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 3 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-4B (PDE4B) 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 PDE4B inhibitor beginning 3 months after injury improves multiple domains of learning and memory. PDE4B subtype-selective inhibitors avoid the well-known emetic side-effect of earlier PDE4 inhibitors that inhibit all subtypes of PDE4. Thus, PDE4B 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 PDE4B inhibitor (A-33) which has limited distribution to brain. Tetra has discovered a new series of PDE4B inhibitors with significantly improved brain distribution. Therefore, the goal of the project is to learn if an exemplar of the new family of PDE4B inhibitors (T-094) has benefit in the post-TBI model with adequate safety and tolerability. This proposal has the following three Aims. Aim 1 will evaluate the efficacy of T-094 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 2, T-094 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 3, T-094 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 >50 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-094 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 Statement: 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 4 million Americans suffer from post-TBI cognitive impairment.
Project Terms: Accidental Injury; Address; Adverse effects; Aftercare; American; Animals; Athletic Injuries; base; Brain; Brain Concussion; Brain Injuries; Canis familiaris; Cardiac; Centers for Disease Control and Prevention (U.S.); Chemicals; Chronic; Clinical Trials; Cognition; Cognitive; Cognitive deficits; cognitive performance; conditioned fear; Data; Development; Dose; Drug Kinetics; Emetics; Esters; Evaluation; Family; Ferrets; fluid percussion injury; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; G Protein-Coupled Receptor Genes; Goals; Human; Impaired cognition; improved; In Vitro; in vivo; Inflammatory; inhibitor/antagonist; injured; Injury; innovation; Ion Channel; Joints; Learning; Legal patent; Liquid substance; Medical; Memory; Military Personnel; Modeling; Monkeys; National Institute of Mental Health (U.S.); novel; P-Glycoprotein; Paralysed; Patients; PDE4B; Percussion; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Post-Concussion Syndrome; pre-clinical; Preclinical Drug Evaluation; Principal Investigator; Prodrugs; programs; Property; Psychotropic Drugs; public health relevance; Rattus; Risk; Rolipram; Safety; Series; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; success; Therapeutic; Therapeutic Agents; Therapeutic Index; therapeutic target; Toxicology; Traumatic Brain Injury; Universities; Vomiting; Water
