By Frances Bishopp

After encouraging results in a Phase I/II study, apoptosis company Cell Pathways Inc. has begun a multinational Phase III trial of its lead drug, FGN-1, as preventative therapy for precancerous colon polyps in patients with adenomatous polyposis coli (APC).

The double-blinded, placebo-controlled trial will take place at six centers in the U.S., and three in Europe and will include 150 APC patients with subtotal colectomies (partial removal of the colon), who will receive a daily dose of 600 mg of drug or placebo for one year.

Placebo patients are expected to continue to produce new polyps; in fact, from the trial's baseline (removal of all polyps), these patients will on average develop 120 percent more new polyps over the course of a year.

At six months, patients on FGN-1, a small molecule, and on placebo will have any new polyps that have developed removed. The endpoint of the trial is to demonstrate FGN-1 significantly reduces, both statistically and clinically, the development of new polyps in the drug-treated group as compared to placebo.

Cell Pathways, of West Conshohocken, Pa., develops therapeutics that have the potential to arrest or reverse carcinogenes, by selectively augmenting the rate of apoptosis in premalignant cells.

Colon polyps are often precursors to colorectal cancers. Patients with APC, a relatively rare inherited disease, form large numbers of colon polyps and face a high risk of colon cancer at an early age.

Approximately 25,000 to 50,000 individuals in the U.S. suffer from APC, with a similar incidence of disease in Europe and Japan.

Colon polyps also occur sporadically, but repeatedly, in a large portion of the general U.S. population. As these lesions are known to precede the development of cancer, sporadic polyp formers also provide a focus for future clinical studies with FGN-1.

"The main treatment for this disease [APC] has been surgical," said Rifat Pamukcu, vice president of research and development and chief scientific officer at Cell Pathways. FGN-1 causes the regression, and prevents development, of polyps, Pamukcu explained, by inducing apoptosis (programmed cell death) selectively in the polyps, but not in normal tissue.

Cell Pathways believes FGN-1 targets the precancerous cells due to an intracellular target that has yet to be described and is currently being investigated by the company. Pamukcu said there is a malfunction in the target that prevents neoplastic cells from undergoing cell suicide or apoptosis. "What our drugs do is correct that problem, so the cells can commit suicide," Pamukcu said.

Preliminary six-month data from the first two-dose groups (200 or 400 mg FGN-1 taken orally twice a day) in the Phase I/II trial of FGN-1 in patients with APC demonstrated regression of small polyps in 11 of 12 patients.

Larger polyps did not appear to be affected at the end of six months, although affects on the larger polyps have been seen beyond six months, Pamukcu said.

Investigators measured significantly higher rates of apoptosis in biopsies taken from the regressed polyps compared to polyp biopsies taken prior to drug treatment.

Similarly, apoptosis rates in regressed polyps were significantly higher than the apoptosis rates exhibited by normal mucosal cells (which remained unchanged throughout treatment), demonstrating the selective activity of FGN-1 on abnormally growing cells.

Patients in the trial experienced no significant adverse events and all participating in the study continued treatment with FGN-1 on an extension study.

FGN-1 is Cell Pathways' only product in the clinic. However, Pamukcu said, the company has 400 more compounds, "much more active than the current one in the clinic, in vitro and some have given positive activity in the animal model stage."

Cell Pathways also expects to initiate clinical trials this year in the treatment of cervical dysplasia (a precancerous condition that can lead to cervical cancer) and the prevention of tumor recurrence in prostate and breast cancer. *