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Exenatide - (synthetic exendin-4) Exenatide is a first-in-class drug candidate for the treatment of type 2 diabetes. Exenatide is initially being developed to improve glucose control in patients with type 2 diabetes who are not using insulin and are not achieving target levels with diet and oral medications. In September 2002 Amylin announced a global agreement with Eli Lilly and Company to collaborate on the development and commercialization of exenatide. Scientific Overview Exenatide is a potent 39-amino acid peptide that exhibits several anti-diabetic, or glucose lowering, actions. It is the first member of a new class of therapeutic medications known as incretin mimetic agents. Exenatide (synthetic exendin-4) is being investigated for its potential to address important unmet medical needs of many people with type 2 diabetes. Clinical trials suggest that exenatide treatment decreases blood glucose toward target levels and is associated with weight loss. The effects on glucose control seen with exenatide treatment are likely due to several actions that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibiting the release of glucagon following meals and slowing the rate at which nutrients are absorbed into the bloodstream. In animal studies exenatide administration resulted in preservation and formation of new beta cells, the insulin-producing cells in the pancreas, which fail as type 2 diabetes progresses. Clinical Trials A small Phase 2 clinical trial of exenatide completed in 1999 in people with type 2 diabetes showed statistically significant reductions in post-meal glucose concentrations, post-meal increases in glucagon concentrations and reductions in the rate of nutrient release from the stomach. Patients also reported sensations of fullness and satiety following exenatide administration. In another Phase 2 clinical trial completed in 1999, the blood glucose concentration during the first five hours following a standardized meal was reduced on average by 34% in participants that were treated with exenatide (compared to participants that were treated with placebo). In addition to lowering post-meal glucose concentrations, exenatide has also been shown to suppress post-meal elevations in serum triglyceride concentrations in people with type 2 diabetes. Elevations in post-meal triglycerides appear to be an independent risk factor for cardiovascular mortality. In June 2001, Amylin announced the results of a Phase 2 clinical trial designed to examine the effect of exenatide on glucose control in over 100 subjects with type 2 diabetes who were not achieving adequate blood glucose control with their current oral medications. In this 28-day trial, patients treated with exenatide, together with their current oral medications, experienced statistically significant lowering of A1C levels by 0.7% to 1.1%, compared to the average reductions experienced by patients treated with their current oral medications and placebo of 0.3%. Moreover, 90% of patients treated with exenatide together with their current oral medications experienced reductions in A1C levels of greater than or equal to 0.5%, compared to 33% of patients treated with their current oral medications and placebo. It is important to note that this was a 28 day study and that A1C measures average blood glucose concentrations over a 3-4 month period. In these clinical trials, exenatide was well tolerated. The majority of reported adverse events in the trials were judged to be mild or moderate in intensity. These events included nausea, which was the most common adverse event, and to a much lesser extent, vomiting. To better understand how to minimize nausea, Amylin performed a Phase 2 dose-escalation trial in which patients achieved a target dose either gradually or suddenly. The data indicated that patients who gradually increased their dose of exenatide had a clinically meaningful reduction in the incidence of nausea over patients who did not receive a gradual dose increase. In September 2001, Amylin announced that another Phase 2 clinical trial indicated that exenatide stimulated insulin secretion and lowered the elevated fasting blood glucose concentrations in people with type 2 diabetes after an overnight fast. Amylin commenced a Phase 3 program for exenatide in December 2001. The Phase 3 program includes three pivotal trials. In all three studies, patients are randomized into three groups, two on exenatide and one on placebo. Those on active drugs receive an introductory 5 microgram dose for one month, given by subcutaneous injection twice a day at breakfast and dinner, followed by six-months of exposure to doses of either 5 micrograms or 10 micrograms given twice a day. The first pivotal study was designed to evaluate the effects of exenatide in people with type 2 diabetes not achieving target blood glucose concentrations using metformin alone prior to entering the study. Metformin is one of several available oral therapies for the treatment of type 2 diabetes. The second pivotal trial is evaluating the effects of exenatide on patients not achieving target blood glucose concentrations using sulfonylureas alone. Sulfonylureas are another form of oral therapy for the treatment of type 2 diabetes. The third of the three Phase 3 pivotal trials is evaluating the effects of exenatide on patients who are currently not achieving target blood glucose concentrations using a combination of metformin and sulfonylureas. All of the treatment groups in each of the three Phase 3 clinical trials are continuing to use their current therapies of oral medications. In August 2002, Amylin commenced an open-label clinical study using a similar protocol to the Phase 3 pivotal trials. This study includes patients not achieving target blood glucose concentrations using metformin, sulfonylureas or both metformin and sulfonylureas. In August 2003, 105 patients in this ongoing open-label study showed mean reductions in A1C of 1.3% at the end of six months. At the end of six months, 44% of these participants had lowered their A1C to the treatment goal of less than or equal to 7% set by the American Diabetes Association. In this trial, the effect of exenatide on A1C appears unaltered by the formation of antibodies. The most common adverse event reported was mild to moderate nausea, consistent with previous exenatide clinical studies. Participants maintain their current diabetes treatment regimens for the duration of the trial. Subjects received an introductory 5-microgram dose for four weeks by subcutaneous injection twice a day at breakfast and dinner. After four weeks, the dose was increased to 10 micrograms twice a day. In November 2003, Amylin reported positive results from the final Phase3 pivotal study of exenatide (synthetic exendin-4), marking the conclusion of the long-term human clinical trials required for regulatory submission to the FDA. All three pivotal studies met the primary glucose control endpoint as measured by hemoglobin A1c (A1C). The average reduction in A1C across the Phase 3 program in patients completing the studies on the highest dose of exenatide (10 micrograms twice daily) was approximately one percent. Additionally, approximately 40 percent of these patients achieved A1C measurements of 7 percent or less. On average, subjects in the Phase 3 program on the highest dose of exenatide also showed statistically significant reductions in body weight of approximately two kilograms. The most common adverse event was mild to moderate, transient nausea. Regulatory Status Amylin filed an Investigational New Drug Application, or IND, for exenatide in January 1999 prior to the initiation of clinical trials. The successful completion of exenatide`s phase 3 pivotal studies was announced in November 2003. A New Drug Application (NDA) is planned for submission to the FDA mid-2004. Target Market The initial patient focus for exenatide is patients with type 2 diabetes who are not using insulin and are not achieving target blood glucose concentrations with diet plus metformin and/or sulfonylureas. The current therapeutic steps available to this patient population are additional oral medications, the addition of insulin to the oral agent regimen or insulin therapy alone. These approaches are often not very successful and are usually associated with inconvenience and side effects, particularly weight gain. Amylin estimates this population of people with diabetes who were using oral medications as of 2001 to be 11.9 million in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, which comprise the seven largest pharmaceutical markets worldwide, of which an estimated 5.9 million people are in the United States. Amylin currently plans to market exenatide in an injectable pen/cartridge delivery system, subject to receiving the necessary regulatory approvals. |
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| aus der Diskussion: | Amylin - Zwei mögliche Blockbuster-Zulassungen im Frühjahr!!! |
| Autor (Datum des Eintrages): | blb (16.01.05 10:16:38) |
| Beitrag: | 5 von 37 (ID:15541115) |
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