By Randall Osborne
In mid-point Phase III trial results, Liposome Co.'s formulation of doxorubicin, Evacet, showed a reduction of side effects and clinical benefit similar to the parent molecule.
Princeton, N.J.-based Liposome expects to file a new drug application for the chemotherapeutic agent with the FDA in the second half of this year.
The news about Evacet came a day after South San Francisco-based Genentech Inc. disclosed strongly positive Phase III data for Herceptin (trastuzumab), which could be used with doxorubicin against metastatic breast cancer. It may complement the anticancer drug Taxol (paclitaxel) as well, said Andrew Janoff, vice president of research and development at Liposome.
"It's a logical combo with Taxol," Janoff said.
Metastatic breast cancer afflicts about 60,000 women every year in the U.S., and leads to about 38,000 deaths. Although doxorubicin has been used against the disease for 36 years, it carries serious side effects, most notably damage to the heart, including congestive heart failure.
"It's mostly irreversible and dose-limiting," Janoff said. "It's a peculiar toxicity."
Other potential side effects are severe nausea and vomiting; ulcers in the lining of the mouth, esophagus and intestines; and bone marrow suppression. The liposomal formulation of Evacet enhances delivery to the target site, thus reducing side effects.
"What we know is that Evacet is less toxic," Janoff said.
In the Phase III mid-point analysis, 144 patients received either Evacet or doxorubicin for at least six weeks. Clinical benefits were equivalent, and those with Evacet fared better in side effects.
Ten percent of Evacet patients experienced nausea and vomiting vs. 25 percent of doxorubicin patients. For stomatitis and mucositis, the numbers were 9 percent vs. 15 percent. Seven percent of Evacet patients had fever and infection, as opposed to 16 percent for doxorubicin patients.
Last June, the company's liposomal prostaglandin E for acute respiratory distress syndrome, Ventus, failed in a Phase III trial, sending Liposome's stock down 61 percent. (See BioWorld Today, June 26, 1997, p. 1.)
Now, the company is pushing ahead with its work on Evacet.
"Pfizer [Inc., of New York] was developing the drug, and they gave it back to us," Janoff said. "There's an agreement, with a royalty back to Pfizer."
Other companies developing liposomal drugs are Sequus Pharmaceuticals Inc., of Meno Park, Calif., and NeXstar Pharmaceuticals Inc., of Boulder, Colo.
Sequus's Doxil, a liposome formulation of doxorubicin, was approved by the FDA in December 1995 for treatment of AIDS-related Kaposi's sarcoma for patients whose disease progressed after combination chemotherapy and those intolerant to such therapy.
The same company's Amphotec, a lipid-based formulation using a one-for-one molecular complex of amphotericin B and a metabolite of cholesterol, cholestryl sulfate, was cleared in December 1996 for treatment of aspergillosis.
NexStar's DaunoXome, a liposomal form of the cancer chemotherapeutic agent daunorubicin for Kaposi's sarcoma, was cleared for marketing in April 1996. In August 1997, the FDA approved NexStar's AmBisome, which is liposomal amphotericin B, as an empiric therapy for fungal infections and visceral leishmaniasis, a parasitic infection.
Liposome disclosed its mid-point Phase III results at the American Society of Clinical Oncology (ASCO) conference, in Los Angeles. The company's stock (NASDAQ:LIPO) closed Wednesday at $6.75, down $0.562.
In other news from ASCO:
* Isis Pharmaceuticals Inc., of Carlsbad, Calif., disclosed Phase I clinical results with two antisense drugs against cancer. Both showed antitumor activity with only modest side effects. The drugs are ISIS 3521/CGP64128A, a selective inhibitor of protein kinase C alpha, and ISIS 5132/CGP69846A, a selective inhibitor of C-raf. The drugs are being developed with Novartis AG, of Basel, Switzerland.
* Jenner Biotherapies Inc., of San Ramon, Calif., reported its cancer vaccine incorporating a recombinant antigen with a proprietary adjuvant induced a strong immune response in prostate cancer patients. The vaccine, OncoVax-P, consists of recombinant prostate specific antigen and a liposome-formulated adjuvant emulsified in light mineral oil.
* Matritech Inc., of Newton, Mass., said its NMP179, a monoclonal antibody developed with the company's nuclear matrix protein technology, detected precancerous cervical abnormalities with a high degree of accuracy in a preclinical study.
* MGI Pharma Inc., of Minneapolis, reported its Phase I study with MGI 114, an anticancer compound, achieved blood levels consistent with those required for antitumor activity with a tolerable toxicity profile.
* NeoRx Inc., of Seattle, said its Avicidin Phase I trials established a maximum tolerated dose of yttrium-90 and showed tumor regressions from a single dose in some patients with advanced cancers resistant to standard therapies. Avicidin is NeoRx's first product to use the company's proprietary technology allowing high doses of radiation to be administered with significantly reduced exposure to healthy organs. (See BioWorld Today, Aug. 13, 1997, p. 1.)
* Pharmacyclics Inc., of Sunnyvale, Calif., disclosed positive interim results of a Phase Ib/II clinical trial of its radiation sensitizer gadolinium texaphyrin for treatment of brain metastases. Overall tumor response rate was 73 percent. The drug accumulated selectively in tumors and not in adjacent normal brain tissue, confirming previous results from Phase I studies.
* QLT Phototherapeutics Inc., of Vancouver, British Columbia, presented favorable results from clinical trials studying photodynamic therapy with Photofrin (porfimer sodium) for injection, as a treatment for certain types of early- and late-stage non-small cell lung cancers (NSCLC). The data included unpublished results that led the FDA to approve Photofrin in January as a treatment for microinvasive endobronchial NSCLC in patients who are not candidates for surgery and radiotherapy. About three-fourths of 120 patients had a biopsy-proven complete tumor response following treatment, and about half maintained it in long-term follow-up.
* SuperGen Inc., of San Ramon, Calif., said interim results form its ongoing Phase II trial of RFS 2000 for pancreatic cancer showed that, among 53 patients, 32 percent were responders, 32 percent were stable and 26 percent were non-responders. Median survival to date is 9.1 months among responders, and 8.8 months among stable patients. A topoisomerase I inhibitor, the drug is a semi-synthetic derivative of a naturally occurring plant alkaloid with cancer-killing properties. It is extracted from the bark and leaves of the camptotheca acuminata tree, which is native to China. *