© 2005 Nature Publishing Group

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FRESH FROM THE PIPELINE

ExenatideMayer B. Davidson, Guy Bate and Peter Kirkpatrick Exenatide

Figure 1 | Pathways of diabetic complications. There are four hypotheses for how hyperglycaemia causes the vascular complications of diabetes: increasing polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms; and increased hexosamine pathway flux9. A unifying hypothesis linking these four mechanisms, in which vascular damage is caused by the activation of these pathways by hyperglycaemia-induced mitochondrial superoxide production, is shown (adapted from REF. 9). GAPDH, glyceraldehyde-3-phosphate dehydrogenase; P, phosphate.

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In April 2005, exenatide (Byetta; Amylin/Eli Lilly) was approved by the US FDA as an adjunctive therapy to improve blood-sugar control in patients with type 2 diabetes. It is the first in a new class of drugs that mimic the activity of natural glucoregulatory peptides known as incretins.

Type 2 diabetes mellitus is already estimated to affect more than 5% of the adult population in Western societies, and its incidence is expected to increase considerably in the future, in partic-ular owing to the dramatic increase in obesity1. The disease is characterized by hyperglycaemia associated with defective insulin production and peripheral insulin resistance, and leads to the development of a range of complications includ-ing nerve damage, renal failure, blindness and the acceleration of cardiovascular disease1.

It is now clear that tight control of hyper-glycaemia can attenuate the development of such complications in patients with type 2 diabetes. Several classes of well-established drugs are available for the management of hyperglycaemia, including metformin, which acts to reduce hepatic glucose production, and sulphonylureas, which increase insulin release from pancreatic islets1. More recently, thiazolidinediones, which primarily bind to peroxisome proliferator-activator receptor-γ (PPARγ) and reduce glycaemia by decreasing insulin resistance, have been introduced1.

Nevertheless, it is often difficult to achieve and maintain sufficient glycaemic control in

patients with type 2 diabetes, and many of the current agents have treatment-limiting side effects1. However, most such agents were developed in the absence of defined molecular targets, and advances in the understanding of disease pathogenesis have provided several new opportunities for therapeutic interven-tion1, including those based on the activity of glucoregulatory peptides known as incretins.

Basis of discoveryThe incretin hormone glucagon-like peptide-1 (GLP1) is naturally released from cells in the gastrointestinal tract in response to food intake, and acts on its G-protein-coupled receptor on β-cells to potentiate glucose-stimulated insulin secretion1. Failure of β-cells to secrete enough insulin to compensate adequately for peripheral tissue insulin resistance is a major cause of hyperglycaemia in patients with type 2 diabetes, and GLP1 was therefore considered as a potential antidiabetic agent.

However, GLP1 is rapidly degraded in vivo by dipeptidyl peptidase IV (DPP-IV). So, both modified GLP1 peptide agonists, such as exenatide, that are resistant to this degradation and DPP-IV inhibitors have been investigated in an attempt to address this issue1.

Drug propertiesExenatide is a synthetic 39-amino-acid peptide amide with the same amino-acid sequence as exendin 4, a peptide isolated from lizard saliva that was found to act as a potent agonist of

mammalian GLP1 receptors2,3. It shows similar glucoregulatory activities to GLP1, including glu-cose-dependent enhancement of insulin secre-tion by β-cells2–4. Importantly, as stimulation of insulin secretion occurs only in the presence of elevated blood-glucose concentrations, the risk of hypoglycaemia, which is a problem with some other antidiabetic agents, such as sulphonyl ureas, should be reduced with exenatide.

Exenatide also reduces food intake and slows gastric emptying, thereby reducing the rate at which meal-derived glucose reaches the circulation3,4. Finally, exenatide lowers serum glucagon concentrations during periods of hyperglycaemia3,4. In patients with diabetes, glucagon levels are inappropriately high dur-ing periods of hyperglycaemia, and lowering serum concentrations of glucagon during such periods leads to decreased hepatic glucose output and decreased insulin demand.

