Restoring the Balance

Young biotech company Rebiotix is using microbiome science to treat gastrointestinal (GI) disease and is involved in a number of clinical trials. Specifically, Rebiotix’ Microbiota Restoration Therapy drug platform aims to deliver human-derived microbes into a sick patient’s intestinal tract. Here, Lee Jones,  founder, president and CEO at Rebiotix, explains how the changing landscape of microbiome R&D is shaping conversations with regulators and helping create metrics for patient norms.

What drew you to the microbiome space?

My introduction to the field came through fecal microbiota transplantation (FMT) – the transplantation of fecal bacteria from a healthy donor to a sick patient – to achieve the restoration of a “balanced” gut microbiome. The concept sounded ridiculous to me at the time! I had spent the majority of my career in the medical devices industry and while it was fueled by innovation and progressive thinking, I had never encountered anything so off-the-wall before as harvesting microbes from a healthy person and using them to treat someone who was ill. 

But the more I read, the more interesting the concept became. I realized that there was huge potential to help many people through this type of treatment – and that bringing about the success of this type of therapy wasn’t really a question of biology, but logistics. Based on my previous experience I knew how to take a product and transform it into something that could be delivered to a patient; I knew how to make a product that could be stored in inventories, invested in, and how to take it through the regulatory process. In 2011, I founded Rebiotix, a biotech focused on transforming the way that GI disorders could be treated using the gut microbiome as the basis of our therapeutics. Our proprietary platform microbiota-based platform – named MRT – uses fecal material from donors to mimic the microbial mix found in the gut of healthy people. These organisms are then subjected to standardized manufacturing processes, quality controls, and stabilization processes with the goal of being able to address unmet medical needs for patients, starting with the life-threatening infection from Clostridiodies difficile, known more commonly as  C. difficile infection.

How has the field changed since you first entered it?

The world has come a long way from believing that all “germs” are bad; we used to think that we were doing a service to patients by ridding them of these nasty organisms. We’ve now come to realize that we live in partnership with them. And without many of these microscopic organisms, our health can be severely compromised. 

When we first started working on our formulations, there weren’t any facilities willing to take on the manufacture of microbially-based therapeutics. No products like this existed in the marketplace, so there was no precedent to follow for facility controls or manufacturing techniques. Without a blueprint to guide their construction, we were breaking new ground in determining how, when, where, and through what processes our products would be made. Rebiotix was the first company to file an Investigational New Drug (IND) application with the FDA for our lead candidate RBX2660, and we needed to hire staff with pharmaceutical, microbiology, engineering, and pathology backgrounds to realize the design of our facility. Like everyone in the industry, their initial frame of reference was to sterilize everything – however, this wasn’t conducive to manufacturing a product whose key requirements were to keep organisms alive! It took a significant amount of imagination and creativity to build a facility and develop manufacturing methods for a product line without killing everything off. It was often a difficult process, but we were forced to change our mindset and embrace the learning curve to be successful. 

This creative approach and use of imagination has lead us to where we are today. We now have two products in our pipeline; one, an investigational enema formulation (RBX2660), and the other, an oral capsule (RBX7455). Both products are currently under clinical study to address recurrent C. diff infection - RBX2660 is currently in a phase III clinical trial, which, if all goes well, will be the pivotal trial needed to approach the FDA for product approval and ultimately provide us the ability to market this technology.

What is the most significant challenge in trying to restore the gut microbiome?

We share our bodies with roughly 100 trillion bacteria, viruses, and fungi. The challenge for industry is understanding how the proportions of each of these organisms vary between people based on their lifestyles, geographical locations and ethnic groupings. What parameters can be defined as “the norm” when we’re all so different? And given the lack of biomarkers for gut microbiome restoration, how can the efficacy of a treatment be demonstrated when we all have different starting points?

Our Chief Scientific Officer, Ken Blount, has developed a prototype metric for identifying the proportion of bacteria we see in people, and how it changes over time, called the Microbiome Health Index (MHI). The MHI gives us the opportunity to begin investigating the impact of our MRT platform formulations on the gut by assessing the profile of bacterial communities before and after receiving a treatment. Today, we are beginning to use this metric to distinguish between healthy microbiomes and those with dysbiosis (microbial imbalance or maladaptation on or inside the body).

The MHI has the potential to help us and others within the industry demonstrate that gut health is more than a subjective or arbitrary state of being. We hope to show that it is measurable and can be compared with a clinical diagnosis, and, therefore, could be useful in understanding what the next steps in a treatment course may need to be. As the field progresses, we hope to be able to better cater to individual patient needs with an increased understanding of the changes their personal gut microflora undergo over time.

How do you see regulatory frameworks changing to support new approaches to drug discovery and development?

Many companies are now pursuing microbiome-derived therapeutics – and working on unique approaches to formulating products to address patient needs. And so, though we may all be in the microbiome industry, no two companies have the same sets of questions or data. The diversity of companies and potential therapeutics gives some within the field a valid cause for concern. What if the regulation that comes into place is too rigid for certain microbiome products and indications?

For that reason, we must ensure that the FDA and biotechnology companies in the microbiome space are on the same page. Rebiotix is a member of the Microbiome Therapeutic Innovation Group, an independent coalition of companies dedicated to the research and development of FDA-approved microbiome-based drug products to address unmet medical needs, improve clinical outcomes, and reduce healthcare costs. The goal of this coalition is to provide the FDA with insight into the work that is ongoing in the industry and to ensure that all research has patient safety in mind; without the patient and clinical data at the center of development, there would be no way to determine the safest ways to continue to innovate. We have been fortunate to have had several meetings with the FDA, who have assured us that, as long as our research rationales are scientifically viable, they are willing to listen and support this type of work.

In my conversations with other members of the group and the wider industry, I’ve come to understand that regulators are highly accessible. They, like us, are learning, and therefore it is important for us to continue sharing information and fostering open dialog.

When I first set up Rebiotix, there was only one tool that could be used for sequencing. Few people had considered developing “bugs as drugs” – the idea that microbes could be medicine had yet to capture the public’s imagination. But as microbiome research has progressed over the last few years, the number of tools and associated technologies available has exploded. Similarly, though regulation may currently seem scant, it will inevitably develop to meet the needs of the industry. 

The microbiome is a source of excitement for everyone. The scientists and clinicians at the forefront of cutting-edge research, the regulators who are helping to shape change, and, perhaps most importantly, the public – the eventual recipients of such therapeutics – have all pushed microbiome research into areas that, until recently, would have been thought of as science fiction. The more steps we take into the unknown, the greater the successes we stand to achieve, and the greater the potential to use this incredible resource to serve unmet medical needs.