Research Project
9788418
Project Summary Metformin is the most prescribed drug for type 2 diabetes (T2D), but patients with impaired renal function cannot benefit because the risk of life-threatening lactic acidosis prevents its use. In addition, metformin has low potency and poor PK properties requiring 850mg doses twice daily for desired efficacy and, importantly, metformin is predominantly (~85%) eliminated in urine (creating a significant risk in patients with impaired renal function who can experience dramatically raised drug levels). A novel biguanide with reduced risk of lactic acidosis has tremendous potential for the treatment of T2D in patients with kidney disease. Recognizing greater opportunities of the biguanide drug class, NovaTarg has synthesized >260 novel biguanides to optimize metformin for use in T2D patients with kidney disease. NovaTarg has discovered a biguanide (NT1195) that is a high affinity substrate for organic cation transporters (particularly OCT3, OCT1 and PMAT) and which activates AMPK in target cells. NT1195 is ~10x more potent than metformin in mouse oral glucose tolerance tests (OGTT). It has a large volume of distribution, suggesting improved penetration of target tissues (adipose, skeletal muscle and liver) and has a half-life of >12h in dog (consistent with once daily dosing in man). NT1195 elimination in urine was found to be low (<5%) and significantly lower than that observed with metformin; thereby reducing the risk of drug accumulation in patients with kidney disease. Taken together, the data outlined in this application indicate that the novel biguanide, NT1195, has the potential for improved efficacy, at a lower dose than metformin, and a desirable PK profile with reduced drug elimination in urine. The low renal clearance of NT1195 provides a level of safety for use in patients with kidney disease not seen in other biguanides. Thus, NT1195 has the appropriate profile to provide a therapeutic option for ~20% of T2D patients with kidney disease (a group poorly served at present). The drug discovery and development plans described in this application highlight a transporter-based approach that has enabled NovaTarg to demonstrate the unique properties of a drug to treat T2D in patients with kidney disease. Further, the early development activities have not exposed impediments in the drug profile and the plan to complete an exploratory IND-enabling are on track. Initiation of clinical studies will be guided by a detailed assessment of NT1195?s therapeutic profile in diabetic and insulin resistant monkeys. This will be achieved through studies of drug pharmacology and tolerability through a collaboration with Dr Kylie Kavanaugh (Wake Forest). Funding of this SBIR Phase 2b will allow us to complete these studies, to file the exploratory IND and to perform Phase 1 investigative clinical studies that will allow us to demonstrate the desired product profile of a novel biguanide to treat T2D in patients with impaired renal function.
