Women’s Health

Disorders of the Urogenital
and Reproductive Tracts

The vaginal microbiome of most women is dominated by specific Lactobacillus species that play an important role in reproductive health by reducing the risk of urogenital infections and obstetric complications, and Lactobacillus crispatus is the most protective vaginal species. Dysbiosis is a disruption of vaginal microbial ecosystem with a loss of protective hydrogen peroxide-producing Lactobacillus and a marked increase in microbial diversity.

Epidemiological studies have shown that vaginal dysbiosis is associated with Bacterial Vaginosis (BV) and recurrent Urinary Tract Infection (rUTI). Dysbiosis is also associated with sexually transmitted infections, including HIV and HPV, and preterm birth.

Antibiotics are used to treat BV and UTI, but recurrences are common. Antibiotics inhibit or kill the bacteria that cause these conditions, but and they do not prevent recurrence since they do not restore protective Lactobacillus. To address this unmet medical need, Osel developed a proprietary Live Biotherapeutic Product (LBP), called LACTIN-V that contains the protective vaginal strain, Lactobacillus crispatus CTV-05. L. crispatus CTV-05 produces lactic acid and hydrogen peroxide, adheres to vaginal epithelial cells, and antagonizes bacteria associated with BV and uropathogenic E. coli, which is responsible for most UTIs. LACTIN-V has also been shown to reduce preterm birth.

Bacterial Vaginosis
Bacterial vaginosis (BV) is a common ecological disturbance or dysbiosis of the vaginal microbiome that accounts for up to 25% of visits to gynecologic clinics in the U.S. and afflicts over 16 million women every year worldwide. The estimated annual global economic burden of treating symptomatic BV is US $4.8M. The US economic burden of BV is nearly tripled when including costs of BV-associated preterm births and human immunodeficiency virus cases. In BV, certain Lactobacillus species, particularly hydrogen peroxide-producing strains, are depleted and replaced with largely anaerobic organisms that can cause an unpleasant “fishy” odor, a burning or itching sensation, abnormal vaginal discharge, and underlying inflammation. BV is a risk factor for pre-term labor, post-caesarean section infections, and sexually transmitted infections, including HIV. BV is treated with oral or topical antibiotics to kill BV-associated bacteria, but up to 75% of women can experience recurrent infections, in part because Lactobacillus are not restored and dysbiosis can persist. Currently there are no approved therapies available to prevent BV recurrence other than prophylactic antibiotics. LACTIN-V restores the vaginal microbiota with a protective L. crispatus strain to prevent BV recurrence.
Recurrent Urinary Tract Infection
UTIs account for almost 11 million physician visits each year in the US, and an equal number in Europe. Up to 33% of women with UTIs develop recurrent infections (>2 per year). Women with recurrent urinary tract infection (rUTI) often demonstrate persistent vaginal colonization with uropathogenic Escherichia coli (UPEC). Studies have shown an inverse relationship between hydrogen peroxide-producing lactobacilli such as L. crispatus and vaginal UPEC colonization in women with rUTI. While a routine UTI is easily treated with a short course of oral antibiotics, treatment of recurrent UTI (rUTI) with multiple courses of antibiotics may lead to resistant strains, diarrhea, and vaginal yeast infections. There are currently no therapies available to prevent UTI recurrence other than prophylactic antibiotics. LACTIN-V promotes vaginal colonization with L. crispatus to prevent the ascension of uropathogens from the lower gastrointestinal tract to the urinary tract and bladder.
Preterm Birth

Preterm birth (PTB), delivery prior to completion of 37 weeks of gestation, is the greatest challenge facing obstetrics in the modern era. It is the world’s leading cause of childhood mortality and is associated with 80% of all neonatal morbidity resulting in major financial and emotional cost to families and society. In 2007, the Institute of Medicine reported that the cost associated with premature birth in the United States was $26.2 billion each year. The preterm birth rate in the US was 10.1% in 2021, over 360,000 PTBs. PTB has several well-established risk factors including a history of PTB and/or mid-trimester loss (>16 weeks). The etiology of PTB is complex, but the cervicovaginal microbiota appears to play an important role in PTB. BV has long been known to be a risk factor for PTB. More recently, diverse vaginal microbiota and L. iners colonization have also been implicated in PTB. Conversely, L. crispatus colonization is associated with term birth.

