Staff Writer

There's no shortage of drugs in development to treat cancer, but far fewer compounds are aimed at prevention.

The strategy isn't unheard of: The selective estrogen receptor modulator tamoxifen, now generic, is approved for both the treatment of breast cancer and to reduce the risk of breast cancer in high-risk patients. And a handful of drugs are approved for actinic keratosis, a common skin condition caused by chronic sun exposure that can lead to squamous cell carcinoma.

Jeffrey Jacob, CEO of Cancer Prevention Pharmaceuticals Inc. (CPP), explained that disease prevention has significantly reduced death rates in other indications, such as with the use of statins in cardiovascular disease. Although the approach has not yet become mainstream in oncology, "we want to be like the Lipitor of cancer," Jacob told BioWorld Today.

CPP's Lipitor-for-cancer contender is CPP-1X, a combination of low-dose difluoromethylornithine (DFMO) and sulindac, a nonsteroidal anti-inflammatory drug (NSAID). Jacob explained that DFMO is an irreversible inhibitor of ornithine decarboxylase, an enzyme that synthesizes polyamines. Polyamines prompt adenomas, a type of polyp or benign tumor with the potential to become malignant.

The drug has a long history: DFMO was originally developed as an intravenous treatment for African sleeping sickness, and a topical version is used to treat excessive facial hair in women. ILEX Oncology Inc. (later acquired by Genzyme Corp., now part of Sanofi SA) once studied the drug for cancer prevention, but eventually dropped the program after a Phase III failure in bladder cancer. (See BioWorld Today, Jan. 20, 2004.)

Jacob explained that DFMO isn't viable as a single agent because, although it inhibits the synthesis of polyamines, the molecules are also ingested as part of a normal diet. The addition of the NSAID, however, upregulates metabolism of polyamines already in the system. The combination of breaking down existing polyamines and preventing the formation of new ones is CPP-1X's "special sauce," Jacob explained.

That theory was tested in a National Institutes of Health (NIH) sponsored Phase II/III trial that randomized 375 patients with a history of colorectal polyps to receive either CPP-1X or placebo daily for three years.

Results reported in 2008 showed the drug reduced the risk of a recurrent adenoma by 70 percent – with 41.1 percent of placebo patients experiencing a polyp, compared to 12.3 percent of treated patients. Advanced adenomas, which are most likely to become colon cancer, were reduced by 92 percent.

Those data were enough to get entrepreneur Jacob excited. He joined up with DFMO pioneers Frank Meyskens, director of the Chao Family Comprehensive Cancer Center at University of California, Irvine, and Eugene Gerner, of the University of Arizona, to found CPP. Based in Tucson, the firm licensed intellectual property covering CPP-1X and started talking to the FDA and European Medicines Agency about a regulatory pathway.

What emerged was a plan for a Phase III trial in familial adenomatous polyposis (FAP), a rare genetic disorder. The trial will run up to two years and will focus on FAP-related events such as surgery, duodenal disease cancer and death. Jacob noted that such events are more clinically meaningful than simply a reduction in polyps.

That point is critical, he explained, because Celebrex (celecoxib, Pfizer Inc.) once gained approval for FAP based on polyp reduction, but the lack of clinical benefit failed to sway physicians, and the indication was eventually withdrawn from the drug's label.

In addition to the FAP trial, CPP is planning a Phase III colon cancer prevention trial in cancer survivors or patients with recurrent adenomas.

The three-year study will be cosponsored by the NIH and will seek to replicate the previous successful study. Jacob noted that while a reduction in adenomas will be the primary endpoint for the trial, such an endpoint is standard in colon cancer patients because adenomas found via colonoscopy would have to be surgically removed.

The company also is working on a companion diagnostic and collaborating with the nonprofit Neuroblastoma and Medulloblastoma Translational Research Consortium on a Phase I/II neuroblastoma trial.

The NIH cosponsored trial is slated to start in the fourth quarter, but Jacob said CPP likely won't start the FAP trial until it closes a round of financing or secures a partner.

CPP has thus far been largely founder funded. The company recently closed a bridge financing round, with the help of investment bank Geller Biopharm, raising an undisclosed amount of money from angel investors and Arizona's Translational Accelerator fund, managed by former ILEX leaders Richard Love and Daniel von Hoff. Jacob said the plan is to raise $20 million to $25 million in equity next, but he noted that CPP also is evaluating partnering options.

Jacob predicted that either the financing or partnership would close by the end of the year, but he noted that the bridge financing gives CPP sufficient cash reserves to carry it into early 2012, just in case.