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Weighing up the evidence

New diabetes drugs show promise with good tolerability profiles and no increase in body mass

The diabetes epidemic, which currently grips much of the western world, is burgeoning due to decreased physical activity, deleterious dietary changes, and an ageing population. Of further concern is the World Health Organisation's prediction that approximately 80 per cent of all new diabetes cases will appear in developing countries, and the projection that by 2025, 76 per cent of the global diabetic population will consist of people from the developing world.

Type 2 diabetes mellitus (T2DM) forms the bulk of the problem. Of an estimated 55 million patients in the US, UK, France, Germany, Italy, Spain and Japan, only 50 per cent are diagnosed. Furthermore, only 80 per cent of those diagnosed actually receive treatment.

Type 2 diabetes mellitus
T2DM is a chronic condition characterised by glucose homeostasis defects leading to abnormally high levels of blood glucose. Glucose homeostasis is the maintenance of blood glucose within a tight range; the peptide hormones insulin and glucagon are instrumental in this process. In T2DM this balance is disturbed by the failure of tissues such as fat and muscle to absorb sufficient glucose from the blood due to resistance to insulin, and by the failure of the pancreatic beta cells to secrete sufficient insulin to combat the ensuing elevated blood glucose.

GLP-1 analogues
Following the ingestion of food two key peptides, known as the incretins, are secreted by the small intestine. These peptides are glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptides (GIP). They, in turn, stimulate the pancreatic beta cells to secrete insulin in a glucose-dependent manner. GLP-1 further contributes to glucose homeostasis by delaying the emptying of the stomach, inhibiting glucagon secretion and stimulating insulin biosynthesis. Hence, under normal conditions, GLP-1 and GIP work to return blood glucose levels to normal levels following a meal.

In patients with T2DM, concentrations of GLP-1 and GIP are disturbed. Postprandial GLP-1 concentrations are decreased while GIP concentrations are normal to elevated. These patients can benefit from the use of GLP-1 analogues, which stimulate insulin secretion in response to rising blood glucose levels, and modulate gastric emptying to slow the entry of ingested sugars into the bloodstream.

In 2005 the GLP-1 analogue exenatide (Byetta), from Amylin Pharmaceuticals and Eli Lilly, was approved by the US FDA for combination therapy with metformin and/or sulfonylureas. Now, a more convenient once-weekly sustained-release formulation of exenatide is in phase III development. Similarly, progress is being made with Roche's taspoglutide and Zealand Pharma's AVE 0010, in phase III and II respectively, with positive efficacy data already released for the latter. Novo Nordisk's liraglutide is even nearer to the market with applications having been filed in the US and Europe in May 2008.

Dipeptidyl peptidase IV inhibitors
In healthy people dipeptidyl peptidase IV (DPP-IV) acts beneficially to rapidly destroy GLP-1 and GIP once they are no longer required. In T2DM, however, this rapidity is detrimental.

Hence, there are drugs from several drug classes targeting this pathway that are now in late-stage clinical development. They have the potential to provide effective improvement in glycaemic control with better tolerability profiles than existing therapies, particularly with respect to weight gain.

Inhibition of the widely distributed DPP-IV cell surface glycoprotein delays its peptidase activity and thereby prolongs the presence of GLP-1 and GIP in the bloodstream. This allows the incretins to remain active for longer and the pancreatic beta cells enough time to secrete sufficient insulin to return glucose levels to normal.

The DPP-IV inhibitors currently available include sitagliptin (Galactiv, Januvia; Merck & Co.) and vildagliptin (Galvus; Novartis), both of which have been launched in fixed combination with metformin. The next of this class is Takeda's alogliptin, which is undergoing preregistration, while saxagliptin (ONGLYZA) is in phase III development by Bristol-Myers Squibb, again in combination with metformin.

Takeda filed a new drug application (NDA) in the US in January 2008 for the oral antihyperglycaemic alogliptin based on data from six phase III trials involving more than 2000 patients worldwide. This drug, currently in phase III clinical development in Europe and in phase II in Japan, was a prominent feature of this year's 68th Annual Scientific Sessions of the American Diabetes Association, held in San Francisco in June. Compared to placebo, alogliptin showed significant reductions from baseline in the proportion of glycosylated haemoglobin (HbA1c) at both 12.5 mg/day and 25 mg/day. Furthermore, alogliptin has shown a good tolerability profile without an increase in body weight. These results were consistent across studies in patients with T2DM inadequately controlled on metformin monotherapy, glibenclamide monotherapy, insulin +/- metformin, pioglitazone +/- metformin or a sulfonylurea, or with a diet and exercise regimen.

Peroxisome proliferator activated receptor agonists
Balaglitazone and aleglitazar are two drugs under clinical development that, like the globally launched pioglitazone, are peroxisome proliferator-activated receptor (PPAR) agonists. Pioglitazone (ACTOS, Glustin, Piozone; ZACTOS) activates the PPAR gamma receptor, which acts as a modulator for transcription of genes that impact glucose and lipid metabolism. Through this mechanism pioglitazone reduces blood glucose and insulin resistance in the liver and peripheral tissues. Adverse events, however, include weight gain and fluid retention.

Balaglitazone is a newer PPAR gamma agonist currently in phase III trials (Dr Reddy's Laboratories, Rheoscience). The prominent difference between balaglitazone and pioglitazone is that they are partial and full agonists, respectively. Researchers have found partial agonism to be an advantageous characteristic associated with fewer side effects. In preclinical studies balaglitazone has shown less fluid retention than full agonists and in completed phase II studies it was well tolerated and did not affect body weight.

Aleglitazar is a PPAR alpha and gamma co-agonist in phase II trials with Roche. The PPAR alpha receptor modulates transcription of genes involved in inflammation, vascular function, and in the uptake of free fatty acids from food. In combination with gamma agonism, this means that aleglitazar can improve T2DM management as well as aspects of cardiovascular disease and metabolic syndrome, both of which are frequent co-morbidities. Filing for this promising drug is projected for post 2010.

As the incidence of diabetes increases around the world, the impetus to find effective treatments with minimal side effects is likewise increasing. An important advance is treatment with DPP-IV inhibitors, such as alogliptin, appears to be "weight-neutral", unlike many current T2DM drug therapies. The same benefit applies for trials of balaglitazone and aleglitazar. This is an important consideration given the escalating incidence of obesity that goes hand-in-hand with the diabetes epidemic. These newly developed drugs, both alone and in combination with existing treatments such as metformin, will be important to watch given the significant improvements likely for patients with type 2 diabetes mellitus.

The Author:
Pipeline was written by Kathryn Armstrong of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on +44 (0)20 7981 0733
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8th January 2009


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