APILIMOD (STA-5326)
IL-12/IL-23 INHIBITOR

Program Overview

Apilimod (STA-5326) is a novel, orally administered, small molecule drug candidate that inhibits 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 T_H1 pathway which drives major chronic inflammatory diseases, including Crohn's disease, psoriasis, rheumatoid arthritis, and multiple sclerosis.

As shown in the images below, there are two primary approaches to reduce the over-production of IL-12 that leads to chronic inflammatory diseases. The first approach involves the periodic injection of monoclonal antibodies that absorb IL-12 after secretion by the cell. The second approach is to inhibit the intracellular production of IL-12, which can best be accomplished by using a small molecule, such as STA-5326.

IL-12, when secreted from cells activates T cells, causing an inflammatory response		IL-12 antibodies can absorb the secreted IL-12, preventing T cell activation		STA-5326 inhibits transcription within the cell so that production and secretion of IL-12 is reduced, also preventing T cell activation

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, rheumatoid arthritis, multiple sclerosis, and CVID. The IL-23 cytokine is critical to the generation of the T cells which produce other pro-inflammatory proteins believed to be important to maintaining the immune response. We believe that the Phase 2 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.

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Clinical Data

In our Phase 1 clinical trials with STA-5326, subjects who received STA-5326 showed a dramatic reduction in IL-12 production. These results, together with Phase 1 data showing an encouraging safety profile, led us to initiate our Phase 2 clinical programs.

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Clinical Trials

Synta is currently conducting a randomized, placebo-controlled Phase 2a clinical trial of apilimod in rheumatoid arthritis (RA). The primary endpoint of this trial is based on an assessment of markers of inflammation in joint tissue after four to eight weeks of treatment. The preliminary results of the first 22 patients in this trial showed encouraging biomarker and clinical signals suggesting activity of apilimod in this indication. We have elected to enroll an additional cohort in the RA Phase 2a trial to explore a higher dose of apilimod.

Synta is awaiting final data from an investigator-sponsored Phase 2 trial of apilimod in Common Variable Immunodeficiency (CVID). However, based on the data we have reviewed to date, we currently have no plans to continue development in CVID.

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Preclinical Data

Preclinical studies have shown substantial efficacy in models of Crohn's disease, rheumatoid arthritis, and multiple sclerosis.

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References for IL-12 Inhibition of Inflammatory Disease

• Nature Review, Immunology, 2005, 5: 521-531: New IL-12-Family Members: IL-23 and IL-27, Cytokines with Divergent Functions.

• The New England Journal of Medicine, 2004, 351: 2069-2079: Anti-Interleukin-12 Antibody for Active Crohn's Disease.

• The Journal of Clinical Investigation, 2004, 113: 1664-1675: Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.

• Nature Reviews, Immunology, 2003, 3: 521-533: The Immunological and Genetic Basis of Inflammatory Bowel Disease.

• 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.

• Nature Reviews, Immunology, 2003, 133-146: Interleukin-12 and the Regulation of Innate Resistance and Adaptive Immunity.

• The Journal of Clinical Investigation, 2002, 110: 843-850: Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation.

• The Journal of Clinical Investigation, 2000, 105: 1799-1806: Distinct roles for the NF-KB1 (p50) and c-Rel transcription factors in inflammatory arthritis.

• 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.

• 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.