SAN FRANCISCO-- Amylin Pharmaceuticals Inc. confirmed that it is awaiting word from FDA regarding a proposed trial design for a cardiac safety study that involves a continuous infusion of exenatide. Amylin needs the study in order to resubmit the NDA for its once-weekly subcutaneous injectable Bydureon (long-acting exenatide), which it plans to do by year's end. The protocol Amylin has proposed promises a faster trial than other options.

During a presentation on Jan. 10 at the 29 annual J.P. Morgan Healthcare Conference, Amylin CEO Daniel Bradbury said the company is aiming to start a "thorough QT" or tQT study of Byetta in this quarter, pending approval of the proposed trial protocol by FDA. Upon questioning by investors, the exec declined to say when exactly Amylin had submitted the plan to the agency.

FDA had issued a second complete response letter for Bydureon, which is partnered with Eli Lilly & Co. and Alkermes Inc., in October and requested a dedicated tQT study with an FDA-approved design (Also see "Amylin Plans Cardiac Safety Study By The Book After Bydureon Rejection" - Pink Sheet, 25 October, 2010.).

A standard part of drug development, the tQT assesses risk for QT prolongation, which has been linked to rare and life-threatening cardiac arrhythmias. Amylin already markets exenatide as a twice-daily injectable under the brand Byetta. But higher levels of drug exposure are more likely to cause QT prolongation and Byetta's half-life is shorter, so the levels don't accumulate as much compared to Bydureon. And in theory this could pose a risk to renally impaired patients.

The plan is to test a continuous infusion of exenatide, the active ingredient in both Byetta and Bydureon, rather than the Bydureon injectable itself. At the time of the response letter, management had suggested the possibility of using infused exenatide to quickly achieve high dose levels representative of Bydureon in renally impaired patients as a shorter option. This allows for speedier titration and treatment periods and trial duration and if approved by FDA would encourage investors. But given heightened concerns about diabetes drug safety, it remains unclear whether the agency will push for testing of Bydureon itself.

According to FDA guidance, tQT trials must conform to a set of standardized protocols recommended by the ICH-E14 guidance. Testing at very high dose (supratherapeutic) levels is required as part of a tQT study. In creating the trial protocol, Bradbury noted that the company has consulted with virtually every QT prolongation expert in the world to come up with its strategy.

Writing in a Dec. 13 note, Jefferies & Co.'s Thomas Wei had said that FDA's endorsement of continuous infusion was important for the product to meet the timeline for a resubmission by the end of 2011. A review of 54 tQT studies listed on the clinicaltrials.gov website suggests that the average trial length is about three months, though the trial of Bydureon will be more complex than most of these studies Wei previously observed in a Dec. 2 note.

Questioned by investors at the J.P. Morgan conference, Bradbury declined to comment on whether the timeline would be faster with the infused exenatide, noting that the FDA still has not approved the trial design.

"At this point it's really difficult for us to respond given that we have not had sign-off from the agency of protocol design," the executive said. "Until we see that and initiate the study and understand any complexities associated with that, we are sticking with our [end-year] guidance,"

Questioned on this, Bradbury noted the company isn't worried that the drug will fail the tQT, pointing out that Bydureon has already been tested in patients with renal impairment as part of the Phase III Bydureon program. The company formally assessed any relationship between QT/QTc intervals and exenatide concentrations in Bydureon-treated patients in the DURATION-1 study.

Amylin also faced questions at the J.P. Morgan meeting about the impact of the Bydureon response letter on Byetta's standing in the market. The once-daily GLP-1 Victoza (liraglutide) recently introduced by Novo Nordisk AS has proven to be a hit (Also see "Victoza Sales Lift Novo Nordisk 2010 Forecasts" - Pink Sheet, 27 October, 2010.).

Execs responded by saying that right after the complete response letter, it surveyed physicians to gauge impact on Byetta's position in the market. The survey showed physicians were not planning to switch their patients off Byetta to other drugs, such as liraglutide, and that the product was not perceived as less effective in light of the complete response letters for Bydureon. Bradbury suggested the Victoza launch has given the GLP-1 space overall a boost.

"We are seeing new physicians we did not see in the Byetta ranks before with increased promotion is benefiting both parties selling GLP-1's today," Bradbury said.

Results from the head-to-head DURATION-6 study of once-weekly exenatide versus once-daily could give Bydureon a competitive advantage, Bradbury said.

"We are confident we can demonstrate superiority," he said.

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

Can Bydureon Bounce Back? Amylin's Proposed Cardio Safety Trial Is A Faster Option

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