August 21, 2008 1:30 pm
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Amylin’s Byetta (exenatide) has been linked to six new cases of pancreatitis, which have led physicians to question the drug’s real-world benefit, Pharmawire reports. The recent news may also impact the FDA’s decision on Byetta LAR, a long-acting once-weekly formulation of exenatide, they cautioned.
Yesterday, the FDA announced that it has received six new reports of patients developing severe hemorrhagic or necrotizing pancreatitis. All cases required hospitalization, with two patients dead and four still in recovery. Last October, the FDA first warned that Byetta may cause acute pancreatitis and reviewed 30 reports of pancreatitis.
Dr Sonal Singh, a diabetes researcher and assistant professor at Wake-Forest University School of Medicine, said this will be a huge issue for the company, as these pancreatitis cases are all spontaneous reports. Singh said he was also wary of under-reporting.
In light of the FDA’s new draft guidance, Singh said there will be tougher standards on new diabetes drugs and their effects on cardiovascular and other micro and macrovascular hard endpoints. ”You have to prove additional improvements, and I’m not sure we know that Byetta has those improvements,” he added.
The recent news also calls into question the approval chances for Byetta LAR, the company’s once-weekly, sustained release, subcutaneous injection of exenatide.
Physicians have cautioned that if the links between Byetta and pancreatitis are strong, then the FDA may adopt a more cautious stance, as the active ingredient in Byetta will remain in a patient’s bloodstream and cannot be taken out of the system once administered.
Dr Narinder Duggal, a clinical pharmacy specialist, internist and medical director of Liberty Bay Internal Medicine in Washington, emphasized the FDA is going to be reactive, conservative and cautious with all new diabetes drugs, especially in light of recent events.
Alice Izzo, a spokesperson for Amylin said exanatide once–weekly is going to be supported by the safety and efficacy of Byetta and other studies. ”Today, there have been no cases of pancreatitis with Byetta LAR,” she said. “The company remains confident of the drug’s submission strategy.”
”It will definitely affect the approval chances for LAR,” said Dr Daisy Merey, a specialist in bariatric medicine for 27 years, who currently has patients on Byetta.
Byetta LAR will take longer to get out of a patient’s system and may have cumulative effects as well, added Merey, who runs her own private practice in West Palm Beach, Florida. She explained that these recent cases of pancreatitis are more severe, compared with the last bout, as this type of pancreatitis actually destroys and kills pancreatic cells.
”If you ask me one thing I do believe, we’re using long acting drugs because Americans love convenience,” Duggal said. However, he added convenience should never replace safety.
Byetta’s main advantage is the progressive weight-loss seen in patients, as a major co-morbidity of Type II diabetes is obesity.
Patient monitoring is also very important, Merey said, but noted that the number of people that die from obesity-related illnesses, and co-morbidities of obesity, still creates a market for drugs such as Byetta.
Companies will always say you cannot associate side-effects with the drug, but Singh believed there is a ”very strong concern” with Byetta - especially as these were cases of hemorrhagic pancreatitis. This is an acute inflammation of the pancreas, which is not only severe, but there is significance in terms of death, he added, as two patients have died.
The FDA has issued an update regarding pancreatitis in patients with Type II diabetes patients taking Byetta. Both Amylin and Lilly are aware of the cases described in the posting, according to an Amylin spokesperson in an email response to this news service.
”Even though there are a small number of cases, patients are taking a medicine that doesn’t provide a lot of clinical benefit,” said Singh. Singh personally does not prescribe Byetta for these reasons, and advises other physicians not to.
”In my opinion, [the companies] need to go back to the lab and study this drug before launching into millions of people. They have to try to find out the effects in real life practice,” said Singh.
The spokesperson said in the email response that in the general population, reports of pancreatitis are considered rare with 15-20% of patients with pancreatitis experiencing complications.
Type II diabetes patients are at an increased risk of pancreatitis as compared to the general population. In patients using Byetta, there have been rare case reports of pancreatitis and very rare case reports of pancreatitis with complications or with a fatal outcome, the spokesperson added.
Dr Joel Zonszein, an endocrinologist at Montefiore Medical Center in New York, said physicians have to be very vigilant about these types of side effects, as pancreatitis is a very severe illness.
The clinical diagnosis of pancreatitis is difficult to make, and Zonszein questioned whether the diagnosis was made with imaging tests, or blood tests showing elevated levels of the pancreatic enzymes, amylase and lipase.
”One of the problems with Byetta is it causes a lot of nausea and vomiting, which are symptoms that can be associated with pancreatitis as well,” said Zonszein. He added that there is currently no direct causal effect that Byetta causes pancreatitis, and that Amylin showed some data on how patients with Type II diabetes have a higher incidence rate of pancreatitis in general.
Duggal, who uses Byetta only as a short-term aid in overweight or obese diabetic patients said, ”It’s utility goes more towards weight loss, then even blood sugar control.”
For example, Duggal noted that a patient with body mass index of 54 has an increased chance of death and stated: ”In that life or death situation, those kinds of patients deserve Byetta.” In that case, he said a drug like Byetta may be lifesaving in the short term.
One competing product, Merck’s diabetes pill Januvia, is going to take advantage of this current situation because the company will say their drug is safer, Duggal said. ”It’s kind of like the shark-eat-shark world of the pharmaceutical industry,” he added.
Yet the issue that is looming over the horizon is whether patients on Byetta may actually regain the initial weight loss seen in the first-year, several physicians stated.
A study presented earlier this year at the American Diabetes Association meeting, by Dr Jennifer Loh of Georgetown University in Washington, found that nearly half of patients taking Byetta for Type II diabetes for more than a year discontinued due to loss of efficacy.
”In a real-world clinical practice, the efficacy of exenatide is not sustained in all patients,” Loh said at the conference.
However, this study has been criticized due to its small sample size, and the data was collected at a single center, said Dr Zachary Bloomgarden, clinical professor at Mount Sinai School of Medicine Division of Endocrinology, Diabetes and Bone Disease.
According to the Georgetown study, out of 30 patients who started on Byetta over a two year period, 18 patients eventually discontinued treatment.
Dr John Buse, an investigator on Byetta’s trials, and president of the medicine and science division of the American Diabetes Association, said the initial weight loss data for Byetta goes out to 3.5 years.
When asked whether the weight loss within the first year is regained over the longer term, he said there is ”maybe a small hint,” but is currently statistically insignificant.
Bloomgarden added there have been reports which show that over three-years, patients on Byetta regain weight.
”Americans always want an excuse for their sins of a nation. Weight will never be reduced, until you make an active change in your lifestyle,” said Duggal.
Lilly and Amylin have been promoting Byetta and have obtained permission from the FDA to use open-label extension studies. In those studies, there is continued weight loss over three years, explained Bloomgarden. An open-label extension study is one where ”you follow patients over time and only the ones who like the medicine stay on it. It’s not totally meaningful,” he said.
Beverly Caskey, a diabetes specialist with Medco Health, said most patients that started Byetta reported an initial weight loss. ”We haven’t received reports, but they might not continue to lose the weight,” she said.
The medical establishment should not just pay lip service that type drugs cure type II diabetes, Duggal stressed. Instead, he said physicians have to “make that the cardinal foundation” that patients must lose their own weight in the diabetes battle.
”If there is one disease that will be the Achilles’ heel of our system it is diabetes. The relative magnitude of increases is unparalleled. It’s driven by weight. We’re skirting the issue,” he said.
Amylin has a current market cap of USD 3.99bn.
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