The need for new medications to treat Substance-Related Disorders (SRDs) is critical since SRDs adversely affect tens of millions of people in the U.S. alone. Currently, no medication approved by the Food and Drug Administration for the treatment of SRDs is optimal. Also, there are no medications approved for cocaine, methamphetamine or cannabis use disorders. The development and approval of new medications based upon recent advances in neuropharmacology and neuroscience has the potential to improve the lives of millions suffering with SRDs. Savant HWP, Inc. is developing a novel, orally active medication, 18-methoxycoronaridine hydrochloride (18-MC), an ?3?4nicotinic cholinergic receptor antagonist that indirectly modulates the dopaminergic mesolimbic pathway via blockade of ?3?4nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala, to treat SRDs. The purpose of this grant proposal is to develop and scale-up GMP production of 18-MC and to complete IND-enabling in vitro and in vivo toxicology studies in support of an IND and First Time In Human (FTIH) studies in individuals with cocaine use disorders. Current data clearly support the ongoing development of 18-MC for the treatment of SRDs. The unmet need for medications to treat cocaine use disorders underscores the importance of our post-grant strategy to move 18-MC into the clinic and FTIH studies in individuals with disorders where cue-induced drug seeking is particularly challenging, such as cocaine use. Current data from the production of 18-MC in batches of less than 30g under research conditions will be used to enable a GMP contract manufacturer to develop and scale-up GMP manufacturing of up to 1.0 Kg batches of 18-MC active pharmaceutical ingredient (API) for use in the development and manufacture of drug product for future clinical studies, ICH stability testing and IND-enabling in vitro and in vivo GLP studies. Data from Savant's research studies will be used to inform IND-enabling GLP studies using GMP 18-MC. GLP in vitro studies will include bacterial reverse mutation, chromosome aberration in human peripheral blood lymphocytes, p450 using human liver microsomes and cardiac action potential duration in rabbit Purkinje fibers and in vivo mouse micronucleus, all of which will precede larger scale animal toxicology studies. IND-enabling GLP murine toxicology studies will include: a 7-day repeat dose study;a 28-day repeat dose study evaluating low, intermediate and high doses to identify the NOAEL and CNS effects;a respiratory safety study;and a cocaine interaction study. IND-enabling GLP dog toxicology studies will include: a dose finding study;7- and 28-day studies with low, intermediate and high doses to identify the NOAEL;a cocaine interaction study;and a single dose cardiovascular effects study.
Although this proposal is focused on treating cocaine abuse, because no treatment for cocaine abuse currently exists, an innovative aspect of this proposal is that 18-methoxycoronaridine hydrochloride (18-MC) has the potential to treat multiple forms of Substance-Related Disorders (SRDs). Furthermore, in developing 18-MC for clinical use, we are targeting a receptor mechanism and a neuronal pathway not yet explored in medication development. 18-MC truly represents a """"""""paradigm shift"""""""" in the overall approach to treating SRDs. The potential benefit is extraordinary, both in terms of lives saved and economic cost to society.