GRAND RAPIDS, MI, United States

Tetra Discovery Partners, Llc

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GRAND RAPIDS, MI, United States

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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 991.39K | Year: 2016

The prevalence of major depression is staggering with around of people experiencing depression at some point in their lives The market for antidepressant drugs is expected to grow at a CAGR of to US $ billion by The World Health Organization predicts that by depression will rival heart disease as the health disorder with the highest disease burden in the world The company proposes to develop a new treatment for major depressive disorder based on inhibition of phosphodiesterase B PDE B Uniquely the Tetra drug will address inflammation as a contributor to depression This is a new mechanism of action for an antidepressant drug which should prove complimentary to current therapeutics The company estimates that of patients with depression have co morbid inflammation and will be ideal candidates for the Tetra drug Addressing inflammation will target currently untreatable patients such as those receiving interferon IFN for viral illness depressed patients with co morbid psoriasis inflammatory bowel disease traumatic brain injury or post traumatic stress disorder Given the limitations of current treatments there is a need for new medications with novel mechanisms of action During the course of the SAR campaign funded by the Phase II SBIR Tetra synthesized over compounds representing multiple chemical series The Tetra compounds are allosteric inhibitors of PDE B that act by closing the CR C terminal regulatory domain across the active site As CR is present in all isoforms of PDE B Tetra compounds have similar potency against dimeric long forms as well as monomeric short forms of the enzyme Inhibition of the monomeric short forms of PDE B is needed for anti inflammatory benefit The binding mode of Tetra PDE B inhibitors is supported by multiple co crystal structures of inhibitors bound to PDE B which are used to guide structure based drug design The best compounds to date are highly potent PDE B IC andlt nM up to fold selective against other PDE enzymes and distribute to brain brain plasma ratio up to Lead compounds have antidepressant like benefit in rodent models Minimum Effective Dose mg kg and reduce TNF expression after brain injury The Phase IIB SBIR project will complete chemical optimization of a PDE B inhibitor for use in human with the goal of developing a drug for the treatment of major depression The prevalence of major depression is staggering with around of people experiencing depression at some point in their lives Thus there is a need for new medications with novel mechanisms of action The company proposes to develop phosphodiesterase B PDE B inhibitors with a unique antidepressant anti inflammatory profile for treating depression


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.06M | Year: 2016

Project Abstract Tetra Discovery Partners is seeking Phase II SBIR funding for a multiple ascending dose human Phase clinical trial of BPN to evaluate safety tolerability pharmacokinetic and cognitive profile in healthy young and elderly male and female subjects BPN is a first in class phosphodiesterase D negative allosteric modulator PDE D NAM that targets the protein kinase A cAMP response element binding protein PKA CREB pathway for synaptic plasticity The compound has the potential to show broad cognitive efficacy across a range of neurologic psychiatric and neurodevelopmental disorders Lead indications are the improvement of cognitive function in the elderly with age associated memory impairment and in patients with Alzheimer s disease Prior experience with BPN in a single ascending dose human Phase clinical trial indicates that the compound is absorbed after dosing by an oral route reaches a level in human blood projected to show cognitive efficacy based on animal studies and is well tolerated The clinical objectives of the multiple ascending dose study are the following To evaluate the safety and tolerability profile of multiple oral ascending dose levels of BPN in healthy young yr and elderly andgt yr subjects To characterize the steady state plasma PK profile of BPN following multiple oral administration in healthy young and elderly subjects To provide assessment of the cognitive effect of BPN in healthy young and elderly subjects The study will enroll up to subjects The number of subjects to be enrolled is a balance between the need to establish safety by exposing a limited number of subjects to the experimental drug versus enrolling an expanded number of subjects to explore potential efficacy The study will enroll sufficient subjects to obtain preliminary cognitive data to inform Phase b and Phase a studies but is not powered to detect small changes in cognition that might be clinically relevant in patients Steady state PK parameters will be compared between young subjects and the initial cohort of elderly subjects and an adjustment in dose will be made if needed As this is the first multiple dose study of BPN in humans safety assessment in young subjects is needed before evaluation of the drug in more vulnerable elderly subjects Cognitive assessments will include measures of verbal learning and memory visual learning pattern separation visual paired associate learning and measures of visual and verbal memory with hr delayed recall PDE D is a well validated target for improving cognition through modulation of the PKA CREB pathway for memory consolidation Compared to the assessment of immediate memory there have been few attempts to assess the effects of investigational drugs on longer forms of memory Should the Phase a study provide an indication of cognitive benefit in elderly subjects a larger Phase b trial will be designed to confirm and extend the results of the initial trial in elderly subjects with age associated memory impairment Project Narrative BPN is a novel first in class phosphodiesterase D negative allosteric modulator PDE D NAM being developed to treat cognitive impairment in Alzheimer s disease Currently over million Americans have been diagnosed with Alzheimer s disease while as the world s population ages there will be a quadrupling of patients world wide to million by There is a clear need for additional drugs to improve cognition in Alzheimer s patients beyond those currently available


Grant
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.


Grant
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


Grant
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


Patent
Tetra Discovery Partners, Llc | Date: 2014-09-26

The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.


Patent
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.


Patent
Tetra Discovery Partners, Llc | Date: 2013-10-24

The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of disease.


Patent
Tetra Discovery Partners, Llc | Date: 2015-11-11

The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of disease.


News Article | September 3, 2015
Site: www.finsmes.com

The round was led by Grand Angels Fund II with participation from Invest Michigan, Biosciences Research & Commercialization Center, Muskegon Angels and J &J Investments. The company intends to use the funds to accelerate development as it prepares for clinical trials in Fall 2015. Founded by CEO by Dr. Mark Gurney, Tetra Discovery Partners is developing a platform of drug products to treat cognitive impairment. Tetra drugs target a family of related enzymes known as Type 4 phosphodiesterases (PDE4). The lead drug targeting PDE4D is being developed for treating cognitive impairment in Alzheimer’s disease or schizophrenia with potential applications for Huntington’s disease.

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