Preclinical testing of a novel non-hormonal intravaginal ring to prevent pregnancy and sexually transmitted infections

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PROJECT II – ABSTRACT Globally, 85 million unintended pregnancies occur per year and more than 1 million sexually transmitted infections (STIs) are acquired every day, emphasizing a clear unmet need for improved contraception and protection against STIs. Currently available multipurpose prevention technology (MPT) products for women that combine contraception and anti-HIV/STI prevention are limited to female and male condoms. The contraception options within MPTs are dominated by hormonal methods. Given the side effects of hormonal contraceptives and high rates of many STIs, non-hormonal MPT may be appealing for some women and would be a new and critically needed area of innovation in the MPT development pipeline to better provide a range of options and increase uptake. In collaboration with several university partners, the Population Council is developing a novel 30-day intravaginal ring (IVR) to prevent unintended pregnancy and STIs (herpes simplex virus, gonorrhea, chlamydia, and possibly HIV) while promoting vaginal health. The IVR releases Copper, Zinc acetate (ZA) and Lactide (CZL-IVR). The overarching goal of Project 2 is to complete preclinical testing for this unique product to determine the target API release and the overall safety and efficacy of our CZL-IVR. This project will define the critical clinical indications that we will pursue and the optimal dosing for this novel triple-API combination. The CZL-IVR will utilize three APIs, enabling Project 2 to calibrate dosages to minimize toxicity and maximize efficacy. The APIs are low-cost, easy-to-obtain chemicals with existing safety profiles, which will mitigate the regulatory challenges associated with products containing multiple APIs. Project 2 includes contraceptive and anti-STI activity testing in vitro (Aim 1) and in vivo in mice and rabbits (Aim 2); pharmacokinetics (PK) and local toxicity studies in vivo in sheep (Aim 3); and in-depth safety/PK and anti- bacterial vaginosis effect assessments (vaginal microbiota, transcriptome and immune mediators) in vivo in rhesus macaques (Aim 4). This project will be closely coordinated with Project 1 to inform IVR loading and selection of the lead IVR. Our multidisciplinary collaborative team is uniquely qualified to advance the development of this novel MPT IVR. The CZL-IVR will address a critical gap in the non-hormonal contraceptive landscape, fill a niche that users want and deliver an important public health intervention. While pregnancy prevention will be the primary indication defining the regulatory approach for our CZL-IVR, the triple-active API strategy offers broader antimicrobial benefits, distinguishes our TPP from others under development, and opens avenues for pursuing regulatory approval for indications beyond contraception. While our ideal product will provide protection from a broad range of STIs, the specific secondary indications we chose to pursue will be based on our preclinical data, regulatory considerations, and advice from our advisory committees.