Tetra Discovery Partners, Inc. — Department of Health and Human Services STTR Phase I: 106

Description

DESCRIPTION provided by applicant This proposal will develop a new small molecule drug to be advanced into human clinical trials in the chronic post TBI patient who still has chronic cognitive impairments months to years after the initial TBI According to the Centers for Disease Control approximately million Americans suffer from post TBI cognitive impairments This includes people sustaining multiple concussions due to sports injury Armed Forces personnel post deployment with post concussive syndrome and persons sustaining accidental injury This is an unmet medical need for which there is no adequate therapeutic agent Our team proposes to develop a phosphodiesterase B PDE B inhibitor as a therapeutic for post TBI cognitive impairment This will be a first in class drug with a novel innovative mechanism of action against a therapeutic target that has not been explored previously in human clinical trials Our preliminary data demonstrate that treatment of brain injured rats with a PDE B inhibitor beginning months after injury improves multiple domains of learning and memory PDE B subtype selective inhibitors avoid the well known emetic side effect of earlier PDE inhibitors that inhibit all subtypes of PDE Thus PDE B inhibitors are potentially breakthrough drugs for treating chronic cognitive deficits after TBI with improved tolerability This Phase I STTR seeks to address limitations of the current PDE B inhibitor A which has limited distribution to brain Tetra has discovered a new series of PDE B inhibitors with significantly improved brain distribution Therefore the goal of the project is to learn if an exemplar of the new family of PDE B inhibitors T has benefit in the post TBI model with adequate safety and tolerability This proposal has the following three Aims Aim will evaluate the efficacy of T in a rat TBI model Multiple memory tasks and domains of memory will be evaluated Go No Go criteria for success will be improvement in cognitive performance in comparison to TBI animals treated with vehicle In Aim T will be evaluated for off target activity against a panel of GPCR ion channels transporters and the cardiac hERG channel Go No Go criteria for success will be acceptable safety margin based on anticipated brain exposure for efficacy In Aim T will be assessed for tolerability in the ferret emesis model to determine the no observable effect level NOEL for emesis Go No Go criteria will be a Therapeutic Index of andgt fold comparing plasma and brain exposure at the NOEL for emetic tolerability in ferret versus plasma and brain exposure that improves cognition in post TBI rats The Phase II project will transition to an SBIR for the evaluation of T in additional TBI models compare metabolite profiles in species to conduct toxicological assessments assess pharmacokinetics in non rodent species and to complete dose range finding toxicological studies in rat PUBLIC HEALTH RELEVANCE In this STTR Tetra Discovery Partners and the University of Miami Project to Cure Paralysis propose to develop a drug to develop a new small molecule drug to be advanced into human clinical trials in the post TBI patient that is patients who sustained traumatic brain injury months to years earlier and who still have chronic cognitive impairment Approximately million Americans suffer from post TBI cognitive impairment