By Mary Welch

In a long and winding road to a new drug application (NDA) filing, Amylin Pharmaceuticals Inc. finally found the right path as the San Diego-based company said its lead diabetes drug, Symlin (pramlintide acetate), produced a statistically significant lowering of the primary glucose control endpoint in a one-year pivotal trial in Type I diabetes.

A NDA filing is on track for mid-2000 in both Type I and Type II diabetes, the company said.

"The drug certainly has had a checkered past," said Daniel Bradbury, senior vice president of Amylin's corporate development. "But it was a complicated trial involving more than 5,000 people with both Type I and Type II diabetes."

Symlin is a synthetic analogue of the human hormone amylin.

The study showed when Symlin was added to a patient's insulin regimen, the primary glucose control endpoint (glycated hemoglobin; HBAlc) was significantly improved at six months, compared to those who took only insulin. For the Symlin 60 micrograms three times a day group, HbAlc was reduced by 0.3 percent at 6 months, compared to those receiving insulin alone (p=0.008).

HbAlc is the accepted clinical standard for evaluating long-term glucose control. The primary endpoint was change in HbAlc from baseline to six months for the Symlin groups compared with placebo groups.

Those receiving Symlin 60 micrograms four times a day also achieved a significant reduction in HbAlc at six months (p=0.011).

For those who completed a year of therapy on Symlin, an HbAlc reduction was accomplished at 0.4 percent at study end compared to those receiving insulin alone. The results are consistent with those seen in earlier Phase III trials in patients with Type 1 diabetes.

"It's hard to design clinical endpoints that show the drug's affect vs. insulin without freezing the insulin - not giving it to the patients, which is unethical," said Joseph Cook, Amylin's chairman and CEO. "You have to find some way to track the drug and educate people on what the data really suggest. It was really important to find a way to design a trial because these are patients who really have limited options."

In order to produce a viable trial, a "stable insulin" group was predefined as those participants who did not vary their insulin usage by more than 10 percent from baseline. Symlin recipients in this "stable insulin" group achieved a reduction in HbAlc of 0.7 percent at one year compared to placebo recipients.

Other results showed that more than 40 percent of all Symlin recipients were glycemic "responders" vs. 20 percent of the insulin-alone group. In addition, those Symlin takers lost weight compared to the insulin-alone group, who gained weight. Symlin recipients also tended to use less insulin.

"No other drug in Phase III trials has had a glycemic lowering effect on Type I diabetes," Bradbury said.

The company intends to file its marketing applications both in the U.S. and Europe in mid-2000 and also is in the process of showing the positive results to potential licensing partners.

"We're very active on that front at the moment and this data certainly is facilitating talks," Cook said. "Potential partners are understanding the importance of the data as well as the importance the Street is putting on it. Our stock price has risen 1,000 percent in the last year. Of course, it started out at 50 cents!"

Calling Symlin "a biotechnology success story of perseverance and support," Cook maintained the company refused to give up on the drug despite Phase III setbacks and its partner, Johnson & Johnson, of New Brunswick, N.J., backing out of its collaboration. At one point, its stock dropped 77 percent, closing at 69 cents, down $2.25. The stock was nearly $15 in August 1997. Amylin's stock (NASDAQ:AMLN) closed Tuesday at $5.843, up $1.093, or 23 percent. (See BioWorld Today, Aug. 19, 1997, p.1; March 3, 1998, p. 1; and Oct. 22, 1998, p. 1.)

"Our patience worked out for the patients," Cook said. "Persistence has its rewards. Part of what caused us to have the perseverance was that there was a tremendous amount of support from investors and patients, all of whom kept telling us that there's something in the drug. We were encouraged by that."

The company focused on that support even when 75 percent of the staff was cut in order to support the trial costs. Last month the company raised $18.5 million in a private sale of stock to finish the Phase III trials and pay for the regulatory applications. (See BioWorld Today, Oct. 8, 1999, p. 1.)

"The layoffs were the toughest decision and those who stayed with the company had no reason to hang on other than a belief in the drug," Cook said. "We just recovered and focused on getting the trials right. We are proud to have maintained our values. We wanted this drug to help people and help the company be responsive to shareholders."

The company's second drug candidate, AC2993 (synthetic exendin-4), is in Phase II trials for the treatment of Type II diabetes. Results should be available by the end of the year.

"This candidate has been shown to be active in animal models when administered via noninjectable routes," Bradbury said. "One criticism of the company is that we were a one-trick pony. This will be helpful in quieting that."