Phase 2 results published for Takeda’s GPR40 agonist TAK-875 – March 9, 2012

Phase 2 results for Takeda’s GPR40 agonist TAK-875 were recently published online in The Lancet (visit http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61879-5/fulltext to access the article). Results from this trial were previously reported at ADA 2011 (see our ADA 2011 Day #5 coverage at http://www.closeconcerns.com/knowledgebase/r/4890a8da) and EASD 2011 (see our EASD 2011 Full Report at http://www.closeconcerns.com/knowledgebase/r/3b0410f4). New in the publication were some additional efficacy and safety data– although nothing in the piece substantially furthered our understanding of the drug or the GPR-40 class. As a reminder, the 12-week trial randomized 426 patients with type 2 diabetes inadequately controlled on diet, exercise, or metformin to receive placebo, glimepiride, or one of five doses of TAK-875 (6.25 mg, 25 mg, 50 mg, 100 mg, or 200 mg) once daily with or without metformin. At 12 weeks, statistically significant reductions in A1c were reported with each dose of TAK-875 versus placebo, plateauing at ~1% with the 50 mg to 200 mg doses (from baseline A1cs ranging from 8.2 to 8.6%). The reductions in A1c and the percentages of patients achieving an A1c < 7.0% were comparable between the 25 mg to 200 mg TAK-875 dose arms and the glimepiride arm. Treatment with 25 mg, 100 mg, and 200 mg of TAK-875 also statistically significantly improved beta cell insulin secretion versus placebo (assessed by the C-peptide: glucose ratio over the first 30 minutes of an OGTT). There was no significant improvement with glimepiride. The authors hypothesized that the improvement in insulin secretion with TAK-875 was likely the result of the drug’s direct activation of beta cell GPR40 receptors – not an indirect insulinotropic effect through the stimulation of GLP-1 secretion. Preclinical studies have identified GPR40 receptors on rodent intestinal enteroendocrine cells, and GPR40 activation in rodents has resulted in increased GLP-1 secretion. However, a previous phase 1 study (n=59) failed to detect increased levels of GLP-1 following treatment with TAK-875, suggesting minimal or no expression of GPR-40 receptors on human enteroendocrine cells. Changes in GLP-1 levels due to treatment with TAK- 875 were not measured in this phase 2 study. With regards to weight, no significant changes relative to baseline were reported at any dose of TAK-875, a positive from our view given that glimepiride led to significant weight gain relative to baseline (1.89 lbs, p=0.004).

The overall incidence of treatment-emergent adverse events was similar for TAK-875 (49%) and placebo (48%), and higher with glimepiride (61%). (Note: overall treatment-emergent adverse events are typically high in clinical trials; in the phase 3 trial DURATION-3 for the GLP-1 agonist Bydureon, 70% of individuals treated with Bydureon and 61% of individuals treated with insulin glargine reported an adverse event). Yet, the percentage of patients experiencing treatment-emergent adverse events judged by the investigator to be related to study drug was lowest in the TAK-875 groups (7%) versus the placebo (11%) and glimepiride (23%) arms. Most (> 95%) events with TAK-875 were reported to be mild or moderate in severity, and there was no dose relationship. Urinary tract infection was the only treatment-emergent adverse event reported in 5% or more of patients in the TAK-875 groups (5%); similar percentages of patients reporting urinary tract infection in the placebo (7%) and glimepiride arms (8%). Notably, the percentages of patients experiencing hypoglycemia were similar with TAK-875 (2%) and placebo (3%), while significantly higher rates were recorded with glimepiride (19%). Serious adverse events leading to treatment discontinuation were reported in three (1%) patients on TAK-875 (coronary artery disease and carotid artery stenosis; cardiac arrest, myocardial infarction, and renal failure; liver function test abnormalities) and two (3%) patients on glimepiride (unstable angina and chest pain; hyperglycemia and urinary tract infection). Finally, mean changes in blood pressure and pulse as well as least-squares mean changes for LDL, HDL, triglycerides, and free fatty acids were similar among all treatment groups.

Overall, these results suggest significant improvement over sulfonylureas with TAK-875 as an insulin secretagogue (equivalent glycemic control, no weight gain, low risk for hypoglycemia). We look forward to hearing results from larger and longer trials, especially with regards to TAK-875’s durability of effect – data from several studies have suggested poorer glycemic control durability with sulfonylureas relative to other anti-diabetic medications. For example, in the ADOPT study, the incidence of monotherapy failure at five years was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. Additionally, the annual rate of beta cell function decline after six months was statistically significantly greater with glyburide (a decrease of 6.1%) than both metformin (a decrease of 3.1%) and rosiglitazone (a decrease of 2.0%). Whether TAK-875 will be associated with improved glycemic control durability due to its glucose dependent action (or other yet identified effects on beta cells) remains unclear. As a reminder, TAK-875 entered phase 3 trials worldwide in late 2011 (see the October 18, 2011 Closer Look at https://closeconcerns.box.net/shared/flt9x4626a91664f0c3f). According to clinicaltrials.gov, there are three phase 3 trials currently recruiting in Japan (NCT01433393, NCT01433406, NCT01433419), two phase 3 trials recruiting globally (including in the US and Europe; NCT01481116 and NCT01456195), and two phase 3 trials expected to initiate later this year. We are intrigued by the possibility of using TAK-875 in combination with incretin-based therapies (particularly DPP-4 inhibitors given their oral administration). Both incretin therapies and TAK-875 stimulate glucose-dependent insulin secretion through separate mechanisms, potentially allowing for more robust glucose control without increased risk for hypoglycemia. Both are also associated with weight neutrality or weight loss. Currently, Takeda is conducting a phase 2 study examining TAK-875 in combination with sitagliptin (clinicaltrials.gov identifier: NCT01414920).

--by Ben Kozak and Kelly Close