Amylin Exenatide NDA Filing Expected Mid-2004; Symlin Launch in Q1

Amylin is eyeing a mid-2004 filing date for its exenatide NDA.

The announcement follows the completion of the final study in Amylin's Phase III program for exenatide (synthetic exendin-4/AC2993) for the treatment of type 2 diabetes in patients who have failed metformin and sulfonylurea.

"The data we collected in this study provides a robust foundation for drafting a label on how to appropriately address initiation and maintenance of exenatide therapy," VP-Clinical Affairs Orville Kolterman, MD, said during a Nov. 25 conference call convened to discuss the study results.

The final Phase III study enrolled 734 patients who had failed both metformin and sulfonylurea. Exenatide patients received 5 micrograms twice a day by subcutaneous injection for one month, followed by six months of either 5 micrograms or 10 micrograms twice daily.

Thirty-four percent of exenatide patients on 10 micrograms completing the trial reduced their hemoglobin A1c levels to less than or equal to 7%. Subjects on the 10 exenatide dose also showed a statistically significant reduction in body weight of about 2 kg. Across the Phase III program, there was an average reduction in glucose levels of 1%.

To evaluate sulfonylurea-related hypoglycemia, patients were also randomized to either maintain their maximally effective dose of sulfonylurea or to reduce their sulfonylurea dose and later titrate the levels to maximize glucose control.

Patients who remained on sulfonylurea upon initiation of exenatide had a 35% incidence of mild to moderate hypoglycemia, versus 15% in the placebo arm. Patients who reduced their sulfonylurea dose prior to exenatide initiation ended the study with a 21% incidence of mild to moderate hypoglycemia, versus 10% for placebo.

The Phase III trial was the third in a series. The first Phase III trial enrolled patients who had failed metformin alone. The results were announced in August. The second pivotal study, completed in November, enrolled patients who had failed sulfonylurea therapy. An open-label continuation study is underway.

Lilly is collaborating with Amylin on exenatide. Lilly paid $80 mil. up-front and purchased $30 mil. in equity in September 2002. The agreement also called for up to $215 mil. in milestone payments to Amylin, including a payment expected before the end of this year (¹ 'The Pink Sheet' Sept. 23, 2002, In Brief).

Amylin will file the NDA in the U.S.; Lilly is responsible for overseas regulatory submissions. The companies will split U.S. profits.

Amylin CEO Ginger Graham declined to discuss the Phase III study results in detail, but said she believes it is unlikely that further studies will be necessary to support approval.

"At this point in the development of exenatide we can say that the overall data set significantly reduces the risk to us that there are issues here that are unresolved about this drug from a efficacy and safety standpoint," Graham said.

"The body of work that must be done" prior to submission "is very substantial," she said. Amylin is "working night and day" putting together "a document that could fill an 18-wheeler," although "we hope to be able to submit that electronically."

Amylin is awaiting approval of the diabetes agent Symlin (pramlintide). An amendment to the NDA was submitted in June following an "approvable letter" in October 2001. FDA's action letter requested a dose-titration trial (² (Also see "Symlin "approvable" letter" - Pink Sheet, 15 Oct, 2001.), p. 32).

Symlin was originally part of a collaboration with Johnson & Johnson, but J&J withdrew from the deal in 1998.

Graham stressed that the protracted Symlin review was not one the company hoped to repeat with exenatide. "In our prior experience with Symlin...our filing time was longer" than that expected for exenatide. "That's not the goal, so we're not using that as our aspiration."

Amylin expects Symlin approval before the end of the year, with a launch in the first quarter of 2004. "We're just still waiting for approval from the FDA. We're anxious, and everyday someone looks at the fax machine and we keep our fingers crossed," Graham said. FDA's user fee date is Dec. 17 (³ 'The Pink Sheet' June 23, 2003, In Brief).