January 15, 2007 (Vol. 27, No. 2)

Platform Designed to Zero in on Cancer More Quickly and Effectively

When James Bianco, M.D., and Jack Singer, M.D., co-founded Cell Therapeutics (CTI; www.cticseattle.com) in 1992, both were oncologists working at an institution that had won a Nobel Prize for pioneering dose-intensive chemotherapy. However, looking 15 years ahead, “we didn’t think that more intensive chemotherapy would be the best solution for patients,” explains Dr. Bianco, president and CEO of Cell Therapeutics in Seattle, WA.

Their mission was to reduce chemotherapy doses by pioneering less toxic and more effective treatments. The company’s motto, Making Cancer More Treatable, is achieved by developing more targeted treatments to prolong life with fewer side effects.

The overall strategy at Cell Therapeutics is to take leading cancer treatment drugs and improve the formulation through the company’s drug delivery platform or acquire companies with promising compounds. Although new cancer drugs like Herceptin or Gleevec specifically target particular tumors, such biotherapeutics account for just 1% of all sales of therapeutic agents worldwide. CTI focuses on four major classes of chemotherapeutic agents that make up more than 90% of chemotherapy sales—taxane, camptothecin, platinates, and anthracycline.

“We see these chemotherapies as the cornerstone of any cancer treatment program for the next 10–20 years,” says Dr. Bianco. “Our portfolio strategy is to develop the next generation of these molecules to address the limitations of the currently marketed products.”

Cell Therapeutics’ drug delivery platform is based on biodegradable polyglutamate polymers linked to existing chemotherapeutics, such as paclitaxel, the active ingredient in Taxol®, one of the most widely prescribed chemotherapies for cancer. The polyglutamate technology was licensed from the University of Texas M.D. Anderson Cancer Center in Houston. CTI holds an exclusive license to the methods.

Cell Therapeutics’ polymer technology can deliver therapies directly to tumors without the need for vectors or direct injections. The amino acid component of the polymer can be altered to target tissues of choice. “Our polymer technology has the potential to exploit the genomic basis of disease and improve future therapeutics,” Dr. Bianco says.

The company’s polyglutamate polymer formulation of paclitaxel, called Xyotax™, does not damage healthy tissue because the polymer inactivates paclitaxel until it reaches tumor cells. Xyotax preferentially favors tumor tissues, which have leaky blood vessels that are more porous to polyglutamate than healthy blood vessels. Once trapped inside tumors, enzymes break down the protein polymer and release paclitaxel.

Since Xyotax localizes in tumors, a higher dose of paclitaxel can be delivered in a shorter time period and with fewer side effects. “Our technology has the ability to create the first biologically enhanced chemotherapeutic agent,” states Dr. Bianco.

So far, the polyglutamate polymer technology has been applied successfully to taxane, generating Xyotax, and camptothecin, producing CTI-2106. In 2003, Cell Therapeutics acquired Novuspharma in Milano, Italy, and its anthracycline derivative pixantrone, which may not cause severe cardiac damage as the current anthracyclines do. “Having a more potent anthracycline that does not cause heart damage could represent a major advance in anthracycline therapies for breast cancer, lymphoma, and leukemia,” Dr. Bianco points out.

Through the acquisition of Novuspharma Cell Therapeutics also obtained a first-in-class bis-platinate compound that disrupts both DNA strands in tumors. The current clinical platinates contain just one platinum molecule that can damage only a single strand of DNA. A stronger platinate that targets both DNA strands “can overcome tumors that develop resistance to platinum,” Dr. Bianco notes.

Clinical Results

In 2005, Cell Therapeutics completed three Phase III trials of Xyotax in various stages of non-small-cell-lung cancer (NSCLC). Known as the STELLAR trials, short for “superior therapeutic efficacy in lung cancer with lower adverse reactions,” these studies compared Xyotax to other taxanes or chemotherapies for NSCLC. Although none of the trials reached the primary end-point of extended survival, patients receiving Xyotax showed lowered cardiac and gastrointestinal toxicities and less nausea, vomiting, anemia, hair loss, fatigue, and mucositis.

One of the most important findings of the STELLAR trials was that Xyotax improved the survival of women more than men. At the annual meeting of the American Society of Clinical Oncology in June 2006, Cell Therapeutics presented composite results for women, showing that Xyotax significantly extended survival in women compared to controls. Furthermore, women younger than 55 showed particular improvement. The median survival time for premenopausal women was 309 days, compared to 181 days for controls. The one-year survival rate for premenopausal women was 43% for Xyotax, but only 19% for controls.

To confirm the significant benefit to women from Xyotax, Cell Therapeutics initiated a Phase III trial called PIONEER that specifically targets women with NSCLC. More women die from lung cancer than any other kind of cancer. Women are also nearly twice as vulnerable to the disease as are men. Xyotax will be compared to standard paclitaxel in 600 women to look for a survival benefit. The FDA granted the company fast-track status for the PIONEER trial.

In September 2006, CTI announced an exclusive, worldwide licensing agreement with Novartis for the further development and commercialization of Xyotax in NSCLC and other cancers. Xyotax is also being evaluted in a Phase III study of 1,500 women as a treatment for ovarian cancer to maintain remission and improve survival. “We want to understand how gender influences biological differences to drug response,” says Dr. Bianco. Estrogen seems to be involved in breaking down the polyglutamate polymer and releasing the paclitaxel to cancer cells. Estrogen also may distribute Xyotax to cells with estrogen receptors. On the other hand, the hormone may speed the release or metabolism of the drug.

Cell Therapeutics is evaluating pixantrone for relapsed, aggressive non-Hodgkin’s lymphoma (NHL) in a Phase III trial called EXTEND that is being conducted under a Special Protocol Assessment from the FDA. In August 2006, CTI released preliminary data from the first 40 patients. A second interim analysis will be made early in 2007 after 100 patients have completed therapy.

Pixantrone is also being studied in combination with Rituxan for NHL. Early data shows that the drug combination prolongs time to disease progression compared to Rituxan alone.

From a platform perspective, Cell Therapeutics is betting that the pharmaceutical industry will move toward personalized therapies that maximize the benefits and minimize the risks for individual patients. “With cancer therapies costing $45,000, pharma should narrow its target to populations who scientifically and clinically benefit from them,” says Dr. Bianco.

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