If the U.S. Food and Drug Administration approves Starlix® (nateglinide) later this year as expected, it could be just the ticket to turn around the fortunes of its manufacturer, Novartis AG (ADR: NVTSY). Starlix promises to be an important drug to help control type 2 diabetes.
Starlix is a smart drug.
Headquartered in Basel, the Swiss pharmaceuticals giant Novartis was born in 1996 from the $63 billion merger of Swiss drugmakers Ciba-Geigy Ltd. and Sandoz Ltd. The plan was to create the world's first life-sciences company, applying technologies learned from plant genetics to both pharmaceuticals and agricultural businesses.
Instead, Novartis in December announced its plans to spin off its crop protection and seeds businesses and merge them with the agrochemical business of another pharmaceuticals giant, London-based AstraZeneca Plc (NYSE:AZN). The new company, Syngenta AG, will be headquartered in Basel and listed on the Swiss, London, New York, and Stockholm Stock Exchanges.
This shift in strategy more narrowly focuses Novartis on its pharmaceutical business at a time when its drug portfolio is mature and it faces increasing competition from generics. In the United States—the world's fastest growing drug market—its market share is declining.
Key to that strategy is the "blockbuster" potential of Starlix and two other drugs awaiting FDA approval (for gastro-intestinal treatment and asthma and allergies). Each of these drugs could generate peak annual sales of $1 billion or more, Novartis Chief Financial Officer Raymund Breu declared at a news conference last year.
Another news report following a Starlix research presentation at the September meeting of the European Association of the Study of Diabetes in Brussels stated that Novartis management expects Starlix to generate peak sales of 1 billion Swiss francs per year, the equivalent of more than $600 million at the current exchange rate. Whether we are talking dollars or francs, this is no small claim.
For this new drug to generate this sort of revenue in a crowded field, Starlix will have to have exceptional qualities. It does.
Until 1995, the sulfonylurea class of drugs was the only choice in the United States other than insulin for treating type 2 diabetes. Certainly you had a choice of brand, but they all work the same way, by squeezing more insulin out of your beta cells and improving insulin's ability to get glucose into the rest of your body. The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed drugs in three other classes.
Novartis already has a catchy concept to drive its Starlix marketing efforts. It is, the company says, a smart drug.
"Novartis believes it can offer an advancement in therapy, differentiated from other competitor agents," its annual report says. "As a ‘smart drug,' with its effect directly proportional to ambient blood glucose levels, Starlix is expected to bring improved disease control."
No other company is marketing any diabetes drug as a smart drug. "I thought that was a very smart idea on their part to come up with that," laughs William Biggs, an endocrinologist practicing in Amarillo, Texas. He says that Novartis invited him along with other endocrinologists to test and preview the drug.
It's a smart drug, Biggs says, because Novartis found that as soon as glucose levels dropped to a normal range the insulin production stopped. "They've got good data on that."
What's at issue here is hypoglycemia, a potentially dangerous condition that occurs when blood glucose levels drop too low. Like the sulfonylureas and Prandin (repaglinide), Starlix works by stimulating insulin secretion from the beta cells of the pancreas. If a drug stimulates too much insulin, the result is hypoglycemia.
Novartis says that in the clinical trials Starlix was well tolerated with an overall safety profile comparable to a placebo. A low incidence of mild hypoglycemia was the drug's only side effect.
Unlike earlier drugs that stimulate insulin secretion, Starlix is fast acting and has a short duration of activity. It is designed to be taken immediately before each meal to reduce mealtime glucose spikes, while Prandin works best if taken half an hour before eating.
But like Prandin, Starlix faces the marketing challenge in getting people with diabetes to take it three times a day. Compliance with drugs taken only once a day is much better, Biggs points out.
Starlix differs from Prandin and the sulfonylureas by restoring the first phase insulin release after a meal, which is critical to blood glucose control. Arturo Rolla, a Boston endocrinologist, explains.
"To have a robust insulin effect you need a burst of insulin at very beginning of a meal to rapidly stop glucose," he says. "If the production of glucose by the liver is not shut off completely, then the blood glucose levels after a meal will go about 25-33% higher."
