Zila's OraTest highly touted by cancer research publication

July 12, 2001
Johns Hopkins University cancer experts proclaim product as a powerful method to detect cancers and lesions.

Zila Professional Pharmaceuticals, a division of Zila, Inc. (Nasdaq: ZILA), international provider of healthcare and biotechnology products and services for dental/medical professionals and consumers, announced publication in the American Association for Cancer Research�s Journal of Clinical Cancer Research (July 2001) of an article by Johns Hopkins University cancer experts demonstrating that Zila�s OraTest� product "represents a powerful method to detect cancers as well as lesions that are likely to progress to cancer." The research team was headed by Dr. David Sidransky, Director of the university�s Head & Neck Cancer Research Center and a world-renown genetics expert.

Going beyond traditional microscopic examination of biopsied tissue, the researchers conducted sophisticated lab tests in search of gene deletions � irreversible cellular mutations that are known to be precursors of cancer. "Genetic alterations are the hallmark of human cancer," they write. OraTest "can detect clinically occult [unobservable] lesions in the progression pathway to oral cancer. Remarkably, the vast majority of other lesions [detected with OraTest] appeared normal under the microscope, but still harbored the critical clonal genetic changes that are necessary for cancer progression."

The Johns Hopkins team obtained oral biopsy tissue collected in a prior OraTest clinical study from 46 cancer patients; some of the data from the earlier study was presented to an FDA advisory panel in January 1999. Some witnesses who appeared before that panel questioned the accuracy of the OraTest product, suggesting that in many instances the product (a mouthrinse sequence) stained healthy cells blue, producing false positive evaluations. The Johns Hopkins experts, using more sophisticated lab testing, directly addressed the accuracy issue: "In the initial [pre-1999] multi-institutional OraTest study, investigators identified cancer in only one third of the 96 biopsied lesions. Our molecular analysis now definitively shows that three quarters of the lesions identified by OraTest are in fact clonal [potentially cancerous]. This study establishes the fact that preneoplastic [precancerous] changes identified by OraTest in this patient population are often clonal and are therefore in the progression pathway to cancer. Accumulating evidence suggests that these clonal patches place these patients in a very high risk category."

Eighty biopsies from 46 of the prior study�s patients were re-examined at Johns Hopkins. All of the biopsied lesions had been identified by positive staining with OraTest. Traditional pathological examination of the biopsies, using a microscope, revealed 13 cases of cancer (squamous cell carcinoma), 11 cases of pre-cancer (carcinoma-in-situ or dysplasia), and 22 cases of apparently healthy tissue. The Sidransky team then subjected all 80 biopsies to genetic testing. Genes normally display heterozygosity, meaning they exist on chromosomes as perfectly matched pairs. When a gene deletion occurs, there is a "loss of heterozygosity", or LOH. In this case, as the cell reproduces, the "daughter gene" will not be an exact duplicate of its "mother", producing a precursor of cancer.

The Johns Hopkins researchers detected LOH in the biopsied tissue of 76 percent of the OraTest-stained lesions. One hundred percent of the squamous cell carcinoma, 82 percent of the carcinoma-in-situ or dysplasia, and, "strikingly", 59 percent of lesions that had appeared normal under the microscope showed LOH during genetic examination.

The article, "Allelic Losses in OraTest Directed Biopsies of Patients with Prior Upper Aerodigestive Tract Malignancy," is authored by Zhongmin Guo, Kengo Yamaguchi, Montserrat Sanches-Cespedes, William H. Westra, Wayne M. Koch and David Sidransky, all of Johns Hopkins University in Baltimore, Maryland. Their work was supported by grants from the National Institute of Dental and Craniofacial Research (a unit of the National Institutes of Health) and Zila, Inc.

Dr. Ralph Green, Vice President and General Manager of Zila Professional Pharmaceuticals, noted, "This research was conducted by preeminent cancer geneticists. In essence, they found that the OraTest product, with its active ingredient Zila� Tolonium Chloride, detects early genetic changes indicative of cancer, but not apparent through normal microscopic examination of biopsied tissue. This underscores the value of OraTest in facilitating aggressive early monitoring and treatment of tissue at risk of progressing to cancer."

Dr. Doug Burkett, Vice President and General Manager of Zila Technical Operations, added, "Based on this work, Zila has filed for additional patents for its technology. Zila is also sponsoring an approximately 600-patient, 40-site, Phase III OraTest clinical study being conducted by ILEX� Oncology Services in support of the OraTest New Drug Application. Based on a presentation to the FDA of the Sidransky team�s findings, the agency has agreed to make detection of these early genetic changes one of the endpoints of the Phase III study."

Time magazine, in its May 28 cover story, "New Hope for Cancer," reported that Dr. Sidransky is "searching for diagnostics that will pick up other cancers in their preliminary stages. Says Sidransky: �Within five years, it might be almost impossible to bring a drug forward without having a test to help doctors decide whom the drug is for.�"

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