3 results on '"Erick Moy"'
Search Results
2. OP0155 Development of A JAK3 Specific Inhibitor Clinical Candidate: Functional Differentiation of JAK3 Selective Inhibition over PAN-JAK or JAK1 Selective Inhibition
- Author
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James D. Clark, Li Li, J.-B. Telliez, Fabien Vincent, Jason Jussif, Erick Moy, Martin Hegen, Yajuan Zhao, Atli Thorarensen, K. Crouse, Wei Li, Lisy Wang, Peter T. Symanowicz, Mary Ellen Banker, and Tsung Lin
- Subjects
Tofacitinib ,business.industry ,viruses ,Cellular differentiation ,medicine.medical_treatment ,Immunology ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,In vitro ,Cytokine ,Rheumatology ,Tyrosine kinase 2 ,Immunology and Allergy ,Medicine ,Tumor necrosis factor alpha ,business ,Receptor ,Janus kinase - Abstract
Background Janus kinase (JAK) inhibitors targeting multiple JAK isoforms, JAK1 and 2, or selective against JAK1 are currently utilized in clinical practice or being developed for the treatment of various inflammatory and oncological diseases. No truly JAK3-selective inhibitor has reached the clinic. JAK3 signal in pairs with JAK1 to transduce signal elicited from six known cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 & IL-21) binding to the gamma-common (g-c) chain cytokine receptors. JAK1 in addition to be required for g-c chain cytokine receptors signaling can also signal in pair with JAK2 or TYK2 and is required for other cytokine receptors signaling such as type I and II interferons and IL-6 and IL-10 families of cytokines. Other cytokines such as IL-12 and IL-23 are signaling via JAK2 and TYK2. Additionally, hematopoietic cytokines such as EPO and TPO as well as cytokines such as IL-3 and IL-5 signal via homodimers of JAK2. Objectives Develop a JAK3 selective inhibitor that will inhibit signaling from the g-c chain cytokine receptors at therapeutic dosing without inhibiting signaling by other cytokines such as hematopoietic cytokines, type I and II interferons and IL-6, IL-12 and IL-10 families of cytokines. Methods A JAK3-specific covalent ATP competitive inhibitor was assessed functionally in vitro and in vivo . Functional differentiation of JAK3 selective inhibition as compare to pan-JAK inhibition (tofacitinib) or JAK1 selective inhibition was also assessed. Results The inhibitor showed JAK3 selective inhibition in biochemical and cellular assays. It inhibits Th1 and Th17 cell differentiation and function. Importantly, sparing JAK1 inhibition, through the selectivity of this inhibitor, preserved anti-inflammatory functions such as the differentiation of alternatively activated M2a macrophages. Unlike pan-JAK or JAK1-selective inhibitors, JAK3 selective inhibition also preserved IL-10-dependent suppression of the production of pro-inflammatory cytokines following LPS treatment in macrophages while maintaining the suppression of TNF and IL-1 responses in IL-27-primed macrophages. Further characterization of this compound in the rat adjuvant-induced arthritis (AIA) demonstrated efficacy at reducing disease pathology. Conclusions We have identified the first trully selective JAK3 inhibitor with potency and properties that make it suitable for further clinical development. Disclosure of Interest J.-B. Telliez Employee of: Pfizer, L. Wang Employee of: Pfizer, J. Jussif Employee of: Pfizer, T. Lin Employee of: Pfizer, L. Li Employee of: Pfizer, E. Moy Employee of: Pfizer, W. Li Employee of: Pfizer, Y. Zhao Employee of: Pfizer, K. Crouse Employee of: Pfizer, P. Symanowicz Employee of: Pfizer, M. Hegen Employee of: Pfizer, M. E. Banker Employee of: Pfizer, F. Vincent Employee of: Pfizer, J. Clark Employee of: Pfizer, A. Thorarensen Employee of: Pfizer
- Published
- 2016
3. OP0147 Lack of Differentiation of Janus Kinase Inhibitors in Rheumatoid Arthritis Based on Janus Kinase Pharmacology and Clinically Meaningful Concentrations
- Author
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Brian Juba, Jason Jussif, Martin E. Dowty, Tsung Lin, Lisy Wang, Erick Moy, Li Li, and J.-B. Telliez
- Subjects
Tofacitinib ,Filgotinib ,business.industry ,medicine.medical_treatment ,Immunology ,Context (language use) ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,Cytokine ,Rheumatology ,Pharmacokinetics ,Erythropoietin ,medicine ,STAT protein ,Immunology and Allergy ,Janus kinase ,business ,medicine.drug - Abstract
Background A number of Janus kinase (JAK) inhibitors are being actively investigated for treatment of rheumatoid arthritis (RA), including tofacitinib, baricitinib, filgotinib (GLPG0634), and decernotinib (VX-509). However, it is unclear how these drugs may differentiate from each other in the clinic based on their profiles of JAK dependent cytokine inhibition. Objectives The aim of this work was to provide an integrated modelling approach using knowledge of both whole cell JAK inhibition potencies and plasma pharmacokinetics to better understand profiles of cytokine inhibition for clinical JAK inhibitors in the context of clinically meaningful doses. Methods IC 50 values for IFNα, IFNγ, IL-6, IL-15, IL-21, IL-10, IL-27, IL-12, IL-23 and erythropoietin (EPO) signalling of tofacitinib, baricitinib, filgotinib, and decernotinib were measured in total lymphocytes, CD34+ cells (EPO) and CD3+ cells (IL-6) in human whole blood by a flow cytometry-based assay, quantifying the phosphorylation state of various STAT proteins. Human daily average plasma concentrations (C av ) were used as reported or predicted for tofacitinib (5 mg BID; 68 nM), baricitinib (4 mg QD; 32 nM), and filgotinib (200 mg QD; 527 nM). Confidence in the prediction of decernotinib pharmacokinetics was considered low because of high in-vitro metabolic instability and was not assessed further. Percent levels of cytokine inhibition (IC xx =100*C av /(IC 50 + C av )) were determined at clinically meaningful doses. Results Each JAK inhibitor showed a relatively similar profile of cytokine inhibition versus type I and II interferons (IFNα, IFNγ), the common γ chain cytokines (IL-15, IL-21), and IL-6 and IL-27 (Fig. 1). Each also showed some decrease in potency for IL-10, IL-12 and 23, and EPO. Comparing between JAK inhibitors, tofacitinib and baricitinib were overall more potent inhibitors than decernotinib and filgotinib. Clinical pharmacokinetics of tofacitinib, baricitinib, and filgotinib were available and used to further compare predicted cytokine profiles of inhibition in patients with RA. The profile of cytokine inhibition for each JAK inhibitor was strikingly similar at clinically meaningful doses (Fig. 1). While the pharmacokinetics were unavailable for decernotinib, the clinical dose ranges being explored are consistent with filgotinib which showed similar in-vitro inhibitory potencies. Conclusions These analyses illustrate the importance of studying a broad range of JAK pairing potencies and clinical concentrations when comparing JAK inhibitor compounds. Clinical profiles of cytokine inhibition for a number of JAK inhibitors in RA are strikingly similar when efficacious doses are considered, suggesting limited potential for differentiation of these JAK inhibitors based on JAK pharmacology. Disclosure of Interest M. Dowty Employee of: Pfizer Inc, T. Lin Employee of: Pfizer Inc, L. Wang Employee of: Pfizer Inc, J. Jussif Employee of: Pfizer Inc, B. Juba Employee of: Pfizer Inc, L. Li Employee of: Pfizer Inc, E. Moy Employee of: Pfizer Inc, J.-B. Telliez Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.2490
- Published
- 2014
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