decernotinib (VX-509) / Vertex - LARVOL DELTA

Risk of Dyslipidemia Associated With Oral Janus Kinase Inhibitors: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. (PubMed, Int J Dermatol) - "Across all indications, the mean difference between JAKi and placebo for individual drug, was increased by 6.07 mg/dL (95% confidence interval [CI], 5.01-7.14) for HDL and 9.05 mg/dL (95% CI, 7.78-10.32) for LDL for baricitinib; HDL 5.4 mg/dL (95% CI, 3.2-7.7) and LDL 12.4 mg/dL (95% CI, 8.9-15.9) for upadacitinib; HDL 7.0 mg/dL (95% CI, 5.7-8.3) and LDL 15.7 mg/dL (95% CI, 12.9-18.6) for tofacitinib; and lastly HDL 3.0 mg/dL (95% CI, 0.2-5.8) and LDL 14.9 mg/dL (95% CI, 3.6-26.3) for decernotinib. This systematic review and meta-analysis highlight the risk of dyslipidemia during treatment with JAKi, which could pose cardiovascular risks. Thus, regular assessments of cardiovascular risk factors and routine lipid monitoring in patients undergoing JAKi therapy may be essential for managing dyslipidemia and evaluating long-term cardiovascular safety."

Clinical • Journal • Retrospective data • Review • Atopic Dermatitis • Cardiovascular • Crohn's disease • Dermatitis • Dermatology • Dyslipidemia • Gastroenterology • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Metabolic Disorders • Psoriasis • Rheumatoid Arthritis • Rheumatology

Comparative Efficacy and Safety of JAK Inhibitors in the Management of Rheumatoid Arthritis: A Network Meta-Analysis. (PubMed, Pharmaceuticals (Basel)) - "This NMA's results indicate that commercially available JAKinibs show superior ACR responses and have comparable tolerability to placebo."

Clinical • Journal • Retrospective data • Review • Herpes Zoster • Immunology • Infectious Disease • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • Varicella Zoster

VX-509 (Decernotinib)-modified tolerogenic dendritic cells alleviate experimental autoimmune neuritis by promoting Th17/Treg rebalance. (PubMed, Int Immunopharmacol) - "The adoptive transfer of VX-509-tolDCs alleviated inflammatory demyelinating lesions in a mouse model of GBS, known as the EAN mouse, by partially restoring the balance between Treg and Th17 cells."

Journal • Immunology • CD4

The efficacy and safety of different Janus kinase inhibitors as monotherapy in rheumatoid arthritis: A Bayesian network meta-analysis. (PubMed, PLoS One) - "Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence."

Clinical • Journal • Monotherapy • Retrospective data • Review • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling. (PubMed, World J Stem Cells) - "VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal, and inhibits the dedifferentiated self-renewal of CCSCs."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • NODAL

Azaindole derivatives as potential kinase inhibitors and their SARs elucidation. (PubMed, Eur J Med Chem) - "Moreover, some of them have been on the market or in clinical trials for the treatment of some kinase-related diseases (e.g., vemurafenib, pexidartinib, decernotinib). In addition, the binding modes of some azaindoles complexed with kinases were also investigated during the SARs elucidation. This review may offer an insight for medicinal chemists to rationally design more potent kinase inhibitors bearing the azaindole scaffold."

Journal • Review • Leukemia • Oncology • ALK • AXL • CDC7 • FGFR4

Downstream effects on cytokine expression profile of six different JAK inhibitors in an in vitro model of immune mediated inflammatory arthritis (EULAR 2023) - "Thus, tofacitinib is a JAK1/3 inhibitor, baricitinib is an JAK2/3 inhibitor, filgotinib and upadacitinib are selective JAK1 inhibitors, decernotinib is a selective JAK3 inhibitor [2] and deucravacitinib is a selective tyrosine kinase 2 (TYK2) inhibitor [3] . Generally, JAKis with JAK1 and JAK3 selectivity decreased total cytokine secretion the most. In selected patients, specific JAKis decreased total cytokine secretion considerably more than the remaining JAKis, while most patients had an equal response to all six JAKis."

Preclinical • Ankylosing Spondylitis • Idiopathic Arthritis • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis • IFNG • IL10 • IL13 • IL1B • IL2 • IL4 • IL6 • JAK2 • JAK3 • TNFA • TYK2

Okadaic Acid Activates JAK/STAT Signaling to Affect Xenobiotic Metabolism in HepaRG Cells. (PubMed, Cells) - "Moreover, using the NF-κB inhibitors JSH-23 and Methysticin and the JAK inhibitors Decernotinib and Tofacitinib, we were also able to demonstrate a connection between OA-induced NF-κB and JAK signaling and the downregulation of CYP enzymes. Overall, we provide clear evidence that the effect of OA on the expression of CYP enzymes in HepaRG cells is regulated through NF-κB and subsequent JAK signaling."

