Pramlintide

Pramlintide (ACO 137, AC 137, Normylin, Tripro-amylin, Symlin^TM) is a synthetic human amylin analogue with proline substitutions at positions 25, 28 and 29 which limits the self-aggregation seen with native amylin. Pramlintide improves glycaemic control and appears to reduce postprandial blood glucose peaks and flatten the glucose peaks and troughs observed in patients with diabetes. The reduction of hypoglycaemia would be an immediate advantage, and the reduction of hyperglycaemia could potentially prevent diabetic complications.

Amylin is currently conducting 6 phase III clinical trials of pramlintide in North America and Europe for the treatment of patients with type 1 and type 2 diabetes mellitus. The phase III programme is called PARADIGM (Pramlintide for Amylin Replacement: Adjunct for Diabetes in Glycemic Management). All 6 studies have the primary goal of demonstrating that pramlintide can help patients with diabetes who use insulin to improve their glucose control and reduce the risk of complications. Four of the studies involve patients with ‘poor glucose control’ (HbA_1c ≥ 8%). The PARADIGM programme is expected to enrol around 2800 patients and should be completed in 1999. Unexpectedly in two 6-month phase III combined European and Canadian studies, a clear drug effectwas not observed at the highest dosage which had been designated in advance for regulatory purposes. Therefore, the results from the primary dosage arms do not complete the regulatory requirements. Amylin plans to reassess the regulatory activities for pramlintide after appropriate consultation with regulatory authorities in the USA and Europe. The enrolment for two 1-year studies in theUSAhas been completed, with more than 880 patients at more than 135 sites. The US FDA and European marketing application for either type of diabetes mellitus is planned for mid-2000.

In a separate phase II programme, Amylin is investigating the use of pramlintide in patients with type 2 diabetes mellitus who are not achieving satisfactory results with oral hypoglycaemic agents but who have not progressed to using insulin.

As an amylin agonist, pramlintide represents a novel approach to treating patients with type 1 and type 2 diabetes mellitus. Pramlintide is the first compound in this class to be developed extensively in clinical trials. The drug requires self-administration of SC injections about 4 times daily which may limit its usefulness in patients with type 2 diabetes mellitus. However, pramlintide may be administered concurrently with insulin in patients with type 1 diabetes mellitus, making this route and frequency of administration less inconvenient in this patient group.