Clinical Studies

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I. Summary_

Recognizing that type 1 diabetes was characterized not only by insulin deficiency, but also by amylin deficiency, Cooper (Cooper, 1991) predicted that certain features of the disease could be related thereto, and he proposed amylin/insulin co-replacement therapy. Although the early physiological rationale was flawed, the idea that glucose control could be improved over that attainable with insulin alone without invoking the ravages of worsening insulin-induced hypoglycemia was vindicated. The proposal spawned a first-in-class drug development program that ultimately led to marketing approval by the U.S. Food and Drug Administration of the amylinomimetic pramlintide acetate in March 2005. The prescribers' package insert (Amylin Pharmaceuticals Inc., 2005), which includes a synopsis of safety and efficacy of pramlintide, is included as Appendix 1.

Advances in Pharmacology, Volume 52 Copyright 2005, Elsevier Inc. All rights reserved.

1054-3589/05 $35.00 DOI: 10.1016/S1054-3589(05)52018-0

Pramlintide exhibited a terminal ti/2 in humans of 25-49 min and, like amylin, was cleared mainly by the kidney.

The dose-limiting side effect was nausea and, at some doses, vomiting. These side effects usually subsided within the first days to weeks of administration.

The principal risk of pramlintide co-therapy was an increased probability of insulin-induced hypoglycemia, especially at the initiation of therapy. This risk could be mitigated by pre-emptive reduction in insulin dose.

Pramlintide dosed at 30-60 mg three to four times daily in patients with type 1 diabetes, and at doses of 120 mg twice daily in patients with type 2 diabetes, invoked a glycemic improvement, typically a decrease in HbA1c of 0.4-0.5% relative to placebo, that was sustained for at least 1 year. This change relative to control subjects treated with insulin alone typically was associated with a reduction in body weight and insulin use, and was not associated with an increase in rate of severe hypoglycemia other than at the initiation of therapy.

Effects observed in animals, such as slowing of gastric emptying, inhibition of nutrient-stimulated glucagon secretion, and inhibition of food intake, generally have been replicated in humans. A notable exception appears to be induction of muscle glycogenolysis and increase in plasma lactate.

II. Pharmacokinetics_

Human amylin was first administered to humans by Gilbey (Gilbey et al., 1989) and others (Bretherton-Watt et al., 1990; Ghatei et al., 1990; Wilding et al., 1994) working with Bloom at the Hammersmith Hospital in 1989. The material showed no activity in those studies, perhaps consistent, as it turned out, with a lack of effect on glucose disposal in clamp experiments, but also consistent with the propensity of human amylin to precipitate from solution and lose activity. Some of the same authors subsequently observed hypocalcemic activity with human amylin in patients with Paget's disease (Gilbey et al., 1991), an observation that was soon repeated by others (Wimalawansa et al., 1992), illustrating that human amylin could retain biological activity under some conditions. Human amylin (designated AC001) was produced at Amylin Pharmaceuticals Inc. and was used in several sponsored studies of the renin-angiotensin-aldosterone system in 1993-1994 (Cooper et al., 1995; McNally et al., 1994a,b; Nuttall et al., 1995a,b; Young et al., 1995) in which the use of the human hormone in humans was used to examine human physiology. But the adverse physi-cochemical properties of AC001 and the loss of several manufactured batches compelled the development of the analog, pramlintide (designated AC137), which was stable in solution and equally active with human amylin.

Clinical Studies 291 ntravenous Bolus Intravenous Infusion

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