This application, in response to PAR-18-219 `Grand Opportunity in Medications Development for Substance-use Disorders', proposes to advance the IND-enabling development of a novel small-molecule drug candidate with a novel first-in-class mechanism as pharmacotherapy for smoking cessation, relapse prevention and longterm abstinence. Relapse to smoking is very common after initial abstinence with pharmacotherapy and represents a major clinical challenge. 24-week abstinence rates for all three available pharmacotherapies is still poor and averages only 22% for varenicline, 16% for bupropion, and 16% for nicotine replacement therapies, compared to 9% for placebo. These poor abstinence rates with current pharmacotherapies are inadequate for overall tobacco harm reduction, given that tobacco use still remains the leading preventable cause of death and morbidity in the developed world. Despite the clear need and possible high impact, there have been no new pharmacotherapy approved for smoking cessation for over a decade since varenicline's approval. There is a crucial need for new approaches and new pharmacotherapy that reduce craving and relapse and can promote sustained abstinence. This application aims to advance the IND development of a novel pharmacotherapeutic with a new first-in-class mechanism for relapse prevention and smoking cessation, that has shown distinctive preclinical efficacy in decreasing cue-induced, stress-induced and nicotine-induced relapse and nicotine self-administration. The lead drug candidate is a new molecular entity targeting a new pharmacological mechanism, the ?3?4 nicotinic acetylcholine receptor (nAChR). The ?3?4 nAChR clearly plays a role in nicotine dependence and drug relapse mechanisms, and genome-wide association studies in a large population of smokers reveal that polymorphisms in the genes encoding the ?3, ?4 and ?5 subunits of the nAChR are linked to increases in risk for nicotine dependence and inability to quit. The lead candidate proposed for development is selected from a novel series of highly potent and selective ?3?4 nAChR ligands, which to our knowledge, are some of the most selective ?3?4 nAChR ligands reported. Importantly, their excellent in vivo efficacy for blocking reinstatement of nicotine seeking (a model of relapse), strongly suggests that targeting the ?3?4 nAChR may provide a superior profile over existing treatments, particularly for improving longterm abstinence and preventing relapse. We have completed several preclinical toxicology and DMPK studies that confirm the suitability of the lead candidate for IND-enabling studies. We propose to continue the development and file an IND to enable the assessment of the safety and efficacy of this first-in- class mechanism in human clinical trials. With our results thus far, we anticipate that we will be able to advance the future clinical development of this drug candidate into a successful smoking cessation medication and a safe effective option for quitting and sustaining long-term abstinence.
PUBLIC RELEVANCE The goal of this application is to advance the development of a new smoking cessation pharmacotherapy, with a new mechanism that addresses the current gap in treatment, viz relapse to smoking and poor abstinence rates seen after 1 year of quitting. This project is of high significance because the proposed medication is targeted to a subtype of the nicotinic receptors that are genetically associated with increased smoking behavior and inability to quit. These new medication candidates show superior efficacy in inhibiting nicotine taking and relapse in animal models, and may have a better outcome than existing treatments for maintenance of abstinence and prevention of relapse. Such new approaches are urgently needed, since the current repertoire of smoking cessation medications are not approved for longer term treatment due to safety concerns and have less than 45% quit success and even poorer abstinence (high rates of relapse) post 6 months. This application seeks support for the development of a novel drug candidate through an Investigational New Drug filing to enable testing in human clinical trials.
