By Jim Shrine

Interim results from Cell Pathways Inc.¿s Phase II/III trial of exisulind showed statistically significant reductions in prostate specific antigen (PSA) levels in patients following radical prostatectomy.

That was a welcome result for the Horsham, Pa., company that three months ago reported the same drug failed to demonstrate significance in another indication, adenomatous polyposis coli (APC). Full results from the prostate cancer trial are expected to be available late in the third quarter.

¿I think this shows we¿re on the right track,¿ Rifat Pamukcu, the company¿s chief scientific officer, told BioWorld Today. ¿There¿s a certain element of validation to our approach.¿ The drug is being developed for a number of indications, and is in about half a dozen other clinical trials.

The Phase II/III study is being conducted in patients with detectable PSA levels that were rising following removal of the prostate, indicating recurrence of disease. The primary endpoint is the mean PSA levels between the drug and placebo groups over one year.

Enrollment was completed in September and about 70 patients are evaluable. All patients were past the six-month point at the time of analysis, half to two-thirds were beyond nine months of therapy, and 12 had completed treatment, Pamukcu said.

The mean PSA levels overall were twofold greater in the placebo group (p = .0004), and when patients were stratified, results from the high- and intermediate-risk groups were as, or even more, significant, with a p value of .0002 in the highest-risk group, Pamukcu said.

If the final analysis from the study continues to support efficacy, Cell Pathways would be expected to conduct additional trials in the prostate cancer indication.

¿To date, there has not been a drug approved solely on a PSA marker for prostate cancer,¿ Pamukcu said, ¿and there¿s still debate about the PSA level and its indication on how the patient is progressing. The studies [would] have to go to a hard disease endpoint, such as recurrence of metastasis. But this gives us encouragement to continue studies in a number of prostate cancer indications.¿

The need for hormonal or chemotherapeutic treatments could be delayed if exisulind successfully slowed or stopped the spread of the cancer.

Exisulind, or Prevatac, is a metabolite of a non-steroidal anti-inflammatory agent called sulindac. It has the same anti-neoplastic activity as the parent compound but does not inhibit the COX-1 and COX-2 pathways, Pamukcu said. The apoptotic compound targets cyclic GMP phosphodiesterase.

Ongoing studies of exisulind include a pivotal Phase II/III trial to prevent recurrence of breast cancer, with completion not expected anytime soon; an open-label Phase II trial in lung cancer; a pilot study in advanced lung cancer; a Phase II trial in Barrett¿s esophagus syndrome; and studies in APC.

Company officials expressed surprise in February when the Phase III study in APC failed to demonstrate statistical significance. (See BioWorld Today, Feb. 3, 1999, p. 1.)

Now that they have had time to look at the data, they realize those in the placebo group were generating between zero and 248 polyps per year while they were expected to get 10 to 40 polyps, Pamukcu said. The broader window meant more patients would be needed to achieve statistical significance, he said, adding that the analysis is nearly complete and a decision will be made after that on how to proceed in that indication.

Following news of the failure in February, the company¿s stock (NASDAQ:CLPA) fell 66 percent to close at $9 per share. The stock gained 75 cents Thursday to close at $10.75.

Cell Pathways has another compound, CP461, that has the same target as exisulind but is 100 times more potent, Pamukcu said, and has others further back that are even stronger. The company recently started a Phase I study of CP461 in healthy volunteers. n