By Katie Gillette, Senior Project Leader, Eliza French, Analyst, Graham Friedman, Analyst, and Olivia Qiu, Associate, DeciBio.
Earlier this year, we explored the microbiome and its role in drug development across various therapeutic areas. This article will focus on one such area of great unmet need and promise: women’s health. We will explore the various microbiomes associated with women’s health, outline trials exploring the role of the microbiome as a diagnostic and research tool in women’s health conditions, and profile select pharmaceutical companies developing microbiome-associated therapies to address these conditions.
Key microbiomes in women’s health
Though many are familiar with the gut microbiome, the female microbiomes also include the vaginal and endometrial environments, each of which have wide implications for women’s health.
Though the vaginal and endometrial bacterial profiles vary widely between ethnicities and even individuals, research suggests that select microbiome species are linked to specific disease states in all populations. For example, in the vagina, the presence of Lactobacillus, particularly Lactobacillus crispatus, correlates with the absence of bacterial vaginosis. This is likely in part because their byproduct, lactic acid, is known to inhibit pathogenic bacteria25. And, in the endometrium, a decrease in Lactobacillus may affect embryo attachment and promote the growth of detrimental bacteria. In fact, the endometrial fluid contains peptides that may protect against a variety of fungi, bacteria, viruses, and other pathogens4.
The influence of these microbiomes extends to children as well. When a child is born vaginally, the mother transfers elements from her vaginal microbiome to the newborn. This transfer imparts immune advantages: Infants born vaginally have a greater concentration of Bacteroides, Bifidobacteria, and Lactobacillus, as well as more diverse microbial compositions in their first weeks of life compared to children born by C-section (caesarean section). This has a measurable impact: Those born vaginally are at a lower risk of developing asthma, juvenile arthritis, and immune deficiencies, among other conditions3.
Other microbiomes can also influence the female reproductive environment. Research in animal models – and, to a lesser extent, human models – suggests that gut microbiome disbiosis, through its role in inflammation and endotoxin release, could lead to the development of PCOS (polycystic ovary syndrome) and endometriosis1,2. Additionally, gut microbiome disbiosis is being explored to understand a broader spectrum of GI and neurological disorders.
The female microbiome as a diagnostic and research tool
Due to the increasing evidence of the microbiome’s influence on women’s health, numerous clinical trials have been initiated to understand the impact of the microbiome on specific conditions and explore the microbiome’s potential as a diagnostic and research tool.
Ongoing impactful trials are investigating the potential for microbiome-based diagnostic tests for endometriosis5 and PCOS6 using blood, faecal, vaginal, and/or endometrial samples. The microbiome also is being explored as a metric to gauge therapeutic efficacy of symptom-based treatment for these conditions. For example, one clinical trial is using PCR to assess microbiota composition before and after a series of interventions for PCOS7. Another such study aims to evaluate vulvovaginal candidiasis treatment by utilising 16S rRNA sequencing and meta-proteomics to characterize bacterial diversity changes pre- and post- drug treatment7.
Fertility is another key area of clinical trial activity within the realm of female microbiome-focused research. Trials are testing the hypothesis that the vaginal/endometrial microbiome may experience significant changes from the follicular phase to the luteal phase and to early pregnancy; studies aim to understand these potential changes and how they might correlate to pregnancy outcomes9. One trial aims to use vaginal swabs to test for vaginal microbiome abnormalities and examine the link between this condition and infertility – particularly in the context of in vitro fertilisation (IVF)10. Another study attempts to anticipate IVF pregnancy outcomes via predictive power of transcriptomic analysis of the cervical and gut microbiomes11.
The microbiome is even beginning to play a role in cancer diagnostics. For example, Micronoma intends to leverage its microbiome-based cancer detection platform to develop blood based assays for lung*, ovarian, and breast cancers. If Micronoma is able to realise these plans, it may be poised to lead the way toward a new mode of diagnosing life-threatening illnesses.
