Challenges for Microbiome-based Drug Development

Challenges for Microbiome drug development

Cast as our enemies for much of modern medical history, bacteria are now emerging as potential treatments for a range of diseases and disorders

Over the past decade, researchers have been exploring how the bacteria that live in and on us affect disease and influence our health.

Called the microbiome, this vast and mostly unexplored microbial community contains around 100 trillion bacterial cells and other microorganisms that live (and die) on the surface of our skin, in our mouths and buried in the coils of our intestines, where they are the most diverse and abundant.

This microbiome is unique to each and every one of us, changes throughout our lives and is affected by a wide range of factors, including diet, age, genetics, environment and many more. We now know it plays a critical role in modulating our immune system, and our microbial health is inextricably linked to our overall health.

In particular, the microbes residing in our gastrointestinal tracts, collectively known as the “gut microbiome,” are essential contributors to metabolism and may hold the promise of new treatments for a range of therapeutic applications.

The gut microbiome and human health

Disruption to the gut microbiome can have negative impacts on human health and is associated with a wide range of conditions from infectious diseases like Clostridium difficile-associated disease (CDAD), to metabolic disorders, gastrointestinal illnesses and neurological conditions. Antibiotics can also cause imbalances in microbiome’s bacterial composition and can lead to the emergence of antimicrobial resistance.

There is, therefore, a growing interest in developing treatments containing living (or dead) microorganisms called live biotherapeutic products or biologics that either alter the gut microbiome or alter its interaction with host tissues.

One such biotherapeutic is faecal microbiota transplantation (FMT), in which faecal matter from a healthy donor is transplanted into the colon of someone suffering from recurrent CDAD a life-threatening condition that can lead to severe colon inflammation and causes around 15,000[1] deaths each year in the United States alone where it is thought to repopulate ‘good’ bacteria killed off by antibiotics.

Researchers are also exploring FMT’s potential for treating other conditions like inflammatory bowel disease, in which imbalances in gut bacteria may cause or worsen the disease, as well as conditions, such as diabetes, obesity and chronic fatigue syndrome.

By cultivating, re-shaping and harvesting the gut microbiome scientists are developing new biotherapeutics for a range of diseases and ailments from Lupus, Crohn’s disease and rheumatoid arthritis to multiple sclerosis and asthma.

And the use of biotherapeutics, including vaccines, blood components, cells, allergens, genes, tissues and recombinant proteins in disease diagnosis and prognosis is expected to rapidly expand over the coming years rapidly, and are poised to transform the treatment of diseases.

The global microbiome therapeutic and diagnostic market, estimated to be worth US$1.13 billion in 2018, is projected to grow by over 19% per year to $2.7 billion by 2023[2], with over 90% of the market dominated by biotherapeutics for treating, curing or preventing diseases and infections.

Manufacturing biologics

Global biotech and pharmaceutical companies are now developing the tools and protocols for analysing microbiome data and ‘translating’ microbiome research into treatments for combating disease and infection.

Working at the forefront of the Australian biotherapeutics sector, Luina Bio is a leading contract development and manufacturing organization with over 20 years’ experience in the production and purification of biologics.

“It has become abundantly clear that the microbiota that humans carry have a significant impact on human health,” says Les Tillack, Managing Director of Luina Bio. “As a consequence, we are now positioning ourselves as a leading manufacturer of biotherapeutics for pharmaceutical and biotech companies within Australia and internationally in the United States, Europe and Asia.”

At its state-of-the-art manufacturing facilities in Brisbane, Luina Bio produces a range of biologics, from whole-cell vaccines, purified plant extracts and probiotics and synthetic molecules for pre-clinical trials, to phase 1 to 3 human clinical trials and commercial veterinary products.

Underpinning Luina Bio’s approach to the development of biotherapeutics is the fermentation of bacteria and yeast cells, including Saccharomyces cerevisiae, commonly known as baker’s and frequently used in research. And Pichia pastoris, a species of methylotrophic yeast widely used for protein production using recombinant DNA techniques.

Unlike the manufacture of pharmaceutical drugs, which are made from chemicals and have simple, well-defined structures, biologics are harvested inside bioreactors containing genetically engineered microbes or mammalian cell cultures and can be whole cells (alive or dead), biomolecules produced by cells, like antibodies, or internal components of cells, such as enzymes.

This brings unique challenges across all aspects of the manufacturing process when creating biologics for use in new biotherapeutics.

For instance, many of the microorganisms are obligate aerobes and require oxygen, while others are strict anaerobes that cannot be exposed to air. Therefore, technical expertise and costly equipment, such as biological safety cabinets, anaerobic workstations for maintaining a sterile and anoxic environment and stainless steel or single-use bioreactors for handling and cultivating the microorganisms are required.

“The main challenge in manufacturing biologics is maintaining the strict anaerobic environment,” explains Jason Ryan, Head of Upstream at Luina Bio. “During manufacture you cannot be in the anaerobic chamber, so you need to maintain both aseptic handling as well as minimising oxygen contamination.”

Also, many biologics are delivered orally and are required to remain in the intestine, where they must be protected from stomach acidity and delivered to a specific location. This presents formulation challenges as the active pharmaceutical ingredients have to be able to survive in the harsh environment of the gastrointestinal tract.

“A close and early collaboration between fermentation and finished dosage formulation company is essential to the success of the manufacturing of microbiome products,” says Michael Kruidenier, Head of Business Development at Quay Pharma, a leading microbiome formulation company. Collaborations like these result in a more streamlined process and saves the customer time and money.

For animal studies, it can be extremely challenging to construct relevant animal disease models, as animal gut microbiomes may not be representative of those in humans. Similarly, for clinical drug development, there is currently no scientific agreement on what constitutes a “normal” gut microbiome, and validated biomarkers for microbiome-associated diseases are still lacking.

“Another challenge is the ongoing analysis of the content and composition of the microbiome itself in the absence of standardized terms, methodologies and data analysis, making clinical development much more difficult and costly,” says Ryan.

There are also regulatory challenges. For example, altering the composition of the gut microbiome is not currently considered an endpoint for drug approval by regulators. Therefore, meaningful clinical endpoints have to be included in the drug development program, increasing the complexity and cost of developing new biotherapeutics.

However, the industry consensus is that these hurdles are by no means insurmountable and that effective collaboration between drug developers and drug manufacturers will be key to translating today’s research into tomorrow’s biotherapeutics.

In keeping with this ethos, Luina Bio recently signed a manufacturing agreement with the French biotech LNC Therapeutics to develop a novel biotherapeutic from a recently discovered family of gut bacteria called Christensenella minuta. This new biotherapeutic will target metabolic disorders, including insulin resistance, obesity and hyperlipidaemia.

“This bacterial strain is key taxon in the human gut microbiome,” says Tillack. “Harnessing its potential represents a significant step in the development of new biologics for a wide range of biotherapeutic applications.”

 

[1] Clinical Trial Testing Faecal Microbiota Transplant for Recurrent Diarrheal Disease Begins

[2] Global Microbiome Therapeutics & Diagnostics Market Analysis & Forecast to 2023

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Categories: Biomanufacturing

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