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GRAND RAPIDS, MI, United States

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

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

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 346.24K | Year: 2015

Tetra Discovery Partners is the recipient of an NIH Blueprint Neurotherapeutics Network award to develop phosphodiesterase D PDE D Negative Allosteric Modulators NAMs for treating memory loss in patients affected by psychiatric and neurologic diseases The Tetra NIH Blueprint drug is projected to reach human Phase I clinical trials in late Through a Cooperative Research and Development Agreement CRADA with Dr Robert Innis and Dr Victor Pike of the NIMH Intramural Program the company has been working in parallel to develop novel PET ligands for imaging PDE subtypes in the human brain The goal of the proposed Phase I SBIR is to develop a PDE D PET ligand useful for assessing target occupancy in human Phase I clinical trials of the Tetra NIH Blueprint drug as well as a PET ligand that will be useful for assessing PDE D levels in patients with psychiatric and neurologic disease PDE D as a target for improving cognition in humans has genetic validation through studies of children with PDE D gene mutations who develop an ultra rare disorder known as acrodysostosis type ACRDY MIM ACRDY is a developmental disorder characterized by intellectual disability brachydactyly nasal hypoplasia and short stature Children with acrodysostosis only achieve an IQ of Thus PDE D is the human ortholog of the Drosophila PDE gene in which the Dunce mutation was the first learning mutation identified in a model organism Rolipram and other PDE inhibitors have been shown to be broadly pro cognitive in numerous animal models of learning and memory while knock out or knock down of the mouse PDE D gene also improves learning and memory Our NIMH collaborators Innis and Pike have shown that PDE PET imaging is altered in patients with major depression Those studies used C R rolipram as a PET ligand for assessing PDE levels however rolipram binds equally to the different subtypes of PDE expressed in brain PDE A PDE B andamp PDE D We therefore want to understand if PDE D levels are altered in major depression and other psychiatric diseases In the Phase I SBIR Tetra will optimize potent and selective PDE D NAMs for C or F labelling by Innis and Pike who will conduct in vivo PET imaging studies Should a suitable PDE D PET ligand be identified the imaging agent could rapidly advance into human clinical trials PUBLIC HEALTH RELEVANCE The company has developed a mechanistically novel class of drugs to address cognitive impairment across multiple psychiatric and neurological indications These new drugs are Negative Allosteric Modulators NAMs of phosphodiesterase D PDE D The SBIR project will develop a PDE D selective PET ligand to be used in human Phase I clinical trials of the cognition drug to assess PDE D target occupancy

University of Miami and Tetra Discovery Partners, Llc | Date: 2013-03-13

Provided herein are methods of improving cognitive ability or memory in a subject that has suffered a brain injury or spinal cord injury by administering a selective PDE4 B inhibitor.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 698.83K | Year: 2011

DESCRIPTION (provided by applicant): The broad goal of the SBIR proposal is to understand the pharmacology of phosphodiesterase 4 (PDE4) allosteric modulation in the CNS as it relates to psychiatric disorders. We recently described the discovery of isoform-selective, allosteric modulators of PDE4D that bind to a high affinity site on an N-terminal regulatory domain known as Upstream Conserved Region 2 (UCR2). The allosteric mechanism of action prevents the compounds from completely inhibiting cAMP hydrolysis, thereby reducing target-based toxicity. PDE4D modulators have greatly improved tolerability than earlier compounds such as rolipram. Rolipram previously was shown to have anti-depressant activity in human Phase II clinical trials but was poorly tolerated due to emesis. Three isoforms of PDE4 are expressed in brain (PDE4A, B and D). It previously has not been possible to develop isoform-selective PDE4 inhibitors, since earlier efforts have targeted the catalytic site, which is highly conserved among the PDE4 subtypes; thus, little is known regarding the pharmacology of PDE4 isoform selective compounds. Our immediate goal is to explore the possible clinical benefit of our investigational new drug, DG-071 in animal models of psychiatric disease, particularlydepression. The proposed studies will determine the feasibility of developing DG-071 for the treatment of depression. The second specific aim of the SBIR proposal is to use structural guidance to design PDE4B selective allosteric modulators that distribute to brain. We will explore PDE4B CNS pharmacology, particularly in models of schizophrenia. The structural and medicinal chemistry studies will determine the feasibility in a Phase II SBIR of developing PDE4B selective allosteric modulators for psychiatric disorders. PUBLIC HEALTH RELEVANCE: Severe forms of depression affect 2-5% of the US population, and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. We are seeking to develop a new treatment fordepression based on allosteric modulation of phosphodiesterase 4D.

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Invest Michigan announced this week that it has invested $275,000 in four early-stage tech startups through the Michigan Pre-Seed Fund 2.0. The four startups also secured co-investments worth $3.4 million from private investors, far exceeding the minimum 1:1 matching funds required by Invest Michigan. “All of the startups we funded look like very promising companies with very strong management,” says Charlie Moret, president and CEO of Invest Michigan. “We look at it as the beginning of a relationship, and we hope to grow with them.” —AdAdapted, $25,000: Based in Ann Arbor, AdAdapted has created a mobile advertising platform that delivers brand messaging without taking the user outside the app. —Denovo Sciences, $125,000: Plymouth’s Denovo Sciences is a cancer diagnostics company developing tools, like liquid biopsies, that detect cancer cells with greater sensitivity than standard approaches. —Tetra Discovery Partners, $100,000: Grand Rapids-based Tetra Discovery is a biotech startup working on a new drug which targets schizophrenia, depression, and other cognitive issues by enhancing memory formation in the brain’s neurons. (Watch for our profile of Tetra Discovery Partners later this week.) “To have the diversity of technology represented by these four companies is pretty exciting,” Moret says. “It’s indicative of the startups occurring here in Michigan. The fund is still very new; to partner with these companies and help with their financing and support as they grow is very exciting for us.” Moret says the $6.8 million Michigan Pre-Seed Fund 2.0, established earlier this year, has gotten more than 60 inquiries so far from startups in need of investment capital. He says the fund will often make relatively small investments as part of a larger, syndicated round. “We’re trying to find companies that demonstrate sustainability in both their technology and business models,” Moret adds. “So far, we’re finding great opportunities. By year’s end, we expect to announce a few more.”

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