Gut feeling: why microbiomes holds so much promise for targeted therapeutics

Charlie Badham, Corporate Development, 4D pharma, spoke to Lu Rahman about the growing significance of microbiomics in the quest for new therapeutics

 

LR: How important are microbiomics in the development of new therapeutics and how does understanding gut bacteria help us find treatments for new diseases?

CB: The microbiome and live biotherapeutic products (LBPs) are an entirely novel concept in medicine. Often likened to a new organ, the microbiome has profound impacts on health and disease, that were almost entirely overlooked until recently.

Live biotherapeutics are unlike any type of drug, using live bacterial cells as potent modulators of host pathways implicated in disease. However, for the drug to be effective you still must understand whatit is doing and howit is doing it.  In LBPs, 4D pharma has identified individual strains of bacteria with particular functional activity that can be aligned with a particular disease pathway or mechanism.

While they have potent activity on their own, it’s also important to consider microbiome-targeted therapies as part of the treatment toolkit, able to modulate and improve the activity of other types of drugs.  Already you can see this is a range of settings, for example boosting the activity of immunotherapies in cancer, or as add-ons to traditional therapies in inflammatory conditions like asthma.

LR: In what areas of disease would you say microbiomics are showing particular promise?

CB: In the early days of microbiome therapeutics, the ‘low hanging fruit’ was understandably considered to be gastrointestinal diseases, such as C. difficileinfection, and this year we have seen positive late-stage clinical data from a multiple companies with therapies derived from FMT to treat this infection.

However, this is just the tip of the iceberg, and the potential of bacterial therapeutics is far greater than just outcompeting another pathogenic bacteria in the gut to prevent re-infection after antibiotic treatment.

As our understanding has progressed of the myriad human systems which bacteria of the gut microbiome impact, the range of diseases that can be targeted with microbiome therapies has become increasingly clear.

4D pharma believes that oncology is probably where live biotherapeutics will make their first significant impact. Earlier this year, 4D pharma produced the world’s first positive clinical data for a live biotherapeutic in oncology, and in a particularly difficult, highly refractory patient population where other therapies have been ineffective.

Longer term, we see huge potential in the bacteria-gut-brain axis as an entirely novel approach to understanding and treating diseases of the central nervous system.  These conditions have proved to be an unfortunately stubborn target for traditional approaches and are desperately in need of new ideas.  We’ve already seen some very exciting results for some of our own single strain LBP candidates in models of Parkinson’s and autism, for example.

LR: What are the challenges of working in this field and how can they be overcome?

CB: These are drugs and should be approached like any other. We are not interested in associations or correlations, comparing the composition of a ‘healthy’ microbiome with that of a patient with disease X, and identifying ‘good’ or ‘bad’ bacteria.

Our discovery platform, called MicroRx, employs a suite of complementary techniques and technologies to identify and characterise the functional profile of individual strains of bacteria in detail.  Importantly, we want to understand how they interact with a modified host biology as  with this foundational understanding you can start a robust, viable development plan.

Once you have achieved the level of scientific rigour necessary to approach LBPs like other drugs, the next fundamental hurdle to making them a reality is being able to manufacture your drug at sufficient scale to conduct clinical trials and then produce a commercially viable product.  As an emerging field there is still a real lack of high quality, large-scale CDMOs with the necessary expertise to make clinical grade LBPs. 4D recognised this major bottleneck early on, and made significant investments in our internal development and manufacturing capabilities, making us a world leader in this field.

Then, once you have a product to take into the clinic, you encounter the challenge faced by many novel therapeutics i.e. lack of regulatory precedent. In practice, regulators have been very cooperative and supportive, allowing 4D and others in the space to successfully carve a regulatory path for LBPs. This has been achieved within the same framework and with the same burden of proof of safety and efficacy as any other drug.

LR: Outline some of the work being carried out by 4D Pharma in this field.

CB: 4D is leading the way in developing live biotherapeutics in a number of areas. Earlier this year, we generated the world’s first positive clinical data for a live biotherapeutics for the treatment of cancer with MRx0518, as part of a clinical collaboration with Merck & Co.

In addition, our IBS candidate Blautix has the potential to be the first disease-modifying therapy able to treat both clinical subtypes IBS-C and IBS-D, by addressing the underlying cause of disease – the microbiome.

