Understanding the microbiome as an ‘overlooked critical organ’

3D rendering of human intestine villi and microbiome

Compared to a ‘critical organ’ that had been largely ignored, companies working to develop microbiome-based therapies believe there is untapped potential in the area. Ben Hargreaves speaks to companies that are developing therapies not just in gastrointestinal conditions but also in broader areas, such an immuno-oncology.

The interest in how the human microbiome influences health has grown substantially in the last decade. PubMed cites 1,822 pieces of research relating to the microbiome in 2011, which grew to 25,153 published in 2021. As more research has been conducted, closer and unexpected links have been found between the microbiome of the gut, as one example, and other areas of the body, such as brain health and the immune system.

The microbiome, as a term, can be related to the nasal, oral, skin, gastro-intestinal, and urogenital regions of the human body, each containing varied microbial communities that have an impact on health. Research into the area is being made possible through advancements in technology, such as being able to sequence genes at scale, allowing researchers to gain more detailed genetic data on the microbiome.

With more research being published, there has arrived greater interest in how individual microbiomes could influence health and there is now a growing market of prebiotic, probiotic and postbiotic commercial products based on the links being made to various health conditions. At the same time, the pharma industry has also started to note the potential for a new treatment paradigm to be developed, and investment into the space has started to increase. As a result, pharma companies such as Merck, Gilead, Genentech, Johnson & Johnson and Takeda have positioned themselves alongside partners to benefit from a potential new wave of treatments.

“More recent research has also suggested that there are links to the health of the heart and to the brain, through an impact on mental health.”

The possibilities

The gut contains approximately one trillion microbes and at least 160 bacterial species that are constantly interacting with one another and with the cell lining of the gut. The gut microbiome has long been linked to gastrointestinal conditions, such as inflammatory bowel disease and irritable bowel diseases, as well as obesity and type 2 diabetes. More recent research has also suggested that there are links to the health of the heart and to the brain, through an impact on mental health, with the latter becoming so established as to become known as the gut-brain axis.

Due to the variety of potential indications that can be targeted in ensuring a healthy gut, the work being carried out by pharma and biotech companies in the space is often concentrated in this area. Seres Therapeutics is a biotech that has specialised in the microbiome space and also possesses one of the assets closest to potential approval in the overall pipeline. Its treatment candidate, known as SER-109, is targeting patients with recurrent C. difficile infection (CDI).

The treatment has been granted US FDA breakthrough therapy designation and orphan drug designation, and has also completed a phase 3 clinical study. In the trial, Seres announced that the product candidate had met its primary endpoint, showing a statistically significant 30.2% absolute reduction in the rate of CDI recurrence compared to placebo. As a result, the treatment candidate is the most advanced one in the overall microbiome pipeline, with an approval holding the potential to advance the entire field, as well as Seres’ own prospects. Speaking to pharmaphorum, the company’s CEO, Eric Shaff, said, “Our investigational SER-109 has clearly validated our approach, and there is tremendous opportunity to apply our microbiome therapeutics more broadly to infection protection across multiple patient populations and disease areas.”

Mid-way through last year, Nestlé confirmed its conviction in the project by consolidating its existing partnership with Seres through paying $175 million upfront for North American co-marketing rights to the potential microbiome therapy. The biotech is eligible to receive a further $125 million if the FDA approves the drug and could receive another $225 million in commercial milestones. If approved by the FDA, the treatment would become the first microbiome-based treatment to receive approval.

In regard to future work, Shaff stated, “Given what we’ve learned from our lead investigational program, SER-109, we’re especially focused on how to use microbiome therapeutics to provide infection protection to medically compromised patients.”

Eyes bigger than the belly

Even though many microbiome-based therapies are looking to gastrointestinal conditions, the rest of the pipeline is much broader. Finch Therapeutics, which is partnered with Takeda on several drug candidates, is developing FIN-211 for autism spectrum disorder (ASD). The company states that a subset of individuals with the condition also exhibit the most common gastrointestinal (GI) disorders, with the expectation that treatment could address both the GI and behavioural symptoms by targeting multiple ASD-relevant pathways.

4D Pharma, another biotech working in the space, has a pipeline of products that predominantly target either immuno-oncology or central system disorders indications. There is now a growing body of research to suggest that the microbiome of a patient can impact responses to immunotherapy. The potential was enough for both Pfizer and Merck to decide to collaborate with 4D to test combination treatments of their immunotherapies, Bavencio (avelumab) and Keytruda (pembrolizumab), respectively. Both treatments will be tested alongside MRx0518, which is also being tested as a monotherapy, after 4D found that the microbiome therapy was able to increase key immune biomarkers associated with anti-cancer immune response and responses to therapy and was associated with better clinical outcomes in early trials.

Compelling advantages

A spokesperson for 4D Pharma explained to pharmaphorum that microbiome-based therapies, or Live Biotherapeutic Products (LBPs) as they are also known, are attractive to use in combination due to their safety profile.

“As naturally occurring non-engineered strains of human commensal bacteria originally isolated from healthy human donors, they are expected to have very clean safety profiles,” they said. “This also means LBPs are attractive as combination therapies, driving better efficacy without additional toxicity concerns.”

Beyond this, the spokesperson added that LBPs could go beyond what is therapeutically possible with traditional small molecules or biologics. This is due to their ability to hit multiple targets with the same drug, which, alongside the expected safety profile of the treatments, could offer advantages over existing treatments.

“More broadly, the microbiome can be thought of as analogous to a critical organ that we previously overlooked or underappreciated, but is involved in the proper functioning of a wide range of human systems from metabolism to immunology (including immuno-oncology) and neurology via the gut-brain axis. By understanding these impacts, the microbiome offers a whole new way to think about treating many different diseases,” the spokesperson concluded.