2004 — 2006 |
Watterson, Daniel Martin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Discovery of a New Class of Neuroproductive Compounds @ Northwestern University
DESCRIPTION (provided by applicant): The long-term objective is to develop a new class of small molecule compounds that are neuroprotective and attractive for future drug development. The short term goal is the discovery of compounds that will confer protection from hypoxia-ischemia (HI) induced brain injury, and have the appropriate molecular properties to serve as lead compounds in future drug development. HI induced tissue injury is a major problem across multiple disease areas. HI induced brain injury, such as found in stroke, is of special concern because of the compromised function of individuals who survive as well as the significant number of deaths each year. Currently, there is an unmet need for safe and effective therapies in this major disease area. The clinical presentation of patients is such that the therapeutic window starts four to six hours after trauma, placing a robust demand on candidate new drugs. The spreading of neuronal death away from the site of initial injury in patients and the pathological changes that occur in animal models have focused attention on programmed cell death, but targeting of late stages in the mechanism have proven disappointing. Therefore, targeting early steps in the pathway prior to cell commitment to death is key. Death inducing protein kinases are early in the mechanism, have been identified as potential therapeutic targets, and feasibility studies with kinase inhibitors that cross the blood brain barrier have provided a proof of concept for kinase inhibition preventing HI induced brain injury. We propose to (1) use the co-crystal structures of the target kinase domain containing bound but inactive compounds as the starting point for (2) structure assisted synthetic design, synthesis and testing of focused libraries of potential lead compounds, and (3) validation of final products in an in vivo animal model. We hypothesize that the structure based molecular fragment approach, used in the context of biological considerations of cellular mechanism and clinical needs, will yield the required lead compounds for this high-risk area of research and development. The successful completion will help validate the emerging use of this structure based approach to medicinal chemistry, provide insight into molecular properties key for blood brain barrier penetrance and efficacy in an area of unmet need in CNS discovery chemistry, and generate broadly useful reagents for in vivo signal transduction research.
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1 |
2006 |
Watterson, Daniel Martin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Anti-Neuroinflammatory Ad Therapeutic @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): The goal of this research is to develop a new class of safe and effective therapeutics that alter Alzheimer's disease (AD) progression by targeting activated glia and the resultant neuroinflammation. The hypothesis being tested is that our orally bioavailable, brain-penetrant, novel anti-neuroinflammatory lead compound that shows efficacy in animal models of AD-relevant pathophysiology can be developed further into a set of drug candidates such that a best clinical candidate can be taken to an IND filing by an identified industrial partner at the completion of the proposed investigations. Our novel class of orally bioavailable, CNSselective, small molecule compounds reduce the up-regulated production of the pro-inflammatory cytokines IL-1? and TNF? by activated glia, with a resultant neuroprotection and suppression of AD-relevant pathophysiology progression. The discovery approach is novel and addresses at the front end several of the root causes for late stage drug development failure. The discovery chemistry uses a fragment-based approach in which a focused expansion of an inactive fragment is done based on a rational hierarchal process that is interdisciplinary, employing decision filters assisted by computational biology, synthetic feasibility, and biological screens. Starting one year ago, we applied this approach to the expansion of the inactive 3-amino-6-phenylpyridazine scaffold and developed a novel set of lead compounds with the appropriate molecular properties and function. The lead compound for this proposal is termed MW01-5-188WH. In a mouse model of AD-relevant pathophysiology, daily oral administration of MW01-5-188WH begun three weeks after the start of controlled intracerebroventricular infusion of human A????? suppresses pathophysiology-associated increases in the hippocampus levels of IL-1? and TNF?, resulting in the improvement of synaptic dysfunction, as assayed by biochemical endpoints, and improvement in hippocampal-dependent behavioral deficits. In addition to being orally biovailable, MW01-5-188WH shows good brain uptake and no detectable tissue toxicity at either acute high doses or chronic therapeutic doses. MW01-5-188WH selectively suppresses CMS inflammation versus peripheral inflammation. The proposed studies are for medicinal chemistry optimization of MW01-5-188WH and biological testing of the analogs for retention of efficacy, selectivity, bioavailability, brain uptake and lack of toxicity while improving key molecular properties, such as aqueous solubility, that have been linked to favorable outcomes in translational research and late stage drug development. The optimization strategy utilizes the established and validated platform that led to the development of MW01-5-188WH. This U01 project has highly feasible annual milestones, with the final one being development of a synthetic protocol compatible with GMP synthesis by an FDA compliant contract research organization. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2008 |
