Women’s Health

Disorders of the Urogenital
and Reproductive Tracts

The vaginal microbiome of most women is dominated by particular Lactobacillus species that play an important role in reproductive health by reducing the risk of urogenital infections and obstetric complications. 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, preterm labor and birth, and low success rates for in vitro fertilization (IVF).

Antibiotics are used to treat urogenital infections, but recurrences are common.  Antibiotics inhibit or kill the bacteria that cause these infections, but and they do not prevent recurrence of infection 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.

Bacterial Vaginosis

Bacterial vaginosis (BV) is a common condition in women 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. BV is characterized as an ecological disorder or dysbiosis of the vaginal microbiome. 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 dysbiosis can persist in many women following antibiotic treatment. Currently there are no approved therapies available to prevent BV recurrence other than prophylactic antibiotics.

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 Escherichia coli. Studies have shown an inverse relationship between hydrogen peroxide-producing lactobacilli and vaginal Escherichia coli 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.
In Vitro Fertilization
Approximately 200,000 assisted reproductive technology (ART) cycles are conducted yearly in the US, mostly in vitro fertilization (IVF). Despite the high cost ($15,000, often out of pocket), the success rate of IVF is quite low; only about 40% per for women under the age of 35 and four-fold lower for women over 40. Infertility is caused by many factors, including ascending infections to the upper reproductive tract caused by vaginal dysbiosis. About one in four women undergoing IVF have vaginal dysbiosis, and the success rate for these women is only about 9% compared to >40% for women with a Lactobacillus-dominated microbiota. No treatments are currently available to improve the success rate of IVF.
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, PPROM, large loop excision of the transformation zone of the cervix (LLETZ), cone biopsy, mid-trimester loss (>16 weeks), short cervix (<25mm) in a previous pregnancy, Caesarean section at full cervical dilatation, trachelectomy, previous cervical tear or congenital uterine anomaly. Bacterial vaginosis is also a known risk factor for PTB.

In pregnancy, vaginal communities depleted in Lactobacillus species are associated with increased risk of preterm pre-labor rupture of the fetal membranes (PPROM) and PTB. Conversely Lactobacillus dominance, particularly by Lactobacillus crispatus, has been shown to be protective of PTB. Other than progesterone and cervical cerclage, there are no treatments to prevent PTB. A Phase 1 study of LACTIN-V in pregnant women at high risk of PTB was recently completed (NCT03992534).

 

HIV
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 reduced the 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.