Synta's Surprise - Pharmaceutical Executive

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Synta's Surprise
A small molecule for autoimmune diseases? No one expected that.


Pharmaceutical Executive


Partnering with a Big Pharma is an option the company is weighing carefully. Synta has capital in place to start Phase III trials but is waiting to see how finances look down the road before making a decision to license out its intellectual property. Even though some clinicians have called STA-5326 a "slam dunk," it still has to prove itself. And the data will not be available until the middle of next year when Synta concludes its Phase II trials in psoriasis and Crohn's disease.

Depth and Breadth To bolster its expertise, last March, Synta brought in Matthew Sherman from Wyeth (formerly the Genetics Institute) as its chief medical officer. At the Genetics Institute, Sherman not only worked on the clinical development of the recombinant human IL-12 protein, he also led the development team that brought Mylotarg (gemtuzumab) to market for acute myeloid leukemia.

"It's interesting, 10 years after working on recombinant IL-12 protein as a potential therapeutic, to be involved as the key point person for an IL-12 inhibitor," Sherman says. "I have a great love for it." He says the IL-12 marker is "the master switch for turning on the immune system. It is the main driver for the TH1 [T-helper 1] arm of the immune system that leads to a multiple of other cytokine inflammatory molecules that are released by the body and can cause a variety of different diseases." That's why IL-12 inhibitors have the potential to treat so many conditions. They target (and stop) the inflammation process in its early stages before it releases the floodgate of cytokines that cause various diseases. (See "Stop the Cascade.")

Sherman's experience will also be important for Synta's other key therapeutic interest: anti-cancer compounds. Also in Phase II trials is a small molecule (STA-4783) that stimulates cancer tumors to express "heat shock proteins" (HSPs). The HSPs cause the tumor to "light up" so the immune system can see it and attack it.

Bahcall describes how the drug works: "One of the reasons cancer is able to grow in an uncontrolled way is that it stays dark to the immune cells, to the internal police system. Our HSP 70 inducer stimulates the surface of tumor cells to express a flag or a beacon to the immune system that something is going wrong. And that protein is called a stress protein or heat shock protein. Those proteins create a signal to the native immune system in the body, like a homing device, that something is wrong and the police should come and take a look."

One caveat for the compound is that it works only as an adjunct to taxane cancer drugs—Taxol (paclitaxel) and Taxo-tere (docetaxel). With other anti-cancer compounds, such as doxorubicin and vincristine, it has no effect. The explanation is that taxanes also have an effect on the immune system, and they combine with the HSP 70 inducer for a "one-two punch." But considering that Taxol is the mostly widely used chemotherapy, the market potential for a "helper" drug could be quite lucrative. STA-4783 is currently being tested in non small-cell lung cancer, melanoma, and sarcoma.

"In the preclinical models, that fact, that it worked best in combination with taxanes, led us to believe that there may be some other effects that might be interesting to explore," Sherman says. The company isn't willing to reveal any more about the compound until it has "adequate intellectual property protection." But Bahcall has high hopes: "We are excited about this, because it is, I believe, the next step in the evolution of treating cancer."

Small-Scale Innovation Synta's R&D team (of 75 people) is busy with nearly a dozen Phase I and II trials and also has preclinical projects in both asthma and diabetes. (See "Small Molecules for Big Dis-eases.") Bahcall credits the company's "running start" to an old-fashioned approach to discovery.


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