Watterson, Daniel Martin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of a Novel Anti-Neuroinflammatory Ad Therapeutic @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): The goal of this research is to develop a new class of safe and effective therapeutics that alter Alzheimer's disease (AD) progression by targeting activated glia and the resultant neuroinflammation. The hypothesis being tested is that our orally bioavailable, brain-penetrant, novel anti-neuroinflammatory lead compound that shows efficacy in animal models of AD-relevant pathophysiology can be developed further into a set of drug candidates such that a best clinical candidate can be taken to an IND filing by an identified industrial partner at the completion of the proposed investigations. Our novel class of orally bioavailable, CNSselective, small molecule compounds reduce the up-regulated production of the pro-inflammatory cytokines IL-1? and TNF? by activated glia, with a resultant neuroprotection and suppression of AD-relevant pathophysiology progression. The discovery approach is novel and addresses at the front end several of the root causes for late stage drug development failure. The discovery chemistry uses a fragment-based approach in which a focused expansion of an inactive fragment is done based on a rational hierarchal process that is interdisciplinary, employing decision filters assisted by computational biology, synthetic feasibility, and biological screens. Starting one year ago, we applied this approach to the expansion of the inactive 3-amino-6-phenylpyridazine scaffold and developed a novel set of lead compounds with the appropriate molecular properties and function. The lead compound for this proposal is termed MW01-5-188WH. In a mouse model of AD-relevant pathophysiology, daily oral administration of MW01-5-188WH begun three weeks after the start of controlled intracerebroventricular infusion of human A????? suppresses pathophysiology-associated increases in the hippocampus levels of IL-1? and TNF?, resulting in the improvement of synaptic dysfunction, as assayed by biochemical endpoints, and improvement in hippocampal-dependent behavioral deficits. In addition to being orally biovailable, MW01-5-188WH shows good brain uptake and no detectable tissue toxicity at either acute high doses or chronic therapeutic doses. MW01-5-188WH selectively suppresses CMS inflammation versus peripheral inflammation. The proposed studies are for medicinal chemistry optimization of MW01-5-188WH and biological testing of the analogs for retention of efficacy, selectivity, bioavailability, brain uptake and lack of toxicity while improving key molecular properties, such as aqueous solubility, that have been linked to favorable outcomes in translational research and late stage drug development. The optimization strategy utilizes the established and validated platform that led to the development of MW01-5-188WH. This U01 project has highly feasible annual milestones, with the final one being development of a synthetic protocol compatible with GMP synthesis by an FDA compliant contract research organization. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2012 |
Watterson, Daniel Martin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of Novel P38 Mapk Inhibitors as Therapeutics For Cns Disorders @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this research program is the discovery of potentially disease-modifying therapies for neurodegenerative disorders. This proposal tests the hypothesis that novel p38 MAPK inhibitors that are orally bioavailable, have good brain uptake, and are non-toxic can be developed into a new class of therapeutics for CNS disorders. The proposed research seeks to develop p38 MAPK inhibitors that can restore pathology associated increased proinflammatory cytokine production toward basal levels with positive neurologic outcomes in animal models. The linkage to the long term goals is that the deliverables emerging from successful completion of the proposed studies will form the foundation of follow-on drug development campaigns for neurodegenerative disorders. Clinical studies have provided a linkage among neurodegenerative disorders, glia activation and increased levels of proinflammatory cytokines, with feasibility studies using macromolecular therapeutics suggestive of a positive clinical effect of proinflammatory cytokine attenuation in Alzheimer's disease. Prior art in animal models has demonstrated a pathophysiology progression role and enhanced sensitivity to synaptic dysfunction and neurologic deficits in animal models where brain proinflammatory cytokine levels are increased. Attenuation of neurologic deficits can be restored by inhibiting the increase in proinflammatory cytokine production. Therefore, an accumulating body of evidence indicates the potential of targeting proinflammatory cytokine up-regulation for attenuation of CNS dysfunction. However, there is an unmet need for bioavailable, CNS-penetrant small molecules amenable to clinical development. We propose to use our integrative drug discovery platform that combines "smart" chemistry with "smart" biology to discover novel lead compounds with attractive physical properties and high potential for CNS penetrance, safety and efficacy, followed by medicinal chemistry refinement into candidates for future clinical development. The molecular target is the serine/threonine protein kinase p381MAPK, a key regulator of proinflammatory cytokine production and an established therapeutic target for peripheral tissue diseases where increased proinflammatory cytokine levels are part of the disease progression mechanism. Specifically, we propose to: design, synthesize, and refine novel p381MAPK inhibitors with potential for oral bioavailability and CNS penetrance; screen compounds to identify orally bioavailable, CNS-penetrant, non-toxic, stable lead compounds that are selective suppressors of increased cytokine production in the brain; and test selected lead compounds for efficacy in Alzheimer's disease-relevant animal models. Successful completion of the proposed investigations will provide a knowledgebase and novel lead compounds for future IND-enabling preclinical toxicology and pharmacokinetics required for initiation of later clinical investigations. PUBLIC HEALTH RELEVANCE Successful completion of the proposed investigations will provide novel, efficacious compounds required for clinical development of new therapies for neurological disorders. [unreadable] [unreadable]
