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Microbiome: are we ready for third generation live biotherapeutics?

By Melanie Toyne-Sewell, managing partner at Instinctif Partners

The microbiome sector has come a long way. From liquidizing fecal matter in a kitchen appliance for direct insertion into the intestine to the encapsulation of dried matter for oral delivery; and now to the creation of live biotherapeutics, single drug products of multiple bacterial strains. 

The application of microbiome therapeutics is also broadening – from the most obvious gastrointestinal (GI) infections and conditions, to boosting the potency of immuno-oncology treatments and perhaps in the future, the treatment of central nervous system (CNS) and metabolic diseases. 

It’s not been an easy ride for this industry to date. Growing bacteria might be a relatively simple process on an agar plate, but manufacture on a much larger scale, using multiple strains, managing dosage before and after the product has passed through a hostile GI tract … and this, even before one considers the regulatory issues around a live product comprising multi-strain organisms. 

However, there is something compelling about seeking new medicines and treatment outcomes using the bacterial environment which is in and around us all. An increasing number of people, from academics to financiers, are convinced the microbiome is already having a major impact on medicine. There are just a few hurdles for the third generation of these medicines to cross before they reach the mainstream in the next 5-10 years. 

Earlier generations of microbiome-based therapeutics

The theory of using bacteria as a therapy has been a reality for years, where doctors have been taking fecal matter from healthy people and inserting it rectally to patients to treat gastrointestinal issues. This method of reestablishing a healthy microbiome as well as treating the infection has been particularly successful in treating recurrent C.difficile infection (rCDI). 

Clinical outcomes for rCDI pre microbiome-products have been poor because current therapies rely on antibiotics to kill the toxin-producing bacteria but they don’t kill off the spores left behind. The subsequent germination of new bacteria causes a loop of infection. However, treating patients with standard of care antibiotics and then a microbiome-based therapeutic to prevent germination and bacterial replication through microbiome repair has revolutionized treatment.

Ferring was the first out of the gate with its U.S. Food and Drug Administration (FDA) approval in November 2022, of its fecal matter therapeutic (FMT) treatment, Rebyota (fecal microbiota, live —jslm) for the prevention of recurrent C.difficile. The therapy delivers a cocktail of gut microbiota to return the gut microbiome to a healthy state. The treatment involves taking stool from healthy donors, industrially processing it and rectally administering it to patients with recurrent CDI.

The second microbiome therapeutics to be approved was by Seres. Seres’ ‘bacteria in a pill’ is the first FDA-approved oral microbiome therapy, and has also obtained Breakthrough Therapy and Orphan Drug designations.  According to a phase 3 trial, Seres’ product, Vowst, contains a type of beneficial gut bacteria called Firmicutes, which prevented CDI from recurring in 88% of patients for eight weeks, while just 60% of patients in the placebo group were free of recurrences.

On approval of Seres’ product, Vowst, Eric Shaff, president and chief executive officer (CEO), reflected the ambition and wider potential application of microbiome-based medicines, when he said: “We think it’s just the beginning of what is possible with microbiome therapeutics.” He went on to reference the potential of Seres’ approach, “…to address a range of infectious diseases in other serious indications with new therapeutic options.”

This ambition certainly includes GI conditions, but also a whole host of other diseases. For example, Seres is also investigating bloodstream infections and graft-versus-host diseases (GvHD). MaaT Pharma is also aiming at GvHD with a phase 3 trial ongoing, and is also in phase 2 to see if its lead programme can enhance the response of patients with melanoma to immune checkpoint drugs. Another leading microbiome company, Vedanta Biosciences is looking at C.diff, but is also looking at solid tumors and gram-negative infections, and has two investigator-sponsored trials for food allergies and hepatic encephalopathy – a neurological disorder due to chronic, severe liver disease. The list goes on. 

This broader ambition beyond GI is mirrored by the next generation of microbiome-based therapeutics. Companies are expanding from using one type of bacteria like Seres with its Firmicutes-based product to ‘one drug products’ comprising multiple strains of bacteria or ‘live bacterial therapeutics’ (LBTs). For instance, Vedanta’s lead candidate consists of eight types of human commensal bacteria strains selected for their ability to provide colonization resistance to C.diff. Based in Cambridge in the U.K., Microbiotica is developing MB097, a LBT comprising nine key species, and is being developed as a co-therapy with immune checkpoint inhibitor therapy in advanced melanoma and non-small cell lung cancer (NSCLC).

The next generation of microbiome-based medicines: live bacterial therapeutics

LBTs represent the next phase of microbiome drug development with great potential because of the combination effect. “Firstly, bacteria can support each other. If you can design and optimize the product for synergy; you can make one bacterium enhance another. You end up with a product where the sum is greater than the whole,” says Dr Sam Possemiers, CEO of MRM Health. “Secondly, if you work with multiple strains and can build in redundancy, you have more than one bacterium that performs a function. This means you have more robust efficacy across multiple individuals (with different microbiomes).”

The future facing the microbiome industry is very exciting and supporters predict major changes within the next 5-10 years. However, there are multiple hurdles ahead which are distinctly different to those faced by ‘regular’ biotechs investigating small molecules or chemical entities.

The biggest difference is that these are live organisms. The specific strains need to be chosen, then they need to be fed, bred and dried, before considering ‘normal’ drug challenges such as formulation and encapsulation to create a product that can be given to a patient. There are also the questions of regulating such a market, judging dosage, when each capsule could have a uniquely different effect on each patient. 

