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Program Overview
About IL 12 / IL 23 Inhibitors
We are developing small molecule drug candidates that inhibit the production of
the cytokines interleukin-12 (IL-12), and interleukin-23 (IL-23), which are
believed to be important regulators of the biological processes underlying
certain autoimmune and inflammatory diseases. The IL-12 cytokine family
(including IL-12 and IL-23) is the master regulator of the TH1 pathway which
drives major chronic inflammatory diseases, including Crohn's disease,
psoriasis, rheumatoid arthritis, and multiple sclerosis.
Mechanism of Action
Our drug candidates selectively inhibit production of the cytokines IL-12 and
IL-23. The IL-12 cytokine is an important "master switch" that triggers the
immune response of the T cell known as T helper type 1, or Th1. T cells play a
critical role in the coordination of the body's immune response, and while Th1
cells are normally involved in the body's defense against intracellular attack
by bacteria and other micro organisms, an overactive Th1 response can lead to
various autoimmune or inflammatory diseases including Crohn's disease,
psoriasis, RA, multiple sclerosis, and common variable immunodeficiency, or
CVID. The IL-23 cytokine is critical to the generation of a class of T cells
known as Th17, which produce other pro-inflammatory proteins such as IL-17,
which are critical in driving chronic inflammation. We believe that the
clinical trial results observed with anti-IL-12/23 antibody therapies validate
the inhibition of IL-12/23 activity as a promising approach for the treatment
of inflammatory and autoimmune diseases.
Research has identified several small molecule IL-12/23 inhibitors that
represent a promising opportunity to develop drug candidates that could be
administered orally and potentially address a wide range of serious
inflammatory diseases with high unmet medical needs.
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References for IL-12/IL-23 Inhibition of Inflammatory Disease
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Inflammatory Bowel Diseases, 2010, 16: (7): 1209-1218: Randomized,
double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor
apilimod mesylate for treatment of active Crohn’s disease.
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Nature Review, Immunology, 2005, 5: 521-531: New IL-12-Family Members:
IL-23 and IL-27, Cytokines with Divergent Functions.
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The New England Journal of Medicine, 2004, 351: 2069-2079:
Anti-Interleukin-12 Antibody for Active Crohn's Disease.
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The Journal of Clinical Investigation, 2004, 113: 1664-1675: Recent
insights into the immunopathogenesis of psoriasis provide new therapeutic
opportunities.
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Nature Reviews, Immunology, 2003, 3: 521-533: The Immunological and
Genetic Basis of Inflammatory Bowel Disease.
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Massachusetts Medical Society, 1997, 337: 1029-1035: A Short-Term Study
of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor a
for Crohn's Disease.
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Nature Reviews, Immunology, 2003, 133-146: Interleukin-12 and the
Regulation of Innate Resistance and Adaptive Immunity.
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The Journal of Clinical Investigation, 2002, 110: 843-850: Critical roles
of c-Rel in autoimmune inflammation and helper T cell differentiation.
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The Journal of Clinical Investigation, 2000, 105: 1799-1806: Distinct
roles for the NF-KB1 (p50) and c-Rel transcription
factors in inflammatory arthritis.
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Keino, et
al: Therapeutic effect of the potent IL-12/IL-23 inhibitor STA-5326 on
experimental autoimmune uveoretinitis, Arthritis Research & Therapy 2008,
10: (5) October 13 2008, R122.
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Wada et al: Selective abrogation of Th1 response by STA-5326, a potent
IL-12/IL-23 inhibitor, Blood, 109: (3), February 2007, 1156-1164.
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Wada et al: IL-12/IL-23 inhibitors: a promising approach to the treatment of
inflammatory disorders, Drugs of the Future 2008, 33: (1) February 2008, 49-63.
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