This is a continuation of my evaluation of Synta Pharmaceuticals. You can find the first 2 posts in the Synta Pharmaceuticals stock evaluation category.

Chronic Inflammatory Diseases

IL-12 and a related protein, IL-23, are cytokines (signaling protein that gets transfered from one cell to another) which stimulates T-cells in the the immune system. T-cells normally attack bacteria and other microorganisms that enter the body. In chronic inflammatory diseases, which includes Crohn’s disease, rheumatoid arthritis, psoriasis, and multiple sclerosis among others, cells in the body express too much of the cytokine IL-12. This stimulates the T-cells to attack the body and an inflammation occurs. If you can stop the IL-12 from signaling to the T-cells, you can stop the inflammation. Typically this inhibition is carried out with antibodies to IL-12, which bind to the cytokine and inhibit its function. But antibodies can have problems with being degraded while in the bloodstream before they reach their target as well as problems with getting them into the patient at a high enough concentration to be effective. In general, small molecules make much better drugs.

STA-5326, an IL-12 inhibitor

STA-5326 (also called apilimod) is a small molecule that acts differently than IL-12 antibodies. The drug acts by inhibiting the transcription of IL-12 so that less mRNA is made. Lowering the mRNA levels results in decreased production and secretion of IL-12. Inhibition of transcription is achieved by preventing c-Rel from entering the nucleus where it acts as a transcription factor and helps stimulate IL-12 mRNA production.

The fact that it can be administered orally is a huge boost since patients (myself included) generally don’t like to have to inject themselves and I believe that all the other IL-12 inhibitors must be administered by injection.

Phase 2 clinical trials for both psoriasis and Crohn’s disease failed, which is a little worrisome, but diseases within the grouping of chronic inflammatory diseases are different enough that it’s probably worth conducting additional trials on other diseases. The psoriasis trial may have failed because the drug is taken orally and the drug may not be potent enough to reach the skin in high enough concentrations. Synta is considering making a topical version to test in an additional clinical trial for psoriasis.

STA-5326 is currently in two separate phase 2a trials, one for rheumatoid arthritis and another for patients with common variable immunodeficiency (CVID). The rheumatoid arthritis trial is only enrolling 20 patients which is probably a sign of their cash flow issues. It may not be enough to get a statistical difference, but they believe they can get enough data by measuring markers of inflammation to make it a positive trial. The second trial for CVID is being done in conjunction with the NIH and my bet is the trial is primarily being done to get the drug approved for CVID so that it can be used off-label for other diseases. Some CVID patients have gastrointestinal manifestations that are believed to be associated with high levels of IL-12 expression in the digestive tract. So they should be able to easily establish the effectiveness of STA-5326 in lowering IL-12 levels. Results for both are expected in 2007.

Next up on babybiotechs.com: The rest of Synta’s pipeline.

Filed under: Synta Pharmaceuticals (SNTA)