Amylin again! i'm still on the sidelines with Byetta LAR. but both companies still say the pancreatitis is not caused by exenatide. will the FDA take that chance?
09:01 Amylin Pharmaceuticals: Physicians cautious about Byetta LAR approval
Story * NDA for Byetta LAR on track for submission to the FDA by the end of 1H09
* FDA still reviewing several prescribing information updates submitted by Amylin and Lilly, including revision of safety language related to pancreatitis
* Physicians still debating over potential cause of pancreatitis
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Amylin Pharmaceuticals' (NASDAQ:AMLN) potential Byetta LAR (exenatide once weekly) approval this year has fallen under physician scrutiny, in light of the unresolved pancreatitis associated with the active ingredient exenatide.
A spokesperson for Eli Lilly said the NDA for exenatide once weekly is on track for submission to the FDA by the end of 1H09.
The company currently markets injectable Byetta to improve glucose control in adults with type II diabetes. It can be used with metformin, a sulfonylurea or a thiazolidinedione. The drug is currently partnered with Eli Lilly (NYSE:LLY), and was approved by the FDA in 2005. Byetta LAR is the long-acting release version of Byetta, and has not been approved yet.
Dr Gerald Bernstein, former president of the American Diabetes Association and vice president for medical affairs at biotech company Generex, said the only reason patients take Byetta is for the weight loss, and once they reach a plateau, they get bored with taking the injection.
"I hope it's not approved, but depending on who sits on the committee, it might be approved," said Dr Sonal Singh, an assistant professor of internal medicine at Wake Forest University Baptist Medical Center. "We don't need more agents. We need better use of available agents."
The FDA last August announced plans to strengthen warnings about the risk of pancreatitis linked to Byetta after two patient deaths and four other hospitalizations in Byetta users. Those patients had hemorrhagic pancreatitis or necrotizing pancreatitis. All six patients were hospitalized, and their Byetta treatment was stopped. Last October, the FDA noted 30 reports of acute pancreatitis, which is sudden inflammation of the pancreas, with the drug. None of those patients had hemorrhagic or necrotizing pancreatitis.
The Eli Lilly spokesperson said the FDA is reviewing several prescribing information updates submitted by Amylin and Lilly for Byetta, including revision of safety language related to pancreatitis. The FDA is also reviewing the submission for Byetta as monotherapy, she added.
In the event the long-acting version is approved, Byetta LAR will probably face strict labeling and patient monitoring guidelines, due to the pancreatitis concern, said Dr Narinder Duggal, a clinical pharmacy specialist, internist and medical director of Liberty Bay Internal Medicine, who specializes in diabetes care. The drug may face use limited to endocrinologists, if the monitoring requirement is too cumbersome, he suggested.
"If I was a betting man, I would say no, they're not going to approve it," Duggal said about Byetta LAR's shot at FDA approval.
A spokesperson for Eli Lilly said the company does not have an answer to whether Byetta LAR be required to have a patient monitoring system for pancreatitis since an NDA has not yet been submitted for the once weekly product.
One physician on background said recent FDA approval decisions have not been very kind, particularly for new diabetes drugs. It may not be a favorable outcome, and the agency may ask the companies for larger trials, he said. The FDA is asking for two-year clinical trials in larger populations. "They may ask for more data, but this is pure speculation," he said. "I've seen the results. The clinical outcomes are very nice compared to short-acting Byetta. It's more weight loss, more glycemic control."
Yet Dr Carol Wysham, a member on Amylin's North American Advisory Board and an endocrinologist at Washington State University, Rockwood Clinic, said based on her interpretation of the data, half the pancreatitis cases reported are not really true cases. Patients are being misdiagnosed based on blood tests and not the full clinical picture. "The statistics don't show any risk [above] what you would expect in the general diabetic population for Byetta. I'm leaning towards the innocent bystander effect," she said.
"I am still absolutely not convinced from my experience. I think we're seeing what happens in the general population. It just happens to be that patients develop pancreatitis after taking Byetta," Wysham said.
One question that remains unanswered is whether Byetta's mechanism of action directly causes pancreatitis, and whether it is a class effect of GLP-1 analogs.
Duggal said he believes the pancreatitis issue mars the entire GLP-1 class, adding that if long-acting exenatide is associated with pancreatitis and receives a black box warning, physicians will be concerned about how long it takes to get the drug out of a patient's system.
"I think if the company is hoping to maintain patent protection or try to get market share, it's going to be a hard sell," said Duggal. "If you ask 20 doctors what Byetta's mechanism of action is - what is the hypothetical mechanism? - I don't think they can tell you."
