Tuesday, June 25, 2013

ADA 2013 - SKL-18287, a Novel Long-Acting GLP-1R Agonist, more potent than Liraglutide

Japan based Sanwa Kagaku Kenkyusho which is a specialty pharmaceutical company focused on diabetes and diabetes-related diseases presented early data on its novel long acting GLP-1R agonist - SKL-18287. SKL-18287 is designed to exhibit DPP4 resistance and multimer formation for improving in vivo stability with several natural amino acid modifications of native GLP-1.

SKL-18287 is currently being developed as QD and QW GLP-1R agonist product.

In a comparative assessment with Liraglutide, SKL-18287 showed agonistic activity to mouse and human GLP-1R in vitro with ED50 values of 1.2 and 274 nmol/L, respectively. The competitive binding curve of SKL-18287 to human GLP-1R was not affected by increment of albumin concentration in the system while that of liraglutide was shifted toward the right side. It is noteworthy that radioactivity was distributed to the pancreas at nearly the same level as that to the plasma which was much more than to the other tissues after subcutaneous injection of 3H-[Tyr]SKL-18287 to Sprague Dawley (SD) rats. 

Impact on HbA1C reduction
As a consequent of this unique tissue distribution of SKL-18287 in vivo, 4 weeks repeated injection of SKL-18287 (6-12 nmol/kg) significantly and dose-dependently lowered HbA1c in Goto-Kakizaki T2DM rats. The reduction in HbA1c during 4 weeks of SKL-18287 administration (-0.26%) was more potent than that with liraglutide (-0.10%) when the same dosage was used. 

Adverse Events
Interestingly, the inhibitory effect on gastric empty of SKL-18287 (12 nmol/kg) was nearly the same as that of liraglutide (8 nmol/kg) in SD rats. It is also known that GLP-1R agonists increase plasma calcitonin via GLP-1R in the thyroid C-cell in rodents. Because of its unique tissue distribution, the increment effect of SKL-18287 on plasma calcitonin in alloxan-induced diabetic mice was weaker than that of liraglutide and exenatide when SKL-18287 exhibited potent blood glucose lowering effect.These results suggest that SKL-18287 is a novel long-acting GLP-1R agonist which keeps a balance between efficacy and adverse effects. Considering these properties, we believe that SKL-18287 has potential as a new class of GLP-1R agonist. 

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