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2008 — 2011 |
Watterson, Daniel Martin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Integrative Chemical Biology of Neurodegeneration: Foundation to Novel Therapies @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Our overall hypothesis is that restoration of up-regulated CNS proinflammatory cytokine production back towards homeostasis can provide attenuation of neurodegenerative disease progression. Specific to this proposal, we hypothesize that this common mechanism of pathophysiology progression can be targeted for decreasing neurodegeneration related to acute brain injury, injury related to chronic neurodegenerative disease, and the contribution of prior acute brain injury to increased susceptibility to the second injury. The three paradigms address disease progression in complex disorders, with the two-hit model addressing prior medical history contributions to later stage disease. The proposed research will use bioavailable, novel small molecule compounds developed in the principal investigator's laboratory to modulate the brain proinflammatory cytokine surge that contributes to hippocampal synaptic dysfunction. The in vivo brain injuries include an acute impact injury as a surrogate for traumatic brain injury (TBI), an Alzheimer's disease (AD)-relevant injury using toxic forms of human Abeta, and a two-hit injury model of TBI followed by a later AD-relevant injury. The pathophysiology progression endpoints include proinflammatory cytokine levels, and the neurological outcomes endpoints include changes in synaptic marker proteins and hippocampus-dependent behavior changes. The two-hit injury studies are a way to explore initially the neglected question of how a prior brain injury can be a susceptibility factor for age-onset AD and other neurological disorders, and to directly address the potential for developing new therapies that alter short and long term outcomes of brain injury on later neurological disease susceptibility, onset and progression. The ability of bioavailable small molecules that attenuate the up-regulation of brain proinflammatory cytokine levels and modulate the neurological outcomes of brain injuries will provide an integrative chemical biology demonstration of the causal relationships between this common pathophysiology mechanism and brain dysfunctions. Successful completion of the proposed studies will provide a firm foundation for future clinical investigations that seek to translate a large body of public health data into potential therapeutic intervention paradigms, and provide an immediate stimulus to ongoing clinical development of new classes of potential disease-modifying therapeutics. PUBLIC HEALTH RELEVANCE: Successful completion of the proposed studies will provide a foundation for immediate translation of basic science into potential disease-modifying clinical interventions using new classes of therapeutics.
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1 |
2009 — 2010 |
Watterson, Daniel Martin |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Drug Discovery Training in Age-Related Disorders @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): We propose to continue an interdepartmental training program for Drug Discovery Training in Age-Related Disorders - a program devoted to providing predoctoral andpostdoctoral scholars with rigorous interdisciplinary training in drug discovery and exposure to multidisciplinary drug development, with a particular focus on age-related diseases. The program is part of the educational activities of the established and successful academic-based Center for Drug Discovery and Chemical Biology (CDDCB). A pioneering aspect of the training program is its emphasis on research training at the interface of structural biology, chemistry, and life sciences, with a strong basic science/clinical interaction. The facilitation of multidisciplinary activities enhances understanding and diagnosis of disease processes as well as the development of fundamental knowledge and tools for intervention. The training program includes 30 basic science and clinical faculty with an established record of cooperation, collaboration, and commitment to mentoring trainees. In addition to a primary preceptor, trainees select a secondary preceptor in a different discipline to provide for an enhanced training experience. To promote the interdisciplinary emphasis of the program, the chosen preceptors should represent at least two of the three overall areas of program emphasis;i.e., structure, chemistry, or biology. The program has a structured curriculum that includes a quarter-long Advanced Topics in Drug Discovery course, training in Ethics, a visiting lecture series, annual symposium, and summer undergraduate research program. Trainees are given opportunities for interaction with individuals from biotech and pharmaceutical companies through program sponsored lectures and workshops, collaborations, participation in the annual symposium and appropriate national scientific meetings. There are also opportunities for international experiences through exchange visits and formalized institutional liaisons. The program provides trainees with a firm foundation to develop their skills as independent scientists with an understanding of the process of drug discovery, and a realistic perspective for how to translate scientific discoveries into clinical applicationsfor age-related disorders. RELEVANCE: Our program addresses a national need for training in translational science, and produces independent investigators prepared to address unmet needs in age-related disorders.
