The FDA Declines to Approve Bydureon, a New Once-Weekly GLP-1 Agonist

Latest exenatide ban prompts cardiovascular study.

By Ben Kozac, diaTribe

Amylin Pharmaceuticals and Eli Lilly, the makers of Byetta, the first ever GLP-1 agonist, have teamed up again to develop a brand new GLP-1 agonist, which they have named Bydureon. While the active ingredient, exenatide, is the same in both Bydureon and Byetta, with Bydureon, it is placed inside microcapsules that degrade slowly within the body. This allows the exenatide to remain active in the body for a much longer period of time. In fact, Bydureon remains in the body so long that injections are only needed once per week, which some patients will really appreciate. By comparison, Byetta injections are taken twice a day, and with Victoza (another drug in the same class), injections are taken once a day. However, the Bydureon needle is bigger. Bydureon is also effective. In a head-to-head study of Bydureon and Byetta called DURATION-1, Bydureon provided individuals with type 2 diabetes greater reductions in A1C, greater reductions in total cholesterol, much lower rates of nausea and vomiting (a few of the more common side effects with GLP-1 agonists), similar weight loss, and similar reductions in blood pressure.

With these promising results, Amylin, Eli Lilly, and Alkermes, the companies involved with the development of Bydureon, submitted an application (called a New Drug Application or NDA) to the FDA asking for approval to sell the drug in the United States. Submission of an NDA is required for all new drugs in the United States and includes all of the laboratory and clinical trial data that the company has gathered for the drug since its discovery. The FDA then reviews this data for up to 10 months to determine whether the benefits of the drug outweigh the risks. If the benefits are determined to be greater, the FDA can choose to approve the drug. If the FDA is unsure, it can send the company what is termed a complete response letter, which lists the additional studies and information it would like to have before making a final decision. After the requested material is supplied, the FDA usually has six months to decide whether to approve the drug or offer another complete response letter.

Excitement ran high last week as the FDA was expected to give its decision on Bydureon for use in the United States. Actually, the FDA responded a first time to the companies in March 2010, issuing a complete response letter asking for additional information on the manufacturing process and the product information sheet that would be provided with the drug to patients and physicians. While disappointing, what was encouraging was that the FDA appeared satisfied with all of the data for Bydureon as no new trials or laboratory studies were requested. As a result, many, including us at diaTribe, had expected Bydureon to gain approval the second time around, especially given the promising results indicated above and the apparent lack of notable safety concerns. But the FDA decided to issue Amylin, Eli Lilly, and Alkermes another complete response letter, this time asking for an additional study examing the cardiovascular effects of elevated exenatide levels and data from DURATION-5, another clinical trial comparing Bydureon to Byetta. On this latter point, the FDA's rationale is clear: a slightly different formulation of Bydureon was used in the first Byetta and Bydureon head-to-head trial, DURATION-1, than would be sold in the US. This new formulation was tested in DURATION-5, and though the companies had provided data previously comparing these two formulations, the FDA wanted confirmation that the new and old formulations behaved the same way.

It is less clear why the FDA is requiring a specific cardiovascular study on higher-than-normal levels of exenatide, Bydureon's active ingredient — we were quite surprised and disappointed by this news, which seems difficult to justify given that other drugs on the market with similar questions have been approved. Likely, the FDA is concerned about the effects that elevated levels may have on the hearts and kidneys of type 2 patients. Because Bydureon is cleared by the kidneys, any impairment to these organs can slow the removal of the drug and lead to higher-than-normal Bydureon concentrations in the body. From that perspective, the FDA's request makes perfect sense. If high concentrations of the drug are harmful, individuals with renal impairment would be at risk for heart complications as they would be exposed to such concentrations for an extended period of time, given Bydureon's naturally long duration of action and their body's inability to remove the drug fast enough. However, the effects of Bydureon on the heart of individuals with mild to moderate renal impairment were already examined in a clinical trial for Bydureon, and no notable effects were detected. Additionally, the specific cardiovascular study requested by the FDA was carried out with Byetta, which also contains exenatide, and a negative effect on the heart was not observed. Finally, a range of studies in mice, rats, and monkeys has failed to demonstrate a negative effect of either Bydureon or Byetta on the heart.

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Last Modified Date: May 15, 2013

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