PD2007 is a selective DAT inhibitor that P2D Bioscience (P2D) is developing for the treatment of obesity. PD2007 is an analog of benztropine (Cogentin) a non-Scheduled, safe FDA-approved drug in clinical use for over 40 years. Structure-activity-relationship studies were conducted to improve PD2007 efficacy while decreasing side-effects. Our SBIR Phase 1 data demonstrate that PD2007 produces sustained weight-loss and decreased body fat. PD2007 appears to decrease body weight by increasing energy expenditure, a novel mechanism of action. PD2007 is radically different from the non-selective DAT inhibitor, amphetamine, a potent anti-obesity drug: For example: 1. PD2007-induced weight-loss appears due to increased energy expenditure unlike the appetite suppressant amphetamine 2. PD2007 is not addicting;amphetamine is an addicting Schedule II drug of abuse 3. PD2007 does not affect blood pressure or heart rate;amphetamine significantly increases both 4. PD2007 is not a stimulant;amphetamine is a widely used stimulant 5. PD2007's pharmacokinetics are consistent with once a day dosing while amphetamine requires multiple daily dosing for efficacy. The purpose of the proposed SBIR Phase 2: 1) Aim 1 will further assess whether PD2007 has a novel mechanism of action in inducing weight-loss - enhanced energy expenditure, and 2) Aims 2, 3, 4 and 5 represent preclinical safety studies responsive to FDA-guidance ICH M3 for the successful submission of a PD2007 Investigational New Drug (IND) application. This IND would allow clinical testing of PD2007 in humans. Specifically:
Aim 1 : Determine if PD2007-induced weight-loss is associated with increased energy expenditure, lipolysis and/or glycogenolysis.
Aim 2 : Assess PD2007 genotoxicity.
Aim 3 : Assess PD2007 absorption, distribution, metabolism and excretion (ADME).
Aim 4 : Assess oral PD2007 safety pharmacology in three studies.
Aim 5 : Assess repeated PD2007 dose toxicity in rats.
In the present application, we propose preclinical studies to determine if PD2007, our anti-obesity drug, has a novel mechanism of action. PD2007 appears to increase energy expenditure and general activity rather than the standard weight-loss method of suppressing appetite. By increasing energy expenditure and general activity, PD2007 would be a healthier way to lose weight. Also, preclinical safety studies will be performed that are required by the US Food and Drug Administration (FDA). These studies, once completed, will allow the study of PD2007 for the first time in humans including those with obesity.