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1 |
2012 — 2016 |
Watterson, Daniel Martin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preclinical Alzheimers Disease Drug Development of Novel Mapk Inhibitors @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the sixth-leading cause of death in the United States, yet it is the only disease among the top 10 without a way to prevent, cure or slow its progression. AD kills more people than diabetes or breast cancer and prostate cancer combined. We hypothesize that AD is a progressive synaptic dysfunction disorder in which the glia-neuron axis is a key player and viable as a therapeutic development paradigm in the search for disease-modifying therapeutics. Appropriate communication and interactions between neurons and glia are key to brain homeostasis, and these dynamics are perturbed in disease. Targeting stressor-induced changes in both glia and neurons that contribute to pathology offers the potential to attenuate disease progression mechanisms present in a diverse array of CNS disorders. Regardless of whether the mechanism is a direct causative one or a contributor to disease susceptibility and onset, small molecule modulators of the process would be a major step in development of therapeutic regimes that add to the armamentarium for intervention. This proposal is focused on the stress-related protein kinase p38? MAPK, a key node in the signal transduction cascades of eukaryotic cells that amplify and transduce stress signals into physiological changes. The kinase is an established drug discovery target for diverse disorders, but only recently has become the focus of CNS drug discovery efforts. The increased pursuit of p38? MAPK as an AD target is due to a combination of landmarks, ranging from the demonstration of kinase activation in human CNS diseases, outcomes from animal model studies, and the demonstration of feasibility for generating CNS-penetrant inhibitors that can improve outcomes in animal models. We propose to use a validated drug discovery engine that successfully delivered novel CNS small molecule drug candidates that progressed to the same IND goal as this proposal and went through first-inhuman phase 1 studies with no adverse events. The specific aims for this project are: Aim 1. Optimize a second-generation inhibitor, MW01-10-181SRM, in order to improve non-GLP ADMET-related properties with retention of target activity, selectivity and in vivo function such that a single candidate can be prioritized for GLP IND-enabling evaluation. Aim 2. Perform GLP preclinical evaluation of a best-in-class candidate compound in order to generate an IND. Aim 3. Submit application for a new molecular entity IND to the FDA for phase 1 first-in-human clinical evaluation in future clinical development. Currently, there are no approved drugs that alter AD pathology progression, and no selective p38? MAPK inhibitor drugs in AD clinical trials (existing preclinical development efforts are focused on multi-kinase inhibitors). Therefore, the proposed development campaign will address scientific gaps in the field, and has the potential to yield novel small molecule candidates for first-in-human studies as deliverables.
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1 |
2015 — 2017 |
Van Eldik, Linda J [⬀] Watterson, Daniel Martin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preclinical Development of a Selective Suppressor of Neuroinflammation For McI/Ad
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the largest global public health crises facing us today, and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent, cure, or slow the progression of disease, and new therapeutic strategies are urgently needed. Our strategy is to target the abnormal glial activation and neuroinflammation that arises early in AD progression and that is becoming of increased interest as a therapeutic target. Dysregulated neuroinflammation responses such as proinflammatory cytokine overproduction from abnormally activated glia are seen early in AD, and are thought to be a key contributor to downstream synaptic dysfunction and cognitive deficits. This raises the possibility that selective targeting of the dysregulated cytokine response may be a useful therapeutic approach. This application seeks three years of support to bring to IND status a novel experimental therapeutic (termed MW151) whose pharmacological mechanism of action is to attenuate disease- and injury-induced proinflammatory cytokine overproduction, thereby reducing downstream synaptic and cognitive dysfunction in multiple animal models of CNS disorders. MW151 is a water-soluble, orally bioavailable, CNS-penetrant, small molecule with outstanding chemical and metabolic stability. MW151 has been extensively de-risked through several non-GLP pharmacological and toxicology screens, and a GMP compatible production scheme has been developed. However, MW151 has not progressed into final GLP preclinical development. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with mild cognitive impairment due to AD. With U01 funding, we will pursue three aims that are milestone-driven with clear Go/No Go decision criteria. Aim 1: Perform preclinical pharmacokinetics and safety assessment of MW151. Aim 2: Produce GMP drug substance (API) and oral drug product. Aim 3: Obtain an IND for future first-in-human clinical investigations. This project will advance development of a promising drug candidate with the potential to prevent the transition to or slow the progression of AD. In addition, successful development of MW151 could have broad clinical applications not only to AD but to a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.
