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 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 (ERß) modulator that promotes
estrogenic action through ERß 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, randomized,
placebo-controlled, parallel-group, clinical trial to determine efficacy of PhytoSERM in symptomatic peri- and
post-menopausal women. Primary objectives are to determine safety and efficacy of PhytoSERM to sustain brain
glucose metabolism as determined by 18F-FDG- PET because the menopausal transition is accompanied by
reduction in cerebral metabolic rate of glucose, which correlates with menopausal symptoms and progression of
AD biomarkers later in life. Secondary objectives will determine efficacy of PhytoSERM on: 1) cognitive function,
2) frequency and severity of vasomotor symptoms and 3) changes in sleep quality and mood symptoms. Tertiary
objectives are to determine 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.” 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 risk of Alzheimer’s in later life.

Grant Number: 5R01AG075122-04
NIH Institute/Center: NIH
Principal Investigator: ROBERTA BRINTON