Women’s health microbiome-based drug development landscape
Despite their limited historical interest, pharma/biotech companies are now increasingly interested in the female microbiome and its role in drug development. Many companies are currently researching multiple classes of potential interventions, such as probiotics, prebiotics, microbiome modulators, bacteriophages, and microbiome-derived compounds.
Many companies have attempted to create validated probiotics aimed at improving women’s health issues. For example, BIOHM, Daye, La Biome, Ombre and Thorne already market probiotics for general vaginal health. Meanwhile, Fertypharm sells a probiotic specifically aiming to improve fertility and reproductive health, and Biosearch Life is developing one of its own.
HiPP and Infinant Health (formerly Evolve Biosystems) are creating probiotics to improve infant gut health – which is closely connected to the maternal microbiome and method of birth. And Institut AllergoSan and Lallemand Health Solutions are developing probiotics for polycystic ovarian syndrome and menstrual discomfort, respectively. Probiotics offer a relatively straightforward, minimally regulated avenue to correcting dysbiosis, and a significant market exists already. However, fewer companies have pursued the avenue of regulated therapeutics.
Osel is one company leading the charge to bring regulated therapeutics to market. Numerous trials and studies have employed Osel’s live biotherapeutic product (LBP)**, LACTIN-V 14. The first such trial using LACTIN-V published results in 2007 and focused on the prevention of recurrent UTIs (rUTIs). Subsequent studies have explored LACTIN-V’s application to bacterial vaginosis (BV), IVF efficacy, and the risk of preterm birth and labour15. LUCA Biologics, a company created with the support of Seed Health, also has LBPs in the works – one, named VMSC-04, is slated to begin its Phase 1b trial for rUTI prevention this year16.
And, in Denmark, Freya Biosciences has published promising data for its LBP aimed at treating vaginal dysbiosis and also lists fertility and IVF applications as longer-term targets 17,18. Meanwhile, Biocodex is already selling a therapeutic fungi and is concurrently running a trial to assess the fungi’s efficacy in treating yeast infections. Other trials are working toward the use of microbiome-targeting live biotherapeutics as an intervention for fertility conditions, with active trials focusing on IVF patients19.
Several academic trials have also tested the efficacy of microbiome transplantation from healthy women to women with dysbiotic microbiomes as well as from mothers to children born by caesarean section20,21,22,23,24. These interventions include synbiotic treatments12 and vaginal microbiome seeding13.
Despite this activity, there are significant hurdles that arise when developing regulated microbiome-based drugs for women’s health. Designing a one-size-fits-all treatment is challenging due to the complexity and variability of the human microbiome. This variety make it difficult to achieve reproducible results in clinical trials. Additional research is needed to fill the gaps in our understanding of which microbial species are important and to develop efficacious therapeutics based on this understanding. Governmental agencies are also still working to establish guidelines for the approval and regulation of microbiome-targeted drugs. Safety concerns seem likely to persist, as altering the microbiome can have unintended consequences.
The microbiome has the potential to be a driver in the era of precision medicine in women’s health, from reproductive health to infectious disease and beyond. Ongoing clinical trials are exploring microbiome-based diagnostics and research tools, and companies like Osel and LUCA Biologics are driving the development of regulated therapeutics. However, significant challenges, including the complexity and variability of the human microbiome, must be addressed. Further research and larger trials are essential to overcome these obstacles and power the microbiome’s promise in women’s health.
About the authors:
Katie Gillette is Senior Project Leader, Eliza French is Senior Analyst, Graham Friedman is Life Science Analyst, and Olivia Qiu is Associate with DeciBio.
* Micronoma has received Breakthrough Device Designation for its OncobiotaLung assay, but has not received FDA approval
** LBP is a category created by the FDA in 2012 for microorganism-containing products “applicable to the prevention, treatment, or cure of a disease or condition in human beings”