Review
Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis
J.J. Paik1, J. Vencovský2, C. Charles-Schoeman3, G.C. Wright4, R.A. Vleugels5, A.S. Goriounova6, P.N. Mudd, Jr7, R. Aggarwal8
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jpaik1@jhmi.edu
- Institute of Rheumatology and Department of Rheumatology, 1st Medical Faculty, Charles University, Prague, Czech Republic.
- Division of Rheumatology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA.
- Association of Women in Rheumatology, New York, NY, USA.
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
- Priovant Therapeutics Inc., New York, NY, USA.
- Priovant Therapeutics Inc., New York, NY, USA. paul.mudd@priovanttx.com
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
CER17712
Review
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PMID: 39008325 [PubMed]
Received: 23/03/2024
Accepted : 27/05/2024
In Press: 15/07/2024
Abstract
Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib’s potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn’s disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).
