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Indibulin

History and Preclinical Development

Molecules that target mitosis and inhibit cell division (antimitotic agents) are a major focus of cancer research and they are among the most widely used anti-cancer drugs in oncology today. Among the more well known antimitotic drugs are the taxanes (paclitaxel, docetaxel) and the Vinca alkaloids (vincristine, vinblastine). Although the taxanes and the Vinca alkaloids are effective, their potential is limited by the development of drug resistance and significant neurotoxicity. There continues to be significant interest in developing new antimitotic drugs that do not elicit drug resistance and that minimize the neurotoxicity associated with currently available agents in this class.

Indibulin (ZIO-301) is a novel anti-cancer agent that binds to tubulin, one of the essential proteins for chromosomal segregation, and targets mitosis like the taxanes and Vinca alkaloids. It is available as both an oral and an intravenous form. Indibulin has a pharmacologic profile that is different from other tubulin inhibitors currently on the market. Indibulin binds to a site on tubulin that is different from the taxanes or Vinca alkaloid binding sites. In contrast to taxanes, which stabilize tubulin polymers, indibulin destabilizes tubulin polymerization.



Indibulin has demonstrated significant and broad anti-tumor activity in many types of cancer cells. These include multi drug resistant tumor cell lines and taxane resistant tumor cell lines. In animal tumor models it was active at non-toxic levels in rat sarcoma AH13, MDR-1 leukemia mouse models and other xenograft models. No neurotoxicity or bone marrow suppression was detected at curative levels in animals.

Clinical development plan

Composite data for indibulin’s two Phase I trials was presented in July 2008 and two separate Phase I/II studies are currently underway, one in combination with Tarceva® and the other in combination with Xeloda®.

To date, the drug has been well tolerated with no signs of neuro- or hematological toxicity. Blood levels of indibulin observed in the PK analysis are above the target exposures seen in both in vivo and in vitro preclinical efficacy models.

While the development program for indibulin is evolving, potential application of indibulin is possible in a wide variety of cancer types.