Metformin, the most prescribed drug for T2D, has significant deficiencies in potency, pharmacokinetics (PK) and safety, especially in patients with kidney disease. Despite these deficiencies no improvements have been made to the biguanide (BIG) drug class. Novel BIGs with greater efficacy and without the risk of lactic acidosis are needed for T2D in patients with impaired renal function. A library of novel BIGs was screened for functional activity against a panel of organic cation transporters (OCTs). This OCT activity profile has allowed us to select BIGs with increased potency, improved PK properties and reduced elimination in urine. NT1195 was identified from this library and examined in more detail. This BIG is 5-10x more potent in mouse OGTT than metformin and is potent in the db:db mouse model, lowering plasma glucose after 8 days of dosing when metformin did not. NT1195 is more effective at elevating GLP-1 levels and inhibited gastric emptying in mice, where metformin did not. Improved potency alone is not sufficient to create the next generation of BIG therapeutics; it is also important to improve drug safety and to reduce the risk of lactic acidosis. Detailed PK studies in mice show that NT1195 has a 28.5h half-life (metformin = 1.97h), high levels of exposure (6x >metformin) and renal clearance that is 50x less than metformin. This latter finding suggests an increase in the safety of NT1195 in patients with impaired renal function, since we anticipate that NT1195 will be cleared by non-renal processes and that drug levels will not be affected by kidney disease. PK studies in cynomolgus monkeys provide similar findings for NT1195 with good exposure and a long half-life after oral administration. Also, NT1195 was found to increases glucose disposal in an IVGTT in insulin resistant monkeys. Safety studies are underway that will prepare NT1195 for a micro-dose study in T2D patients with and without kidney disease.
K.W. Batchelor: None. J.N. Livingston: Consultant; Self; CohBar, Inc. Employee; Self; NovoTarg Therapeutics. K.K. Brown: None. K. Kavanagh: Research Support; Self; Takeda Development Centre Europe Ltd. J.E. Cobb: Consultant; Self; NovaTarg Therapeutics.
National Institute of Diabetes and Digestive and Kidney Diseases