Pramlintide: (AC 137, AC 0137, Symlin, Tripro-Amylin).

Adis CommentsPramlintide [AC 0137, AC 137, tripro-amylin, Symlin] 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 diabetic patients. The reduction of hypoglycaemia would be an immediate advantage, and the reduction of hyperglycaemia could potentially prevent diabetic complications. Development - US: Amylin has submitted an NDA in the US for pramlintide acetate (Symlin trade mark ) as an adjunctive therapy for the treatment of type 1 and type 2 diabetes mellitus. However, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee at their meeting on 26 July 2001, voted not to recommend approval of pramlintide for type 1 and type 2 diabetes. Although eight out of nine Committee members were convinced of the potential of pramlintide therapy, the Committee expressed concerns regarding safety issues and requested additional data addressing these concerns. Finally, on 12 October 2001, Amylin received an 'approvable letter' for Symlin- for the treatment of diabetes. In April 2002, Amylin commenced a trial in 250 patients with type 1 diabetes to evaluate the safety issues regarding cases of severe hypoglycaemia with pramlintide in combination with insulin reported in this group of patients. The trial will investigate dose titration in the initial first month of the treatment period combined with insulin adjustment for the optimisation of glucose control. Patients are then treated for 6 months at a steady-state dose of pramlintide or placebo, accompanied by the additional insulin adjustments. Amylin has completed patient enrolment in September 2002. Final approval is subject to satisfactory results from this safety and dose titration study and the four small pharmacology studies already completed or underway. Amylin plans to file an amendment to the pramlintide's NDA in the Q1 of 2003. Development - non-USA: A wholly owned subsidiary of Amylin Pharmaceuticals, Amylin Europe, filed a regulatory submission with the European Agency for Evaluation of Medicinal Products (EMEA) and Switzerland for pramlintide for the treatment of both type 1 and type 2 diabetes under the centralised procedure. Amylin completed pivotal phase III clinical trials with pramlintide acetate (Symlin trade mark ) for the treatment of type 1 and type 2 diabetes mellitus in North America and Europe. However, in October 2002, Amylin announced that following consultation with the Committee for Proprietary Medicinal Products (CPMP) of the EMEA, it has found that additional information is necessary to proceed with review of the MAA for pramlintide for diabetes. Since, the centralised procedure does not allow the adding of new information to the application that is already under review, Amylin has decided to withdraw the MAA for pramlintide. The company will continue discussions with the EMEA to clarify the information required for a resubmission of the application. The submission for pramlintide in Switzerland is currently under review. In a separate phase II programme, Amylin is investigating the use of pramlintide in type 2 diabetes mellitus patients who are not achieving satisfactory results with oral hypoglycaemic agents but who have not progressed to using insulin. Collaborations: Pramlintide was under joint development with Amylin Pharmaceuticals and Johnson and Johnson, as an injectable partner hormone for insulin for the treatment of both type 1 and type 2 diabetes mellitus. The terms of the agreement between Amylin and Johnson and Johnson were that Amylin had primary responsibility for development and regulatory submissions, while Johnson and Johnson had primary responsibility for marketing; development costs and eventual profits were to be shared equally. Later, Johnson and Johnson decided to terminate the collaboration to commercialise pramlintide. An earlier development collaboration betweion between Amylin and Glaxo Wellcome was also discontinued. However, Amylin is in new ongoing discussions with collaborative partners for pramlintide in Europe and Japan. Amylin has signed an agreement with CP Pharmaceuticals in the UK to manufacture pramlintide.