A drug's journey from idea to reality

The biotechnology start-up he had cofounded and built into a publicly traded company was spiraling out of his control. His older brother, Manny, an inspiration and business partner, was fighting leukemia that would soon take his life. And the FDA had just shot down the diabetes drug he'd been working on for two decades.

But Cincotta wouldn't give up on the dream he'd been pursuing since he was a 21-year-old graduate student, working on Syrian hamsters. Intrigued by how the animals slip from their lean summer condition into a fat, nearly prediabetic state before their winter hibernation, he had found a way to tinker with their brain chemistry and effectively reset their metabolism. Cincotta was certain that he had discovered something big, and he wondered: Could he do the same thing in people?

That work "set my mindset of trying to pursue this, at all costs, forever," Cincotta said.

Late Tuesday afternoon - 28 years to the day after he began those intriguing experiments in hamsters - Cincotta's dogged persistence was rewarded. The Food and Drug Administration approved his drug to treat type 2 diabetes, in combination with exercise and diet.

The medicine's winding, years-long path to approval is in many ways a typical story in drug development. Even products based on the best of ideas might be abandoned as development costs soar and experiments falter. It takes a dedicated, driven team, and often luck, to succeed.

"The bottom line in cases where you have small companies that are entrepreneurial in nature, is, typically, it takes one person with a tremendous amount of commitment and, one might say, a 'never-say-die' attitude," said Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development.

Cincotta's tiny company, VeroScience, still faces major challenges: It must find a marketing partner, and there are already many other diabetes drugs on the market, including some that diabetes specialists say are superior.

VeroScience's drug, Cycloset, is a new formulation of bromocriptine, already used to treat Parkinson's disease. It lowers blood glucose levels, but Dr. Martin Abrahamson, medical director at the Joslin Diabetes Center, said the drug is not as effective at lowering glucose as other diabetes drugs on the market. He also said that a barrier to the widespread use of the drug might be one of its side effects, nausea, and noted that in a clinical trial of the drug, nearly half of the Cycloset-treated patients stopped taking the medication early.

Doctors involved in the clinical studies, which included a yearlong, 3,000-patient trial, agreed there are other diabetes drugs that are more potent, but they said Cycloset has benefits, such as no increased risk of any cardiovascular problems.

"It represents, in my opinion, a novel approach to treating diabetes," said Dr. J. Michael Gaziano, a cardiologist at Brigham and Women's Hospital and in the VA Boston Healthcare System, who led the 3,000-patient safety trial. What's new, he said, is "thinking about diabetes as a disease that has a central neurologic component to it."

After devising that idea at Louisiana State University with his adviser, Albert Meier, Cincotta finished his graduate work and moved to Massachusetts General Hospital before leaving in the early 1990s to work full time at Ergo Science Corp., the company he cofounded in the Charlestown Navy Yard to work on the project.

David K. Stone, then a managing director and head of the biotechnology research team at the investment firm Cowen & Co., recalled meeting Cincotta then, while scouting for companies to take public. In 1995, Ergo Science raised $23 million in its initial offering. Later, it raised an additional $32 million in a second offering, and $20 million in a licensing and investment agreement with Johnson & Johnson.

In 1997, Ergo Science Corp. filed a new drug application with the FDA. Things moved along steadily until an advisory panel unanimously recommended against approving the drug, and the FDA rejected it in 1998 because of concerns that the risks outweighed the drug's benefits.

Cincotta was crushed, but, with a small team, decided to appeal the decision, even as the company was moving toward abandoning the drug.

The FDA then changed its position, telling the company that it could resubmit the drug for approval, but only after a large and expensive safety study. Ergo Science decided to sell the drug.

"What often happens is a drug looks OK, but not great, and you need to go on and do more studies, larger studies," Stone said. "If either investors or corporate partners decide they don't want to try again . . . as a small, money-losing biotech company you don't always get a second chance."

Eventually, Ergo Science sold the drug to Pliva, a company in Croatia. Cincotta worked on raising money to run the large clinical trial required by the FDA, founded VeroScience in the meantime, and finally bought the drug back.

It's hard to say when the drug will make it to market. Steve Yoo, a research associate at the New York offices of investment bank Leerink Swann, said the drug will enter a field where many therapies and many classes of drugs already exist. He, like many others interviewed, had not previously heard of VeroScience or its drug. He noted that not every drug that gets approved makes it big. Exubera, for example, an inhalable insulin marketed by Pfizer, was approved among much excitement, but it never caught on.

Cincotta is charging ahead. While searching for a marketing partner, he is hatching plans to investigate the mechanism of Cycloset, which is unknown, and to do more studies.

"Did I think it would take 30 years to get . . . to where we are today?" Cincotta said, thinking back to his graduate school days, when he thought bringing the drug to market wouldn't take long.

"I was ultra, ultra naïve at that point. I was a kid. It took a lot longer than just a few years."

Carolyn Y. Johnson can be reached at cjohnson@globe.com.