R01AG075122

Phytoserm Efficacy to Prevent Menopause-Associated Decline in Brain Metabolism and Cognition: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial - Project Summary/Abstract

Women are at greater lifetime risk for Alzheimer's disease (AD). One potential factor contributing to the greater lifetime risk of AD is the midlife menopausal endocrine aging transition when multiple AD risk conditions can emerge. These conditions are consistent with prodromal/preclinical features of the disease. While estrogen or hormone therapy administered when menopausal women are symptomatic could reduce the 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 the 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 (ERβ) modulator that promotes estrogenic action through ERβ in the brain while being inhibitory in reproductive tissue. Phytoserm is a rationally designed formulation of three phytoestrogens, each 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, randomized, placebo-controlled, parallel-group clinical trial to determine the efficacy of Phytoserm in symptomatic peri- and postmenopausal women. The primary objectives are to determine the safety and efficacy of Phytoserm to sustain brain glucose metabolism as determined by 18F-FDG-PET. This is important because the menopausal transition is accompanied by a reduction in cerebral metabolic rate of glucose, which correlates with menopausal symptoms and progression of AD biomarkers later in life.

The secondary objectives will determine the efficacy of Phytoserm on: 1) cognitive function, 2) frequency and severity of vasomotor symptoms, and 3) changes in sleep quality and mood symptoms. The tertiary objectives are to determine the impact of Phytoserm on exploratory MRI outcomes, including 1) gray matter volume in AD-vulnerable regions, 2) white matter fiber integrity by diffusion tensor imaging, 3) intrinsic connectivity measured by resting-state functional MRI, 4) cerebral blood flow determined by arterial spin labeling (ASL), and 5) blood-based biomarkers relevant to AD risk.

The 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. The Phytoserm clinical trial also contributes to achieving the National Alzheimer's Disease Project Act (NAPA) to effectively prevent and treat AD by 2025 Goal 1B. Phytoserm addresses a critical unmet need in women's health to reduce the risk of Alzheimer's in later life.

University Of Arizona

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Tucson, Arizona 85721 United States

Single Zip Code

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the total obligations have increased 197% from $2,121,223 to $6,295,083.