“These results suggest that exisulind may delay disease progression in men with recurrent prostate cancer and thus prolong the time period between initial post-surgical PSA rise and the need for androgen deprivation therapies,” said Erik T. Goluboff, MD, assistant professor of urology at Columbia University College of Physicians & Surgeons and director of urology at the Allen Pavilion of NewYork-Presbyterian Hospital, principal investigator of the study. “Hormonal therapy produces high response rates in metastatic prostate cancer, but patients develop resistance over time. The side effects of hormonal treatment can significantly impact the patient’s quality of life. New treatment options that might delay the need for such side effect prone therapies could provide great benefit in the management of prostate cancer.”
The primary efficacy measurement for the one-year, single-agent study was the difference in the change in PSA levels from baseline between the placebo-treated and exisulind-treated groups. The clinical effect of exisulind therapy was initially observed two to three months after commencing treatment, and continued throughout the study. The investigators also evaluated the patients PSA doubling times prior to the start of therapy and during treatment. Study data showed that exisulind significantly suppressed the rise in PSA levels compared with placebo in the overall group (p=0.017). The results were also statistically significant in exisulind-treated men classified as at “high-risk” for the recurrence of measurable metastatic disease (p=0.0003) and for men who could not be classified according to risk (p=0.0009). In addition, the median PSA doubling time (PSADT) was lengthened in high-risk patients on exisulind (p=0.048), with the median PSADT increasing from 5.63 to 8.84 months compared with a decrease from 4.9 to 2.39 months for placebo. Mean PSADT also increased in high-risk patients receiving exisulind (8.12 to 29.75 months) and decreased for patients on placebo (7.34 to 4.49) months. There was a similar, but not statistically significant increase in PSADT for intermediate-risk patients receiving exisulind compared with those receiving placebo. The low-risk patients, whose pre-study PSADT exceeded 20 months, did not show a significant change in PSADT during the 12-month treatment period.
Dr. Goluboff said, “Due to the slower disease progression in low-risk men, there was no significant difference in the PSA rise in the placebo-group compared to exisulind-treated men. However, it is possible that a significant difference between treated and placebo groups might be seen in these low-risk men after longer-term exisulind therapy.”
The paper reports that exisulind was well tolerated by the treated patients. The most commonly reported adverse events observed in the exisulind group included weakness, dyspepsia, elevated liver enzymes, nausea, abdominal and back pain, and viral infection. Elevations of liver enzymes were mild to moderate in severity, generally occurred early in therapy and were reversible upon dose reduction. Adverse biliary events occurred in two patients receiving exisulind; both patients had evidence of underlying gallstone disease. The authors report that few patients experienced adverse events that demonstrated a possible or probable relationship to exisulind treatment and most adverse events were mild or moderate and reversible.
At the end of the study, investigators allowed those patients who had remained on treatment for the full 12 months to continue. Sixty patients entered the extension study, with 33 placebo patients initiating exisulind therapy and 27 patients continuing on exisulind.
"We are pleased that Cell Pathways is developing their innovative technology for the treatment of prostate cancer," said Hank Porterfield, chairman of the board of US-TOO. "Men with prostate cancer greatly need new treatment options. This clinical trial suggests that exisulind may slow the progression of prostate cancer without the typical side effects of hormonal and chemotherapy." US-TOO is the largest prostate cancer support group in the world, with over 500 chapters. The organization's mission is to foster research in new treatments and provide education on the need for early detection, diagnosis and treatment.
About PSA as a Marker for Prostate Cancer
In men who have had their prostate removed following a diagnosis of prostate cancer, a rising PSA level is widely accepted as a marker of disease progression and is used by many physicians to determine treatment. Research has shown PSA levels to correlate directly with clinical and pathological tumor stage, and it is commonly used to monitor disease progression following radical prostatectomy. PSA levels are reduced to undetectable levels in most men following radical prostatectomy; rising or detectable levels of PSA provide a strong indication of the presence of clinically undetectable metastatic disease or disease remaining after surgery. Therefore, a slowing of the rise of PSA levels would suggest a delay in disease progression in such men.
To date, the U.S. Food and Drug Administration has not approved a treatment for prostate cancer based solely on effect on PSA levels. Prevailing thought suggests that to achieve FDA approval, efficacy would have to be shown in a clinical endpoint such as survival or tumor regression.