Journal • Hepatology • Inflammation • Oncology • NF-κβ • STAT3

Azacytidine Inhibits Megakaryopoiesis Via the Induction of Immunogenic RNA Species and Activation of Type-I Interferon Signaling (ASH 2019) - P3; "Eltrombopag (EP), a second-generation small molecule thrombopoietin receptor (TPO-R) agonist was effective in raising platelet counts in patients with MDS as a single agent, as well as in combination with certain standard of care therapies...Importantly, inhibition of IFN-I signal activation using the JAK3 inhibitor decernotinib, the IFNα/β-blocking peptide, B18R, or RNA interference-mediated knock-down of SOCS1 counteracted the inhibitory effects of AZA on TPO-R stimulation and restored megakaryopoiesis...Findings of our study are consistent with and provide a molecular explanation for the observations made in the context of the SUPPORT study. In the future, it will be critical to better understand and potentially counteract the megakaryopoiesis-inhibitory effects by IFN-I pathway activation upon AZA therapy in patients with MDS/AML."

CD34

Advance in bone destruction participated by JAK/STAT in rheumatoid arthritis and therapeutic effect of JAK/STAT inhibitors. (PubMed, Int Immunopharmacol) - "Tofacitinib, Baricitinib, Peficitinib and Filgotinib are now being used in patients with moderate to severe RA, as well as in patients with RA who have an inadequate response to methotrexate therapy and bone destruction...JAK inhibitors have been reported to have better efficacy and lower adverse effects compared with methotrexate and adalimumab. In addition, two JAK inhibitors are currently in development: the JAK1 selective Upadacitinib, and the JAK3 selective inhibitor Decernotinib. In addition to the above JAK inhibitors, some small molecular compounds inhibit bone destruction by inhibiting the Phosphorylation of STAT3. In this paper, the research progress of bone destruction participated by JAK/ STAT in rheumatoid arthritis and therapeutic effect of JAK/STAT inhibitors were reviewed."

Journal • Review • Immunology • Inflammation • Inflammatory Arthritis • Osteoporosis • Rheumatoid Arthritis • Rheumatology • HIF1A • IL17A • IL1B • IL6 • JAK1 • JAK3 • STAT3 • TNFA • TNFRSF11B

Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes. (PubMed, Pharmacol Res) - "This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy."

Journal • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • FABP5 • IL22 • STAT3

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research. (PubMed, RMD Open) - "JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence."

Journal • Ankylosing Spondylitis • Atopic Dermatitis • Cardiovascular • Crohn's disease • Dermatitis • Dermatology • Gastroenterology • Gastrointestinal Disorder • Herpes Zoster • Immunology • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Lupus • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • Systemic Lupus Erythematosus • Ulcerative Colitis • Varicella Zoster • Venous Thromboembolism

Underpinning IL-6 biology and emphasizing selective JAK blockade as the potential alternate therapeutic intervention for rheumatoid arthritis. (PubMed, Life Sci) - "JAK inhibitors, namely Tofacitinib, Baricitinib, Decernotinib, Upadacitinib, Peficitinib, and Filgotinib, have demonstrated clinical efficacy in recent decades as an alternative therapeutic strategy to abrogate IL-6 mediated aberrant activity in RA. This approach substitutes for the side effects incurred due to the IL-6 targeted therapies. This review discusses the history of research into IL-6 biology and therapies that target the IL-6 driven JAK/STAT pathway, including the successes, challenges, and drawbacks, emphasizing RA."

Journal • Review • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Neutropenia • Rheumatoid Arthritis • Rheumatology • Thrombocytopenia • IL6

Role of Janus Kinase Inhibitors in Therapy of Psoriasis. (PubMed, J Clin Med) - "Tofacitinib, ruxolitinib and baricitinib belong to first generation JAK inhibitors and decernotinib and filgotinib belong to second group. However, JAK inhibitors, due to their lack of increased incidence of side effects compared to other biologic drugs, can be included in the psoriasis treatment algorithm because they are orally taken. Nevertheless, further studies are needed to evaluate long-term treatment effects with these drugs."

Journal • Review • Dermatology • Immunology • Inflammation • Psoriasis

Repurposing of gastric cancer drugs against COVID-19. (PubMed, Comput Biol Med) - "In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC."

Journal • Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • FGFR2 • SYK • TYK2

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. (PubMed, Ann Rheum Dis) - "This 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."

Clinical • Journal • Immunology • Rheumatoid Arthritis • Rheumatology

Current jakinibs for the treatment of rheumatoid arthritis: a systematic review. (PubMed, Inflammopharmacology) - "Jakinibs in monotherapy or in combination with methotrexate can be considered a viable alternative in the treatment of moderate-to-severe RA. Even after failures with combination of cDMARDS and bDMARDS, jakinibs demonstrated efficacy."

Journal • Review • Immunology • Inflammatory Arthritis • Nephrology • Renal Disease • Rheumatoid Arthritis • Rheumatology

Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Auto Immun Highlights) - "The adjunction of JAKi to MTX is not associated with an increased risk of malignancy when compared to MTX alone. There is no increased risk of SAE and deaths when compared to MTX alone in patients with RA."

