Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings

Genovese, Mark C.; Yang, Fang; Østergaard, Mikkel; Kinnman, Nils

doi:10.1136/annrheumdis-2015-208901

Cited by 47 publications

(34 citation statements)

References 16 publications

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“…Decernotinib (JAK-3i) and peficitinib (non-selective JAKi) were effective as monotherapy and in combination with csDMARDs or MTX in various populations 73–82…”

Section: Resultsmentioning

confidence: 99%

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis

et al. 2020

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ObjectivesTo inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).MethodsA systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019.Results234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products.ConclusionThis SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR’s RA management recommendation.

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“…Decernotinib (JAK-3i) and peficitinib (non-selective JAKi) were effective as monotherapy and in combination with csDMARDs or MTX in various populations 73–82…”

Section: Resultsmentioning

confidence: 99%

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis

et al. 2020

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“…However, it could also be posited that the restricted blockade of cytokines could also mean reduced efficacy. In fact, decernotinib is a selective inhibitor of JAK3 and phase 2 trials have shown efficacy in RA . However, decernotinib also exhibited CYP3A4‐mediated drug–drug interactions thereby affecting metabolism of statins and other drugs .…”

Section: Next‐generation Selective Jakinibsmentioning

confidence: 99%

“…In fact, decernotinib is a selective inhibitor of JAK3 and phase 2 trials have shown efficacy in RA. [162][163][164] However, decernotinib also exhibited CYP3A4-mediated drug-drug interactions thereby affecting metabolism of statins and other drugs. 165 PF-06651600 is another selective JAK3 inhibitor being studied in RA, alopecia areata, CD, and UC 149,166 (NCT02974868, NCT02958865, NCT02969044, NCT03395184).…”

Section: Jak3 Inhibitorsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

130

100

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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“…It has comparable efficacy to tofacitinib for RA, both as monotherapy and in combination with methotrexate 172,173,175 . These results were encouraging, but the development of neutropenia in decernotinib-treated patients was puzzling.…”

Section: Next-generation Jakinibsmentioning

confidence: 95%

“…This is because JAK3 transmits signals via common γ-chain associated cytokines, which prinicipally affect immune cells (Figure 2) 16,17 . In vitro assays indicate that decernotinib may have some activity against JAK1, however, and the drug has been reported to cause neutropenia in clinical trials 171172,173 . Thus, the degree of JAK3 selectivity has yet to be fully determined.…”

Section: Next-generation Jakinibsmentioning

confidence: 99%

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Schwartz¹,

Kanno²,

Villarino³

et al. 2018

Nat Rev Drug Discov

287

109

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Proof provided by biological therapies that cytokines are truly key drivers of immune-mediated diseases has spurred effort in targeting their associated signaling pathways. Small-molecule drugs that inhibit Janus kinases (jakinibs), which are essential signaling mediators downstream of many pro-inflammatory cytokines, have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies like rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds which claim greater selectivity are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens, and how best to identify patients that will benefit from jakinibs. This review will discuss the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents, and the use of jakinibs in a spectrum of immune and inflammatory diseases.

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Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings

Abstract: NCT01754935; results.

Cited by 47 publications

References 16 publications

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

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