Isabelle de Cremoux, CEO and managing partner of Seventure, one of Europe’s leaders in financing innovation and a world leader in life science microbiome investment, listed the challenges: “Producing reproducible batches of living organisms, which are not well described and characterized, cultivating anaerobic organism, cultivating ecosystems of micro-organisms which need one another to survive, solving the long term stability – keeping the bugs alive in a drug delivery form (capsule etc) which was developed for powder or liquid, but not for living microorganisms, and shaping a regulatory framework which is not yet entirely finalized for such disruptive innovation.” 

 In this section, we look at these challenges in brief:

1. Developing multiple strains for LBTs

Products started as donor-derived extracts. In the next generation of microbiome-based therapeutics, the emphasis is on selecting multiple strains which work together. There are two lines of thought around production: manufacturing ‘bugs’ in isolation, then mixing them together to create an LBP at the end of the process. Now, some companies such as MRM Health are looking at manufacturing products in a co-culture mode which is looking promising if its interim clinical data around its ulcerative colitis programme is concerned.

The challenge is understanding how different strains of bacteria work together and what they do once they reach their destination

Professor of Translational Dermatology at Manchester University and founder of several microbiome companies, including listed company SkinBioTherapeutics, Cath O’Neill said: “As we create one drug product [containing multiple strains of bacteria], dosing becomes even more of a challenge. If you combine bacteria together, you get competition for nutrients and some bacteria might do better than others. You might end up with different proportions of different bacteria, and that’s not including the fact you might lose some as they go through the gastrointestinal tract. The dosing is difficult to judge to have the effect.”

And some strains of the same genus of bacteria need to be considered, which is why companies like Microbiotica are developing programmes based on strain-level microbiome analysis linked to patient phenotypes. Deep sequencing will help with analysis of the genetics of the different strains. This is already happening. However, to do this fully, the extent of analysis will require very large populations of people, across different ethnicities. 

2. Nutrition for growth and activity

The next challenge is the type of nutrient that bacteria are grown in that can change things completely. How one bacteria metabolizes nutrition, not only affects the proportion of other bacteria around it, but can have significant impact on physiological effects. For instance, the cross-feeding interactions between bifidobacterium and butyrate-producing colon bacteria such as Faecalibacterium prausnitzii. The resulting levels of butyrate created are directly linked with the level of inflammation found in the gut.  

3. Formulation – drying and encapsulation

Drying is the next step and works well in this field, as long as in the reconstitution step, the bacteria can grow again and retain their characteristics. This step is relatively straightforward for bacteria that like oxygen, however, gut bacteria prefer the anaerobic environment of the gut. Therefore, they need more protection from oxygen during the drying process.

And, with any pharmaceutical, half the battle is getting the drug to the right location to interact with the right target in the right way. As we move from  fecal bacteriotherapy (FBT) to LBTs, formulating these products in capsules to carry live organisms through the hostile environment of the stomach, and then into the intestinal tract is a massive challenge. Seres and other companies seeking oral formulations are using encapsulation to protect their products. 

4. Regulation

Before now, regulators have had to oversee products made up of a single active pharmaceutical ingredient, where the mechanism of action is mostly known. The introduction of biologics and LBTs has increased the complexity of clinical trials. 

According to Isabelle de Cremoux at Seventure, the final channel is the shaping of the regulatory environment. “Being a worldwide leader in investing in the microbiome industry, we acknowledge that in addition to investing in companies developing products, we also have had to help in solving the bottlenecks in the microbiome industry, and supporting the companies enabling the technologies.” 

In the case of microbiome-based products, the therapeutic benefit comes from the bacteria being alive. And it’s not just the direct effect of the bacteria, but also the environment and metabolism of the nutrients around them, introducing a host of new challenges including reproducibility and comparability between studies.

Professor Cath O’Neill is fully aware of the regulatory challenges in this sector. “We are not at the point where we truly understand what these bacteria do. We can identify the difference from normal, but can’t always say for certain what the bacteria are doing.” 

To give the regulatory authorities credit, they are working hand in hand with the microbiome industry. The Pharmabiotic Research Institute (PRI) is Europe’s first Microbiome Regulatory Science expertise center, and in July 2022, it was invited to join the Human Microbiome Action consortium to reach an international consensus on -OMICS standardization, pre-clinical models, clinical trial design etc. 

Microbiome therapeutics: live bacterial therapeutics as standard?

If the growing amount of research and funding entering this sector is anything to go by, there is a swell of support for the -OMICS sector.

As Dr Possemiers says, “[Given the location of most bacteria in the body], the first products on the market are in infectious disease, of course. [However], if we can bring through a product in inflammatory or metabolic disease, then we will have a novel modality.” 

And it’s not just the impact such products have on their own, but the co-therapy strategy which really excites him. 

He adds, “The immune-gut link could be the making of this field. The approach is a co-therapy strategy. If you can increase the potency of immuno-therapy, with minimal impact, you can have a big impact on survival. This area is really one to watch.”

And, finally, the fact that ESMO 2023 featured the microbiome prominently as one of the four key aspects at play in oncology, starts to put the next generation of products firmly on the map. 

Isabelle de Cremoux sums it up beautifully: “FMT is used mainstream already, 2 drugs are approved, 1 LBP has filed for approval, several drugs are used under early-access-programs. You would be surprised to see how frequently we are contacted by patients, physicians, patient associations, hospitals around the globe looking for help to find where they can have access to microbiome therapeutics.” 

The next 5-10 years are going to be an exciting one for this ‘new’ category of future medicines.