Journal • Retrospective data • Review • Genetic Disorders • Immunology • Inflammatory Arthritis • Non-melanoma Skin Cancer • Oncology • Rheumatoid Arthritis • Rheumatology • Skin Cancer • Solid Tumor

Chemical proteomics reveals target selectivity of clinical Jak inhibitors in human primary cells. (PubMed, Sci Rep) - "Miniaturization of the procedure enabled determining the target selectivity of the clinical BCR-ABL inhibitor dasatinib in peripheral blood mononuclear cell (PBMC) lysates from individual donors. Profiling of a set of Jak kinase inhibitors revealed kinase off-targets from nearly all kinase families underpinning the need to profile kinase inhibitors against the kinome. Potently bound off-targets of clinical inhibitors suggest polypharmacology, e.g. through MRCK alpha and beta, which bind to decernotinib with nanomolar affinity."

Clinical • Journal

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future. (PubMed, Biomolecules) - "The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use."

Journal • Review • Immunology • Rheumatoid Arthritis • Rheumatology

JAK Inhibitors: Prospects in Connective Tissue Diseases. (PubMed, Clin Rev Allergy Immunol) - "We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren's syndrome, and vasculitis, based on laboratory and clinical research findings. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs."

Journal • Review • Dermatomyositis • Immunology • Lupus • Myositis • Pediatrics • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

Incyte Corporation (INCY): Underappreciated pipeline supports long-term view (istockanalyst) - "Data from 3 proof-of-concept trials for...INCB039110 (‘110) are expected in October (psoriasis), November (rheumatoid arthritis)..."; Anticipated VX-509 data in RA in 2013; Anticipated patent expiry of INCB039110 in 2031, ruxolitinib in 2026 & baricitinib in 2029, respectively.

Anticipated P2 data • Anticipated patent expiry • Immunology • Psoriasis • Rheumatoid Arthritis

Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review. (PubMed, Immunotherapy) - "This review compares and contrasts the efficacy of JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib) in RA including: early RA methotrexate-naive patients, post methotrexate failure and post biologics. Trials in monotherapy, combination with disease modifying drugs such as methotrexate, and comparing with adalimumab in biologic-naive patients were studied...There is a class effect of adverse events. Serious infections occur at a rate similar to other advanced therapies in RA, although more reactivation of herpes zoster occurs."

Journal • Herpes Zoster • Immunology • Rheumatoid Arthritis • Rheumatology • Varicella Zoster

[VIRTUAL] JAK KINASE INHIBITORS AND VARICELLA ZOSTER VIRUS INFECTION IN PATIENTS WITH RHEUMATOID ARTHRITIS. SYSTEMATIC REVIEW OF THE LITERATURE. (EULAR 2020) - "See the following terms: rheumatoid arthritis, herpes zoster and the different JAK kinase inhibitors studied: tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib. Opportunistic HZ infection have been reported between 1% and 11% in JAKi clinical trials. The results of the included studies seem to suggest that selective JAK1 inhibitors (Upadacitinib and Filgotinib) develop HZ as a treatment complication less frequently than other JAKi, but more studies are needed to support this conclusion."

Clinical • Review • Herpes Zoster • Immunology • Rheumatoid Arthritis • Rheumatology • Varicella Zoster

[VIRTUAL] ASSOCIATION BETWEEN JANUS KINASE INHIBITORS AND ALL-CAUSE MORTALITY IN PATIENTS WITH RHEUMATOID ARTHRITIS (EULAR 2020) - "Compared with placebo, no significant difference was observed in tofacitinib (RD,0.01 events/person-year; 95% CI, -0.01 to 0.02; P =0.52); barictinib (RD,-0.00 events/person-year; 95% CI, -0.01to 0.01; P =0.59); upadacitinib (RD,0.00 events/person-year; 95% CI, -0.02to 0.03; P =0.71); perficitinib (RD,0.00 events/person-year; 95% CI, -0.05 to 0.06; P =0.86); decernotinib (RD,0.02 events/person-year; 95% CI, -0.03 to 0.06; P =0.44); fligotinib (RD,0.00 events/person-year; 95% CI, -0.05 to 0.06; P=0.85). In pairwise comparisons, no dose-dependent impact of Jakinibs on all-cause mortality was not observed in tofacitinib (5mg vs. 10mg, bid), baricitinib (2mg vs. 4mg, qd) upadacitinib (15mg vs. 30mg, qd). Compared with placebo, there was no significant difference in the all-cause mortality rate observed in patients receiving Jakinibs treatments, but post-marketing data in real-life setting are sorely needed to ascertain their safety in general population. Large, prospective,..."

Clinical • Diabetes • Hematological Disorders • Immunology • Metabolic Disorders • Pulmonary Embolism • Rheumatoid Arthritis • Rheumatology