# Development of EGX358, an ER-beta Agonist to Treat Hot Flashes & Menopause-Related Memory Loss

> **NIH NIH R43** · ESTRIGENIX THERAPEUTICS, INC. · 2022 · $299,056

## Abstract

There are >60 million women over age 50 in the U.S., of which more than half experience negative symptoms
of menopause. Our market research indicates that major symptoms of menopause for which women desire
treatment are hot flashes and memory dysfunction. While at least 70% of women suffer these symptoms during
the menopausal transition, few effective treatments are available. Estrogen therapy (ET) has been the primary
treatment 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 forgo
treatment or to use ineffective or unproven alternative treatments. Not only is the lack of safe and effective
treatments disruptive to women’s lives, but women whose menopausal symptoms go untreated incur greater
healthcare costs, more physician visits, and lower work productivity than women who use ET or are
asymptomatic. The primary culprit in the negative effects of ET is estrogen receptor alpha (ERα), one of two
intracellular ERs through which estrogens affect cellular function. Whereas activation of ERα is associated with
ET-induced health risks, ERβ activation benefits vasomotor function and cognition. Thus, selective activation of
ERβ may reduce menopausal symptoms without incident risk of detrimental health outcomes. Estrigenix’s
mission is to develop drugs to help women live healthier and longer lives. The overall objective of this proposal
is to optimize and develop our lead compound, the novel ERβ agonist EGX358, as a therapeutic to treat hot
flashes and memory decline in menopausal women. This research is innovative because EGX358 is the most
selective ERβ agonist reported to date, and is in a unique structural class possessing a cyclohexane-based
saturated ring system, substituted with a hydroxymethylene group. Our central hypothesis is that EGX358 will
alleviate symptoms of menopause, including hot flashes and memory decline, in a middle-aged mouse model of
menopause, and is suitable for further preclinical studies based on preliminary pharmacokinetics and process
chemistry. This hypothesis is based on our studies using a young ovariectomized mouse model of menopause
showing that acute and/or chronic oral EGX358 treatment alleviates drug-induced hot flashes and enhances
memory formation, without affecting breast cancer cell proliferation or causing off-target effects on nuclear
hormone 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 of
menopause, 2) demonstrate minimal toxicity and favorable pharmacokinetic (PK) stability for EGX358 (or an
optimized analog), 3) develop process chemistry scaleup synthesis of EGX358 suitable for method transfer to a
cGMP lab to produce sufficient material for clinical trials. This Phase II enabling work will demonstrate that
EGX...

## Key facts

- **NIH application ID:** 10546666
- **Project number:** 1R43AG079715-01
- **Recipient organization:** ESTRIGENIX THERAPEUTICS, INC.
- **Principal Investigator:** William A Donaldson
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,056
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546666

## Citation

> US National Institutes of Health, RePORTER application 10546666, Development of EGX358, an ER-beta Agonist to Treat Hot Flashes & Menopause-Related Memory Loss (1R43AG079715-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10546666. Licensed CC0.

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