Assistant Managing Editor

VeroScience LLC emerged from stealth mode Wednesday to report that its lead product Cycloset gained FDA approval, making it the first dopamine agonist for treating Type II diabetes and also the first diabetes drug to get the agency's nod under the new cardiovascular safety guidelines adopted for diabetes drugs last year.

It was big win for Tiverton, R.I.-based VeroScience, which has operated quietly since its founding in 2001. But work on Cycloset goes back much farther, having been started 28 years ago by the company's founder and president, Anthony Cincotta, who first began working on the program as a graduate student at Louisiana State University.

In 1989-90, Cycloset moved into Cincotta's first company, Ergo Science Inc., which developed the program through an approvable letter in 1999, at which time Cincotta left the firm. Two years later, he started up VeroScience, and brought back Cycloset, sharing rights with big pharma firm Pliva. VeroScience later reacquired Pliva's share of the program with the help of small firm S2 Therapeutics Inc., of Bristol, Tenn., which now holds all the marketing rights to Cycloset and has served as the funding source for Cycloset development, Cincotta said.

It's not unusual for drugs to move from company to company during the course of its development. "But what is unique is that I have been associated with [Cycloset] throughout all of its different homes," he told BioWorld Today.

While its mechanism of action has not yet been fully elucidated, and there's "still more work to be done," Cincotta said Cycloset was developed based on the discovery that dopamine activity affects annual metabolic cycles of animals in the wild.

Animals entering annual states of hibernation or migration become obese and insulin-resistant - essentially prediabetic - yet as they move into the next season's cycle, those conditions vanish with no lingering effects, indicating an "endogenous clock in the brain [that regulates] neurochemistry changes as they go throughout the year," he said.

Cincotta and his team mapped out a blueprint of animals' summer and winter cycles and found that the "24-hour activity of dopamine varied between winter animals and summer animals." Further research confirmed that the presence or absence of dopamine could produce or reverse the animals' prediabetic conditions, and similar results were observed in human trials, he said.

Cycloset is designed as a once-daily, quick-release product, to be administered in the morning, as a "single pulse to the body to provide that circadian peak at that time," Cincotta said. "The idea is to copy the way nature returns prediabetic to normal."

In clinical testing, Cycloset clearly improved glycemic control. When taken in the morning, patients showed improved postprandial glucose without increased plasma insulin concentrations and demonstrated beneficial effects on postmeal glycemic control hours after the drug has been cleared from circulation.

Importantly, Cycloset also demonstrated in a 3,000-patient safety trial that it did not increase the risk of adverse outcomes, particularly cardiovascular risks, which gained greater regulatory scrutiny after meta-analysis published in a 2007 issue of the New England Journal of Medicine reported that patients taking Avandia (rosiglitazone), a thiazolidinedione drug marketed by London-based GlaxoSmithKline plc, had a 43 percent greater risk of myocardial infarction than patients receiving other diabetes treatments or placebo.

Those disconcerting data prompted a regulatory panel review and revised FDA guidance calling for stringent cardiovascular safety studies prior to approval of new diabetes drugs. (See BioWorld Today, July 3, 2008, and Dec. 18, 2008.)

Fortunately for VeroScience, the company's clinical program for Cycloset involved a similar safety trial design. When Cycloset was deemed approvable 10 years ago, the agency asked for a safety trial, and "really, the guidance they came out with last year reflected" the trial design already in progress for Cycloset, Cincotta said. "So we were actually ahead of the game here."

Cycloset was cleared as both a monotherapy and as adjunctive therapy to existing drugs such as sulfonylurea and metformin plus sulfonylurea. With about 21 million people in the U.S. suffering from Type II diabetes, Cincotta estimated that as many as two-thirds could be eligible for Cycloset treatment, since a "majority of patients are not in good control" of their disease on existing therapies.

But before they can get the drug to patients, VeroScience and S2 Therapeutics will have to find a global marketing partner. "We hope to do that in a few weeks so we can launch the product as soon as possible," he said.

The companies also are in the process of preparing a European filing.

Cincotta said the firm plans to test Cycloset in prediabetic patients as well, for potential label expansion, and also is interested in pursuing early evidence hinting that the drug could even provide a cardiovascular benefit for diabetics. That research still is in its early days, but data accumulated to date suggested that "further investigation along those lines is warranted," he said.

The potential of cardiovascular improvement is "extremely exciting," he added. "That could end up being a very important contribution to the diabetes drug armamentarium."

Published  May 7, 2009