KDAc Therapeutics, Inc. — Department of Health and Human Services SBIR Phase I: R43

Description

DESCRIPTION provided by applicant Drug addiction is a serious and growing public health problem in the US Combining medications with cognitive behavioral therapy CBT is an effective way for patients to attain and sustain abstinence yet current safe medications are limited and there are no FDA approved therapeutics for cocaine addiction where CBT alone has poor success and relapse rates are high Histone deacetylase HDAC inhibitors such as SAHA Vorinostat or sodium butyrate facilitate extinction of drug seeking in animal models consistent with the growing understanding of epigenetic mechanisms in learning and memory and providing proof of concept for such a pharmacotherapeutic approach The problem is that all FDA approved and current pre clinical HDAC inhibitors are a not sufficiently isoform selective inhibiting many of the HDAC isoforms b not safe for non oncological application toxicity driven by both HDAC inhibition and off target effects and c have poor CNS drug like properties Highly isoform selective HDAC inhibitors are needed to mitigate these risks and increase the therapeutic window We believe HDAC is the best target as genetic or pharmacological inhibition of HDAC persistently enhances long term memory Furthermore blocking HDAC pharmacologically or genetically enhances extinction of drug seeking behavior and blocks reinstatement Preliminary Data KDAc Therapeutics is developing novel highly optimized selective HDAC inhibitors and our lead development candidate KDAC has been extensively characterized in vitro and in vivo Its preliminary pre clinical ADME PK toxicological profile coupled with good CNS drug properties and initial efficacy in learning and memory paradigms enables its use in definitive proof of concept studies in animal models of drug addiction Hypothesis We hypothesize that KDAC or other KDAc compounds when delivered at relatively safe exposure levels will enhance extinction of drug seeking behavior in rodent models revealed as effects on rate of extinction across days and persistence of extinction against reinstatement challenges Specific Aims Evaluate KDAC in vivo efficacy and target engagement in two rodent models of addiction Develop and characterize second generation nd gen novel compounds focusing on improved HDAC selectivity potency and CNS drug like properties and Evaluate optimal nd gen compounds for in vivo efficacy and measure select surrogate markers to correlate behavioral effects with HDAC target engagement This Phase I study will allow us to determine the feasibility of HDAC selective inhibition and demonstrate definitive proof of concept in models of drug addiction Specifically we aim to establish robust efficacy with an HDAC selective KDAc compound and will define both the necessary compound attributes needed for efficacy and the therapeutic window and identify a suitable development candidate as co therapy to prevent relapse of drug addiction PUBLIC HEALTH RELEVANCE Extensive brain research has deepened our understanding of the circuitry underlying many complex behaviors revealing that drug addiction can also be viewed as a disease of learning and memory with classic Pavlovian conditioning at play essentially reinforcing the behaviors of drug addiction and helping explain the neurobiological challenges of attaining and sustaining drug abstinence when reliant solely on cognitive behavioral therapy CBT One key process of memory formation that neurobehavioral research has identified and implicated in drug addiction is that of extinction KDAc Therapeutics has developed compounds that enhance memory extinction and could potentially help prevent relapse in drug addiction thus we seek to investigate these compounds in animal models of drug seeking behavior