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  • br Opportunities The ever expanding diabetes


    Opportunities The ever-expanding diabetes market is one of the driving forces for the development of new antidiabetes drugs. Diabetes mellitus influenced an estimated 371 million humans during 2012 worldwide, and this figure is projected to increase in every country. According to International Diabetes Federation (IDF), more than US$471 billion were spent on diabetes-related healthcare during 2012 ( Also during 2012, the pharma industry generated antidiabetes drugs worth US$35.6 billion and this figure is predicted to reach US$55.3 billion by 2017 ( In addition to the epidemic growth in the number of patients with diabetes, other reasons for the focus of the pharma industry on the development of antidiabetes drugs include the unmet medical needs of current antidiabetes drugs and the fact that no single drug is likely to reverse all aspects of DM [24]. As pancreatic β Radicicol are progressively destroyed, patients with diabetes rely on more than one diabetes drug, eventually leading to insulin treatment. Moreover, all current diabetes drugs have adverse effects. For example, insulin and its analogs [e.g. Lantus® (Sanofi-Aventis) and NovoRapid® (Novo Nordisk)] have adverse effects including hypoglycemic events and weight gain. Therefore, there is a strong need for novel orally available antidiabetes drugs that have minimal adverse effects, with GPR119 agonists currently one of the potential candidates.
    Threats In connection with the expanding diabetes market and the urgent need for better antidiabetes agents, many investigational diabetes drugs are being developed [25], which are likely to be in direct competition with GPR119 agonists for market space (Table 2). In addition, currently available antidiabetes drugs are another threat to GPR119 agonists. Metformin is the first-line drug of choice for patients with diabetes, particularly in those who are overweight but with normal kidney function [26]. Metformin is also one of the least expensive antidiabetes agents and has fewer adverse effects compared with other antidiabetes drugs. DPP-4 inhibitors are another possible competitor to GPR119 agonists because they are small and orally available compounds that improve glycemic control in patients with T2DM without increasing the risk of hypoglycemia or causing weight gain [27]. DPP-4 inhibitors are currently gaining more market share following the decline in use of glitazone drugs (e.g. owing to increased myocardial infarction risk by rosiglitazone use and the risk of bladder cancer associated with the use of pioglitazone [28]). Although the pharmaceutical industry has delivered multiple antidiabetes medications, such as insulin and DPP-4 inhibitors, that successfully delay the development of diabetes-related complications, the industry is now experiencing unprecedented challenges, including low productivity, dwindling pipelines and increasing research and development (R&D) costs [29]. Therefore, the current status of the industry could be another threat to the development of GPR119 agonists, because the enthusiasm for GPR119 agonist development is likely to decline in the same way as that for other programs directed at newer and better drugs. Recent US Food and Drug Administration (FDA) guidance regarding the cardiovascular risk of new antidiabetes therapies partly contribute to this increased R&D cost. The FDA guidance specifies that patients at high risk of cardiovascular events need to be included in phase II and III clinical trials to obtain meaningful results (
    SO strategy If one takes into consideration the points highlighted in the Strengths and Opportunities sections, a GPR119 agonist development program can be aggressively pursued. The main adverse effects of current antidiabetes drugs include hypoglycemia (e.g. insulin), weight gain (e.g. sulfonylureas), cardiovascular events (e.g. glitazones) and GI upsets (e.g. metformin). As previously mentioned, representative GPR119 agonists, MBX-2982 and PSN821 caused no serious adverse events (SAEs) during phase I clinical trials with high doses. MBX-2982 was evaluated at doses of 10–1000mg and exhibited no dose-related adverse events. It has completed four phase I studies and one phase II study, in which it increased insulin and active GLP-1 levels ( During the phase I trial of PSN-821, the drug was safe and well tolerated up to 3000mg. During the phase II trial of MBX-2982, the dosages (once daily) were 25mg, 100mg or 300mg using sitagliptin 100mg as a comparator. During the phase II trial of PSN-821 (twice daily), the dosages were 75mg, 250mg and 625mg ( Given that the recommended start-up dose of metformin is usually 500mg twice daily, the doses of MBX-2982 and PSN-821 are allowable as long as they show consistent efficacies.