New Drug Selectively Induces Apoptosis in Neoplastic Cells

NEW YORK—Clinical trials of the experimental oral agent exisulind (Prevatac) are underway for chemopre-vention of a variety of cancers, according to a report at Current Concepts in Cancer Therapy II, a scientific symposium sponsored by Long Ridge Associates.

A metabolite of sulindac, a nonsteroidal anti-inflammatory drug, exisulind selectively induces apoptosis in neoplastic cells, said Rifat Pamukcu, MD, chief scientific officer and senior vice president for research and development at Cell Pathways, Inc., Horsham, Pennsylvania. [See the box for an explanation of the drug’s mechanism of action.]

SAANDS: How They Work

Both exisulind and CP461, a more potent compound now entering clinical safety trials, are selective apoptotic antineoplastic drugs (SAANDs), Dr. Rifat Pamukcu, of Cell Pathways, Inc., said at Current Concepts in Cancer Therapy II.

SAANDs inhibit a cyclic GMP phosphodiesterase, uncovered in the company’s research, that appears to interfere with signaling to regulate abnormal cell growth and initiate apoptosis.

By selectively blocking that enzyme, SAANDs allow the apoptotic message to go through, triggering destruction of abnormal cells without affecting neighboring normal ones. “They do not inhibit the cyclooxygenase pathways,” Dr. Pamukcu said.

“The FDA has designated exisulind an orphan drug meriting fast-track development for aden-omatous polyposis coli (APC),” Dr. Pamukcu said, and its first trials were in patients with this hereditary disease, which is also known as familial adenomatous polyposis (FAP).

Exisulind is now being tested in other precancerous lesions and in recurrence prevention in some cancers. Treatment of frank cancers is also being explored, but most research to date has been directed toward chemoprevention. “For every one person with cancer,” Dr. Pamukcu observed, “there are 10 people with a precancerous lesion.”

The initial trial in 18 patients with APC who retained their rectum after colectomy was designed to determine the maximum tolerated dosage. The optimal dose turned out to be 600 mg daily.

“The highest daily dose tested, 800 mg, induced active regression of the existing polyps,” Dr. Pamukcu reported, “but after 3 to 5 weeks, about half the patients showed very-low-grade liver enzyme elevations. These reversed completely when dosage was dropped to 600 mg, where good regression of polyps is still achieved.”

In 16 patients, polyps of 6 mm or less regressed, and larger polyps remained stable. No increase in cell apoptosis was seen in normal mucosa, however.

The first patient enrolled, an 18-year-old woman with more than 100 polyps in her rectum “had been told that if she did not respond to the drug, she would lose her rectum within a year,” Dr. Pamukcu said. After 6 months at the lowest dose tested, 400 mg daily, her polyps began disappearing. At 45 months, she is the patient longest on exisulind and still has her rectum.

The subsequent international double-blind, placebo-controlled phase III trial enrolled 73 APC patients with subtotal colectomies. “It was a prevention trial so all polyps were aggressively removed at baseline,” Dr. Pamukcu said, “and then any new polyps that formed were removed at 6 and at 12 months.”

The results showed a greater than 50% reduction in new polyp formation, compared with placebo, among the 34 eligible patients who completed the 12-month study (P < .05). Eligible patients were those who formed approximately 10 to 40 polyps per year.

Based on these findings, Cell Pathways plans to submit a New Drug Application for exisulind to the FDA later this summer. In light of the relatively low percentage of patients who met inclusion criteria in this study, the company will also assemble additional clinical data from other ongoing APC trials of exisulind, to be added to the NDA later this year.

Prostate Cancer Study

Interim data from a double-blind placebo-controlled trial of exisulind in 96 postsurgical prostate cancer patients suggest it may be effective in preventing recurrences, Dr. Pamukcu said. Limited to patients with radical prostatectomies whose PSA levels had been rising for at least 4 months, the trial is to run for a year, with patients receiving 250 mg of the drug daily.

“The early data show a flattening of the PSA rises after 2 to 3 months,” he said. “Because the patients do not have prostates,” he added, “they have no source of PSA other than their microscopic metastases.” Other prostate cancer trials are planned with exisulind, Dr. Pamukcu said, particularly in hormone-refractory patients.

Already underway are a trial aimed at preventing breast cancer recurrences in patients in remission after treatment for a recurrence; a phase II trial in Barrett’s esophagus; and a phase IB/II trial in lung cancer. Dr. Pamukcu also noted that animal studies have shown a significant impact of exisulind on bladder carcinoma.