Novel Biguanides to Treat Type 2 Diabetes

Project SummaryMetformin is the most prescribed drug for typediabetesT Dbut patients with impaired renal function cannot benefit because the risk of life threatening lactic acidosis prevents its useIn additionmetformin has low potency and poor PK properties requiringmg doses twice daily for desired efficacy andimportantlymetformin is predominantlyeliminated in urinecreating a significant risk in patients with impaired renal function who can experience dramatically raised drug levelsA novel biguanide with reduced risk of lactic acidosis has tremendous potential for the treatment of T D in patients with kidney diseaseRecognizing greater opportunities of the biguanide drug classNovaTarg has synthesized andgtnovel biguanides to optimize metformin for use in T D patients with kidney diseaseNovaTarg has discovered a biguanideNTthat is a high affinity substrate for organic cation transportersparticularly OCTOCTand PMATand which activates AMPK in target cellsNTisx more potent than metformin in mouse oral glucose tolerance testsOGTTIt has a large volume of distributionsuggesting improved penetration of target tissuesadiposeskeletal muscle and liverand has a half life of andgth in dogconsistent with once daily dosing in manNTelimination in urine was found to be lowandltand significantly lower than that observed with metforminthereby reducing the risk of drug accumulation in patients with kidney diseaseTaken togetherthe data outlined in this application indicate that the novel biguanideNThas the potential for improved efficacyat a lower dose than metforminand a desirable PK profile with reduced drug elimination in urineThe low renal clearance of NTprovides a level of safety for use in patients with kidney disease not seen in other biguanidesThusNThas the appropriate profile to provide a therapeutic option forof T D patients with kidney diseasea group poorly served at presentThe 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 T D in patients with kidney diseaseFurtherthe early development activities have not exposed impediments in the drug profile and the plan to complete an exploratory IND enabling are on trackInitiation of clinical studies will be guided by a detailed assessment of NTs therapeutic profile in diabetic and insulin resistant monkeysThis will be achieved through studies of drug pharmacology and tolerability through a collaboration with Dr Kylie KavanaughWake ForestFunding of this SBIR Phaseb will allow us to complete these studiesto file the exploratory IND and to perform Phaseinvestigative clinical studies that will allow us to demonstrate the desired product profile of a novel biguanide to treat T D in patients with impaired renal function Project NarrativeMetformin has been used to treat typediabetesT Din humans for more thanyearsyet it has low potencypoor PK properties and has a black box warning restricting its use in patients with impaired renal functionNovaTarg has addressed these issues with the discovery of NTa novel biguanide with high potencygood PKsuitable for once daily dosingand andltrenal clearancereducing the risk of lactic acidosis for patients with kidney diseaseNTrepresents a breakthrough medicine for typediabetes patientsparticularly those with kidney disease who cannot benefit from metformin