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New uses for old drugs being sought

Variety of colorful pills arranged in white paper medication cups.Sherry Young - Fotolia

Headache, nausea, diarrhea: Side effects can be nasty.

But a laundry list of adverse reactions can actually give scientists an important clue. It means the drug is potent in many different ways — and could, perhaps, be used to treat a different disease than the manufacturer intended.

This idea is propelling the quiet but important trend of drug repurposing, in which researchers wind back the clock to see if they can coax further use out of a long-approved, and often inexpensive, drug.

Drug repurposing got a black eye recently when Marathon Pharmaceuticals rejiggered a steroid that’s been around for decades and won approval to use it to treat the rare disease Duchenne muscular dystrophy. Marathon priced the drug, which costs just $1,000 a year outside the United States, at $89,000 a year.


Marathon’s actions spurred a public outcry over drug pricing and led to a congressional inquiry.

But plenty of repurposing efforts are still underway.

Why? There are more than 1,500 drugs approved by the Food and Drug Administration. Getting a new one to market can take decades and can cost hundreds of millions of dollars. Finding a new use for an old drug is a whole lot cheaper. The poster child for the practice: sildenafil citrate, a little blue pill developed to treat high blood pressure and chest pain. It turned out to have a delightful side effect — vasodilation of the nether regions — and wound up being the blockbuster Viagra.

“The pessimistic view is that, if you’re taking a drug that interacts with several targets, welcome to the world of side effects and toxicity,” said Stephen Naylor, a health care consultant who’s studied drug repurposing extensively. “The glass-half-full approach, though, is that these other targets are an opportunity for repurposing.”

Small molecule drugs, which make up the vast majority of medicines approved by the FDA, are especially likely to cause side effects — and thus, to be potentially useful against other diseases, Naylor said.


To uncover the possibilities, a team of researchers at Vanderbilt University is probing the genomes of more than 230,000 people to find links between disease and drugs. The program, called the Accelerating Drug Development and Repurposing Incubator, pans through a trove of anonymous clinical and genetic data, looking for rare genetic variants that are known to be linked to disease.

From there, scientists examine which molecular pathways, or proteins, are linked to that particular snippet of DNA. Their goal: to find a drug approved for one disease that might also work on the molecular pathway responsible for a second disease.

The institute has identified 13 existing drugs, most of which are available in generics, that might be smart candidates for repurposing.

Independent scientists say the methodology makes sense: “It’s clear that Mother Nature is the original repurposer — not of drugs, but of pathways, and of genes,” said Dr. Christopher Austin, director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

One example is the drug misoprostol — long used to treat esophageal ulcers and also to terminate pregnancies.

Through genetic analysis, Vanderbilt has found that misoprostol behaves in a similar manner as a gene called PTGER2, which is linked to ulcerative colitis. Vanderbilt is designing a clinical trial to see if the drug can reduce symptoms in patients with ulcerative colitis. And it’s already filed for patent protection for this new indication. That’s way faster than research team members could move if they were developing a drug from scratch.


“We skip so many steps because we have a clue as to what the drug is going to do before you normally would,” said Jill Pulley, executive director of the Vanderbilt Institute of Clinical and Translational Research.

The toughest bit of drug repurposing: There’s little financial incentive for drug companies to explore new uses for drugs that have been developed decades back — unless they are willing to charge sky-high prices and risk stirring public anger.

“If you want to repurpose a generic drug, how are you going to do it with no profit margin?” Austin said. “The NIH can’t afford to throw $50 million, or $100 million, in cash at every one of these problems — even if they’re good ideas.”

When they find a good drug to repurpose, companies typically will reformulate it slightly so they can claim a patent, which in turn will allow them to make a profit.

David Dill, an entrepreneur in the Philadelphia area, is trying to make the system work for him.

His company, Wellesley Pharmaceuticals, is kicking off a clinical trial that tests a pill that combines acetaminophen and ibuprofen to treat nocturia — the urgent need to urinate in the middle of the night. He has secured nine patents on a low-dose, extended release version of the combo pill. Because Advil and Tylenol have long been deemed safe by the FDA, fewer clinical trials are necessary than if he had come across a new molecule in his lab.


“Like most drug discoveries through the centuries, I came across this idea by accident: I was using the drugs for another purpose and realized it had a side effect that was useful,” Dill said. “And then I realized that nobody in the world seemed to know about this.”

Dr. Bruce Bloom is tackling the issue from another angle. He’s building a database — the CureAccelerator — that allows researchers to share ideas on better ways to repurpose drugs.

One of his early successes is with thalidomide, the sedative drug infamously known for causing severe birth defects when taken by pregnant women looking to control their morning sickness.

In 2000, Cures Within Reach — Bloom’s nonprofit — helped fund a Phase 2 trial at the Mayo Clinic that showed thalidomide was effective in treating multiple myeloma. Because the drug had been approved for treating leprosy in 1998, safety trials could be bypassed — and later-stage clinical study forged ahead. It’s now an approved therapy for multiple myeloma.

Bloom, a dentist by training, runs the nonprofit full time and describes himself as a “drug repurposing champion.”

“It’s a faster, cheaper, safer, and more predictable way of driving therapies to patients,” he said.

Meghana Keshavan can be reached at Meghana.Keshavan@statnews.com. Follow Meghana on Twitter @megkesh