By Randall Osborne

After an up-and-down ride with its lead drug candidate, pramlintide for diabetes, Amylin Pharmaceuticals Inc. plans to extend the duration or add patients to all four of its ongoing Phase III studies, a move that is expected to delay by 12 to 18 months the filing of a new drug application with the FDA.

In October, after partner Johnson & Johnson provided a $30.6 million loan to move ahead with pramlintide, Amylin said it expected regulatory approval of the drug in the second half of 1999. That amount is part of $57 million available to Amylin in loans from Johnson & Johnson, of New Brunswick, N.J., as part of their agreement. (See BioWorld Today, Oct. 2, 1997, p. 1.)

Amylin, of San Diego, announced in August results from the first two of its six Phase III trials of pramlintide, a synthetic analogue of the human hormone amylin, which is deficient in diabetes patients who use insulin. By replacing amylin, scientists hope to improve metabolic control for insulin-using diabetics without increasing hypoglycemia and weight gain.

Data from the first two trials, for Type I and Type II diabetes, showed a mixed outcome. The Type I study of 477 patients over a 12-month period showed pramlintide's intent-to-treat effects on lowering blood glucose and improving weight and cholesterol profiles were statistically significant.

However, in the Type II study of 539 patients, glucose was lowered on an intent-to-treat basis in two of the three pramlintide groups to a statistically significant degree after six months, but not after 12 months. Though Amylin characterized the August news in Type I as "positive" and in Type II as "encouraging," Amylin's stock (NASDAQ:AMLN) dropped 43 percent when the news broke. (See BioWorld Today, August 19, 1997, p. 1.)

A year before, Amylin had won a vote of confidence from its collaborator, Johnson & Johnson, which agreed to pay Amylin $7 million for meeting its first pramlintide milestone. Johnson & Johnson also committed another $15 million in equity payments. (See BioWorld Today, Aug. 8, 1996, p. 1.)

Delays Have Little Effect On Stock

On Wednesday, after Amylin made known its changes to the four remaining Phase III trials, the company's stock closed at $7.875, down $0.875. On Thursday, the closing price was $8.062, up $0.187.

"We have a nice, clear route mapped out," said Richard Krawiec, director of corporate communications for Amylin.

"There's a trade-off between risk and time," he said. "We've decreased the risk, and enhanced the probability of a favorable regulatory submission, in trade for a little more time. That's something Wall Street understands."

As a result of the changes in the four ongoing trials, the study of Type I diabetes in the U.S. will add 80 patients, bringing its total to 480, and will finish in the second half of 1999 rather than the second half of 1998. The Type II diabetes trial in the U.S. will add no patients, staying at 600, but will be delayed according to the same schedule.

In the European studies, the Type I trial will add 80 patients, bringing the total to 480, and the Type II will add none, staying at 400. Both will finish in the fourth quarter of 1998 rather than the second half of that year, as originally was planned.

"Those are really on track," Krawiec said.

Other Trials Ahead Of Schedule

Amylin also will accelerate the start of two other Phase III trials that may back up the results from the ongoing four, Krawiec said. The two clinical-practice trials will explore ways to use insulin and pramlintide together.

"If these are useful, especially if they provide labeling information, then we'll use them," he said. "The four paradigm studies will really form the core of the submission [to the FDA for a new drug application]."

Part of the delay in finishing those four trials involves stabilizing patients' insulin therapy to more accurately measure pramlintide's effect, Krawiec said.

"The patients now must have stable insulin [dosages] for three months; if they don't, they never get on the trial," he said. In the studies from which Phase III results were announced in August, eligible patients' insulin levels needed to be stable for only a week.

"We had a baseline that was changing, and we think we've designed the right experiments," Krawiec said. "That's been part of the stock rebound."

Changing baseline or not, 75 percent of the patients who finished the trials that generated the August data said they wanted to continue with pramlintide, which they must inject separately from insulin, at least as the drug is now being formulated, Krawiec said.

"Phase II insulin-mixing studies have been completed, and more will start up next year," he added. So far, no safety concerns have been found.

Delaying the finish of the Phase III trials has "not as much of a monetary impact as people would think," Krawiec said. "The way the Johnson & Johnson agreement is written, they're already paying half the development costs, and if we increase the budget, they're obligated to loan us the money for the increase, for our 50 percent share."

Krawiec said Johnson & Johnson has invested $155 million in pramlintide. "There's still a ways to go," he said. "We want to do this right." *

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