IND-enabling development of MM-009, a reservoir-intravaginal ring for ultra-highrates of month-long lactic acid release to treat and prevent bacterial vaginosis

Summary Millions of women in the U.S. suffer from bacterial vaginosis (BV), a vaginal condition characterized by marked overgrowth of polymicrobial bacterial populations that greatly increases risks of preterm pregnancy and other sexually transmitted infections. Antibiotics only provide transient relief from the foul-smelling discharge caused by BV, and cannot treat recurrent BV or prevent BV from recurring (sometimes at a frequency up to twice a month). There is no product on the market that can provide sustained protection against BV. In exploring potential non-antibiotics-based interventions for BV, we became motivated by the highly reproducible clinical observation that women with Lactobacillus crispatus-dominant vaginal microbiome are highly resistant to BV. “Healthy” lactobacilli (LB), in particular L. crispatus, secretes lactic acid (LA) that acts as a broad- spectrum microbicide that suppresses various BV species, with much greater activity than acetic acid. We recently determined the rate at which healthy lactobacilli continuously produce LA. Hence, for the first time, we know the rate at which LA should be supplied to the vagina to treat and prevent BV. These insights have guided our development of “MM-009”, a LA-releasing intravaginal ring (LA-IVR) that can provide release of LA over at least 30 days, at rates designed to treat and prevent BV while not suppressing healthy LB. Our first- generation MM-009 lowered the vaginal pH in macaques substantially without causing any toxicity, as well as release enough lactic acid to promote a LB-dominated microbiome for over a week. We further tested this MM- 009 in a sheep vaginal model and observed similar results validating high rates of LA release and lack of toxicity. Noting the lack of toxicity in our current formulation and the potential to further increase rates of LA release, we have now developed a second-generation MM-009 as a proprietary reservoir-IVR system that allows us to precisely tune LA release rates with near zero-order release kinetics, achieving LA release at rates orders of magnitude greater than what had been previously reported. Building off of these promising results, our goal in the first portion of this Phase 2 proposal is to select a lead candidate LA-IVR in the well-established sheep vaginal model for safety and pharmacokinetics (Aim 1). The latter part of this Phase 2 proposal, guided by the pre-IND feedback from the FDA, will focus on the developing cGMP production processes for MM-009 that will support production of MM-009 for IND-enabling and Phase 1-2 studies (Aim 2). Lastly, we will execute key IND-enabling studies, including GLP sheep toxicology, rabbit vaginal irritation, and biocompatibility studies (Aim 3). The simplicity of our MM-009 LA-IVR design ensures both ease of production and likely very low manufacturing costs of the eventual MM-009 product, which in turn should maximize potential public health impact and commercial viability of the product both in the U.S. and in low and middle income countries worldwide.