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Manufacture Advanced Medicine

The Fourth Therapeutic Class: Live Biotherapeutics

What led you to the live biotherapeutic field?

My background is in genetics. Interestingly, I started off in microbial genetics at a small biotech in the early 1990s. In addition to a passion for the science, I was also interested in the business side of things, so I decided to go back to university to study law. There, I learned more about corporate finance and started working for a private equity and venture capital firm. They wanted to get into healthcare and biotech, so I was able to become an investment manager. 

And that led me to set up my own fund with my business partner, Alex Stevenson, mainly focusing on small biotech businesses. We had a lot of success, but we always felt under pressure from investors to deliver quickly – which can be difficult in a field with a high rate of clinical failure – so we started looking for something reliable that could succeed over the longer term. Once we heard about the microbiome, we felt we had our answer.

How did you find out about the microbiome?

In 2011, our fund was looking at around 300 early stage research projects a year to invest in. One of those companies was a shark antibody business, based out of Aberdeen University, which Pfizer inherited from Wyeth. We travelled up to have a look at the technology and while we were there asked if we could take a look at some of the other stuff they had too.

There was a group that had identified two bacteria that could dampen down the immune system. They were actually planning on using the bacteria in pig feeds to prevent disease in piglets when they’re being weaned. But we looked at the data – which included mechanistic details – and thought “there’s a therapeutic here.” We decided to invest in a research project within that group and after realizing that there are many other bacteria with different mechanisms of action – all of which should be inherently safe and free from side effects – we began to appreciate the potential of the microbiome as an untapped resource for pharmaceutical development. With this in mind, we founded 4D pharma.

Why are live biotherapeutics inherently safe and what does that mean for drug development?

Microbes already exist inside the human body, which makes them inherently tolerable and unlikely to produce side effects. This is huge from a drug development perspective. Pharma companies lose around 30 percent of products at each clinical stage. Why? More often than not due to safety and toxicology. Often you’ll see this cited as a reason for high drug prices too – companies have to charge high prices for their successful drugs to recuperate the funds they lost for the unsuccessful ones. What if clinical trials were tests of efficacy alone because the products are inherently safe and tolerable? The huge development risk would be slashed. 

And from the patient perspective, I’m sure everyone reading this has been touched by cancer in some way, and many will have seen how ill people feel when they’re taking some of the commonly prescribed chemotherapies. It’s not uncommon for someone to opt against an effective treatment because of the potential side effects. Another example is Crohn’s disease, which can severely impact a patient’s life – even in terms of growth and puberty. Patients (or their parents) often have to decide whether or not to take an immunosuppressant with some very serious side effects. With live biotherapeutics, you can develop a treatment that is likely to be safe and easily delivered by an oral capsule – as opposed to expensive, immunosuppressive injections.

Which projects are you most excited about?

I’m most excited about our oncology program and our prime candidate MRx0518. We are currently working on a clinical trial with Merck & Co. and their checkpoint inhibitor, Keytruda. Keytruda is, of course, a successful drug that is generating close to $4 billion in sales in a single quarter. But there are some major limitations. Firstly, it only works in three-out-of-ten patients; secondly, some patients, such as those with non-small cell lung cancer carrying certain mutations, don’t respond. Naturally, Merck is interested in finding ways to expand the number of patients that Keytruda can treat.  

Our preclinical research showed that MRx0518 can reduce tumor volumes and tumor size as a monotherapy. And when you dose MRx0518 with a checkpoint inhibitor, you see a synergistic effect. So we’re trying to find out whether MRx0518 is effective in checkpoint inhibitor refractory patient populations – patients who have stopped responding to drugs like Keytruda. The question is: can we re-stimulate the immune system? 

Usually when you re-treat a patient who has already stopped responding to a checkpoint inhibitor you would expect something like a five percent response rate – so we set the bar in our combination trial at 10 percent. In our initial population of 12 patients with growing tumors, some of whom had received seven or eight different prior treatments, five had durable responses to MRx0518 in combination with Keytruda. That was a fantastic result and we’re excited to conduct later stage trials, with an approval next year potentially on the cards.