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0.943 |
2019 — 2021 |
Van Eldik, Linda J [⬀] Watterson, Daniel Martin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
First-in-Human Sad & Mad Trials For Mw151, a Novel Alzheimer's Disease Drug Candidate That Attenuates Proinflammatory Cytokine Dysregulation
PROJECT SUMMARY/ ABSTRACT This administrative supplement application to R01 AG061898 requests costs to perform activities that are within the scope of the R01 project, but were unforeseen at the time of award of the grant. The R01 project is to conduct phase 1 clinical studies of MW01-2-151SRM (=MW151), a novel, brain-penetrant, orally bioavailable, small molecule therapeutic candidate for Alzheimer?s disease (AD). MW151 targets a particular form of dysregulated inflammation, injurious proinflammatory cytokine overproduction in the brain, that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. Thus, this project is advancing clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism. Because of the urgent need to develop disease-modifying therapeutic strategies for AD, it is critical to complete the phase 1 safety trials and continue to move MW151 forward in development. This administrative supplement is requested because of two major unforeseen circumstances. First, the conduct of the phase 1a clinical trial was substantially delayed because of COVID-19 restrictions on human studies imposed in March 2020 at the Duke clinical site. This delay has resulted in the necessity for additional drug storage time and longer-term stability testing that were not planned for. Second, the FDA has recently issued a new guidance document in September 2020 related to control of nitrosamine impurities in drugs that we need to address in the MW151 development program. Therefore, we will pursue two specific aims in the supplement. Aim 1: Management of MW151 drug substance and drug product. We will maintain MW151 drug substance and reference standard storage, perform additional re-tests, and do QC and stability tests on the drug substance and the drug product over a longer time frame than originally planned. The plasma samples for MW151 PK measurements will also be stored for longer than anticipated before analysis, so we will need to add two additional stability time points to the validated bioanalytical method. Aim 2: Nitrosamine assessment. Because of the increasing number of approved drugs that have been recalled or put on clinical hold by the FDA because of nitrosamine contamination, the FDA recently issued a guidance document for immediate implementation. Therefore, MW151 API will be subjected to a nitrosamine risk assessment. Depending on the level of risk determined, the presence or absence of nitrosamine(s) will be measured with a validated high resolution, high sensitivity LC-mass spectrometry method. If a nitrosamine contaminant is present at levels above the FDA-recommended Acceptable Intake Limits, then future studies will develop strategies for changes in the manufacturing process to reduce or prevent nitrosamine impurities before MW151 is brought into phase 2 clinical trials.
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0.943 |
2019 |
Shifrin, Victor Watterson, Daniel Martin |
R44Activity Code Description: To support in - depth development of R&D ideas whose feasibility has been established in Phase I and which are likely to result in commercial products or services. SBIR Phase II are considered 'Fast-Track' and do not require National Council Review. |
First-in-Human Study of Mw151, a Novel Drug Targeting Neuroinflammation @ Immunochem Therapeutics, Llc
ABSTRACT Alzheimer's disease (AD) is one of the largest global public health crises facing us today, yet there are no effective therapies available to prevent, delay, or slow AD progression. Dominant approaches based on a set of prevailing core hypotheses about druggable pathways and targets have failed. Therefore, there is a need for novel and alternative pathways distinct from those pursued over the past two decades. Our strategy is to target a particular form of dysregulated neuroinflammation, injurious proinflammatory cytokine overproduction that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek Fast-Track SBIR funding for a first-in-human (FIH) study of MW01-2-151SRM (=MW151), a novel, CNS-penetrant, orally bioavailable, small molecule drug candidate that selectively suppresses stressor- induced proinflammatory cytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses in diverse animal models where proinflammatory cytokine dysregulation is established as a contributor to neurologic injury or susceptibility to neurologic injury. MW151 is chemically and metabolically stabile, has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology screens following ICH/FDA guidance. These include respiratory and cardiovascular safety pharmacology screens, rat and dog 28-day repeat administration toxicology studies, and genotox analyses. Further, a MW151 analog developed for the more demanding i.v. route of administration has been substantially de-risked in a phase 1b clinical trial. Overall, MW151 is a highly de-risked and promising candidate for clinical development as an oral formulation for the treatment of AD or related disorders. Aim 1: Prepare regulatory and other processes for a FIH SAD trial. The tasks include preparation and regulatory approval of required clinical trial documents, and the validation of methods for measurement of MW151 in human plasma. Aim 2: Conduct a single ascending dose (SAD) phase 1a trial of MW151. The SAD study will determine safety and tolerability and maximum tolerated dose of MW151 as well as its pharmacokinetic (PK) profile in a SAD paradigm in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 1b/2a clinical trials. Aim 3: Prepare regulatory and other processes for a multiple ascending dose (MAD) phase 1b trial. We will design a multiple ascending dose (MAD) clinical study of MW151 in healthy volunteers, including a cohort of elderly healthy subjects. This project will advance clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.