Novartis faces another marketing challenge in differentiating Starlix from Prandin, which certainly has not been a blockbuster drug. Co-marketed by Novo Nordisk A/S (NYSE:NVO) and Schering-Plough Corp. (NYSE:SGP), Prandin hit the market two years ago with less than resounding notice.
This problem comes from confusion among many knowledgeable observers who believe incorrectly that both drugs are in the meglitinide class. In fact, many of the earlier animal studies of Starlix call it a meglitinide analog, meaning that it is chemically similar.
However, Starlix is the first in a totally new class of diabetes drugs. It is a derivative of the amino acid phenylalanine and has a chemical and pharmacological structure distinct from any other diabetic drug.
Biggs and another endocrinologist, Edward S. Horton, director of clinical research at the Joslin Diabetes Center in Boston, are in agreement about the way Starlix works and how it differs from earlier drugs. But Horton, who was the lead investigator of one of the phase III clinical trials of Starlix, differs with Biggs, who is concerned about use of a drug that stimulates insulin secretion rather than targeting insulin resistance, the other cause of type 2 diabetes.
Biggs and many of the endocrinologists who previewed Starlix in his group were uncomfortable with giving something that releases more insulin, he says. "That is more of a short term strategy."
Horton, on the other hand says that there is no evidence that beta cells fatigue and wear out the pancreas because of the use of drugs. "In other words, you are not whipping the beta cells to death. There is evidence that the beta cells do fail gradually over time. But there is no evidence that drugs hasten the process. I know that it is a popular conception that people have, but it is not true."
A more important marketing challenge for Novartis may be its lack of experience in marketing diabetes drugs. In Japan, Yamanouchi Pharmaceutical Co. Ltd. has marketed the drug as Starsis® since last August. Nippon Hoechst Marion Roussel Ltd. markets it as Fastic®.
Yet Novartis has decided to market Starlix itself in the United States, Horton says. "They feel that they are a big enough company that they want to market it alone. This is their entrance into the diabetes field."
Yet Novartis isn't coming out of nowhere. It is one of the world's five largest pharmaceutical companies. Starlix comes from the Sandoz side of the company, and Sandoz has a long and well-respected history in the endocrine world, Horton says. "They have had a lot of endocrine products. Their biggest has been Sandostatin, but there is not a huge market for most of the endocrine products that they have."
Sandostatin LAR® is now approved for acromegaly, carcinoid tumors, and vasoactive intestinal peptide tumors. It is in phase III clinical trials for proliferative diabetic retinopathy, which would make it, if approved, only the second Novartis drug targeting people with diabetes.
Within the large market that constitutes people with type 2 diabetes—more than 10 million diagnosed cases in the United States alone—Novartis could profitably target several niches.
Michael David Hein, an endocrinologist who is the founder and director of the Endocrine Treatment Centers in Providence, Rhode Island, sees a role for Starlix in type 2 individuals who haven't achieved adequate control from drugs that target insulin resistance. Another group who could benefit, he believes, are elderly, institutionalized, or mentally incompetent type 2 individuals whose food intake is variable and cannot be guaranteed, where he would not want to use a drug that produces long-lasting hypoglycemia if the food isn't eaten.
Biggs, on the other hand sees the market for Starlix as people with fairly early type 2 diabetes. "These are people with mildly impaired glucose tolerance who have a near normal fasting but become hyperglycemic after meals."
The problem here is that very few people monitor their blood glucose an hour or two after a meal. "We have been training everybody to monitor their blood sugars before meals," he says. "Usually with type 2 diabetics we are thrilled to get two or three readings a day and none of them are postprandial. We are going to have to get a whole new mindset getting people to do some testing after a meal."
Rolla agrees on the importance of Starlix in controlling mealtime spikes. The association between type 2 diabetes and cardiovascular complications is more directly tied to mealtime spikes than it is to fasting levels, he says. We likewise have evidence, he says, that glycohemoglobin levels depend more on mealtime spikes than on fasting levels.
The end result of the introduction of Starlix may be a revolution in blood glucose monitoring, Rolla maintains. More endocrinologists are going to start asking people with type 2 diabetes to test two hours after a meal, rather than testing fasting levels. Rolla says that has been his emphasis for the past four or five years.
But how much will that revolution, if it comes, help Novartis? Biggs thinks that Starlix will be valuable. But he doesn't think that it will be a billion-dollar drug.
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