Bernstein, who has done significant research in this area, explained that all of the incretin mimetics work, in part, by slowing down the discharge of food from the stomach to the duodenum. This slows down the absorption rate of glucose, and slows down the digestion of carbohydrates. Gastric motility studies conducted 15 years ago on a large group of patients with clinical diabetes showed that gastric motility was altered, diminished or dysfunctional in 50% of the population.
"Now if you take a stomach that is already having trouble with gastric emptying, and you add a drug that enhances that, you could get a patient from a sub-clinical to clinical state. That's why a lot of patients [on Byetta] have ulcers and throw up," Bernstein said.
Physicians said the key question remains whether the whole process contributes to pancreatitis. "My own feeling is, if it's that direct, you would have seen more cases of pancreatitis [with Byetta]. We haven't seen a case at our clinic," Bernstein said.
Rajinder Dawra, an assistant professor who has conducted extensive research on the pathophysiology of acute and chronic pancreatitis at the division of basic and translational research at the University of Minnesota, explained that delayed gastric emptying should help prevent pancreatitis rather than cause pancreatitis.
Byetta, or exenatide is a synthetic version of exendin-4, a peptide that stimulates GLP-1.
The development of acute pancreatitis is likely due to pancreatic acinar cell injury, which leads to blockage of the secretion and intracellular activation of digestive enzymes, Dawra said. RyR (ryandine receptors) calcium signaling has been shown to be involved in pathological digestive enzyme activation in pancreatic acinar cells.
Dawra further hypothesized that exendin-4 induced cAMP causes aberrant calcium-receptor response through RyR in some individuals resulting in intracellular digestive enzyme activation and in the development of pancreatitis. Exendin-4 binding on acinar cells generate cAMP, which is known to modulate RyR in calcium signaling.
Acinar cells are an integral part of the exocrine system, which is involved in digestion. Therefore, exendin-4 potentiates secretion of factors involved in digestion such as cholecystokinin or carbamylcholine. Therefore, it is unlikely that Byetta contributes to secretory blocks, Dawra explained.
Duggal said his sense is that the pancreatitis cases are specific to exenatide. By blocking a receptor, you're causing more of a gap in the pathway, as opposed to shutting off the pathway. "It's irreversible, which is what we saw with COX-2 inhibitors like Merck's Vioxx. There were irreversible side effects," he said.
"You can look at a lot of drugs in the historical database. The one receptor, one pathway inhibitors, cause downstream effects," said Duggal.
Dr Daisy Merey, a specialist in bariatric medicine in Miami, and the author of Beyond Diet and Exercise, said in her clinic, she has never had any reports of pancreatitis or problems with her patients. "I still prefer to give Byetta versus insulin," she said.
But, she noted, "We're being constantly bombarded by new drugs, but we don't really know much about them. We know the mechanism of action, but is that enough? We don't know the long-term side effects."
Dr Joel Zonszein, director of the clinical diabetes center at the University Hospital of the Albert Einstein College of Medicine, a Division of Montefiore Medical Center, said the FDA language used to define pancreatitis is accurate, and many diabetic patients have other diseases.
Novo Nordisk's liraglutide, a competing GLP-1 analog, should be approved by April 2009, if everything goes well, said Zonszein. "I don't agree it is not a class effect [of GLP-1s]. There is no evidence. In early studies with liraglutide, they also saw some cases of pancreatitis. We don't know the true incidence of pancreatitis," he said.
Zonszein further suggested that some Type II diabetes patients are more susceptible to developing pancreatitis, and he explained that as exenatide slows down gastrointestinal motility in patients, that may cause some problems with the pancreatic duct, and some pancreatitis may be due to this mechanism of action.
"My feeling is, it may be a class effect, although it is rare. If Byetta LAR stays in the patient for a whole week, what is that going to do? We really don't know. We need very large studies," said Zonszein.
The success of these two drugs in the marketplace, given the similar efficacy, will ultimately come down to a marketing war between Eli Lilly and Novo Nordisk, physicians said.
Yet physicians did not believe Byetta LAR would ever replace Sanofi-Aventis' Lantus (insulin glargine). "I don't think it will replace Lantus. That's a pipedream. We're going to use safer therapies that have a known safety record," said Singh.
DURATION-3, the third trial in a planned program of superiority clinical studies, compares Byetta-LAR to Lantus in patients using oral diabetes medications. Results from this study are expected in the 3Q09.
"Byetta LAR replacing Lantus, not in a million years," said Bernstein.
Amylin has a market cap of USD 1.44bn.
by Kimberly Ha and Sasha Damouni
Source Pharmawire
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