Do you understand the mechanism behind the effect?

To successfully develop a live biotherapeutic, we believe it’s vital to distill down the essential components of the microorganism and understand how it works at the molecular level –  we try to treat these products like any other pharmaceutical. Taking this approach, we’ve discovered that a specific region on MRx0518’s flagellum acts as an agonist for TLR5 on the cell surface, which triggers a signaling cascade leading to immune stimulation. We’ve carried out studies with flagellin knockout MRx0518 and found little to no TLR5 activation or immunostimulatory effects.

Are there many manufacturing challenges associated with live biotherapeutics?

For live biotherapeutics broadly, there is a potential for change to occur between batches and over time if not properly controlled because of the complexity of the product. This problem is multiplied exponentially if the product contains multiple organisms. We’re only dealing with single-strains, which allows us to more easily control the identity, purity, potency, and stability of our products. 

Another challenge is that there aren’t many CDMOs out there with the experience of manufacturing live biotherapeutics, so we decided to manufacture in house. The main challenge for us was ensuring that our bacteria are not exposed to oxygen during the process (they are anaerobic). To do this, we had to develop some novel manufacturing techniques. For example, we use a ‘Quality by Design’ approach to efficiently and effectively optimize fermentation and lyophilization conditions, as well as developing in-house some of our own hardware used in the production process.

So there are challenges, but they aren’t insurmountable. We have an cGMP-certified live biotherapeutic manufacturing facility in Spain and we’ve put nine programs through our manufacturing process – with some products having a stable shelf life of two years and counting. 

Interestingly, we’ve also found that scaling up into larger tanks has actually improved titers – our production engineer tells me it has to do with fluid dynamics favorably altering the flow of nutrients in the bigger vessels.

Given the novelty of the field, what are the regulatory hurdles?

When we launched the company in 2011, the FDA hadn’t even defined a live biotherapeutic. The first definition came in 2012. That said, we’ve found the regulators to be very easy to work with. Their main concern is, of course, safety. But they are also scientists. If you can present a logical argument – supported by a solid dataset – they tend to be receptive. In fact, Alex was asked, on behalf of the MHRA, to work on the European Pharmacopeia chapters on quality standards for live biotherapeutics, so we’ve had a role in setting the regulations for live biotherapeutics. And, as I’ve said, live biotherapeutics are microorganisms that exist in the human body, which makes them inherently safe – and that really helps allay the concerns of the regulators.

How would you summarize the potential of the field?

In more recent years, the microbiome has garnered a lot of attention. But back in 2011, if you were to tell someone that your plan was to isolate bacteria from someone’s fecal sample, put it in a capsule, and feed it to a patient to cure Crohn’s disease, they would have thought you were mad. Fast forward to 2020 and it’s looking like we might be able to address neurological conditions, such as Alzheimer’s and Parkinson’s, with the microbiome – two of the biggest problems we face as an aging society. If you’d have told me this three years ago, I might have thought you were mad! But that’s where we are today. 

From our perspective, we’re closing in on bringing a live biotherapeutic drug to market. But we’re talking about a single strain of a single microorganism. The human microbiota consists of something like 1000 different species of microorganisms, so it’s fair to say we haven’t even begun to scratch the surface of what might be possible in terms of pharmaceutical development. We’re talking about an entirely new class of medicines with the potential to transform how we treat many diseases.

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About the Author

James Strachan

Over the course of my Biomedical Sciences degree it dawned on me that my goal of becoming a scientist didn’t quite mesh with my lack of affinity for lab work. Thinking on my decision to pursue biology rather than English at age 15 – despite an aptitude for the latter – I realized that science writing was a way to combine what I loved with what I was good at.

From there I set out to gather as much freelancing experience as I could, spending 2 years developing scientific content for International Innovation, before completing an MSc in Science Communication. After gaining invaluable experience in supporting the communications efforts of CERN and IN-PART, I joined Texere – where I am focused on producing consistently engaging, cutting-edge and innovative content for our specialist audiences around the world.

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