By Jim Shrine

Special To BioWorld Today

Amylin Pharmaceuticals Inc.'s stock toppled 77 percent after the company disclosed results from two European/Canadian Phase III studies in which its diabetes drug, pramlintide, failed to show statistically significant results.

Last August, San Diego-based Amylin reported data from other Phase III trials that ended with similarly mixed outcomes.

"I think it's time to recognize the fact that this is not going to work," said William Tanner, an analyst with Vector Securities International Inc., in Deerfield, Ill. "There are no data out there that would suggest pramlintide will be a drug. I don't believe they are being entirely forthright in acknowledging that."

Amylin's shares (NASDAQ:AMLN) closed Wednesday at $0.69, down $2.25. The stock was nearly $15 last August, when the other pramlintide data were disclosed and the share price dropped below $8.50. (See BioWorld Today, Aug. 19, 1997, p. 1.)

Along with the Phase III data, the company reported third-quarter financial results showing a net loss of $16 million for the quarter and $25 million in cash on hand.

Amylin has cut its work force 75 percent — from about 190 employees to 45 — in order to reduce the burn rate and get the company into mid-1999, when it expects results from two more Phase III trials of pramlintide, ongoing in the U.S.

Richard Krawiec, Amylin spokesman, said two dosing arms in the Type I study and one in Type II diabetics in the most recent studies did achieve statistical significance in reducing average blood glucose. However, he said, statistical analysis methods required that the dose selected for regulatory purposes — 90 micrograms, three times per day — show statistical significance, and the drugs failed in both studies.

But the arms that showed significance in the six-month European trial are being replicated in the ongoing one-year trial, Krawiec said.

Analyst Skeptical Of Continued Push For Approval

"Outside experts tell us [that], when we analyze these data around the middle of next year, if those arms confirm the response of statistical significance we saw in the six-month study, we would have a fileable package for regulatory authorities in the U.S. and Europe," Krawiec told BioWorld Today.

Tanner said Amylin's move to continue development of pramlintide "typifies the arrogance we're seeing in the biotechnology industry. I don't believe they can resurrect this drug with the last two [ongoing U.S.] studies."

Even if the data from those studies are encouraging, they probably would not be enough to support approval, said Tanner, who has dropped coverage of Amylin.

The company began clinical development of pramlintide, a synthetic analogue of the hormone amylin, in 1993. Amylin replacement therapy is designed to help insulin-using diabetics improve metabolic control without increasing hypoglycemia and weight gain.

The six-month European studies in Type I and II diabetes each had three dosing arms plus the placebo arm. In the Type I study, 90 micrograms were given three times per day, 60 micrograms three times per day or 90 micrograms twice daily. In the Type II study, the dosage arms consisted of 90 micrograms three times daily, 90 micrograms twice daily and 120 micrograms twice daily.

In both studies, statistically significant weight loss was seen in the treated groups. The drug was not well tolerated in the 90-microgram arms of the Type I study, however, because of nausea and higher hypoglycemia.

There are four arms in each of the two ongoing U.S. studies also, and they total about 900 patients. Krawiec said all patients have been enrolled. "If we can confirm the statistically significant arms of the study we reported [most recently], that could provide the basis for a regulatory filing," he said, adding that the method of analysis has not been decided.

J&J Spent $175M Before Abandoning Project

Former development partner Johnson & Johnson (J&J), of New Brunswick, N.J., gave six months' notice in March that it was pulling out of the 1995 pramlintide collaboration. Amylin has received about $175 million from that collaboration, Krawiec said, and owes J&J $36 million from a loan. (See BioWorld Today, March 3, 1998, p. 1.)

Terms of the loan call for payback based on sales after pramlintide is approved. If the drug does not reach market, the loan is secured by certain Amylin patents, Krawiec said.

Tanner said the accumulated deficit for Amylin's pramlintide development is about $250 million. "They have more debt than cash, basically no leverage to strike a deal with a corporate partner, and a product most will see as damaged goods," he said.

Krawiec, however, said trial results have shown pramlintide "has a strong effect for approximately one-third of the patients. For those patients and others, it is important we continue development of this drug. We are working to refine those patients who would potentially benefit the most, and now we have more information on the appropriate range of doses."

Amylin also has completed Phase I studies of the diabetes drug AC2993, an exendin-4 peptide, and plans to start Phase II studies early next year. Krawiec said results are expected by about mid-1999. *