A Quantitative Epigenetic Test for Guiding Smoking Cessation Therapy

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Smoking is the most common preventable cause of morbidity and mortality in the United States. Each year, smoking causes the premature death of over 450,000 Americans and $200 billion of economic damage. Effective treatment is possible but barriers to its implementation limits the success rate of smoking cessation in the general population to about 5%. Notably, reward based incentive smoking cessation methods could triple or quadruple that abysmal response rate. But their implementation is hindered by a number of factors-most importantly, the lack of a good biomarker for quantifying the decrease of cigarette consumption or reduction in harm (RIH). In a very successful prior R43 project, we demonstrated that methylation at cg05575921, as quantified by our Smoke Signature assay, increases as a function of successful smoking cessation and that DNA methylation at cg05575921 reliably distinguishes non-smokers from smokers (with an AUC of 0.99), and 2) methylation at cg05575921 regresses to mean as a function of the success of smoking cessation. However, our data are incomplete since the cohorts used in this Phase I study were limited in size and ethnic diversity. In this Phase II project, we will confirm and extend those findings into a more generally representative population and develop CLIA compliant processes that can be used to translate this Phase I finding into FDA approved, digital droplet PCR (ddPCR) test (a.k.a Smoke Signature™) for monitoring of smoking cessation. In this Phase II project, we will collect and characterize an ethnically diverse group of 250 subjects as they undergo smoking cessation therapy. We will then determine their DNA methylation as a function of smoking cessation success. From this, we will produce a refined reversion curve that can be used in biomarker guided therapy and create other data for the FDA submission of our assay. Our project will have high commercial and clinical impact because the Smoke Signature™ assay could create the basis for an improved clinical paradigm for the treatment of smoking and be an unambiguous indicator of smoking for civil (e.g. insurance companies etc) assessments of smoking status. Our plan is highly feasible because of Behavioral Diagnostic's control of relevant intellectual property, expertise in clinical epigenetics, an operational ddPCR methylation assay, access to subjects and staff of experienced clinicians. It is innovative because epigenetic techniques have not yet been incorporated into behavioral medicine. The project will led by our Chief Executive Officer, Dr. Rob Philibert, who is an internationally known expert in clinical epigenetics. He will be assisted by a team of co- investigators who are leaders in their fields. We are aided by Bio-Rad, a company that stands to gain from our success. As a direct result, we will create the data to support the submission of the assay to the FDA and a knowledge base for clinicians to assess the success of smoking cessation.