On schedule, Amylin Pharmaceuticals has submitted a new drug application for the incretin mimetic Byetta LAR (exenatide once weekly) in type 2 diabetes, shortly after shedding 200 sales staff in a bold new restructuring move.

Amylin and partners Lilly and Alkermes announced the submission May 5 and a user fee date is now expected in March 2010.

San Diego-based Amylin had notified investors that it would submit the NDA by the end of the first half of this year and some had not expected this development until June.

"The submission reflects the crossing of a key milestone, and we expect shares of Amylin and Alkermes to be up on the news," wrote J.P. Morgan analyst Cory Kasimov in a May 5 note.

Twice-daily Byetta is approved as an add-on therapy with metformin, a sulfonylurea, or a thiazolidinedione, and an application for a monotherapy indication is long overdue at FDA (¹ Also see "FDA Review Of Byetta Monotherapy Heads Into 2009" - Pink Sheet, 8 December, 2008.).

The new NDA was supported by the 300-patient DURATION-1 trial, comparing the LAR product with Byetta (² Also see "Amylin’s Byetta LAR Lowers Glucose, Weight" - Pink Sheet, 9 June, 2008.). In that study, the once-weekly treatment resulted in statistically significant reductions in A1C compared to twice-daily Byetta. The most commonly reported side effect was nausea, which was typically mild and transient.

But while Byetta LAR has a strong product profile, "significant upside is likely to be capped by multiple risks," particularly the ongoing regulatory uncertainty on the thyroid C-cell cancer signal for human incretin glucagon like peptide-1 drugs, Kasimov noted.

FDA's Endocrinologic and Metabolic Drugs Advisory Committee recently had a split vote on the relevance to humans of C-cell tumors seen in rats and mice with clinically relevant exposure to Novo Nordisk's GLP-1 analog Victoza (liraglutide) (³ Also see "No Victory For Victoza: FDA Panel Splits On Whether Cancer Signal Should Block Approval" - Pink Sheet, 2 April, 2009.).

Differentiating Byetta from Victoza, shadowed by cancer risk

In an interview, Amylin's Senior VP-Research and Development Orville G. Kolterman differentiated Byetta from Victoza. Unlike other GLP-1s, which are metabolized in the body and circulate in the bloodstream, Byetta is removed from the body by the kidneys, he points out.

"I don't think it's fair to view all [GLP-1] molecules as being the same or interchangeable. There may be significant differences," the executive said.

Results from a rat study evaluating cancer risk for Byetta became available in the fourth quarter of 2008 and were immediately submitted to FDA, he said.

The study showed development of c-cell adenomas across a range of exenatide once weekly doses. The incidence of malignant c-cell tumors, or c-cell carcinomas, was statistically significantly increased only in female rats treated with the highest dose in the study, which was 25 to 30 times higher than what would be used in humans. In addition, non-statistically significant, numerical increases in malignant c-cell tumors occurred in males at all doses (two times the dose used in humans). The clinical relevance of these findings remains to be established, the company said.

Byetta's label already includes a warning about C-cell tumor risk and it seems likely that this language would be expanded in a label for the extended release version, he said.

Another part of the application relates to heart safety. All new type 2 diabetes drugs must now satisfy FDA's new cardiovascular safety guidance, which requires inclusion of sicker patients in trials and a meta-analysis ruling out risk (⁴ Also see "FDA’s Diabetes Guidance On CV Risk Will Get First Test With Pending NDAs" - Pink Sheet, 22 December, 2008. p. 25).

The agency has indicated it would accept a meta-analysis of data from Byetta for the LAR application because the active ingredient for both formulations is the same.

Since the product's manufacturing site shifted, drug makers also had to prove comparability of the commercial product to the one used in clinical trials.

Another potential risk for Byetta LAR is the link to pancreatitis (⁵ Also see "Byetta Safety Concerns Could Set Roadblocks Ahead For New GLP-1s" - Pink Sheet, 21 August, 2008.).

Using data from UnitedHealth, Amylin conducted an epidemiology study that showed Byetta does not increase risk of acute pancreatitis compared to other type 2 diabetes medications, but it's unclear whether this has reassured doctors.

Byetta sales have been weak, with prescription trends continuing to be down 15 to 16 percent on a yearly basis, though price increases have partially offset the decline, wrote Leerink Swann analysts Steve Yoo and John Sullivan in a May 5 note.

"Although the rate of decline in prescription growth seems to have stabilized at the mid-teens, we do not yet see a bottom or a return to growth despite recently published literature that suggests there is no increased pancreatitis risk with Byetta therapy," the analysts wrote.

As part of the review process for Byetta as a standalone therapy, the agency has considered the pancreatitis risk in great depth for labeling purposes and this could help speed the LAR application, Kolterman said.

Other factors holding back Byetta sales include the nausea side effect and lack of convenience compared to other drugs on the market, such as Merck's Januvia (sitagliptin).

Amylin slashes sales force after Byetta disappoints

On May 4, Amylin announced it was merging its primary care and specialty sales forces into a single group focused on high-volume prescribers in diabetes and endocrinology. In the process, it will cut 200 jobs, equivalent to 35 percent of the workforce, winding up with a total of 325. The move should save $20 million this year and $45 million in 2010, the company said, though the change will also involve a restructuring charge of from $13 to $15 million.

Last November, Amylin had cut 340 employees and reduced 2009 cash expenses by more than $80 million, in a bid to placate investors concerned about Byetta's lackluster performance (⁶ Also see "Next Chapter In The Amylin Chronicles: Job Cuts, Restructuring" - Pink Sheet, 11 November, 2008.). At the time, the firm vowed to become cash-flow positive by the end of 2010.

Amylin will be spending more time reaching specialists while Lilly will step up its primary care sales activities, according to Amylin spokesperson Alice Izzo.

"The alliance is not changing its total footprint in the marketplace. Amylin's sales force will be more focused in endocrinology and diabetes, but overall we are not changing the support for the brand," she said.

On the news, Cowen analyst Phil Nadeau noted that Byetta continues to struggle.

"With Byetta's sales force being downsized and reorganized, we think it is unlikely there will be a major re-acceleration of scrips anytime soon," he wrote in a May 5 note.

Consequently, Cowen cut its 2009 sales estimate from $689 million to $660 million.

- Emily Hayes (e.hayes@elsevier.com)

Amylin Submits Once-Weekly Byetta After Shedding 200 Sales Reps

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