PROJECT SUMMARY Cigarette smoking is a significant public health concern impacting 34 million adults in the USA by increasing their risk for cancer and cardiovascular disease, including 16 million living with chronic smoking-related diseases. National campaigns for smoking cessation have been promoted by public authorities, and other groups. In addition, pharmaceutical-grade nicotine replacement therapy (NRT) products have been developed to assist with cessation (gums, lozenges, patches, etc.). Sadly, current standard NRT dosing is not effective for many smokers since nicotine is provided at much lower doses than cigarettes. Many smokers switched to using e-cigarettes (ECs) with cartridges (electronic nicotine delivery systems or ENDS). ENDS closely mimic the act of smoking and provide rapid nicotine dosing that can be scaled back manually. Recent studies have shown limited effectiveness data in support of the continued use of EC in smoking cessation plans, but more data are needed. Hence, effectiveness must still be improved for NRTs since addiction is complex, and current NRTs lack similar nicotine dosing and sensorimotor mimicking compared to smoking cigarettes. This highlights a significant, unmet clinical need for an NRT combining the behavioral aspects of smoking with automated nicotine dosing. Hava Health Inc. leverages these behavioral aspects with flavorless formulations and automated, gradual nicotine reduction controlled by an app to improve smoking cessation. Therefore, the goal of this Phase I project is the development of Have Health’s Hale Vaporizer System, a proprietary NRT using an automated ENDS including the Hale vapor device, flavorless nicotine formulations, and a phone app that automatically lowers nicotine intake gradually over time. For Specific Aim 1, testing will be conducted of the Hale vaporizer’s performance and aerosol safety profile with a finished version of the device. This will include device safety testing in aerosolizing custom nicotine and non-nicotine formulations. In Specific Aim 2, a limited in vivo dose-range finding study to translate former findings to a more clinically relevant model. Studies will be initiated in rats introduced to aerosol via smoke machines, in a repeat dose nose-only inhalation toxicology study. At specified time points post exposure to vapor, we propose collecting and testing: a) blood for nicotine concentration b) lung tissue for toxic or tissue specific effects. To our knowledge, no commercially available NRT is available using flavorless nicotine formulations and an automated electronic delivery system that is not manually adjusted by the patient. The proposed studies are necessary for further development of the Hale Vaporizer System into a best-in-class NRT to help improve compliance by aiding smokers along the path to smoking cessation in a timely manner.

PROJECT NARRATIVE To combat the deleterious effects of cigarette smoking and to improve the effectiveness of smoking cessation efforts, Hava Health Inc. developed the Hale Vaporizer System, a proprietary nicotine replacement therapy (NRT) using an automated electronic nicotine delivery system. This innovative system contains the Hale vapor device, flavorless nicotine formulations, and a phone application that automatically lowers nicotine intake gradually over time, while minimizing nicotine withdrawal symptoms. In this proposal, Hava aims to address the unmet clinical need for an NRT combining the behavioral aspects of smoking with automated, gradual nicotine reduction by testing the performance of the Hale vaporizer prototype and pod formulations, and aerosol effects in vivo to improve the delivery system.