Second Chances for Shelved Compounds

Reexamining once-promising agents for new targets brings benefits and challenges

Only about 1 in 5 agents tested in phase I oncology trials eventually pass muster with the U.S. Food and Drug Administration (FDA). Today, as they face expiring patents on blockbuster drugs, tightened R&D budgets, and narrowing drug development pipelines, pharmaceutical companies are increasingly looking to see if compounds that failed or were shelved might have other uses.

Rescuing undeveloped compounds or finding a new use for a developed drug isn't unheard of. Thalidomide, used as an antiemetic and sedative until it was linked to birth defects and banned in 1961, was later found to have antitumor properties. Going by the brand name Thalomid (Celgene), the drug was approved in 2006 to treat multiple myeloma.

However, rescuing compounds and repurposing drugs comes with challenges—namely, who owns the patent and how much “life” is left in it.

“You can't use the drug without permission of the original inventor while it's on patent; once it's off patent, doctors can use the generic,” explains Mason Freeman, MD, director of the Translational Medicine Group at Massachusetts General Hospital in Boston, MA. “Who's going to pay for development if there isn't a patent in place?”

For shelved compounds, patent life becomes an issue. Even if an agent receives FDA approval, a company might not have a lot of time to promote it and recoup its investment before a generic could enter the marketplace. That can make companies leery about developing them.

“Unfortunately, that's the sad reality,” agrees Joel Dudley, PhD, director of biomedical informatics at the Icahn Institute for Genomics and Multiscale Biology and assistant professor of genetics and genomic sciences at Mt. Sinai Medical Center in New York, NY.

Freeman and Dudley note, however, that a shelved compound or an approved drug with limited patent life might attract interest if researchers find a better way to deliver the agent or alter its formulation, creating new, patentable intellectual property (IP).

To help minimize any financial risk and advance potential therapies, collaborative efforts are taking off. Last spring, NIH's National Center for Advancing Translational Sciences (NCATS) unveiled the pilot Therapeutics Discovery program, which connects academic researchers with industry in an effort to find uses for partially developed compounds. Eight companies—AbbVie (formerly Abbott), AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, and Sanofi—signed on, making 58 total compounds available to researchers. All of the compounds have cleared key steps in the development process but aren't FDA approved, explains Christine Colvis, PhD, director of the Therapeutics Discovery program.

With template agreements for IP rights in place, “investigators will be able to take advantage of all the work that pharma has already done,” says Colvis, adding that the compounds have been in development for 6 or 7 years, on average.

Interested scientists submitted grant applications to NCATS, which plans to award approximately $20 million this month to fund 6 to 8 research projects.

Pharmaceutical giant Roche is taking a different approach. In November, the company partnered with the Broad Institute in Cambridge, MA, to screen more than 300 Roche compounds against the Broad's repository of disease “signatures” and patient profiles. Originally developed for cancer and a variety of other indications, the compounds failed to meet critical phase II milestones or were halted for business reasons.

“With complex biology and compensating pathways, the original hypothesis could be completely wrong,” explains Karen Lackey, PhD, head of medicinal chemistry at Roche. “If you've put all this energy into creating a safe, target-directed clinical asset, it's reasonable to be more open with the hypothesis and see if that target is important in a different disease. Let the science tell you what to try.”

What intrigues Dudley most about rescuing compounds and finding new uses for drugs is that the research can lead to unexpected findings. Using bioinformatics approaches to analyze patient records as well as the expression and regulation of genes and proteins “may reveal some nonobvious therapeutic mechanism,” he says.

With researchers at Stanford University in Palo Alto, CA, Dudley's lab has been studying the off-patent antidepressant imipramine, which seems effective against small cell lung cancer (SCLC). During subsequent in vitro and animal studies to test the drug against neuroendocrine tumors, they discovered that it hit a pathway not previously recognized in SCLC.

“You can take what you learn from one disease to develop drugs for another,” says Dudley. “That's what makes this work exciting.” –Suzanne Rose

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.