Phase I Amount
$1,337,363
Women are at greater life-time risk for Alzheimer's disease (AD). One potential factor contributing to greater life-time risk of AD is the midlife menopausal endocrine aging transition when multiple AD risk conditions can emerge and which are consistent with prodromal / preclinical features of the disease. While estrogen or hormone therapy administered when menopausal women are symptomatic could reduce risk of AD, the fear of breast cancer leads many women to forego this approach. An innovative alternative to estrogen therapy is to target estrogen action in brain while avoiding estrogen-associated proliferation in breast tissue. To achieve that goal, we propose Phase 2 clinical development of "PhytoSERM", a selective estrogen receptor beta (ERÃ) modulator that promotes estrogenic action through ERÃ in brain while inhibitory in reproductive tissue. PhytoSERM is a rationally designed formulation of 3 phytoestrogens (each are Generally Recognized as Safe by the FDA). Our earlier NIA supported PhytoSERM Phase 1b/2a clinical trial determined that PhytoSERM was safe and well-tolerated, exhibited predictive pharmacokinetics in peri- and postmenopausal women and identified responder phenotype (https://clinicaltrials.gov/ct2/show/NCT01723917). Proposed herein is a Phase 2, double-blind, parallel-group, randomized, placebo-controlled clinical trial with an open-label extension to determine efficacy of PhytoSERM in symptomatic peri- and post-menopausal women. Primary objectives are to determine the efficacy of PhytoSERM to alleviate menopausal symptoms, mainly hot flashes. Secondary objectives are to evaluate the effect of PhytoSERM on: 1) cognitive function, 2) sleep disturbances, and 3) non-neurologic menopausal symptoms, including bone mineral density and body composition. Tertiary objectives are to determine impact of PhytoSERM on blood-based AD biomarkers. This Phase 2 PhytoSERM clinical trial addresses multiple strategic directions of the National Institutes on Aging's 2020-2025: Aging Well in the 21st Century ref Specifically, Goal C-3 to: "Develop effective interventions to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases" and "Conduct clinical studies / translation of new interventions to the clinical setting." Goal D-4: Translate basic discovery into effective treatment and/or prevention strategies for AD/ADRD and" Goal F-4: Support research on women's health." PhytoSERM clinical trial also contributes to achieving the National Alzheimer's Disease Act (NAPA) to effectively prevent and treat AD by 2025 Goal 1B. PhytoSERM addresses a critical unmet need in women's health to reduce risk of Alzheimer's in later life.
Public Health Relevance Statement: PROJECT NARRATIVE Women are at greater lifetime risk for Alzheimer's disease (AD). One potential contributing factor is the midlife neuroendocrine aging transition. PhytoSERM addresses a critical unmet need in women's health for an alternative hormone therapy that is both safe and efficacious for menopausal symptoms and to reduce risk of AD later in life.
Project Terms: aberrant sleep; disrupted sleep; disturbed sleep; impaired sleep; irregular sleep; sleep disruption; sleep dysregulation; Protein Isoforms; Intervention; Participant; Prevention strategy; Modeling; Perimenopause; response; Hot flushes; reproductive; Estrogen Receptor beta; Animal Model; Toxic effect; Selective Estrogen Receptor Modulators; Cell Body; pharmacokinetics and pharmacodynamics; ages; advanced age; elders; geriatric; late life; later life; older adult; Formulation; older person; senior citizen; Bone Mineral Density; rational design; Brain Nervous System; Encephalon; Blood Reticuloendothelial System; Breast Cancer; malignant breast tumor; Alzheimer's disease related dementia; Alzheimer's disease biomarker; Clinical Study; Alternative Health; clinical development; lipidomics; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; oral supplementation; randomized placebo-controlled clinical trial; 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; associated symptom; safety and feasibility; brain health; blood-based biomarker; estrogenic; Therapy Clinical Trials; Cognitive; Perimenopausal; peri-menopausal; peri-menopause; National Institute on Aging; preventing; Symptoms; interventional strategy; Intervention Strategies; critical period; Outcome; effective intervention; Mammary Gland Parenchyma; treatment strategy; effective therapy; Biological Markers; Vasomotor; neuronal survival; Small Business Innovation Research Grant; Breast Cancer Risk Factor; age related; Alzheimer's disease risk; neurotoxicity; Alzheimer's disease model; lifetime risk; Goals; Health; Glucose; Alzheimer's Disease; Age; Genotype; Elderly; Aging; Metabolism; Menopause; precision medicine; soy; open label; pre-clinical; innovation; Clinical Research; Clinical Trials; Cognition; aged; Plants; Development; Night Sweating; Estrogens; Neuronal Plasticity; Neurosecretory Systems; Isoflavones; Blood; Brain; Breast; malignant breast neoplasm; Body Composition; Bone Density; Hormones; Disease; Double-Blind Method; middle age; mortality; Mitochondria; Phytoestrogens; Risk; Research; Rodent Diseases; Research Support; Safety; Uterus; Woman; Personal Satisfaction; Drug Kinetics; Fright; Women's Health; Female; Phenotype; Cells; Exhibits; Legal patent; Pathology; effective treatment; AD model; alzheimer model; developmental; Sleep disturbances; equol; Time; Translating; Translations; Tissues; Genistein; daidzein; precision-based medicine; Estrogenic Agents; Estrogenic Compounds; breast cancer risk; bio-markers; biologic marker; biomarker; open label study; preclinical; National Institute of Aging; age dependent; Alzheimer risk factor; alzheimer risk; ERbeta; ERß; Estrogen Receptor ß; neuron toxicity; neuronal toxicity; Breast Tissue; Mammary Gland Tissue; SBIR; Small Business Innovation Research; innovate; innovative; oral supplement; co-morbid symptom; co-occuring symptom; comorbid symptom; concurrent symptom; cooccuring symptom; symptom association; symptom comorbidity; blood-based marker; life-time risk; Preventative strategy; Preventive strategy; Toxicities; model of animal; model organism; hot flash; Endocrine Therapy; Hormonal Therapy; estrogen treatment; treated with estrogen; treatment with estrogen; SERMs; Isoforms; Animal Models and Related Studies; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Female Health; 4',7-Dihydroxyisoflavone; diadzein; Neurological; Genestein; Genisteol; Prunetol; Post-Menopause; Post-menopausal Period; Postmenopausal Period; post-menopausal; postmenopausal; Phyto-Estrogen; Therapeutic Estrogen; Endocrine Gland Secretion; Therapeutic Hormone; mid life; mid-life; middle aged; midlife; Intermediary Metabolism; Metabolic Processes; mitochondrial; CNS plasticity; central nervous system plasticity; neural plasticity; neuroplastic; neuroplasticity; Neuroendocrine; Neuroendocrine System; Fear; Estrogen Therapy; Life; Endocrine; hormone therapy; Inflammatory; Patents; well-being; wellbeing; Pharmacokinetics; Disorder; D-Glucose; Dextrose; Postmenopause; Frequencies; PK/PD; Therapeutic; Severities; Metabolic; Neurologic; Chronic; Clinical; base; cognitive function; Phase; Menopausal Symptom; AD related dementia; ADRD; Alzheimer related dementia; Alzheimer's biomarker; Alzheimer's disease biological marker; Alzheimer's biological marker; prevent; Address; Dose; womb; Body Tissues