Clinical dataThe efficacy and safety of exenatide (5 or 10 µg as a twice-daily subcutaneous injection) was evaluated in three 30-week double-blind, pla-cebo-controlled trials involving 1,446 patients with type 2 diabetes whose glycaemic control was inadequate with metformin alone, a sulpho-nylurea alone or metformin in combination with a sulphonylurea4–7. The primary endpoint in each trial was the mean change from base-line glycated haemoglobin (HbA1C) levels, an indicator of average blood-sugar levels for the past 3–4 months; HbA1C levels in non-diabetic patients typically range from 3.0–6.0%.

The addition of exenatide to a regimen of metformin, a sulphonylurea or both resulted in statistically significant reductions from base-line HbA1C levels after 30 weeks compared with addition of placebo4. The proportion of patients achieving HbA1C values ≤7% in the three trials ranged from 27.4–46.4% for patients receiving exenatide, compared with 8.8–13.0% in patients receiving placebo4.

IndicationsExenatide is approved by the FDA as an adjunctive therapy to improve glycaemic con-trol in patients with type 2 diabetes mellitus who are taking metformin, a sulphonylurea, or a combination of metformin and a sulpho-nylurea but who have not achieved adequate glycaemic control4.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | SEPTEMBER 2005 | 713

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ANALYSIS | TYPE 2 DIABETES

hyperglycaemia to diabetic complications9,10, and which are therefore potential therapeutic targets for ameliorating these complications, are shown in FIG. 1. Aldose reductase inhibi-tors, which target the polyol pathway, have been studied for at least 20 years. They have shown some benefit in diabetes, albeit with significant side effects, and continue to be studied. Human studies with aminoguanidine, an inhibitor of advanced glycation end-product (AGE) formation that had remark-able success in diabetic animals were stopped because of unanticipated side effects, but other inhibitors of AGE production (as well as agents that break down AGEs) continue to be developed. The protein kinase C β inhibi-tor ruboxistaurin has recently been reported to reduce visual loss and preserve kidney function in patients with diabetes, and could soon be submitted for regulatory approval. Studies on the hexosamine pathway are still confined to animals, but a thiamine derivative (benfotiamine) that decreased levels of glycer-aldehyde-3 phosphate in vitro prevented the early changes of retinopathy in diabetic rats10.

How well do emerging therapies such as exenatide address the unmet needs? Exenatide has the potential to meet some of the unmet needs discussed above. GLP1 receptors also reside in the hypothalamic appetite centre, and the subjects in the clinical trials receiving the active drug lost weight. Although this might have been in part due to the initial nausea associated with exenatide, weight loss continued after the nausea disappeared and also occurred in those who did not experience nausea. Furthermore, in vitro and animal studies have shown that GLP1 might help preserve β-cell function. So, exenatide could help combat two characteristics of type 2 diabetes: obesity and deterioration of insulin secretion.

In addition to DPP-IV inhibitors, several other drugs are in the later stages of develop-ment. Inhaled insulin has been submitted to the FDA for approval, and insulin sprayed onto the buccal membranes in the mouth is being stud-ied. Drugs that target both PPARγ and PPARα are also being evaluated. Fibrates, which target PPARα, are used to reduce triglyceride levels, which are usually elevated in people with type 2 diabetes and which are associated with cardio-vascular disease. So, dual PPARα/γ modulators might combine the therapeutic activities of both thiazolidinediones and fibrates.Mayer B. Davidson is at Charles R. Drew University, Los Angeles, California 90059, USA. Guy Bate is at IMS Health, 7 Harewood Avenue, London NW1 6JB, UK. Peter Kirkpatrick is at Nature Reviews Drug Discovery. e-mails: madavids@cdrewu.edu; gbate@uk.imshealth.com; p.kirkpatrick@nature.comdoi:10.1038/nrd1828

1. Moller, D. E. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414, 821–827 (2001).

2. Goke, R. et al. Exendin-4 is a high potency agonist and truncated exendin-(9–39)-amide an antagonist at the glucagon-like peptide 1-(7–36)-amide receptor of insulin-secreting β-cells. J. Biol. Chem. 268, 19650–19655 (1993).

