Washington Editor

While shares of Novo Nordisk rose 3.3 percent Tuesday on the news that the FDA had approved its once-daily injectable glucagon-like peptide-1 (GLP-1) receptor agonist Victoza (liraglutide) for Type II diabetes, it was competitors Amylin Pharmaceuticals Inc. and Alkermes Inc. whose stock benefitted the most, surging 9 percent and 7.2 percent, respectively.

Analysts predicted that Victoza's OK as an adjunct to diet and exercise to improve glycemic control in adults with Type II diabetes has potentially positive implications for an approval for exenatide once weekly, a long-acting form of Byetta, a twice-daily GLP-1 inhibitor marketed jointly by Amylin and its partner Eli Lilly and Co, whose stock also got a slight bump Tuesday.

Exenatide once weekly, which has a Prescription Drug User Fee Act action date of March 5, is based on Alkermes' Medisorb injectable long-acting release drug delivery technology.

Shares of San Diego-based Amylin (NASDAQ:AMLN) jumped $1.56, to close at $19.01, while Waltham, Mass.-based Alkermes' stock (NASDAQ:ALKS) closed at $11.56, up 78 cents.

Bagsvaerd, Denmark-based Novo Nordisk's stock (NYSE:NVO) gained $2.16, to close at $68.04, while Indianapolis-based Lilly's shares (NYSE:LLY) closed at $36.16, up 41 cents.

While Victoza's labeling carries a black-box warning that highlights the risk of thyroid C-cell tumors, which so far has only been shown in rodents, Byetta's labeling does not include that warning.

Piper Jaffray analyst Sam Fazeli called the boxed warning a "worst case" outcome for Victoza, essentially leaving Byetta as the "first choice," despite that drug's twice-daily injection routine and higher incidence of nausea and vomiting. The fact that Byetta does not have the black box could suggests that exenatide once weekly may escape such a restriction, he surmised.

But Fazeli noted that it still was possible that the thyroid risk warning could make it into the labeling for Byetta, approved in 2005, and exenatide once weekly if data from an expected Byetta epidemiology study from Amylin show a similar trend.

At a meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee last April regulators raised concerns over data from other investigational long acting GLP-1s that suggested the C-cell tumor results were likely a class effect. (See BioWorld Today, April 6, 2009.)

Those concerns called into question the size and composition of the exenatide once-weekly's clinical database.

The panel at last April's meeting had voted 6 to 6, with one abstention, that thyroid C-cell tumors in animal studies of Victoza should preclude the drug's approval for Type II diabetes. While it is not known if Victoza could cause thyroid cancer in humans, including medullary thyroid carcinoma, a rare form of the disease, the labeling restricts the drug against use as a first-line treatment until additional studies are completed that support expanded use, regulators noted in a statement.

Victoza's boxed warning also includes a contraindication for patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2.

Alan Moses, chief global medical officer at Novo, noted that the risk of medullary thyroid carcinoma "represents a very, very small percentage of the population.

"We don't believe, particularly in speaking with clinical leaders in endocrinology, that this will be a major challenge for physicians, but something that they need to be aware of and something that we are committed to following," he told BioWorld Today.

During a conference call with investors, Mads Krogsgaard Thomsen, Novo's chief science officer, noted that Victoza was approved with a risk evaluation and mitigation strategy (REMS) plan, which includes a patient-friendly medication guide and a communication plan targeted to health care providers. The REMS also required an ongoing evaluation of the understanding of the potential risks among patients and health care providers.

The FDA is requiring Novo to establish a cancer registry to monitor the rate of medullary thyroid cancer in the U.S. over the next 15 years.

Victoza's labeling also notes that there were more cases of pancreatitis among patients treated with the drug than those with a comparator drug, and that Victoza has not been studied sufficiently in patients with a history of pancreatitis. Therefore, the labeling warns to "use with caution" in those patients.

Byetta's labeling includes a warning about postmarketing reports, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, associated with the drug.

Byetta's labeling also notes that the drug has not been studied in patients with a history of pancreatitis and advises prescribers to use other antidiabetic therapies in those patients.

While Victoza was not associated with an increased risk for cardiovascular events in people at low risk for those events, Novo must conduct a study to specifically evaluate the cardiovascular safety of the drug in a higher risk population.

The company also is required to conduct a five-year epidemiological study using a health claims database to evaluate thyroid and other cancer risks, in addition to risks for seriously low-blood glucose levels, or hypoglycemia, pancreatitis and allergic reactions.

Novo's Moses noted that, while Byetta and exenatide once weekly are molecules derived from the salivary secretions of the helamonster, Victoza is 97 percent identical to native GLP-1. "We view liraglutide actually as a very effective competitor against other oral agents as well as against exenatide," Moses said.

Although Victoza is not a first-line therapy, "We believe this class of molecules should be introduced relatively early in the treatment of Type II diabetes," generally after an earlier agent, typically metformin, has failed to produce glycemic control, he said.

Moses noted that Victoza's convenience is not just that it is a once-daily therapy, but that it also can be administered at any time of the day, independently of meals, which he called a "tremendous advantage" and a "boon" for treatment adherence. Plus, Moses said, the drug is administered with a "very fine needle, which is quite literally painless for a majority of the people. It should be pretty well accepted."

Published  January 27, 2010