We also have clinical programmes in asthma,COVID-19, and IBD, plus a deep preclinical pipeline including second generation oncology candidates, LBPs for inflammatory diseases like multiple sclerosis and arthritis, and candidates targeting neurodegenerative diseases like Parkinson’s.

Beyond  our internal development pipeline, in late 2019 we entered into a research collaboration with Merck & Co using our MicroRx platform to discover and develop LBPs for vaccines, a completely new area for 4D and one in which we are pleased to be working with the world leading innovator in the space.

LR: Can you tell us more about the novel therapeutic you have developed for COVID-19 treatment

CB: We identified a strain of bacteria, known as MRx-4DP0004, that has a unique immunomodulatory profile able to address certain aspects of pathological inflammation, without being broadly immunosuppressive. In animal models of severe asthma, this strain showed a dramatic ability to prevent inflammation and protect lung tissue, by reducing the infiltration of immune cells into the lungs. Specifically, MRx-4DP0004 was able to inhibit aspects of the innateimmune system including key cytokines and cell types like neutrophils and eosinophils, without suppressing the adaptiveimmune system. We started a clinical trial of MRx-4DP0004 in asthma in July 2019.

As the COVID-19 pandemic gathered speed, and as the first immunology data from early cases in China was published, we recognised that the hyperinflammatory response associated with more severe COVID-19 was highly aligned with the activity profile we had seen with MRx-4DP0004.  Neutrophilic inflammation appears to be a key driver of severe disease, which we known MRx-4DP0004 can address. A number of anti-inflammatory immunosuppressants are being tested for COVID-19, but as a viral infection, you do not want to impair the appropriate adaptive immune response, which is key for dealing with infections.

Further, while we are initially developing MRx-4DP0004 to treat airway inflammation, it has also shown activity in animal models of systemic inflammatory diseases like MS and arthritis.  Though the key battle ground in COVID-19 is the lungs, inflammation is often systemic and can affect other organs and tissues, so the systemic immuno-modulatory activity of MRx-4DP0004 is particularly desirable.

LR: The company develops science and deliver therapeutics – what does the business do to try to guarantee its work is commercially viable / successful?

CB: Fundamentally 4D is, and has always been, driven by the science.  This is illustrated by our pipeline in two ways.  Firstly, the diverse diseases we have been able to target, from cancer to neurodegeneration, by identifying single strains of bacteria with particular functional characteristics.  Secondly, and related to this, is the phylogenetic diversity of our candidates – we are not restricted to a certain taxon or group, we screen our vast and diverse library for their functional activity, irrespective of taxonomy.

Once certain the foundational science is robust, we then work to ensure the translatability of these initial signals into therapeutic activity in patients.  We select preclinical models to demonstrate activity to the same high standard as any other drug.  Over and above this, though, we have also developed additional tools unique to microbiome therapeutics, such as ‘humanised’ animal models with a human gut microbiome, to reaffirm this activity in context.

We put a lot of work into the development of our candidates before entering the clinic, ensuring a clinically and eventually commercially viable product.  Having this infrastructure and expertise in-house allows us to integrate ‘manufacturability’ into our early candidate selection and development, reducing risk down the line.

We then design robust clinical trials.  Our Phase II trial of Blautix for IBS will be the largest randomised controlled trial of a LBP conducted to date, and using the FDA-recommended primary endpoint for approval of an IBS drug, following conversations with the agency.

While we have made great progress, we are not resting on our laurels.  To realise the true value of the MicroRx platform, which has already demonstrated utility in a broad set of therapeutic areas, we are exploring additional research collaborations with partners who have complimentary disease area specific expertise.  This is exemplified by our collaboration with Merck & Co. in the vaccines space and the MD Anderson Cancer Center in the US, the world’s biggest cancer hospital and a leader in oncology innovation

With any new area of science, not just pharmaceuticals, you may be limited by the tools at your disposal.  In the last few years the tools and techniques to study the microbiome and its interactions with the human host have improved immensely, while their accessibility has improved and costs have come down.

A challenge, or pitfall, particularly present in the microbiome field, is the need to separate correlation from causation. A number of researchers in the space have taken the approach of comparing, say, a ‘healthy’ microbiome with that of a patient with disease X, or patients who do or do not respond to a particular treatment, looking for bacteria that are more or less abundant in one group.

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