Epigenetic Pharmacotherapy for Addiction

PROJECT SUMMARY
This proposal aims to develop a new small molecule drug to be advanced into human clinical trials for the
treatment of cocaine addiction According to the National Institute on Drug Abuse illicit drug use cost the
United States more than $ billion annually in expenses related to crime lost work productivity and health
care Approximately million Americans aged or older have used cocaine in the past month and cocaine
addiction is an unmet medical need for which there are no adequate FDA approved therapeutics Our team
proposes to develop a CNS penetrant inhibitor of the bromodomain and extraterminal domain BET family of
proteins This will be a first in class drug with a novel innovative mechanism of action that has not been
explored previously in human clinical trials to treat addiction
Our preliminary data demonstrate that BET proteins are upregulated and recruited to promoter regions of
addiction related genes in the nucleus accumbens following repeated cocaine administration and that inhibition
of these proteins with a BET inhibitor attenuates transcriptional and behavioral responses to cocaine Thus
BET inhibitors are potentially breakthrough drugs for treating cocaine seeking and taking behaviors However
currently available BET inhibitors have several limitations poor brain penetration high microsomal clearance
etc and are unsuitable as drugs for CNS related disease This Phase I STTR seeks to address the liabilities
of the currently available BET inhibitors which have limited distribution to brain Epigenetix Inc has identified a
new BET inhibitor EP with significantly improved brain distribution Therefore the goal of the project is
to learn if EP has benefit in the animal models of addiction with adequate safety and tolerability This
proposal has the following Specific Aims Aim will evaluate the efficacy of EP in an animal model of
addiction using intravenous cocaine self administration short and long access procedure In Aim EP
will be evaluated for off target activity against a panel of GPCR ion channels transporters and the cardiac
hERG channel In Aim in vivo CNS safety of EP will be evaluated using a functional observational
battery
The STTR project will transition to an SBIR for the preclinical development of EP The Phase II SBIR will
evaluate the efficacy of EP in non human primate models of addiction assess pharmacokinetics in the
selected non rodent species for toxicology provide IND enabling data and illicit venture capital investment for
potential clinical trials PROJECT NARRATIVE
This research study will investigate novel epigenetic based therapies for the treatment of cocaine seeking and
taking behaviors in animal models of addiction Results from these experiments may lead to new advances in
the treatment of cocaine addiction