PROJECT SUMMARY: The ultimate goal of the project is to develop the first disease-modifying (“curative”) and non-hormonal therapeutic for endometriosis. Endometriosis is considered the greatest overlooked epidemic in women’s health, affecting approximately 10% of women worldwide. It is a major cause of infertility and disability among adolescents and women across all ethnicities. Shockingly, to date, there is no cure for this chronic and prevalent disease that takes 6-10 years to be diagnosed. Currently, the management of endometriosis is through hormonal treatment, pain therapies, or surgical interventions—which fail to reverse the disease or address the root cause— are often insufficient. Hormone pills and GnRH antagonists (causing “medical menopause”) prescribed to patients with endometriosis can induce many undesirable side effects. Many women who undergo endometriosis excision will have recurrence within 5 years of surgery. Hysterectomies are recommended for women who do not experience relief through less invasive methods. NICHD has made the development of a non-hormonal therapeutic for endometriosis a high priority goal, which corresponds with the 2021-2025 NIH-wide strategic plan and “bold prediction” of advancing one non-hormonal therapeutic for endometriosis to clinical trials. Our group intends to accomplish this “bold prediction” with this Phase IIB SBIR application. Our team developed a novel therapeutic option for endometriosis by targeting a downstream component of a pathway known to contribute to endometriosis pathogenesis, endometrial migration and invasion. We successfully accomplished our milestones from both Phase I and II of our SBIR Fast-Track Grant. A lead candidate was identified that has therapeutic efficacy with no observable toxicity. The lead candidate specifically and selectively inhibits this downstream component and shows success in cell potency assays, apoptosis assays, serum stability, membrane permeability, and vaginal absorption without irritation. In vivo, the lead candidate importantly demonstrates endometriotic lesion regression accompanied by increased apoptosis, decreased proliferation, and decreased downstream target genes without inducing toxicity or alterations in estrous cyclicity. Thus, our lead candidate exhibits great potential to act as an endometriosis therapeutic to eliminate lesions. Other molecules have regressed endometriosis progression in academic settings, but have off-target or upstream pathway targets that make them undesirable therapeutics as undesired side effects are induced. During Phase IIB, we will determine a minimal efficacious dose of the lead therapeutic, optimize formulations of the lead candidate, and finish IND-enabling toxicology studies for submission of an IND package to the FDA. By doing so, we will develop a non-hormonal therapeutic that is disease-modifying; consequently, due to the high unmet need for endometriosis therapeutics, successful completion of our aims will ...