Cell Pathways Demonstrates Chemopreventive Activity of FGN-1 In Model Of Colon Carcinogenesis.

WEST CONSHOHOCKEN, Pa.--(BUSINESS WIRE)--July 14, 1997--An orally active investigational drug called FGN-1 (sulindac sulfone) under development by Cell Pathways, Inc. shows chemopreventive activity against colon cancer, according to a new publication in the July 15 issue of Cancer Research.

The publication describes research showing that FGN-1 treatment produces a dose-dependent reduction in colon tumor incidence, tumor multiplicity and tumor burden in an animal model of carcinogenesis. Moreover, FGN-1 achieves its chemopreventive effects without inhibiting prostaglandin synthesis, thus potentially avoiding the gastrointestinal toxicities associated with non-steroidal anti-inflammatory drugs (NSAIDs).

Rifat Pamukcu, M.D., vice president of research and development and chief scientific officer of Cell Pathways commented, "Epidemiological studies suggest that aspirin and other NSAIDs have protective effects against colorectal cancer. Certain NSAIDs, such as sulindac, also have known chemopreventive activity against precancerous colonic polyps. However aspirin and other NSAIDs inhibit prostaglandin synthesis, leading to gastrointestinal and renal (kidney) toxicities that limit these drugs' usefulness for long-term chemopreventive therapy. In contrast, FGN-1 exhibits the chemopreventive properties of NSAIDs without their undesirable effects on prostaglandin synthesis, and thus may hold a safety advantage over NSAIDs for chronic use."

The researchers studied the effect of three dose levels of FGN-1 (500, 1000, and 2000 ppm) on tumor formation and prostaglandin levels when added to the diets of rats injected with a potent carcinogenic agent to induce colon cancer. Rats fed with the NSAID drugs sulindac and piroxicam served as positive controls, and an additional group of rats received no chemopreventive drugs. After 31 weeks of treatment, the rats receiving FGN-1 at 1000 and 2000 ppm, sulindac and piroxicam had significantly fewer colonic adenomas and carcinomas compared with rats fed a control diet, as measured by tumor incidence, multiplicity and tumor burden. The FGN-1 treated rats also showed a dose-response relationship for tumor inhibition. Prostaglandin levels were significantly depressed (ranging from approximately 16 to 40 percent of control levels) in the colons of rats treated with sulindac or piroxicam, while levels of that hormone remained essentially unchanged compared to controls in rats receiving FGN-1. Moreover, in the FGN-1 treated animals, the researchers saw no significant inhibitory effects on various enzymes responsible for regulating prostaglandin levels.

In addition to FGN-1's chemopreventive activity on the formation of colorectal tumors, the compound has demonstrated significant dose-dependent inhibitory effects in animal models on the growth of chemically induced lung and mammary cancers. FGN-1 has also shown activity in augmenting apoptosis (programmed cell death) in a significant number of clinically important tumor cell lines (including colon, cervical, prostate, skin, lung, breast, etc.).

Cell Pathways is currently conducting Phase III clinical trials of FGN-1 for the prevention of precancerous colon polyps in patients with adenomatous polyposis coli (APC), a disease where patients form large numbers of colon polyps and face a high risk of colon cancer at an early age. In a previous Phase I/II clinical trial, patients treated with FGN-1 experienced regression in their polyps after six months of therapy. At the expected clinical dose, investigators saw no clinically significant adverse events as a result of treatment. Patients participating in the Phase I/II study have continued treatment with FGN-1 on an extension study, most for over one year.

The company expects to begin a pivotal trial during 1997 in individuals who form precancerous colon polyps sporadically, but repeatedly, thus placing them at a higher than normal risk of colon cancer. Cell Pathways also plans to initiate clinical trials in other precancerous conditions including cervical dysplasia (a precancerous condition that can lead to cervical cancer) and the prevention of tumor recurrence in prostate and breast cancer.

Cell Pathways has demonstrated that FGN-1 achieves its chemoprotective effects by augmenting apoptosis in abnormally growing cells through a mechanism of action that is separate and fundamentally different from the cell cycle pathways targeted by most chemotherapeutic drugs. In a study published in the June 15 issue of Cancer Research, company scientists and their collaborators showed that FGN-1 increases apoptosis in both proliferating and non-proliferating tumor cells without arresting the normal cycle of cell division or altering the cells expression of the p53 tumor suppressor gene. In addition, the researchers demonstrated that FGN-1 induces apoptosis in cell lines lacking a functional p53 protein. In contrast, cell cycle arrest and inhibition of rapidly proliferating cell populations are hallmarks of efficacy for most chemotherapeutic drugs, as well as their toxicity to tissue that have rapid rates of cell turnover.

"We are extremely excited about Cell Pathways' discovery of a previously unknown apoptosis pathway," commented Dr. Pamukcu. "This discovery may enable the development of a new class of selective and less toxic chemotherapeutic agents for treating cancer and preventing its recurrence with chronic therapy."

Cell Pathways, Inc. is a privately held company engaged in the development of pharmaceuticals that selectively induce apoptosis, or "programmed" cell death, in abnormally growing cells. The company's product development addresses three potential market opportunities: the treatment and prevention of precancerous lesions that would otherwise progress to cancer; the treatment of cancer itself; and the treatment of other diseases associated with excessive cell growth. Cell Pathways is headquartered in West Conshohocken, Pennsylvania, a suburb of Philadelphia.

CONTACT: Cell Pathways, Inc.

Rifat Pamukcu, 610/941-2929

or

J. Kureczka Associates

Joan Kureczka/Jesse Fisher, 415/821-2413