Long Island scientists work to repurpose old medicines for new uses

As U.S. drug regulators were announcing approval of the first multimillion-dollar medication last month, dozens of medical scientists on Long Island and beyond were quietly working on ways of repurposing old medicines into effective new uses. 

Familiar medications, forgotten ones and those shelved because newer versions pushed them out of favor are poised for new roles in the treatment of an array of medical disorders, including cancer, heart conditions and infectious diseases. Some compounds under consideration for repurposing cost only pennies per dose.

“The repurposing of drugs opens new possibilities for medications that are effective and cost-effective,” said Dr. John Haley, a pathologist at Stony Brook University School of Medicine, who is working on a collaborative project to turn a shelved diabetes drug into a new treatment for colon cancer.

“This drug never had a name. It’s an abandoned drug,” Haley said of the medication that was developed years ago by pharmaceutical giant Roche. The company turned away from the drug when it didn’t seem to work efficiently against type 2 diabetes.

But Haley said those corporate misgivings were not a concern to him and his colleagues. Even though Roche gave up on the drug, Stony Brook scientists are studying the medication’s chemical structure because they see how it can be transformed into a potent anti-cancer drug. Haley and his colleagues have had encouraging laboratory results even as they foresee years of work ahead.

“We are changing the drug slightly,” Haley said of tweaking the medication’s chemical backbone, honing it to have more precision against cancer cells.

Haley emphasized that not all repurposing   emerges from carefully designed studies such as his. Some repurposed medications come from “happy accidents.”

“Sometimes people are looking for one thing and stumble upon something else — serendipity,” Haley said. “If you think about all of the variables and all of the different drugs and chemical compounds that are out there — Pfizer alone has about 2 million compounds — being lucky turns out to be very important.”

One of the most dramatic comebacks for an abandoned drug involves the antibiotic sirolimus, which was shelved in the 1970s because it didn’t effectively kill bacteria. Sirolimus since has been repurposed multiple times. It’s now the coating on coronary stents, the tiny mesh-like tubes that prop open blood vessels once clogged with plaque. The drug prevents the re-buildup of vascular gunk.

Sirolimus also has been repurposed into an anti-rejection drug for people who’ve undergone organ transplants, and additionally is now a treatment for a rare lung disease called lymphangioleiomyomatosis. 

Dr. Francis Collins, director of the National Institutes of Health — and a longtime proponent of drug repurposing — helped establish the National Center for Advancing Translational Sciences, which cast a spotlight on repurposing with the center's launch in 2011. Collins estimates that medical science has definitive data on the molecular underpinnings of 4,000 diseases, but only a mere 6 percent of those disorders have safe and effective drugs to treat them. Numerous researchers are trying to change that imbalance and, like Collins, believe an answer exists in repurposing.

The National Center for Advancing Translational Sciences maintains the NCATS Pharmaceutical Collection, which includes vast catalogs of already-approved medications from which scientists can choose compounds to conduct drug-screening studies.

The search for effective new drugs from the chemistry of old ones arrives in the shadow of the U.S. Food Drug Administration’s approval in May of Zolgensma, a gene therapy infusion that is given once, and is the world's first multimillion-dollar drug. The cost: $2.1 million for the single dose. 

The cutting-edge treatment is for a rare genetic disorder in infants called spinal muscular atrophy, and is a product of AveXis, a division of Novartis. Zolgensma isn't even the first drug developed to treat the disorder. Dr. Adrian Krainer of Cold Spring Harbor Laboratory and colleagues pioneered Spinraza, marketed by Biogen Inc. It was approved in 2016. The cost isn't cheap: $750,000 for the first infusion and roughly half that for subsequent doses.

Doctors involved in repurposing research believe it’s possible to provide new treatments for rare and common medical conditions without blockbuster price tags.

Dr. Sharon Nachman, chief of pediatric infectious diseases at Stony Brook Hospital, has directed her attention on a nearly forgotten leprosy drug known as clofazimine.

Leprosy, a biblical horror that raged for centuries, still lurks in the United States, although rarely. About 100 cases are diagnosed annually, according to data from the Centers for Disease Control and Prevention. The agency has found that most cases of the bacterial infection are seen in Southern states.

Nachman, however, isn’t interested in clofazimine for leprosy. She wants to repurpose it as a treatment for pediatric drug-resistant tuberculosis in underdeveloped countries. In Africa and other parts of the developing world, multidrug resistant TB has become a public health nightmare. Stubborn bacteria have learned to outfox almost every medication in doctors’ arsenals.

“This drug is old, old, old. We’re talking 50 years old,” Nachman said of clofazimine, an antibiotic. Despite its age, it’s new to TB bacteria.

“Leprosy is a cousin to TB. They’re both slow-growing. So the idea is: Let’s take this off the shelf and test it for safety and efficacy,” said Nachman, who is allied with IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trial Network.

She wants to ensure that clofazimine is safe for children with TB. The drug had been used successfully in multidrug therapy for leprosy, Mycobacterium leprae, and ultimately could prove to be an important addition for pediatric patients with TB, Mycobacterium tuberculosis.

Drug resistance is a major global health concern, and doctors have turned to other shelved antibiotics from long ago to address the escalating problem of multidrug-resistant bacteria.

At Cold Spring Harbor Laboratory, Professor Lloyd Trotman, an expert in prostate cancer, especially the form of the disease that lacks the tumor-suppressing protein called PTEN, has discovered a secret about the malignancy: When prostate tumor cells without PTEN are exposed to the type 2 diabetes drug metformin or compounds similar to it, the cancer cells die.

Metformin, a pennies-per-dose medication, has been examined by other tumor biologists because of its ability to act as a powerful anti-cancer agent. At the annual meeting of the American Society of Clinical Oncology earlier this month, Canadian doctors presented evidence that showed how metformin effectively treated non-small lung cancer.  

“It’s essentially our understanding of the drug’s target that’s evolving and changing,” Trotman said of cancers in general. The more that is learned about the molecular roots of a cancer, the easier it is to think outside the box about potential new treatments, he said.

Dr. Gerald Bernstein, an endocrinologist and coordinator of the Friedman Diabetes Program at Lenox Hill Hospital in Manhattan, said metformin probably works against cancer for many of the same reasons that it controls diabetes.

“The main thing that it does is interfere with the excess production of glucose by the liver,” Bernstein said, noting that cancer cells thrive on glucose — sugar — and reducing it removes fuel for cancer cell growth. He said studies also have found it to be effective against some forms of breast cancer.

“It is a great drug. And yes, I take it myself,” said Bernstein, who has type 2 diabetes.

He noted that most patients who are prescribed metformin, which is sold under the brand name Glucophage, take the generic form, which costs about $4 for 60 tablets at prescription discounters such as Walmart. Metformin could help usher in an era of low-cost cancer treatment, Bernstein said.