Mark E. Gurney - US grants

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 &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, particularly depression. 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 for depression based on allosteric modulation of phosphodiesterase 4D.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an increasing medical burden due to the aging demographics of the US population. The most common form of dementia among older adults, AD affects parts of the brain important for memory formation and retrieval, seriously impairing a person's ability to live independently and cope with daily activities. In collaboration with the NIH Blueprint Neurotherapeutics Program, we seek to develop phosphodiesterase Type 4 (PDE4) allosteric modulators for improving cognition in accordance with the Target Product Profile below. Ideally, the therapeutic will improve cognition in MCI patients and impact AD pathophysiology, thereby slowing conversion to probable AD. Drug PropertiesMinimum Acceptable ResultIdeal ResultPrimary Drug IndicationImprovement of cognition in persons with Mild Cognitive Impairment (MCI) due to probable ADSlowing of conversion from MCI to probable ADPatient PopulationPatients with MCI due to probable AD according to the NIAA/AA working group criteriaPatients with MCI due to probable AD according to the NIAA/AA working group criteriaDelivery ModeOralOralTreatment DurationChronicChronicRegimenOral, once dailyOral, once daily

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 & 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, particularly depression. 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.

DESCRIPTION (provided by applicant): Tetra Discovery Partners proposes to develop a new treatment for major depressive disorder based on inhibition of phosphodiesterase 4B (PDE4B). 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. Addressing inflammation will target currently untreatable patients, such as those receiving interferon-a (IFNa) 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. The prevalence of major depression is staggering with around 20% of people experiencing depression at some point in their lives. The company estimates that 10-20% of patients with depression have inflammation and will be ideal candidates for the Tetra drug. The market for antidepressant drugs is expected to grow at a CAGR of 3.2% to US $10.9 billion by 2018. The World Health Organization predicts that by 2020, depression will rival heart disease as the health disorder with the highest disease burden in the world. The Phase II SBIR project will complete chemical optimization of a PDE4B inhibitor for use in human and the preclinical safety and toxicity studies needed for filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) for human clinical trials in major depression.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an increasing medical burden due to the aging demographics of the US population. The most common form of dementia among older adults, AD affects parts of the brain important for memory formation and retrieval, seriously impairing a person's ability to live independently and cope with daily activities. In collaboration with the NIH Blueprint Neurotherapeutics Program, we seek to develop phosphodiesterase Type 4 (PDE4) allosteric modulators for improving cognition in accordance with the Target Product Profile below. Ideally, the therapeutic will improve cognition in MCI patients and impact AD pathophysiology, thereby slowing conversion to probable AD. Drug PropertiesMinimum Acceptable ResultIdeal ResultPrimary Drug IndicationImprovement of cognition in persons with Mild Cognitive Impairment (MCI) due to probable ADSlowing of conversion from MCI to probable ADPatient PopulationPatients with MCI due to probable AD according to the NIAA/AA working group criteriaPatients with MCI due to probable AD according to the NIAA/AA working group criteriaDelivery ModeOralOralTreatment DurationChronicChronicRegimenOral, once dailyOral, once daily

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an increasing medical burden due to the aging demographics of the US population. The most common form of dementia among older adults, AD affects parts of the brain important for memory formation and retrieval, seriously impairing a person's ability to live independently and cope with daily activities. In collaboration with the NIH Blueprint Neurotherapeutics Program, we seek to develop phosphodiesterase Type 4 (PDE4) allosteric modulators for improving cognition in accordance with the Target Product Profile below. Ideally, the therapeutic will improve cognition in MCI patients and impact AD pathophysiology, thereby slowing conversion to probable AD. Drug PropertiesMinimum Acceptable ResultIdeal ResultPrimary Drug IndicationImprovement of cognition in persons with Mild Cognitive Impairment (MCI) due to probable ADSlowing of conversion from MCI to probable ADPatient PopulationPatients with MCI due to probable AD according to the NIAA/AA working group criteriaPatients with MCI due to probable AD according to the NIAA/AA working group criteriaDelivery ModeOralOralTreatment DurationChronicChronicRegimenOral, once dailyOral, once daily

? 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 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.

Tetra Discovery Partners is the recipient of an NIH Blueprint Neurotherapeutics Network award to develop phosphodiesterase-4D (PDE4D) 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 2015. 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 PDE4 subtypes in the human brain. The goal of the proposed Phase I SBIR is to develop a PDE4D 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 PDE4D levels in patients with psychiatric and neurologic disease. PDE4D as a target for improving cognition in humans has genetic validation through studies of children with PDE4D gene mutations who develop an ultra-rare disorder known as acrodysostosis type-2 (ACRDY2; MIM 600129). ACRDY2 is a developmental disorder characterized by intellectual disability, brachydactyly, nasal hypoplasia and short stature. Children with acrodysostosis only achieve an IQ of 50-80. Thus, PDE4D is the human ortholog of the Drosophila PDE4 gene in which the Dunce mutation was the first learning mutation identified in a model organism. Rolipram and other PDE4 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 PDE4D gene also improves learning and memory. Our NIMH collaborators, Innis and Pike, have shown that PDE4 PET imaging is altered in patients with major depression. Those studies used C-11 (R)-rolipram as a PET ligand for assessing PDE4 levels, however, rolipram binds equally to the different subtypes of PDE4 expressed in brain (PDE4A, PDE4B & PDE4D). We therefore want to understand if PDE4D levels are altered in major depression and other psychiatric diseases. In the Phase I SBIR, Tetra will optimize potent and selective PDE4D NAMs for C-11 or F-18 labelling by Innis and Pike who will conduct in vivo PET imaging studies. Should a suitable PDE4D PET ligand be identified, the imaging agent could rapidly advance into human clinical trials.

