PROJECT ABSTRACT/SUMMARY Vaginal Atrophy (VA), a component of Genitourinary Syndrome of Menopause, is a chronic and progressive condition that affects approximately 50% of post-menopausal women due to estrogen deficiency. Without treatment, symptoms such as vaginal dryness, burning, discharge, itching, irritation, painful intercourse, and recurrent urinary tract infections worsen over time. This results in an adverse impact on the quality of life, sexual health, and emotional well-being of affected women. About 1.1 billion women worldwide are projected to be in menopause by 2030. In the United States, 50 million women are currently in menopause and approximately 2.2 million women are projected to enter menopause yearly. Therefore, given the growing population of post- menopausal women, many women are potentially at risk for VA. The first-line pharmacologic treatment recommended for VA is vaginal estrogen therapy. However, despite its effectiveness, most women refuse hormonal therapy due to concerns about side effects associated with estrogen therapies, such as thromboembolic disorders, dementia, and cancer. Alternatives such as vaginal lubricants and moisturizers usually provide only short-term relief, and do not treat the underlying condition. In addition, though non-ablative laser or thermal intra-vaginal devices may be effective, they are relatively expensive and are not FDA-approved for treatment of VA due to a insufficient safety and efficacy data. Our company, Moremmé, is developing a patent-pending combination of hormone-free natural bioactives loaded in a novel prebiotic mucoadhesive gel delivery system for intravaginal drug delivery. These bioactives synergistically address key symptoms of VA by hydrating and repairing the vaginal wall while keeping the vaginal microbiome in homeostasis. We demonstrate that within a range of effective concentrations, our formulations are non-toxic to cultured human vaginal cells and promote production of proteins that help rebuild the vaginal wall. The overall objective of this proposal is to test and establish the efficacy of our formulations in reversing signs of VA in vivo. To achieve this, Aim 1 will optimize bioactive loading and release from the gel formulations. Aim 2 will assess safety and tolerability of the optimized formulation prototypes using a 3-D human vaginal tissue model, while Aim 3 will determine efficacy of the formulations in reversing signs of VA in a rodent model. Upon successful completion of this Phase I project, we will have optimized loading and release of bioactives from the gel matrix, determined formulation tolerability in human vaginal tissues, and established effectiveness in treatment of VA in vivo. This work will provide preliminary data and proof of concept to support a future Phase II SBIR application for product development and commercialization activities for a hormone-free vaginal suppository for treatment of VA in post-menopausal women. This will ultimately offer a viable alternative for millions of aging women who desire a safe, effective, and hormone-free alternative for treatment of VA.

PROJECT NARRATIVE Approximately 50% of post-menopausal women worldwide suffer from Vaginal Atrophy, a component of Genitourinary Syndrome of Menopause, which is a chronic, progressive condition occurring due to menopause- related estrogen deficiency. The work proposed in this application aims to optimize loading and release of Moremme’s natural, hormone-free bioactive gel formulations, assess biocompatibility in a human vaginal tissue model, and establish efficacy in a rodent model of Vaginal Atrophy. Our goal is to develop a safe, effective, hormone-free vaginal suppository as an alternate and more acceptable treatment option for women suffering from Vaginal Atrophy.