Exendin 4 and exendin 3 are 39-amino acid peptides isolated from Heloderma lizard venom.1The two molecules differ at amino acids 2 and 3, are agonists of glucagon-like peptide 1, and exhibit glucose-lowering effects in animal models of diabetes. Amylin Pharmaceuticals has acquired exclusive patent rights for two exendin compounds from the originator, Dr John Eng (Bronx, New York, USA). Exendins have demonstrated stimulation of secretion of insulin in response to rising blood glucose levels, and modulation of gastric emptying to slow the entry of ingested sugars into the bloodstream. Due to these effects, exendins provided a glucose-lowering ability in animal models of diabetes. Synthetic exendin 4 (AC 2993) has potential as a therapy for type 2 diabetes mellitus.Amylin Pharmaceutical has chosen synthetic exendin 4 as a clinical candidate for further development. Three phase II clinical studies have been completed in patients with type 2 diabetes mellitus in the UK and the USA. On 24 June 2001 Amylin announced the results of a phase II trial of AC 2993 that determined the effect on glucose control in patients with type 2 diabetes not responding adequately to current oral therapies. The 28-day, placebo-controlled trial in over 100 patients at multiple centres demonstrated that exendin 4 significantly lowered glycosylated haemoglobin level compared with controls. Amylin's pivotal phase III clinical studies development programme ‘AC 2993: Diabetes Management for Improving Glucose Outcomes (AMIGO)’ comprises three studies: a first phase III trial of AC 2993 in approximately 400 patients with type 2 diabetes has been initiated on 10 December 2001. A randomised, three-group study (two on AC 2993 and one on placebo) will evaluate an introductory 5μg dose of AC 2993 (SC injection twice daily for 1 month), which will be followed by doses of either 5μg or 10μg (twice daily for 6 months) in combination with metformin. Patients completing the study will be offered entry into an open-label extension study. The second phase III clinical study has begun in January 2002. This study will evaluate effects of AC 2993 in combination with sulfonylureas. The third study has been initiated in March 2002, and will investigate the effects of AC 2993 in combination with metformin and sulfonylureas. This randomised study will enrol approximately 800 patients with type 2 diabetes. All patients will continue to receive metformin and sulfonylureas during the study. Patients completing the study will be offered entry into an open-label extension study.Amylin and Alkermes have signed an agreement to cooperate on the development, manufacture and commercialisation of AC 2993 for type 2 diabetes mellitus. Under the agreement, Amylin is getting an exclusive worldwide license to Alkermes' Medisorb®formulation technology of injectable sustained-release AC 2993 as well as other exendins and related compounds. The microsphere-based technology incorporates drug molecules into a matrix of poly-(DL-lactide-co-glycolide), a common, biodegradable medical polymer PLG.Under the terms of agreement, Alkermes will receive research and development funding and milestone payments, and also a combination of royalty payments and manufacturing fees based on product sales. Alkermes undertakes the responsibility for the development of several initial formulations of the long-acting drug and manufacturing the final product, while Amylin will be responsible for clinical trials, regulatory filings and worldwide marketing. The goal of the AC 2993 LAR development programme is a once a month injectable formulation of AC 2993. A phase I study of the long-acting release formulation, AC 2993 LAR, began in Europe in March 2001 and was completed in Q3 2001. A long-acting, sustained-release formulation of AC 2993 lowered both pre-meal and post-meal glucose concentrations during a 24-h period in patients with type 2 diabetes. This result, along with the previous phase I studies with AC 2993 LAR formulation that demonstrated a sustained-release of AC 2993 over 30 days, will provide for the incoming, dose-ascending, phase II study in patients with type 2 diabetes that is scheduled for Q1 2002.In March 2001, it was announced that Amylin has signed a license agreement with the US National Institutes of Health (NIH), under the terms of which Amylin obtained exclusive worldwide rights to patent applications for use of AC 2993 for conversion of non−insulin-producing cells into insulin-producing cells. Amylin will pay license fees to the NIH and will perform research with regard to this use of AC 2993.