Therapeutics
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27 Dormandy, JA et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet, 2005. 366(9493): p. 1279-89. 28 Sarafidis, PA and Bakris, GL. Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int, 2006. 70(7): p. 1223-33. 29 Sanyal, AJ et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med, 2010. 362(18): p. 1675-85. 30 Lecka-Czernik, B. Aleglitazar, a dual PPARalpha and PPARgamma agonist for the potential oral treatment of type 2 diabetes mellitus. IDrugs, 2010. 13(11): p. 793- 801. 31 Coll, T et al. Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome. Curr Mol Pharmacol, 2009. 2(1): p. 46-55. 32 Keech, A et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005. 366(9500): p. 1849-61. 33 Chew, EY et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med, 2010. 363(3): p. 233-44. 34 Cariou, B, Zaïr, Y, Staels, B, Bruckert, E. Effects of the new dual PPAR/ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care, 2011(in press).
profile, notably due to its activity on PPAR. It thus targets multiple micro- and macrovascular risk factors including hyperglycemia and insulin resistance, atherogenic dyslipidemia, the proin- flammatory state, and liver dysfunction. GFT505 is currently being developed for T2DM (HbA1c reduction), with a potential to address NAFLD/NASH, cardiovascular prevention in diabetics, and the microvascular complications of diabetes.
GFT505 has undergone Phase IIa clinical trials in pre-diabetic patients and in patients with athero- genic dyslipidemia (high triglycerides, low HDL- cholesterol)34. The data from pre-diabetic patients demonstrate that GFT505 treatment for 28 days results in a significant decrease in fasting plasma glucose, fasting plasma insulin and improvement of the insulin resistance index (HOMA). Furthermore, patients showed a significant reduc- tion in LDL-cholesterol, in parallel with a reduc- tion in triglycerides and an increase in HDL-cho- lesterol. Importantly, a study conducted in healthy volunteers demonstrated that GFT505 significant- ly lowered the fasting free fatty acid (FFA) plasma concentration, and potentiated the effect of a meal test on plasma FFA, which is indicative of increased insulin sensitivity35.
GFT505 also shows significant beneficial effects on various abnormalities associated with NAFLD/NASH. Notably, GFT505 treatment reduced liver enzymes (alanine aminotransferase ALAT, gamma-glutamyltransferase GT), and had anti-inflammatory effects34. Moreover, all trials have confirmed the excellent tolerability of GFT505, and the absence of PPAR-related side- effects34,35. GFT505 is currently in advanced Phase II clinical trials. Taken together, these clinical results provide com- pelling arguments for PPAR agonists as a potential treatment for T2DM and associated disorders. Moreover, the beneficial effect of the PPAR/ ago- nist GFT505 on liver enzymes in Phase IIa indicates that PPAR agonism may show a unique potential for the treatment of NAFLD/NASH, for which no approved treatment exists.
A novel approach to new target identification
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Beyond the present potential T2DM therapeutic targets being addressed, there is a need to identi- fy other innovative non-glucosecentric approach- es. Access to appropriate patient cohorts and clinical samples is important for novel target identification studies. A public/private research consortium (IT-Diab) has recently been estab-
lished that focuses on recruiting rare patient cohorts for the purpose of identifying and vali- dating new therapeutic targets in T2DM. One such cohort involves the recruitment of 500 pre- diabetic patients who will be followed longitudi- nally for up to five years, or until the onset of T2DM. Blood and tissue samples collected from these patients at regular time-points, followed by transcriptomics and proteomics studies, will pro- vide valuable insight into the mechanisms and players involved in the progression from predia- betes to diabetes.
Another potential source of samples for the iden- tification of novel targets is patients undergoing bariatric surgery, a common therapeutic solution to morbid obesity. Interestingly, a meta-analysis of 136 studies involving patients undergoing bariatric surgery showed that T2DM was completely resolved (defined as the ability to discontinue all diabetes-related medicines and to maintain blood glucose at normal levels) in an impressive 77% of affected patients36.
The mechanism of diabetes resolution after bariatric surgery remains unclear, but is appar- ently independent of weight loss, since diabetes remission generally occurs in the days and weeks following surgery, prior to significant weight loss. It is believed that surgical manipulation of the gastrointestinal tract plays a direct role in T2DM regression due to effects on metabolic pathways resulting in enhanced insulin sensitivi- ty and/or improved -cell function. Two major hypotheses have been proposed to explain the dramatic effects of bariatric surgery on glycemic control. The ‘lower intestinal hypothesis’37 sug- gests that the rapid delivery of nutrients to the lower intestine enhances the stimulation of intes- tinal L cells that produce GLP-1, leading to improved insulin sensitivity. The ‘upper intestin- al hypothesis’38 suggests that the exclusion of a short segment of upper small intestine from con- tact with ingested nutrients may result in reduced production of anti-incretins such as ghrelin, with subsequent improvement of glucose tolerance. It is, of course, highly plausible that both these mechanisms contribute to the anti-diabetic effects of bariatric surgery39.
Whatever the ultimate mechanisms implicated in diabetes regression after bariatric surgery, this dra- matic effect, as well as the growing prevalence of bariatric surgery interventions, provides a pool of patients that can be studied with the aim of identi- fying novel factors that may be implicated in T2DM development. The IT-Diab consortium is therefore recruiting a cohort of more than 600
Drug Discovery World Summer 2011
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