Ability of Aptosyn and Taxotere to Inhibit Tumor Growth and Metastasis, Prolong Survival in Animal Model of Human Lung Cancer Published in Clinical Cancer Research.

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HORSHAM, Pa.--(BW HealthWire)--March 18, 2002

Key Data Led to Ongoing Phase III Lung Cancer Study of Drug

Combination

Cell Pathways, Inc., (Nasdaq: CLPA) today announced that key preclinical data regarding the company's lead compound, Aptosyn(R) (exisulind) in combination with Taxotere(R) (docetaxel) has been published in the March issue of the journal Clinical Cancer Research. The publication details findings that a combination of the two drugs significantly prolonged survival, inhibited tumor growth and metastases, and increased apoptosis in a rat model of human non-small cell lung cancer. These preclinical results validate the rationale for initiating clinical trials of the combination of Aptosyn(R) and Taxotere(R) in advanced non-small cell lung cancer. The ongoing Phase III registration trial of this drug combination is continuing in patients with non-small cell lung cancer (NSCLC).

"Docetaxel improves the survival of patients with advanced NSCLC, but five year survival remains poor and few patients experience a complete remission," said Paul Bunn, M.D. of the University of Colorado Cancer, lead investigator of the publication. "This study, conducted in rats implanted with human lung tumors, demonstrated a synergistic activity between exisulind and docetaxel leading to significantly prolonged survival in animals receiving that combination compared to controls or those receiving either drug alone. Moreover, this finding was supported by studies of cell cultures and on biopsied tumors from treated animals. The results demonstrated that anti-tumor activity produced by the drug combination occurred through combined pathways, including apoptosis and inhibition of cell growth."

"These exciting preclinical results, in a form of cancer that has been relatively resistant to treatment, led to our conducting clinical trials of the Aptosyn(R)/Taxotere(R) combination in patients with NSCLC," said Rifat Pamukcu, M.D., chief scientific officer of Cell Pathways and an author of the publication. "A 600-patient, Phase III clinical trial in that indication is currently underway at multiple centers throughout the United States. Our goal is to complete enrollment of that study during the second half of this year."

Study Results

The researchers investigated exisulind and docetaxel alone and together in a variety of dosing combinations in rats implanted with human lung cancers. Both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases and increased apoptosis in tumor tissue compared to control animals. However, the combination of the two drugs produced a statistically significant increase in survival, as well as a reduction in metastases, compared to either agent alone. Animals treated with optimal doses of exisulind (50mg/kg) and docetaxel (5mg/kg or 5mg/kg followed by 2.5 mg/kg) had the best survival rates and significantly lower metastases. In one experiment, the survival rate in rats receiving the combination was 100% at 80-days post tumor implantation (p less than 0.001), when the experiment was ended. In a second study, survival in two groups treated with both drugs was also statistically significant, with mean survival reaching 63.2 days (p less than 0.0004) and 65.2 days (p less than 0.0001), respectively, as compared to the controls with a mean survival of 35.7 days.

Multiple Avenues of Anti-cancer Activity

Cell culture studies with exisulind have found that the drug increases the apoptotic rate in human lung cancer cells. Therefore, Cell Pathways researchers reasoned that the combination of exisulind with other chemoprevention agents or standard cytotoxic chemotherapy agents that increased growth inhibition should have an additive or synergistic action. In the published studies, the researchers extended these observations to the combination of exisulind and docetaxel both in vitro and in vivo.

"Docetaxel alone is known to induce apoptosis, inhibit angiogenesis (new blood vessel formation) and produce anti-proliferative effects in tumor cells. When combined with exisulind, however, increased apoptosis is noted even with docetaxel doses that normally have no measurable effect on either apoptosis or cell proliferation," said Dr. Pamukcu. He noted that other researchers have shown that exisulind also inhibits angiogenesis in vivo, suggesting that the beneficial effects of the exisulind/docetaxel combination may be attributed to increases in all three markers of drug activity.

Anticancer activity of SAANDs

Aptosyn(R) (exisulind) is the first generation in a new family of anticancer compounds called Selective Apoptotic Antineoplastic Drugs (SAANDs). Cell Pathways scientists and their collaborators have demonstrated that SAANDs exert their apoptotic effects by inhibiting certain cyclic GMP phosphodiesterases that are over-expressed in a variety of tumor types. This cGMP-PDE inhibition leads to activation of another intracellular signaling molecule, protein kinase G, triggering a cascade of downstream events leading to apoptosis.

Company researchers recently presented data at the American Association of Cancer Research's (AACR) Apoptosis and Cancer: Basic Mechanisms and Therapeutic Opportunities in the Post-Genomic Era meeting demonstrating the expression of two cGMP-PDE gene families (PDE 1 and 5) in NSCLC lung tumors, and showing that inhibition of these SAANDs targets would trigger apoptosis in those lung cancer cells. W.J. Thompson, Ph.D., vice president of Research & Discovery, also reported at the meeting that a second generation SAAND, CP461, additionally decreased the proliferation rate of the treated cells, an effect not seen with exisulind.

"The combined apoptotic and anti-proliferative activity of CP461 may explain its greater potency than exisulind," said Dr. Thompson. He noted that Phase I/II clinical trials of CP461 as a single-agent are currently ongoing in chronic lymphocytic leukemia, renal cell carcinoma and hormone-refractory prostate cancer, and that Cell Pathways plans to study CP461 in combination with docetaxel and other chemotherapeutic agents.

Cell Pathways, Inc., headquartered in Horsham, Pennsylvania, is a development stage pharmaceutical company focused on the research and development of novel and unique medications to prevent and treat cancer, the commercialization of these compound and the marketing and selling of oncology-related products made by others. For additional information on Cell Pathways, Inc., visit the Company's web site at http://www.cellpathways.com.

Editors Note: Aptosyn(R)is a registered trademark of Cell Pathways, Inc. and Taxotere(R)is a registered trademark of Aventis Pharmaceuticals Inc.

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