Project Abstract Tetra Discovery Partners is seeking Phase II SBIR funding for a multiple ascending dose, human Phase 1 clinical trial of BPN14770 to evaluate safety, tolerability, pharmacokinetic and cognitive profile in healthy young and elderly male and female subjects. BPN14770 is a first-in-class phosphodiesterase-4D negative allosteric modulator (PDE4D-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 BPN14770 in a single ascending dose, human Phase 1 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: 1. To evaluate the safety and tolerability profile of multiple oral ascending dose levels of BPN14770 in healthy young (21-45 yr) and elderly (>65 yr) subjects. 2. To characterize the steady state plasma PK profile of BPN14770 following multiple oral administration in healthy young and elderly subjects. 3. To provide assessment of the cognitive effect of BPN14770 in healthy young and elderly subjects. The study will enroll up to 84 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 1b and Phase 2a 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 BPN14770 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 24 hr delayed recall. PDE4D 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 1a study provide an indication of cognitive benefit in elderly subjects, a larger Phase 1b trial will be designed to confirm and extend the results of the initial trial in elderly subjects with age-associated memory impairment.

The prevalence of major depression is staggering with around 20% of people experiencing depression at some point in their lives. The market for antidepressant drugs is expected to grow at a CAGR of 3.2% to US $10.9 billion by 2018. The World Health Organization predicts that by 2020, 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 4B (PDE4B). 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 10-20% 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 400 compounds representing multiple chemical series. The Tetra compounds are allosteric inhibitors of PDE4B that act by closing the CR3 C-terminal regulatory domain across the active site. As CR3 is present in all isoforms of PDE4B, 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 PDE4B is needed for anti-inflammatory benefit. The binding mode of Tetra PDE4B inhibitors is supported by multiple co-crystal structures of inhibitors bound to PDE4B which are used to guide structure-based drug design. The best compounds to date are highly potent (PDE4B IC50 < 10 nM), up to 300 fold selective against other PDE4 enzymes, and distribute to brain (brain/plasma ratio up to 6.7). Lead compounds have antidepressant-like benefit in rodent models (Minimum Effective Dose = 0.01-0.1 mg/kg) and reduce TNF expression after brain injury. The Phase IIB SBIR project will complete chemical optimization of a PDE4B inhibitor for use in human with the goal of developing a drug for the treatment of major depression.

Tetra Discovery Partners is submitting a Phase II SBIR application to develop a phosphodiesterase-4D (PDE4D) PET tracer for imaging the distribution of the enzyme in human brain. Tetra is a clinical stage biotechnology company that is developing BPN14770, a PDE4D negative allosteric modulator (PDE4D-NAM), as a treatment for cognitive impairment in Alzheimer?s disease, other dementias and psychiatric disorders including schizophrenia and major depressive disorder (MDD). Human studies with the PDE4D PET tracer may benefit patients by improving understanding of how changes in cAMP signaling and altered regulation of PDE4 subtypes contribute to the pathophysiology of disease. The PET tracer will be useful for determining the dose of BPN14770 to be used in pivotal human clinical trials by assessing PDE4D target occupancy in brain. The target occupancy study adds value to the BPN14770 neurotherapeutic and is a critical gate keeper for partnering the drug program with a larger pharmaceutical company. Tetra has completed a successful Phase I SBIR in which a lead PET tracer has been developed that shows specific, displaceable binding to PDE4D in rhesus monkey brain. PET imaging was performed in monkeys as only primate PDE4D contains a key phenylalanine residue on the UCR2 regulatory domain required for PDE4D subtype selectivity. The PET imaging study revealed an intriguing pattern of specific PDE4D binding in regions of the brain known to be important for cognition, namely prefrontal cortex, temporal cortex and hippocampus. However, accumulation of radiolabeled metabolites precludes further advancement of the compound. The Phase II SBIR proposes a straightforward chemical optimization strategy to address this issue. The goal of the Phase II SBIR is to optimize a PDE4D PET ligand for advancement into human clinical trials.

Under the parent grant, Tetra Discovery Partners is developing phosphodiesterase 4B (PDE4B) allosteric inhibitors as a treatment for major depressive disorder. 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 10-20% 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. The supplemental fund request will allow the company to assess the benefit of lead PDE4B allosteric inhibitors in preclinical mouse models of Alzheimer?s disease.