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0.91 |
2019 — 2020 |
Watterson, Daniel Martin |
R42Activity Code Description: To support in - depth development of cooperative R&D projects between small business concerns and research institutions, limited in time and amount, whose feasibility has been established in Phase I and that have potential for commercialization. Awards are made to small business concerns only. |
Production and Quality Analysis of Clinical Drug For a Novel Cns Protein Kinase Inhibitor Therapeutic Candidate @ Neurokine Therapeutics, Llc |
0.906 |
2020 — 2021 |
Arancio, Ottavio (co-PI) [⬀] Watterson, Daniel Martin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preclinical Development of a Novel Small Molecule Inhibitor of Alzheimer's Disease-Related Cognitive Impairment @ Northwestern University At Chicago
ABSTRACT Alzheimer's disease and related dementias (AD/ADRD) have a significant societal impact, yet there are no disease modifying interventions. Root causes of prior clinical trial failures provide instruction for plans to reinvigorate the AD/ADRD therapeutic discovery and development process. Specifically, a diversified portfolio of candidate therapeutic approaches is available based on clinical observations, genetic associations, pathology outcomes and biochemical mechanisms. However, many are neglected in terms of funding and technical pursuit. The prior emphasis on a pathology-based pathway can be avoided by retaining a therapeutic emphasis on discrete but complementary aspects of pathophysiology progression mechanisms. Synaptic dysfunction is one example with diverse potential targets. Synaptic dysfunction underlies subtle amnesic changes occurring prior to the development of the classical histopathologic hallmarks. Deteriorated synaptic strengthening is associated with remodeling of various neurotransmitter systems, including cholinergic, noradrenergic, dopaminergic and serotonergic systems. The serotonergic system is both an underexplored therapeutic mechanism and is especially attractive considering that serotonin is more than a neurotransmitter. Further, clinical findings that 5-hydroxytryptamine receptor 2b (5-HT2bR) expression is increased in AD patient brains and that AD patients respond to a non-selective 5-HT2bR antagonist suggest the potential utility of optimized 5-HT2bR antagonists in AD. We developed a small molecule, MW01-8-071HAB (=MW071), that suppresses LTP defects as well as associative and spatial memory in models of amyloid-beta (A?) and tau elevation. Functional screens for off-target agonist and antagonist activity with 158 known GPCRs demonstrated that MW071 is a selective 5-HT2bR antagonist. Importantly, MW071 lacks 5-HT2BR agonist activity. Avoiding agonist activity is landmark. Approved drugs with 5-HT2bR agonist activity have high risk for cardiac valve toxicity, resulting in withdrawal or black box warnings. Therefore, the promising efficacy in AD relevant models, a pharmacological profile that includes highly selective antagonist activity in the absence of agonist activity, and the availability of a back-up candidate (MW109) adds to the overall appeal of MW071 as a starting point. Our proposed early-stage studies will further de-risk MW071 and MW109 in order to generate and qualify a candidate for a future IND-enabling late stage U01 application: Aim 1. Perform secondary pharmacology analyses following FDA guidance, as a necessary prelude and a firm foundation for future GxP IND-enabling preclinical safety and toxicology research. Aim 2. Validate the efficacy of MW071 and MW109 in prevention/reversal of synaptic and memory impairments in AD-relevant animal models. Quantitative milestones will determine progression through Go/No Go decision points. Successful outcomes and deliverables will allow for future support of GxP IND-enabling evaluation and first-in-human assessment.
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