FDA Requests More Data for Once-Weekly Exenatide

Yael Waknine

October 29, 2010

October 29, 2010 — The FDA has issued a complete response letter regarding a once-weekly extended-release formulation of exenatide injection (Bydureon; Eli Lilly and Co; Amylin Pharmaceuticals, Inc; and Alkermes, Inc), a GLP-1 receptor agonist used to improve glycemic control in patients with type 2 diabetes.

In the letter, the FDA requested a thorough QT study to evaluate the effects of elevated exenatide plasma levels, such as those caused by renal impairment, on heart rate. The agency also asked for safety and efficacy data from a head-to-head study (A Randomized, Open-Label, Parallel-Group, Comparator-Controlled, Multicenter Study to Evaluate the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly in Subjects With Type 2 Diabetes Mellitus [DURATION-5]) comparing once-weekly exenatide with the currently approved twice-daily product (Byetta; Amylin Pharmaceuticals, Inc, and Lilly USA) to ensure appropriate labeling for the commercial formulation.

"My understanding is that the FDA wanted more data on Bydureon to be sure it was safe, not that there was any signal that it isn't safe," explained Anne Peters, MD, FACP, CDE, director of the University of Southern California Clinical Diabetes Program, in Beverly Hills, in an interview with Medscape Medical News. Dr. Peters noted that the original amount of data submitted may have been less than that required for a totally new drug, so that some of the safety/efficacy questions were based on the "Byetta experience."

The new drug application originally submitted by the companies in May 2009 included data from the DURATION-1 head-to-head clinical study of both exenatide formulations, safety data from the DURATION-2 study comparing once-weekly exenatide with sitagliptin plus a thiazolidenedione, and more than 7 years of clinical experience with twice-daily exenatide.

In March 2010, the FDA issued an initial complete response letter requesting information primarily related to the finalization of the product labeling — with an accompanying risk evaluation and mitigation strategy — and clarification of existing manufacturing processes; no clinical trials were requested at that time.

Cardiovascular Risk

"We have thoroughly assessed the [electrocardiogram] data from the DURATION program and believe that Bydureon demonstrated no increased risk of cardiovascular complications due to QTC prolongation, arrhythmias, or conduction disorders," said Dan Bradbury, Amylin president and chief executive officer, in a conference call held on October 19, 2010, noting that no meaningful QT changes were observed in DURATION-1 study patients with any form of renal impairment.

In an interview with Medscape Medical News, Alan J. Garber MD, PhD, commented that the FDA's request for additional QT data is a relatively unusual decision, noting that "what makes it unusual is that the product's been on the market for a number of years, and there's been no suggestion of arrhythmia or electrocardiographic change, so far as I know."

He added, "it's one thing to have an exposure risk for things that are on the label already, such as pancreatitis...but this QT stuff is out of the blue. And so without knowledge of a prior precedent, I'm not sure what the agency is concerned about."

Dr. Garber is professor of medicine, biochemistry, and molecular biology in the Molecular and Cellular Biology Division of Diabetes, Endocrinology, and Metabolism at Baylor College of Medicine in Houston, Texas.

According to Bradbury of Amylin, "the recent attention drawn to the cardiovascular safety profiles of therapies for type 2 diabetes may have led to additional emphasis on the value of a positively controlled [thorough QT] study." As reported by Medscape Medical News, cardiovascular safety problems have been identified in the thiazolidenedione agents rosiglitazone (Avandia; GlaxoSmithKline) and pioglitazone (Actos; Takeda).

DURATION-5

As with the DURATION-1 study, DURATION-5 was a head-to-head study of the once-weekly and twice-daily formulations of exenatide — the difference being that the study drug was commercial-scale material, rather than development-scale material.

"It's speculation, but if [the FDA] is concerned that there's a difference between the prototype and the actual marketed product, they may want to take a look at the data a bit more carefully," noted Dr. Garber.

Positive 24-week results from the DURATION-5 study released in December 2009 were similar to those of DURATION-1 and showed that once-weekly exenatide 2 mg is significantly more effective than the 10-μg twice-daily formulation for controlling diabetes, as evaluated by mean decrease in hemoglobin A1c levels from baseline (−1.6% vs −0.9 % points; mean A1c level, 7.1% vs 7.7%); significant weight loss also was observed in both treatment groups by the end of the study (mean, 5.1 pounds vs 3.0 pounds).

The findings suggest that once-weekly exenatide may achieve hemoglobin A1c level reductions similar to those achieved with liraglutide, a once-daily GLP-1 receptor agonist approved by the FDA in January 2010. As previously reported by Medscape Medical News, a head-to-head study of once-daily liraglutide 1.8 mg (Victoza; Novo Nordisk) and twice-daily exenatide 10 μg (the Liraglutide Once Daily Compared With Exenatide Twice Daily [LEAD-6] study) showed a 1.12% mean decrease in hemoglobin A1c levels at 26 weeks (vs 0.79% for twice-daily exenatide); mean weight loss was similar for both treatment groups (−3.24 kg vs −2.87 kg).

"I'm sure that once-weekly [dosing] is an improvement over once-daily [dosing] in terms of glucose control, and probably your patient persistence and adherence to the medication," said Dr. Garber, noting that no head-to-head study data of once-weekly exenatide and liraglutide are currently available.

Clinical Perspective

"[T]he obvious concern with a once-weekly drug is that it lasts in the body for a long time if there is an adverse reaction," commented Dr. Peters, noting that existing data suggest the product is safe, the drug delivery system has been used with other drugs, and twice-daily exenatide has been on the market for about 5 years. "There is a certain comfort in all of that," she added.

Speaking to the FDA's decision, Dr. Peters said that she was disappointed overall. "I think I have some patients who want a once-a-day drug [such as liraglutide], and others who will prefer once-weekly medication...some of the issues I have had with the twice-daily Byetta is patients forgetting to give the second shot."

Dr. Garber noted that once-weekly exenatide would be a valuable addition to patient care. "Byetta twice daily has a patient persistence and adherence issue, particularly because it has requirements for spacing with regards to meals...it becomes much, much less time critical when you have a long-acting agent like [once-weekly exenatide]."

"We are committed to working closely with the FDA to resolve the issues raised in the complete response letter so that Bydureon can be approved, and we can make this important treatment available to patients with type 2 diabetes as quickly as possible," said Orville G. Kolterman, MD, Amylin's senior vice president and chief medical officer, in a company news release. The company hopes to submit its reply to the complete response letter by the end of 2011.

Dr. Peters has done consulting for and is on the speaker's bureau for Amylin, Lilly, and Novo Nordisk. Dr. Garber consults and speaks for Novo Nordisk.

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