FDA's "complete response" letter for Byetta LAR (proposed brand name is now Bydureon ) doesn't lay out major requirements from Amylin, which announced the letter March 15, and the drug's approval and launch by year-end appear likely, analysts say.

The adult onset type 2 diabetes drug is a long-acting version of Amylin's already marketed GLP-1, Byetta (exenatide), designed to overcome some of the flaws in that first-generation drug, which have hampered its sales.

FDA issued the "complete response" letter for Bydureon late on March 12, its PDUFA date, though Amylin did not publicize the release until March 15.

The letter addresses issues with final product labeling and the related REMS (Risk Evaluation and Mitigation Strategy) and seeks to clarify "existing manufacturing processes," Amylin said in a press release. These demands appear modest, given that the agency did not request additional pre-clinical or clinical trial data, or further analysis of existing data; nor did it mention the December 2009 483 inspection report associated with Amylin's new Ohio-based manufacturing site, which the agency posted on its Web site on Friday (Also see "Eyes On Byetta LAR: PDUFA Date Passes But Analysts Bet On 2010 Approval" - Pink Sheet, 12 March, 2010.).

Amylin executives discussed FDA's letter with analysts in a follow up conference call on March 15, but didn't elaborate on details of the agency's requests. The company is presenting the letter as a minimal issue, which will not take long to resolve.

The action letter is "a significant step forward" in bringing the drug to market, said Orville Kolterman, Amylin's senior vice president of R&D. "We have a clear path forward and are working diligently to submit our response to the FDA in the next few weeks," he said. Amylin executives said that, although they are still analyzing the letter's demands, they do not expect to have to meet with the FDA to resolve the outstanding issues.

The manufacturing issues raised in the "complete response" letter relate to only to "technical details," the firm clarified. The observations in the 483 report had been previously addressed, the execs said.

The "complete response" is also notable for other things it did not seek, such as more information about the potential link between GLP-1s and medullary thyroid cancer and, separately, the increased incidence of pancreatitis. Amylin plans to submit by March 31 results of a calcitonin screening study (using UnitedHealth's i3 Aperio registory) to assess the relative risk of thyroid cancer among patients using exenatide; calcitonin is a biomarker in humans for thyroid cancer. But Amylin execs said that study wasn't a factor in the letter.

Less clear was whether labeling involving pancreatitis risks was part of the ongoing discussion. Because Bydureon is a line extension of Byetta, and pancreatitis risks for the latter drug are well known, the issue came up on the analysts' call. Still, "There are no new signals," Kolterman told analysts. "Really, it is sort of steady as she goes in that sphere," he said.

A proposed label is going back and forth. The Bydureon REMS would be a distinct program from the REMS from Byetta, though the existing program could lay a framework.

As the letter seems to address only minimal lingering concerns (that the company thinks it can address quickly), Amylin execs said they weren't sure why the agency chose to issue a "complete response" letter, rather than ignore the user fee deadline. But FDA seems determined to keep to its PDUFA timeline and reduce missed deadlines. The agency has already extended Bydureon's action date because of the days closed due to recent unusually severe weather in Washington, D.C.

Or, as some analysts speculated, the use of an action letter instead of a missed deadline could mean there are still some concerns about acute pancreatitis, which is a known issue with Byetta and other drugs acting on the GLP-1 pathway, and which some have worried might be a bigger problem for the long-acting version of the drug--a concern the company sought to defray.

Teasing Out a Timeline for OK: Odds are on Late Fall

Given the nature of the response, analysts do not expect the drug to face more major hurdles to approval, and they began trying to tease out a timeline for the agency's final decision. That timeline now centers on how long it takes Amylin to respond to the agency's requests (the company says it will be a matter of weeks) and whether the full response is categorized as a Class I or Class II resubmission. Despite nudging from analysts, Amylin executives refused to speculate about which designation their filing will be.

The less complex Class I category would entail a two-month review clock after Amylin's response, meaning a potential launch date mid-year. The more complex Class II responses warrant a six-month review period, which would push a final FDA decision to fall at the earliest. To date, the agency has categorized all or nearly all resubmissions with a REMS component as Class II, leading most analysts to speculate that the decision would come in mid-to-late fall, and a launch shortly thereafter.

With that timing, analysts are projecting a range of sales for 2010 and beyond. "We view this as a net positive for Amylin and Alkermes [which makes the drug delivery device used for Bydureon], as an FDA request for additional pre-clinical or clinical work could have delayed the LAR launch by at least six months," wrote Lazard Capital Markets analyst Terence Flynn, who as of March 15 moved out his estimate that LAR would launch in the third quarter of 2010 to the fourth quarter. As a result, he reduced his 2010 LAR U.S. sales estimate to $54 million from $138 million, but maintained his 2011-2012 estimates of $440 million and $650 million, respectively.

Amylin's future rides on the success of Bydureon, which addresses some of the problems inherent in Byetta. Amylin, along with partner Eli Lilly, had high hopes for Byetta when it launched in 2005, as the first in a new class of drugs which could offer type 2 diabetics better control over blood glucose levels, while helping them to better control their weight even as most of the standard therapies for type 2 diabetics led to weight gain. Byetta hasn't lived up to its promise, however, and Amylin is hoping that Bydureon's formulation will eliminate some of Byetta's off-putting side effects, such as nausea and the inconvenient dosing.

Good news is in the eye of the beholder, and the Bydureon "complete response" letter was a positive for Amylin/Lilly competitor Novo Nordisk, which launched a competing once-daily GLP-1 analog, Victoza (liraglutide) in the U.S. in mid-February (Also see "FDA Clears Victoza, But Warnings And More Studies Pose Hurdles" - Pink Sheet, 1 February, 2010.). Victoza is currently competing against short-acting Byetta, and eventually will go up against Bydureon, once that drug is approved.

-- Wendy Diller (w.diller@elsevier.com)

FDA's "Complete Response" Letter For Byetta LAR Isn't Too Onerous, Amylin Says

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