Status of Exisulind Development in Prostate Cancer
“While the FDA has not approved a treatment for prostate cancer based solely on the treatment’s ability to slow the rise in PSA, PSA is a useful surrogate marker for the presence, recurrence or progression of the disease under certain but not all circumstances,” said Rifat Pamukcu, M.D., chief scientific officer of Cell Pathways. “As a result, based on data from this study and other research showing additive or synergistic effects between exisulind (Aptosyn™) and docetaxel (Taxotere®) in a variety of tumor types, Cell Pathways is planning to conduct a Phase III study of the Aptosyn™/Taxotere® combination in hormone-refractory prostate cancer patients. Clinical success in late-stage disease may benefit men who are in great need of new options.”
About Exisulind (AptosynÔ) and other SAANDs
Exisulind (AptosynÔ) is the first member of a new class of compounds called SAANDs (selective apoptotic antineoplastic drugs) that selectively trigger programmed cell death, or apoptosis, in precancerous and cancerous cells but not normal cells. Research by Cell Pathways and others has demonstrated that these drugs achieve their pro-apoptotic effect by inhibiting specific cyclic GMP phosphodiesterases, thus allowing death of the abnormal cells to occur through apoptosis. Both exisulind and a second-generation SAAND compound, CP461, are in human clinical development as potential treatments for a variety of cancers.
Cell Pathways, Inc. headquartered in Horsham, Pennsylvania, is a development stage pharmaceutical company focused on the research, development and commercialization of novel and unique medications to prevent and treat cancer. For additional information on Cell Pathways, Inc., visit the Company’s web site at http://www.cellpathways.com.
Editors Note: Aptosyn™ is a trademark of Cell Pathways, Inc. and Taxotere® is a registered trademark of Aventis Pharmaceuticals Inc.
Certain statements in this release, and oral statements made with respect to this release, constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are those which express plan, anticipation, intent, contingency or future development and/or otherwise are not statements of historical fact. These statements are subject to risks and uncertainties, known and unknown, which could cause actual results and developments to differ materially from those expressed or implied in such statements. Such risks and uncertainties relate to, among other factors, limitations on, or absence of, the predictive value of data obtained in laboratory tests, animal models and human clinical trials when planning additional steps in product development; this risk that the company does not conduct a Phase III study of Aptosyn™ in prostate cancer patients; uncertainty that additional studies, if any, undertaken in prostate cancer may not be positive; uncertainty of obtaining regulatory approval of any compound for any disease indication; the risks that clinical studies do not result in the safety and efficacy necessary to obtain regulatory approvals; the risks of conducting clinical trials of our drugs in combination with other drug therapies; the absence of approved products; history of operating losses and the need for further financing; early stage of development; the costs, delays and uncertainties inherent in scientific research, basic pharmaceutical research, drug development, clinical trials and the regulatory approval process, with respect to both our current product candidates and our future product candidates, if any; dependence on the development and market acceptance of one or more of our product candidates for one or more significant disease indications; uncertainty and adversity arising from the action of the U.S. Food and Drug Administration, in issuing a “not approvable” letter with respect to the New Drug Application submitted for Aptosynä (exisulind) for familial adenomatous; the timing and scope of any approval which might be received, or any failure to receive approval, for any compound for any indication in the future whether due to adequacy of the development program, changing regulatory requirements or otherwise; the volatility of the market price of our common stock; our ability to sell securities registered under the shelf registration statement; acceptance of any product candidates by physicians and providers of healthcare reimbursement; the actions of competitors; the pace of technological changes in the biopharmaceutical industry; dependence upon third parties; the validity, scope and enforceability of patents; the risk of our pending class action securities litigations; potential product liability claims; and availability and adequacy of insurance. These and other risks are detailed in our reports filed from time to time under the Securities Act and/or the Securities Exchange Act, including the sections entitled “Business,” “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and “Other Events” in our annual reports on Form 10-K, quarterly reports on Form 10-Q and periodic reports on Form 8-K and in such registration statements on Form S-3 as we may file from time to time. You are encouraged to read these filings as they are made. They are available over the Internet from the SEC in its EDGAR database at http://www.sec.gov and from the Company. Given the uncertainties affecting pharmaceutical companies in the development stage, you are cautioned not to place undue reliance on any such forward-looking statements, any of which may turn out to be wrong due to inaccurate assumptions, unknown risks, uncertainties or other factors. No forward-looking statement can be guaranteed; actual future results may vary materially. Both forward-looking statements and statements of historic fact must be understood in the context of the risks referred to above which characterize our development-stage business. We undertake no obligation to update or revise the statements made herein or the risk factors that may relate thereto.
Journal
The Journal of Urology