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Amylin Analogue Sent Back for More Data on Hypoglycemia.

BETHESDA, MD. -- Pramlintide acetate as adjunctive therapy for insulin-treated diabetes was considered to not be approvable at this time by a Food and Drug Administration advisory panel.

Members of the FDAs Endocrinologic and Metabolic Drugs Advisory Committee agreed that the novel compound is effective at lowering postprandial glucose levels and that additional safety data could render it approvable. Episodes of hypoglycemia raised concerns about the drug's safety.

"This drug has considerable promise and the concept is attractive ... But there's not yet enough information [for the panel] to vote with conviction. Our experience with adverse events in the past makes us skittish in doing that," said acting panel chair Dr. Robert A. Kreisberg, dean of the school of medicine, University of South Alabama, Mobile.

Pramlintide acetate, manufactured by San Diego-based Amylin Pharmaceuticals Inc., is an analogue of the neuroendocrine hormone amylin. The company is seeking FDA approval of the injectable compound, called Symlin, for use before meals in concert with insulin in patients with type 1 or type 2 diabetes.

Amylin is secreted by the pancreatic beta cells along with insulin in response to meals. It inhibits nutrient-stimulated (but not hypoglycemia-stimulated) glucagon secretion, and it prolongs gastric emptying. It may inhibit food intake as well, said Dr. Andrew Young, Amylin's vice president for research.

The hormone is absent in people with type 1 diabetes. It is usually present in people with type 2 diabetes but is not secreted efficiently in response to meals.

Injectable pramlintide--a nonaggregating, soluble, and stable analogue of amylin--reduces postprandial glucose and hemoglobin [A.sub.1C] levels without a concomitant increase in insulin dose. And, in contrast to insulin or sulfonylureas, pramlintide promotes weight loss, said Dr. Orville G. Kolterman, Amylin's senior vice president for clinical affairs.

The company presented study results involving 1,982 people with insulin-treated type 2 diabetes and 2,551 with type 1 diabetes. Baseline hemoglobin [A.sub.1C] values were 8.9% in those with type 1 disease and 9.2% in those with type 2 disease.

At 26 weeks, hemoglobin [A.sub.1C] levels were 8% or less in 35% of those with type 2 diabetes who injected pramlintide either 120 [micro]g twice a day or 150 [micro]g three times daily along with insulin. Similar hemoglobin [A.sub.1C] levels were achieved by 21% of those given placebo plus insulin. Hemoglobin levels were reduced to 7% or less in 8% of those taking pramlintide vs. 2% of those on placebo, said Dr. Kolterman, also adjunct professor of medicine at the University of California, San Diego.

At 26 weeks, the patients taking 150 [micro]g pramlintide before meals had lost approximately 3 pounds and the placebo plus insulin group had gained about 2 pounds. In those with type 1 diabetes, 47% had achieved a hemoglobin [A.sub.1C] level of 8% or less at 26 weeks with a pramlintide dose of 30-60 [micro]g three times daily. Of those on placebo, 28% had a hemoglobin [A.sub.1C] of 8% or less. Levels of 7% or less were seen in 14% of those given pramlintide and in 7% of those taking placebo.

The most prevalent side effect was nausea, which occurred in more than half of the type 1 patients. Nausea was described as mild in 22%, moderate in 22%, and severe in 7%. The problem dissipated after the first 4 weeks of treatment, Dr. Kolterman said.

Hypoglycemia, particularly during the first 4 weeks of therapy was more common with pramlintide, and concerns about this risk dominated the advisory panel's discussion. Among those with type 1 diabetes, the average number of episodes was 3.2 per subject per year in pramlintide users vs. 1.6 events per subject per year in the placebo group. This difference in events evened out by the fourth week.

Dr. Dragos Roman, an FDA reviewer, observed that hypoglycemic episodes requiring assistance were twice as common with insulin plus pramlintide as with insulin plus placebo among the type 1 diabetics during the first month of treatment, and three times as common in those with type 2 diabetes. Two patients taking pramlintide died of causes possibly associated with hypoglycemia--one during a nocturnal seizure, and the other in a motor vehicle accident. Driving-related events and other types of trauma were four times more common in the first month among type I patients with pramlintide and insulin as in those on insulin plus placebo.

The investigators noted that hypoglycemia was reduced by starting patients with type 1 diabetes at a pramlintide dose of 30 [micro]g or lower and reducing preprandial insulin doses by 10%-20%. Dr. Roman, speaking for the FDA, responded that "such an approach seems prudent, [but] it has not been tested in a clinical trial."

FDA reviewer Dr. Robert I. Misbin observed that the fall in [HbA.sub.1C] levels associated with pramlintide tended to creep back up to baseline values by 26 weeks. "Efficacy as we see it, was not sustained."

Dr. Misbin acknowledged that the drug was associated with weight loss, but questioned whether the benefits exceed the downsides, including a high dropout rate due to nausea, the need for three to four injections per day in addition to insulin, and the increased risk of hypoglycemia: "Is a. small drop in body weight worth a 5.8% increase in severe hypoglycemia?"
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Publication:Internal Medicine News
Geographic Code:1USA
Date:Sep 1, 2001
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