Executive Lay Summary

Women are at greater lifetime risk for Alzheimer’s disease (AD). One potential factor contributing to greater life-time risk of Alzheimer’s is the midlife endocrine aging transition. While estrogen therapy administered when women are symptomatic can reduce risk of AD, the fear of breast cancer leads many women to forego this therapy. An innovative alternative to estrogen therapy is to target estrogen action in the brain to prevent AD while avoiding estrogen-associated proliferation in breast tissue. To achieve that goal, we have developed “PhytoSERM”, a selective estrogen-receptor-beta (ERß) modulator that promotes estrogenic action through ERß in brain while largely inactive or inhibitory in reproductive tissue. Our earlier NIA supported 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).  We continue the development of PhytoSERM by conducting an NIA supported phase 2 clinical trial testing the efficacy of PhytoSERM to sustain brain glucose metabolism on¹⁸F-FDG-PET in symptomatic menopausal women.

Proposed herein is a funding proposal to evaluate AD blood-based biomarkers and carry out supplemental activities in the current phase 2 clinical trial of PhytoSERM.  The Primary objective is to evaluate a panel of AD blood-based biomarkers in the phase 2 study population.  Secondary objectives will advance the phase 2 clinical trial by 1) enabling trial execution supplemental activities and 2) conducting PhytoSERM pills stability analyses and enabling GMP storage.

The supplemental activities included in this proposal will enable the successful completion of the phase 2 PhytoSERM clinical trial and provide important information based on the biomarker profiling of this study population. The development of PhytoSERM addresses a critical unmet need in women’s health for an alternative to estrogen therapy that is both safe and efficacious for menopausal symptoms and reduce risk of AD in later life.