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A rush for sweet success

Three hundred agents in active development to find antidiabetic drug with reduced side-effects

Diabetes engraved into sugar cubes Diabetes mellitus is a metabolic disorder characterised by abnormally high levels of blood sugar resulting from a lack of insulin production (type 1) or insulin resistance and/or production (type 2). Gestational diabetes is an additional type that occurs in a small percentage of pregnant women due to insulin resistance. The worldwide prevalence of diabetes mellitus in 2007 was 246 million patients and it is estimated that this figure will rise to a massive 380 million by 2025. Patients with diabetes have an increased risk of cardiovascular disease and serious microvascular diseases, such as retinopathy, renal failure and peripheral neuropathy, as well as macrovascular diseases, including coronary artery disease, stroke and amputations. In adults, type 2 diabetes mellitus (T2DM) accounts for about 90–95 per cent of all diagnosed cases of diabetes.

The risk of developing T2DM increases with age, the onset of obesity and lack of physical activity. In addition to diet and exercise, pharmacological intervention plays a major role in managing this disorder and, in addition to the agents currently available to patients, research is turning up new options that may one day find their place in managing this debilitating disease.

Classic agents
Metformin is one of the most commonly prescribed first-line oral antidiabetic agents. It effectively lowers blood glucose and often leads to modest weight reduction in obese patients with T2DM. Prolonged use of metformin, however, causes gastrointestinal and renal adverse effects.

Glimepiride, a third-generation sulfonylurea, and repaglinide, a representative of meglitinides, both increase insulin secretion and are as effective as metformin in glycaemic control, but are associated with body weight gain and/or hypoglycaemia. Acarbose, miglitol and voglibose all reduce carbohydrate absorption through inhibition of alpha-glucosidase enzymes and, therefore, reduce high blood sugar following a meal (postprandial hyperglycaemia, PPG). Typically, these agents are used in the early stages of the disease or where the predominant problem is PPG.

Pioglitazone (Takeda) and rosiglitazone (GlaxoSmithKline), belonging to a class of chemicals called thiazolidinediones (TZDs), were introduced in the late 1990s to treat T2DM. By activating peroxisome proliferator-activated receptors (PPARs), these agents directly target insulin resistance, which develops when cells of the body are unable to respond to insulin.

Although these agents offer an alternate mechanism for effectively reducing blood glucose, they are known to cause weight gain, fluid retention that can lead to heart failure, and bone fractures. Indeed, they carry a black-box warning for the increased risk of congestive heart failure. In particular, rosiglitazone has been associated with an increased risk of myocardial infarction (MI), with one study reporting this to be 43 per cent for patients taking rosiglitazone. Although the most recent data from the randomised RECORD trial in 4,447 patients, published in The Lancet, showed that rosiglitazone did not increase the risk of cardiovascular disease or deaths, it did show that the agent increased the risk of bone fractures by 57 per cent, especially in women. The use of TZDs, therefore, appears to be limited by the safety issues, especially those related to weight gain, fluid retention and fractures. To emphasize this point, in the past few years, development of eight TZDs has been discontinued at phase III or later because of serious adverse events associated with the drugs.

Why new drugs?
Not only are some of these agents dogged by poor adverse event profiles, they often fail to achieve adequate glycaemic control (even when given as combination therapy) as patients undergo progressive β-cell failure – the hallmark of T2DM. Eventually, injection of exogenous insulin is required to control the disease, but this means that dosages have to be closely monitored to avoid low blood sugar and weight gain.

Hence, both physicians and patients prefer to use alternative oral or conveniently injectable agents before switching to insulin. The need for additional novel antidiabetic agents, especially those with mechanisms of action different to existing ones, is mirrored in the burgeoning antidiabetic drug pipeline where more than 300 programmes (agents) are in active development.

Recently launched products

Generic Name
Trade Name (Company)
Efficib (Almirall)
Type 2 diabetes
Antithrombin (Recombinant)
ATryn (Lundbeck)
Thromboembolic events
Tramadol HCl extended-release tablets
RYZOLTTM (Purdue Pharma)
Chronic pain
PreHistin (Cobalis Corp)
Oral-lyn (Generex)
Type 1 and type 2 diabetes
Certolizumab pegol
Cimzia (UCB)
Crohn's disease
Fluitran (Shionogi & Co.)
Oxybutynin transdermal
GelniqueTM (Watson)
Overactive bladder
Vimpat (UCB)
Albumin-bound paclitaxel
Abraxane (Abraxis Bioscience)
Breast cancer
Botulinum toxin A
DysportTM (Medicis)
Glabellar lines
Candesartan cilexetil/hydrochlorothiazide
Blopress Plus (Takeda)
Essential hypertension

In the pipeline

Oral DPP-4 (dipeptidyl peptidase 4) inhibitors and injected GLP-1 (glucagon-like peptide 1) agonists have emerged as hot areas of research in the management of T2DM. This is because, in addition to glycaemic control, these agents provide weight maintenance and cardiovascular benefits. More importantly, they seem to preserve β-cell function and thus influence the underlying cause of T2DM.

