Dose-ranging safety and efficacy studies to advance novel mechanism-of-action small molecule leads to treat obesity-linked type 2 diabetes

ABSTRACTA staggeringof US adults are obeseSince obesity greatly dysregulates glucose homeostasisalmost all obese individuals suffer from TypediabetesT Dor prediabetesThese diseasesand accompanying comorbid chronic health complicationsare largely responsible for burgeoning US healthcare costsUnfortunatelylife style modification programstypically the first line treatment for obesity linked T Drarely produce sustained weight loss that is necessary to alter T D and prediabetes severity and progressionThusanti diabetic drugse ginsulinmetforminare required to lower plasma glucose levels in obese diabetic patientsThese drugs do not target the root cause of glucose dysregulation in obese individualsbut largely modulate downstream glucose production and or excretion mechanisms to symptomatically lower blood glucose levelsIt isthereforenot surprising that current anti diabetic drugs require lifelong administrationproduce numerous chronic use adverse effectshave high non adherence ratesand do not generate longterm cost savingsGiven the high prevalence of obesity linked T D and inadequate treatment optionsthere is a critical need for new drugs that sustainably reduce T D and prediabetes in obese AmericansTo address this challengeRidgeline Therepeutics is developing novel oral drugs that reduce excess body fat to restore glucose homeostasis in obese diabetic patientsOur small molecule drugs selectively target nicotinamide N methyltransferaseNNMTan adipocyte centric enzyme newly discovered to regulate white adipose tissueWATmetabolism and mediate obesity linked insulin resistanceThese new therapeutics are expected to improve the underlying WAT linked dysfunctional metabolic state of obese diabetic patientsleading to sustained and persistant reductions in body weight and excess WATuntil circulating glucose levels are normalizedWhen tested in the translationally relevant mouse model of diet induced obesityDIOour lead candidate significantly reduced whole body weightproduced drastic shrinkage of WAT mass and adipocyte sizeand returned blood cholesterol to levels observed in normal weight individualsImportantlyfood intake was not altered with compound treatmentsuggesting no impact on appetite suppressionMoreoverpreliminary pharmacokineticsafetyand functional studies have shown that our leads are stablesafehighly oral bioavailableand efficaciousThese results suggest our technology has enormous potential as a new treatment for obesity linked T D prediabetesTo further derisk our technologywe will complete dose ranging oral delivery studies to characterize the safety and efficacy of our drug leadProject aims includein vitro ADME Tox profilingrigorous long term safety studiesandcomprehensive efficacy studies to demonstrate significantly improved T D biomarkers in treated animalsOur accomplished scientific team will complete these aims and guide our technologyderisking programPreclinical development and IND enabling studies will follow this STTR Phase I project PROJECT NARRATIVEThis project will complete critical dose ranging studies to significantly derisk our novel small molecule anti diabetes therapeutic leads that selectively target nicotinamide N methyltransferase and increase the metabolism of white adipose tissuei ebelly fat