Phase I Amount
$1,124,972
This R44 application is focused on preparations for a phase 1b clinical study to look for early clinical signs of efficacy/proof-of-concept by evaluating the response to treatment of relevant serum and CSF biomarkers in a double blinded study of patients with Alzheimer's Disease. The proposed work is designed to support longer term dosing required to see an effect on biomarkers. The prevalence of AD is increasing worldwide. There remains an urgent need for disease modifying drugs for AD that are cost-effective and easy to administer. This program is progressing to fill the need with an economical, disease-modifying drug that is stable, oral, and can be self-administered. If successful, it will have a tremendous impact on the more than 6.5 million Americans who currently have AD (projected to be 12.7 million by 2050) and their caregivers, and will help reduce the current cost of $321 billion (projected to be $1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). We have now completed all preclinical work for our IND application to FDA for our first-in-human phase 1a study. A summary of this work follows: TO-0582 demonstrated pharmacologic activity in two mouse models of tauopathy (the htau model that has human tau with all 6 isomers best representing tau aggregation in AD and in the JNPL3 mouse model that has a P301L mutation and represents four-repeat tauopathies), reasonable pharmacokinetic characteristics, minimal DDI potential, lack/minimal effects on cardiovascular, pulmonary and CNS systems, and a lack of genotoxicity. Relatively modest, non-adverse toxicity was observed in 28-day rat and dog GLP toxicity studies. The no adverse effect level for both the rat and dog 28 day studies were the highest dose tested. Thus, TO- 0582 is an excellent candidate for clinical development for treatment of neurodegenerative diseases. Manufacture of kilogram quantities for non-clinical safety studies (NCSS) and drug pre-formulation work has been completed. A GMP batch was also prepared for the manufacture of our drug product OLX-07010. We are preparing our electronic IND application for our phase 1a study that will be submitted to FDA by mid-April 2022 and anticipate first-in-human studies will begin in June of 2022. The Aims of the proposed program are: Aim 1 Perform 26-weeks oral toxicity study (GLP) in Rats with a four-week recovery period (GLP). This includes scaling up the manufacture of TO-0582 to 5 kg level. Aim 2: Conduct a therapeutic therapeutic efficacy study in TAPP mice; and Aim 3: Conduct an acute therapeutic efficacy study TAPP mice. The second and third Aims will evaluate biomarkers that could translate into the planned Phase 1b clinical AD study and to show efficacy of the compound in a mouse model with tau and amyloid beta pathology, acute and chronic dosing studies will be performed in the tau-APP (TAPP) mice which will support transition of clinical work from healthy volunteers to patients. As the National Institute on Aging is the primary Federal agency for AD research, the development of a DMT for AD, has the highest relevance for its mission.
Public Health Relevance Statement: PROJECT NARRATIVE There is a critical unmet need for a disease-modifying drug for Alzheimer's disease (AD); of the ten leading causes of death in the United States, only AD cannot be prevented, slowed or cured and is increasing in incidence. This program is highly important because it is designed to fill this need with a disease-modifying drug that, if successful, will have a tremendous impact on the more than 6.5 million Americans who currently have AD (projected to be 12.7 million by 2050) and their caregivers, and will also help reduce the current cost of $321 billion (projected to be $1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). This R44 application is focused on conducting 26 week GLP safety studies, and in vivo efficacy studies with translatable biomarker characterization to support a planned Phase 1b clinical study in AD patients designed to provide an early signal that the drug may be effective.
Project Terms: Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Biological Assay; Assay; Bioassay; Biologic Assays; Brain; Brain Nervous System; Encephalon; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cause of Death; Clinical Research; Clinical Study; Diet; diets; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Future; Goals; Human; Modern Man; In Vitro; Incidence; Inflammation; Isomerism; isomer; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung; Lung Respiratory System; pulmonary; Metabolism; Intermediary Metabolism; Metabolic Processes; Transgenic Mice; Mission; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nerve Degeneration; Patients; Pharmacokinetics; Drug Kinetics; Pharmacology; Protein Phosphorylation; Phosphorylation; Sprague-Dawley Rats; Common Rat Strains; Rat; Rats Mammals; Rattus; Research; Development and Research; R & D; R&D; research and development; Safety; Self-Administered; Self Administration; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Technology; Testing; Toxicology; Translating; United States; Work; Neurofibrillary Tangles; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; tangle; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Caregivers; Care Givers; Blinded; method development; Acute; Chronic; Clinical; Phase; Biochemical; Series; Blood Serum; Serum; Recovery; Therapeutic; fluid; liquid; Liquid substance; Research Specimen; Specimen; programs; Kilogram; Event; Oral; System; Amentia; Dementia; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; Cardiopulmonary; American; genotoxicity; Toxicities; Toxic effect; novel; intervention therapy; Therapeutic Intervention; Modeling; Adverse effects; Tauopathies; tau associated neurodegeneration; tau associated neurodegenerative process; tau induced neurodegeneration; tau mediated neurodegeneration; tau neurodegenerative disease; tau neuropathology; tauopathic neurodegenerative disorder; tauopathy; preventing; prevent; small molecule; Dose; Preventive; Age-Months; Data; Therapeutic Studies; Therapy Research; in vivo; Validation; Preparation; Process; Development; developmental; safety study; pre-clinical; preclinical; preclinical study; pre-clinical study; National Institute on Aging; National Institute of Aging; cost; tau aggregation; abnormally aggregated tau protein; filamentous tau inclusion; microtubule associated protein tau aggregation; microtubule associated protein tau deposit; paired helical filament of tau; self-aggregate tau; tau PHF; tau accumulation; tau aggregate; tau fibrillization; tau filament; tau neurofibrillary tangle; tau oligomer; tau paired helical filament; tau polymerization; tau-tau interaction; Ï aggregation; design; designing; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Outcome; cost effective; Prevalence; innovation; innovate; innovative; healthy volunteer; mouse model; murine model; beta amyloid pathology; beta amyloid associated pathology; ß-amyloid pathology; therapy development; develop therapy; intervention development; treatment development; treatment response; response to therapy; response to treatment; therapeutic response; therapy response; Biological Markers; bio-markers; biologic marker; biomarker; pharmacokinetic characteristic; manufacturing scale-up; cognitive testing; cognitive assessment; Formulation; small molecule inhibitor; bioprinting; bio-printing; clinical candidate; efficacy study; preclinical development; pre-clinical development; first-in-human; first in man; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; Alzheimer's disease therapeutic; Alzheimer's therapeutic; Alzheimer's disease patient; Alzheimer's patient