Sitagliptin (Merck), vildagliptin (Novartis), saxagliptin (Bristol-Myers Squibb, AstraZeneca, Otsuka), and alogliptin (Takeda) are the most advanced DPP-4 inhibitors available/under review for T2DM. Sitagliptin is the first-in-class, market-leading agent and it appears to have no safety issues so far. However, it does have a relatively modest effect on blood sugar and is regarded as expensive. Vildagliptin is being marketed, but only in Europe, but is linked to skin lesions (in animal studies) and renal impairment. Saxagliptin and alogliptin are currently under regulatory review with the US Food and Drug Administration (FDA).

As there are no head-to-head trial data available for these four agents, it is difficult to assess their relative position in the management of T2DM. In addition to these, two more DPP-4 inhibitors; dutogliptin (Pheomix and Forest) and linagliptin (Boehringer Ingelheim) are being tested in phase III trials, with 11 more in phase II and 10 in phase I trials.

Competing with sitagliptin is the first-in-class GLP-1 agonist, exenatide (Amylin, Eli Lilly), the widespread use of which has been compromised by the need for its twice-daily injections and by 'rare', but serious, cases of acute pancreatitis.

To address the inconvenience of delivery, makers of exenatide are developing a once-weekly formulation of exenatide long-acting release (exenatide LAR), which is currently under review with the FDA. Results of the DURATION-2 study presented at the American Diabetes Association's 2009 meeting showed that once-weekly exenatide was superior to sitagliptin or pioglitazone in glycaemic control, weight gain and safety. More importantly, there was no evidence of increased risk of pancreatitis.

The agent has the potential to become the gold-standard for T2DM by 2012, according to a survey conducted by Decision Resources, a pharmaceutical market research firm. Novo Nordisk's liraglutide once-daily injection is another promising GLP-1 agonist that is also under regulatory review with the FDA. LEAD 6 data published in The Lancet show that the agent was associated with better glucose control and was better tolerated than twice-daily exenatide. However, liraglutide did appear to have an increased risk of papillary thyroid cancer: 1.8 per cent per 1,000 patient-years, compared with 0.6 per cent for exenatide.

The GLP-1 pipeline includes five phase III compounds – albiglutide (Syncria, GSK, Human Genome Sciences), LY2189265 (Eli Lilly), taspoglutide (Roche, Chugai) and AVE0010 (lixisenatide; Zealand Pharma, sanofi-aventis) – eight phase II and eight phase I compounds.

In spite of severe safety issues with pioglitazone and rosiglitazone, development of TZDs targeting PPARs is continuing. Balaglitazone (Dr Reddy's Lab), MBX 102 (Metabolix) and rivaglitazone (Daiichi Sankyo) are TZDs that are currently being tested in phase III trials, with 18 more candidates in phase II and eight in phase I trials. Recently announced results from the phase II SYNCHRONY study show that aleglitazar (Roche), a dual PPARαγ agonist, had better lipid parameters and lower weight gain and fluid retention than pioglitazone. Interestingly, Roche plans to begin phase III trials of aleglitazar for the treatment of patients with T2DM who have had a heart attack. If aleglitazar can cut the risk of successive coronary events, it will have a major impact on the antidiabetic drug market, because no diabetes medication has been shown actually to reduce cardiovascular risk in patients following an acute coronary event.

Alternative strategies
Recently, the FDA approved bromocriptine mesylate quick-release tablets (Cyloset, VeroScience) for the treatment of T2DM. Bromocriptine is a dopamine receptor agonist that has been used for decades to treat diseases like Parkinson's, but just how it improves glycaemic control is unclear. The next promising class of oral diabetic agents is likely to be sodium glucose cotransporter (SGLT) inhibitors. They maintain blood glucose level by mediating re-absorption of filtered glucose in the proximal tubules of the kidney and also absorption of glucose in the small intestine. Dapagliflozin (Bristol Myers Squibb and AstraZeneca) is a leading SGLT type 2 inhibitor, currently in phase III trials and there are at least 17 other SGLT inhibitors in phase II or phase I trials. Other mechanisms of action currently being targeted include inhibitors for protein tyrosine phosphatase, glycogen phosphorylase and fructose-biphosphatase, modulators of glycogenolysis/gluconeogenesis, glucagon receptor antagonists and glucokinase activators.

In reaction to the safety issues related to TZDs, the FDA has raised the safety bar for approving new diabetic agents. According to the new guidance announced in December 2008, the agency wants new T2DM drugs to be tested for heart risks in phase II and III trials, and the trials have to be long enough to provide data on long-term risk for these chronically used therapies. FDA's tight scrutiny is likely to delay approval of new agents, including once-weekly exenatide, liraglutide, saxagliptin, and alogliptin. Takeda has already delayed its EU filing for alogliptin from 2009 to 2012, and is planning to conduct additional long-term studies in approximately 2,500 patients.

The Author
Pipeline was written by Yahiya Syed of Adis International (Wolters Kluwer Health), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733.
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7th August 2009


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