Other than vaginal progesterone treatment and cervical cerclage, there are no treatments to prevent PTB. FDA removed Makena from the market in 2023 due to lack of efficacy in a confirmatory Phase 3 trial. A Phase 1 study of LACTIN-V in pregnant women at high risk of PTB was recently completed (NCT03992534).

Women worldwide continue to be infected with HIV at an alarming rate, and young women are disproportionately represented among those newly infected. In women most new HIV infections occur by the mucosal route during unprotected vaginal sexual intercourse. Several commensal Lactobacillus species generally dominate the vaginal microbiota of healthy women of childbearing age and are associated with vaginal health. These Lactobacillus species are associated with reduced risk of bacterial vaginosis (BV) and sexually transmitted infections, including human immunodeficiency virus (HIV). Lactobacilli produce lactic acid that contributes to the maintenance of a low vaginal pH (3.6-4.5) and may inhibit genital pathogens, including HIV. Diverse, Lactobacillus-deficient cervicovaginal bacterial communities were recently shown to be associated with increased HIV acquisition and mucosal inflammation in young South African women.
HPV, Cervical Dysplasia and Cancer

Annually, over half a million invasive cervical cancer (ICC) cases occur globally, with 8 in 10 cases in sub-Saharan Africa. Low human papilloma virus (HPV) vaccination rates, less efficient and infrequent screening, and incomplete or delayed treatment in high-risk populations in the US and globally contribute to an elevated risk of cervical dysplasia and progression to cancer. Although the incidence of cervical cancer decreased over the past 30 years, it remains high in sub-Saharan Africa and among minority populations in the US. Most cervical cancer is the long-delayed consequence of HPV infection, and many clinical risk factors are thought to be surrogates for HPV exposure or altered viral clearance. Treatments of precancerous lesions can be either excisional or ablative; excisions have been associated with adverse pregnancy outcomes, bleeding, and infection.

The composition of the cervicovaginal microbiome is known to impact reproductive health, including HPV and cervical cancer. In a meta-analysis of 15 prospective studies representing 101,049 women, vaginal dysbiosis was associated with a two-fold increase in risk of high-grade cervical intraepithelial neoplasia (CIN) or cancer. In a prospective longitudinal cohort, a non-Lactobacillus dominant cervicovaginal microbiome was associated with high-risk HPV progression, mediated by elevation of microbial diversity. Vaginal dysbiosis may promote cervical cancer through mucosal disruption, pro-inflammatory environment, and loss of Lactobacillus crispatus. In contrast, a L. crispatus-dominant cervicovaginal microbiota is associated with the regression of CIN disease. Recent longitudinal studies assessing cases of HPV clearance noted an associated reduction in microbial diversity and a resurgence of lactobacilli, as well as a decrease of inflammatory cytokines. Since LACTIN-V has the potential to both optimize the cervicovaginal microbiome and reduce inflammation, we plan to test the ability of LACTIN-V to facilitate HPV clearance and prevent CIN disease progression. The study has been approved by the National Cancer Institute.

The most recent significant development in the treatment paradigm of cervical cancer was the addition of chemotherapy to radiation therapy in the 1990s. Despite standard-of-care chemoradiation therapy (CRT), 40% of women with cervical cancer will experience relapse and die. There are currently no curative options available for patients who experience recurrence or progression after definitive CRT aside from potential pelvic exenteration. In HPV-related cervical cancer, the reduced prevalence of L. crispatus and an L. iners-dominant microbiota has been associated with high-grade dysplasia or cancer development. L. iners has emerged as a pathobiont only recently through intensive microbiome and genomic analyses. Genetically distinct, pathogenic cervical cancer-derived sub-strains of L. iners have been identified that are associated with poor clinical response to CRT, and significantly reduced recurrence-free and overall survival in both an initial and a validation patient cohort at two institutions. By eliminating L. iners with Gassericin K7B, we expect to improve CRT treatment outcomes and reduce recurrence of cervical cancer.