Feeding the Microbiome: How MMTs Could Change the Landscape of Therapeutics

We now know that the microbiome is implicated in various different disease states, and as such, microbiome therapeutic strategies are being developed. Typically, these strategies have focused on "adding" or "removing" bacteria.

Kaleido Biosciences are taking a different approach. They are the first company to adopt a chemistry-driven strategy to drive the functional outputs of the microbiome organ, building a portfolio of novel product candidates known as Microbiome Metabolic Therapies (MMTs).

Technology Networks recently spoke with Johan van Hylckama Vlieg, Ph.D., Chief Scientific Officer at Kaleido Biosciences, to learn more about the development of MMTs, and how Kaleido are advancing a pipeline of MMTs for a variety of disease indications.

Molly Campbell (MC): Why is it important to leverage the microbiome to treat disease and improve human health? And what exciting breakthroughs have been made in this area in recent years?

Johan van Hylckama Vlieg (JHV): I think it's fair to say that the microbiome is probably one of the most exciting areas in the in the life science field. That sounds like a big statement, but it is really true. I think over the last 10-15 years we have seen microbiome science grow, and what we know now is that these bacteria live in and on our bodies as we grow and are very much involved in health and disease. When I did my PhD, I was always told that bacteria live in our gut and that they are vastly complex communities. We can't cultivate them, and so they are very hard to study, etc.

However, over the last few years, sequencing technologies and powerful bioinformatics tools have really allowed us to systematically scan the composition and activity of these communities in different health and disease states. Now we know that in certain diseases, such as brain related diseases or cancer, your microbiome is different. It is behaving differently. That's not just an effect of the disease. It is actually, in many cases, part of the cause of the disease. This makes the microbiome a target for interventions. If you can change the microbiome, you can alter the disease path. Around six to seven years ago, it was demonstrated that by doing a faecal microbiota transplantation, taking out a diseased microbiome and replacing it with a healthy microbiome, you are able to really treat (in some cases) severe infectious diseases.

This prompted a whole range of new ideas on how to modulate and change the microbiome in order to bring health benefits. What Kaleido does, in a very unique way, is change the food supply for the microbiome, and change the conditions in the gut. By changing the composition of the microbiome, we can change or prevent disease pathways.

MC: Please can you tell us about Kaleido's Microbiome Metabolic Therapies (MMT)?

JHV: Most endeavors in this field aim to identify which microbes are missing in a sick person and try to isolate them, before then bringing them back as single strains or a combination of strains and, sometimes, a whole community. Whilst I think this has therapeutic potential in various areas, what we are starting to see is that in practice to really change your microbiome, it is not that easy. I think this is to do with the fact that the microbiomes are dysbiotic in people for a reason. It also has to do with signals that come from the host side that then drive this. What we are trying to do is really target the root cause, making sure that we use our glycans to change the gut environment so that we favor the proper microbiome composition. This sounds a little abstract, but it is actually very intuitive.

Science is only giving more data that glycans are compounds that are beneficial for health. We have started to understand that glycans are a major food stock for the bugs in our guts. We have engineered further on that specific notion, as we are trying to synthesize glycans with very specific structures. We take the structure that you find in naturally occurring glycans, but we alter the way in which they are connected, their branching structure and the length of the glycans is controlled by the way we make them. This gives us the potential to utilize and synthesize a very diverse array of different structures which favour specific subsets of bacteria in the microbiome. Because these compounds are so similar to naturally occurring glycans that are Generally Recognized as Safe (GRAS) by regulatory bodies, yet still unique and synthetic. Another advantage is that because these compounds are GRAS, we are able to run clinical trials under regulatory environments to test the activity in target populations very quickly. This addresses one of the major issues in the pharma industry. It's so hard to select compounds and predict how they will behave. This translational challenge is a major issue in many classical pharma development pipelines.

Here, we have the ability to really accelerate trial phases and go very quickly from our test tubes into human trials, validating whether what we are seeing in the lab actually holds true in people as well.

MC: Can you tell us more about the MMTs that have progressed to human clinical trials?