3. Joy, S. V. et al. Incretin mimetics as emerging treatments for type 2 diabetes. Ann. Pharmacother. 39, 110–118 (2005).

4. FDA labelling information [online], <http://www.fda.gov/cder/foi/label/2005/021773lbl.pdf> (2005).

5. Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).

6. Kendall, D. M. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28, 1083–1091 (2005).

7. DeFronzo, R. A. et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28, 1092–1100 (2005).

8. U.K. Prospective Diabetes Study Group. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44, 1249–1258 (1995).

9. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

10. Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005).

11. International Diabetes Federation <http://www.idf.org/>.12. American Diabetes Association <http://www.diabetes.org/>.13. IMS Health analysis, IMS MIDAS Quantum, MAT (Dec 2004).

What are the current major unmet needs in the treatment of type 2 diabetes?At diagnosis of type 2 diabetes, β-cell function is reduced to ~50% of normal and continues to decrease in spite of therapies that effectively reduce hyperglycaemia8. This necessitates continual intensification of therapy such that patients progress from diet/exercise to monotherapy with one oral drug to combina-tion therapy with two or more classes of oral medications to insulin with or without oral agents. Therefore, a great unmet need is the development of treatments that will preserve β-cell function.

Other unmet needs are therapies that will prevent the development of the micro- and macrovascular complications of diabetes (independent of simply lowering glycaemia) and that will treat them directly when they do arise. Four pathways that connect the effect of

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Analysing clinical issues in the treatment of type 2 diabetes is Mayer B. Davidson, M.D., Professor of Medicine at Charles R. Drew University, Los Angeles, USA.

Box 1 | Market analysis

Analysing the market for diabetes treatments is Guy Bate, Ph.D., Principal, Product and Portfolio Development, IMS Consulting and Services, IMS Health, London, UK.

Diabetes market. There are an esti mated 190 million people with diabetes globally11, with ~18 million in the United States alone (6% of the US population)12. Global prevalence is expected to reach more than 300 million over the next 20 years11.

The value of the pharmaceutical market for diabetes across the United States and the top five European markets in 2004 was US$11.7 billion13; this does not include treatments for the complications of diabetes. The US contributes more than 70% of this value, with 2004 sales of US$8.5 billion13. The diabetes market is growing strongly, and US value grew 12% in 200413. In Europe, the fastest growing market is the UK, with 2004 growth of more than 20%13.

Of current drug classes, the thiazolidinediones have the strongest sales across the top six markets at almost US$3.5 billion in 200413. Intermediate- and fast-acting insulins take second place, with 2004 sales of nearly US$3 billion, followed by sulphonylureas (US$1.1 billion)13. The dominant growth drivers in the diabetes market are the long-acting insulins, which sold US$0.93 billion in 2004, up nearly 70% from 200313.

Exenatide. Most patients with type 2 diabetes have blood-sugar levels that are inadequately managed, despite the range of treatments currently available. Additional treatment options that provide effective control over blood sugar are much in demand and this is the market gap that exenatide might address. The agent is indicated as add-on therapy in patients poorly controlled on oral antidiabetics, and there could be as many as 8–9 million such patients in the United States. With its novel mode of action, exenatide should complement patients’ existing regimen.

The FDA has also issued an approvable letter for use of exenatide as a monotherapy. This could see the product being initiated earlier in the progression of the disease and competing with sulphonylureas and biguanides. However, one potential disadvantage of exenatide relative to current oral therapies is its requirement for twice-daily injections. In view of this, it is likely to be used in more advanced diabetes as an alternative to starting on insulin injections. Here, its reduced risk of hypoglycaemia relative to insulin will be a key advantage. Exenatide’s use as monotherapy might be limited unless it is significantly more effective than oral agents.

Liraglutide (Novo Nordisk) presents future competition to exenatide; a key advantage could be an extended half-life, which might allow once-daily dosing. However, an extended-release formulation of exenatide is being developed, which will be an important addition to the franchise.

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