selective JAK1 inhibitor, in a preclinical model of cutaneous lupus erythematosus. Methods: Female MRL/lpr mice were randomized to treatment groups at 11 weeks old to receive twice daily oral doses of vehicle (0.5% methyl cellulose) or INCB054707 at 10, 30, or 90 mg/kg for 10 weeks. Efficacy was determined by weekly scoring of the changes in skin, lymph node size, and proteinuria. At study termination (week 21), inguinal lymph nodes and spleens were excised and weighed, skin lesions and kidneys were excised and fixed for histopathologic analysis, and serum was collected for pharmacokinetic analysis and ELISA. Autoantibody presence in the serum was detected using a commercial anti-dsDNA ELISA kit. Results: In vitro enzymatic selectivity screening of INCB054707 revealed JAK1 IC50 = 8.9 nM versus JAK2 IC50 = 463 nM, resulting in a JAK1/JAK2 selectivity ratio of approximately 52-fold. Spontaneous skin lesions were observed in 90%+ of vehicle treated mice by 18 weeks of age, with the majority located around the head and nape of the neck. Histologically, lesions were characterized by combined lymphocyte infiltration and epidermal thickening. In contrast, therapeutic INCB054707 treatment dose-dependently reduced the incidence and severity of cutaneous lesions (p < 0.05). In addition, INCB054707 treatment abrogated lymphoid tissue and spleen enlargement (p < 0.0001) in a dose-dependent manner. Kidney damage was only partially improved by INCB054707 at the highest (90 mg/kg) dose. Quantification of anti-dsDNA antibodies by ELISA revealed a profound, statistically significant reduction of antigen-specific autoreactive IgG immunoglobulins in the serum (p < 0.0001). Total immunoglobulin titers were not reduced. Conclusion: These data are consistent with immunomodulation and show that oral INCB054707 treatment, resulting in JAK1-specific inhibition, has the potential to modulate ongoing inflammatory (autoimmune) cutaneous skin disease. References: [1] Luis Uva, et al. Cutaneous Manifestations of Systemic Lupus Erythematosus. Autoimmune Dis. 2012; 2012: 834291. [2] O'Shea, et al. The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annu Rev Med. 2015; 66: 311–328. [3] Ivashkiv, et al. Regulation of type I interferon responses. Nat Rev Immunol. 2014; 14(1): 36–49. Disclosure of Interests: Brittany Fay Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Xin He Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Alexander Margulis Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Yan-ou Yang Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Yu Li Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Wenqing Yao Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Eduardo Huarte Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Paul Smith Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Monika Scuron Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation.