Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis
Language English Country Italy Media print-electronic
Document type Journal Article, Review
PubMed
39008325
DOI
10.55563/clinexprheumatol/eeglsa
PII: 21096
Knihovny.cz E-resources
- MeSH
- Dermatomyositis * drug therapy enzymology immunology diagnosis MeSH
- Heterocyclic Compounds, 3-Ring * therapeutic use adverse effects pharmacology MeSH
- Janus Kinase Inhibitors * therapeutic use adverse effects MeSH
- Protein Kinase Inhibitors * therapeutic use adverse effects MeSH
- Janus Kinase 1 * antagonists & inhibitors metabolism MeSH
- TYK2 Kinase * antagonists & inhibitors metabolism MeSH
- Humans MeSH
- Pyrroles * therapeutic use adverse effects MeSH
- Signal Transduction drug effects MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene MeSH Browser
- Heterocyclic Compounds, 3-Ring * MeSH
- Janus Kinase Inhibitors * MeSH
- Protein Kinase Inhibitors * MeSH
- JAK1 protein, human MeSH Browser
- Janus Kinase 1 * MeSH
- TYK2 Kinase * MeSH
- Bridged-Ring Compounds MeSH
- Pyrimidines MeSH
- Pyrroles * MeSH
- TYK2 protein, human MeSH Browser
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).
Association of Women in Rheumatology New York NY USA
Department of Dermatology Brigham and Women's Hospital Boston MA USA
Division of Rheumatology University of California Los Angeles School of Medicine Los Angeles CA USA
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