Transforming the vaginal microbiome to combat infertility 

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microbiome

Freya Biosciences is a clinical-stage biotech company with headquarters in Copenhagen, Denmark, and Boston, Massachusetts. It is dedicated to reimagining women’s health and redefining fertility for those previously deprived of options. 

With a focus on microbial immunotherapies, Freya addresses immune drivers underlying a range of reproductive health conditions.

The company recently received $38 million Series A financing to advance the clinical development of its lead drug candidate, an investigational vaginal microbial immunotherapeutic. 

The treatment is to address infertility in women with dysbiotic vaginal microbiota who are undergoing assisted reproductive technology (ART). 

This week’s conversation is with Freya’s chief science officer and co-founder Johan van Hylckama Vlieg.

Origins of the company

Freya Biosciences was created primarily because women’s health is largely understudied and underfunded, van Hylckama Vlieg said. He added that drug development in the women’s health area is not where it should be. 

However, things are changing. There is more attention and funding, and big pharma is paying more attention to the field. Van Hylckama Vlieg is, by training, a microbiologist, and he noted that there is a great deal of attention being paid to the microbiome. 

Vaginal microbiome

While much of this interest has been on the gut microbiome, the skin microbiome and vaginal microbiome have also been studied.

“The notion of the immune system being so much driven by the microbiome means that almost any drug development area that focuses on the immune system, whether it’s decreasing inflammation or maybe improving immunotherapies in the cancer area, always has to consider the microbiome,” van Hylckama Vlieg explained. 

“In the gut microbiome, we see a lot of innovations in that area. I think the vaginal microbiome is unique in the sense that it’s actually way less complex than the gut microbiome. 

“At the highest level, it exists in two states. It is either dominated by vaginal lactobacilli, which produce lactic acid, have a low pH, and are generally associated with improved outcomes. Less risk for infectious disease and better reproductive health outcomes. Or, it’s in a dysbiotic state, which is characterized by highly complex communities, often strict anaerobes, and also many of these bacteria are described to drive inflammation. 

“So, from a drug development point of view, that is really attractive because you can actually have a very clear therapeutic target. And that dysbiotic state is increasingly associated with worse outcomes clinically; preterm birth, lower pregnancy success rates, recurrent pregnancy loss, all of those areas.”

Reproductive immunology

He noted that a lot of drug development in reproductive health has focused on targeting hormonal dysfunction. More recently, the area of reproductive immunology has gained a lot of attention. 

“We bring microbes, immune system, inflammation, and reproductive health together. And that’s where we really want to focus.” 

During pregnancy, van Hylckama Vlieg noted, there is genetic material not from the woman that needs to not be rejected. Freya is specifically targeting the phase where early rejection of the embryo can take place. This is done by removing the inflammatory signal that can prompt rejection.

Reversing dysbiotic microbiomes

However, the company’s CSO says Freya is not “another microbiome company.” 

“We’re about treating women and helping them get into the right physiological state, in the right immunological state, to bring that therapeutic benefit in reproductive health,” he said. 

The company created a technology platform to look at many samples to discover the microbiome composition and create an immune marker profile. 

“Then you can look for associations,” van Hylckama Vlieg said. 

“And the beauty is that we actually found very robust associations between specific microbiomes, specific lactobacillus dominance, and a lower inflammatory tone, while this dysbiotic microbiome, dominated by pro-inflammatory bacteria in the vagina leads to a higher immune tone and specifically the higher expression of inflammatory markers. So that’s been a treasure trove for us to build our therapeutic platform.”

Because the platform identified the correlation between the microbiome, immune zone, and ultimately pregnancy success, the company looked to develop a microbiome therapeutic to reverse dysbiosis, restore lactobacillus dominance and improve pregnancy success rates. 

Altering the microbiome

“We decided to turn the classical drug development funnel upside down. In a classic drug development paradigm, you would start with looking at these associations, isolating bacteria, maybe putting them in an in vitro model, maybe even in a mouse model. 

“We decided not to do this because I think over the years the track record of this approach in the microbiome field has not been too impressive. And humans are the only mammals that are truly dominated by lactobacilli. We used an in-human discovery platform. And that’s very much inspired by the work that’s been done on fecal microbial transplants in the gut microbiome field.” 

“We decided to turn the classical drug development funnel upside down.”

Johan van Hylckama Vlieg

Essentially, van Hylckama Vlieg explained, donors are identified with a ‘desired’ microbiome composition. 

In this case, this is a specific lactobacillus dominant microbiome, which is then collected. Women are then screened for a dysbiotic microbiome. Those that have a dysbiotic microbiome are then dosed with material from the donors with a healthy vaginal microbiome.

With some gut microbiome treatments, antibiotics are first given to ‘clean away’ bad bacteria. However, Freya undertook a study in Ireland where they simply dosed without a pre-treatment of antibiotics.

The 34-patient study, which the company recently reported the results from, saw a 50% response rate. 

“So, in 50% of the cases, you saw bacteria from the donor grafting in that recipient. And in many cases, they actually become dominant. They wipe away the dysbiotic microbiome. And that also is then translated to a change in immune profile. So changing to lactobacillus dominance actually decreases inflammation.” 

Clinical trials

The study also allowed for more analysis to build a library of strains that drive colonization. These are now being produced to go into a phase 1 trial in 2024.

van Hylckama Vlieg said the recent funding will allow Freya to complete a phase 2 trial, most likely in a population undergoing IVF. 

“We should be able to correlate the change of the microbiome to the change in the immune system to ultimately an effect on pregnancy. That’s what we really want to achieve.” 

While this work continues, van Hylckama Vlieg stressed the company is also developing its pipeline to take on other areas of inflammatory immune-driven disease of the female reproductive tract. 

Other targets

Menopause is also a potential target, as van Hylckama Vlieg said it is still an unmet medical need. 

“There are a number of hormonal changes that then indirectly drive changes of the vaginal microbiome. Surprisingly, the amount of high-quality data in this area is still not very large,” he said. 

“There are many smaller studies, but it definitely is unfavorable for a lactobacillus dominant community. And one of the main mechanisms behind this, as is postulated, is that actually menopause leads to less production of glycogen, which is one of the main food sources for the lactobacilli in the vagina. And that could be one of the factors that’s involved. But again, it’s potentially a very interesting area and a clear unmet medical need that can and should be addressed.”

To learn more about this topic:

Here are some links to more articles on the subject of the vaginal microbiome and women’s health.

Six women’s health companies you should know about (Labiotech.eu)

Towards a deeper understanding of the vaginal microbiota (Nature journal)

Microbiome: are we ready for third generation live biotherapeutics? (Labiotech.eu)

Explore other topics: Microbiome

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