JHV: We have focused our initial lead programs in areas where the biology is relatively well understood. What we are doing is really novel, and we want to make sure that our first programs have the highest chance of success. So, we have focused on two specific areas that are most progressed in the clinic. Once class of compounds will reduce the production of ammonia from the microbiome. Ammonia is produced in through multiple mechanisms that are largely bacteria driven.

By taking fecal microbiome samples and exposing these in the lab to our library of MMTs (glycans), we have identified a number of compounds that significantly reduce the production of ammonia in these in these faecal samples. We have chosen two of these compounds that are now advancing in the clinic, focusing on two specific medical indications. One of them is urea cycle disorders, a group of genetic disorders where people cannot properly remove ammonia from the blood. This specific compound is now in a phase two trial that has just kicked off. The other indication we have chosen is hepatic encephalopathy, a liver dysfunction where people are not able to clear ammonia from their blood. The third area is a very interesting one. One of the major health issues, and the World Health Organization has declared a state of emergency here, is the emergence of pathogenic bacteria that are multi-drug resistant.

One of the things that we've seen is that if you expose a microbiome that contains pathogenic bacteria to some of our MMT compounds, they very specifically favour the beneficial bacteria and microbiome, the pathogenic bacteria do not have access to the MMTs as a growth substrate. You outcompete pathogens by exposing them to these compounds. Here we have selected a lead MMT in our in our laboratory environment system, and these are in a clinical study at the moment. These clinical programs will have important deliveries over the months and years.

MC: How have you developed the platform to create MMTs?

JHV: We have really, very thoroughly thought about what microbiome science has taught us over the last 15 years or so, and we have also taken into consideration the major challenge of translating laboratory results to something that works in people and accelerating that pathway. Furthermore, we have thought thoroughly about the fundamental microbial ecology. So, what is needed? What are the best modalities to change a dysfunctional microbiome? The core notion has really been that it's not about just putting something back. By putting it back we will probably not sustain health. Taking all these factors together, we identified these glycan structures as the best modality to modulate and improve a dysfunctional microbiome.

The beauty is that actually, if you think about screening profiles in a human microbiome, it is relatively simple. You can take a little bit of faeces from a healthy or a sick person, isolate it in the lab, and incubate it with your compound of interest, and [simply] measure the impact of the MMT on the microbiome.

Two classes of index we typically look at is, how does the composition change, and we also look at the output of specific metabolites. One of the readouts is how does the ammonia production respond, or how is it influenced by the exposure of each of these individual microbes to the MMT. That's the core of our technology. Our initial thinking once we have a suitable compound is how fast can we get it in a human trial. These glycans are highly soluble fibers, and that means, from a manufacturing point of view, they defy other direct substance manufacturing challenges.

MC: What challenges do you face in the discovery and testing of the MMTs?

JHV: As in any drug development program, it's always about choosing the right opportunity. We have a massive breadth of patient indications and populations that might benefit from MMTs. On the other hand, you need to focus and deliver on the key targets that really will prove the technical aspect of the MMTs.

We recently announced a collaboration with, I would say, the absolute leading scientists in this area where we will focus on immuno- oncology. One of the key new developments in cancer treatments is a class of biologics that unlock the potential of a person's immune system to fight the cancer. This approach has shown some spectacular successes in specific types of cancer, especially in melanoma. But, we also see that sometimes only a portion of the of the cancer patients respond to immunotherapy.

A breath-taking finding over the last two or three years is that the ability to respond to these therapies is very much correlated to the composition of the microbiome in your guts. Of course, the activity of your immune system is very much related to the activity of the microbiome. We are starting to see how a "normal" responder [to immunotherapy] microbiome is different from a non-responder microbiome. We believe that with our MMTs, we have the potential to change a non-responder microbiome to a responder microbiome. We're trying to test that now in the lab and using the appropriate models that that people in the field find most translationally relevant. We'll get a readout on that data within the next year. I think the excitement and the potential that we feel here wakes us up with a lot of energy in the morning and helps us work until late at night.

Johan van Hylckama Vlieg, Ph.D., Chief Scientific Officer at Kaleido Biosciences, was speaking with Molly Campbell, Science Writer, Technology Networks.