There are >60 million women over age 50 in the U.S., of which more than half experience negative symptomsof menopause. Our market research indicates that major symptoms of menopause for which women desiretreatment are hot flashes and memory dysfunction. While at least 70% of women suffer these symptoms duringthe menopausal transition, few effective treatments are available. Estrogen therapy (ET) has been the primarytreatment for menopausal symptoms, with the hormone therapy market expected to reach $28 billion by 2022.However, ET is associated with increased risks of cancer and heart disease, leading many women to forgotreatment or to use ineffective or unproven alternative treatments. Not only is the lack of safe and effectivetreatments disruptive to women's lives, but women whose menopausal symptoms go untreated incur greaterhealthcare costs, more physician visits, and lower work productivity than women who use ET or areasymptomatic. The primary culprit in the negative effects of ET is estrogen receptor alpha (ERα), one of twointracellular ERs through which estrogens affect cellular function. Whereas activation of ERα is associated withET-induced health risks, ERβ activation benefits vasomotor function and cognition. Thus, selective activation ofERβ may reduce menopausal symptoms without incident risk of detrimental health outcomes. Estrigenix'smission is to develop drugs to help women live healthier and longer lives. The overall objective of this proposalis to optimize and develop our lead compound, the novel ERβ agonist EGX358, as a therapeutic to treat hotflashes and memory decline in menopausal women. This research is innovative because EGX358 is the mostselective ERβ agonist reported to date, and is in a unique structural class possessing a cyclohexane-basedsaturated ring system, substituted with a hydroxymethylene group. Our central hypothesis is that EGX358 willalleviate symptoms of menopause, including hot flashes and memory decline, in a middle-aged mouse model ofmenopause, and is suitable for further preclinical studies based on preliminary pharmacokinetics and processchemistry. This hypothesis is based on our studies using a young ovariectomized mouse model of menopauseshowing that acute and/or chronic oral EGX358 treatment alleviates drug-induced hot flashes and enhancesmemory formation, without affecting breast cancer cell proliferation or causing off-target effects on nuclearhormone receptor binding or tissue pathology. Our hypothesis will be tested in three specific aims designed to:1) demonstrate that EGX358 can reduce hot flashes and enhance memory in a middle-aged mouse model ofmenopause, 2) demonstrate minimal toxicity and favorable pharmacokinetic (PK) stability for EGX358 (or anoptimized analog), 3) develop process chemistry scaleup synthesis of EGX358 suitable for method transfer to acGMP lab to produce sufficient material for clinical trials. This Phase II enabling work will demonstrate thatEGX358 improves memory and reduces hot flashes in a mouse model of menopause, has acceptable PK-PD(pharmacokinetic-dynamic) properties, is safe, and can be synthesized in sufficient quantities for clinical studies.
Public Health Relevance Statement: Project narrative:
Circulating estrogen loss at menopause is associated with negative symptoms including hot flashes and
memory dysfunction, yet women are reluctant to seek treatment because estrogen therapy is associated with
increased health risks attributed to actions of estrogen receptor alpha (ERa). Estrigenix scientists have devel-
oped a novel highly selective estrogen receptor beta (ERb) agonist for which we seek Phase I funding to con-
duct pharmacodynamic, pharmacokinetic, and scale up studies towards the goal of capturing part of the global
hormone therapy market, which is expected to reach $28.4 billion by 2022. The proposed research is relevant
to public health because safely and effectively treating menopausal symptoms will reduce women's suffering
and will directly addresses the National Institute on Aging's Strategic Goal C to develop effective interventions
to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases, disor-
ders, and disabilities.
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