Supporting Commercialization of Live Biotherapeutic Products for Microbiome-Based Therapies

INDUSTRY LEADER INSIGHT

There are around 200 private and public companies developing microbiome-based therapies intended to treat a wide range of serious diseases, with large pharmaceutical companies showing increased interest by partnering with early innovators. While most of these investigational treatments are in the earliest phases of development, many have reached early clinical development, and more than a dozen are in phase II/III trials.

Commercialization of these products may be hindered, however, by the lack of sufficient manufacturing capacity. To support the advancement of this important field, Arranta Bio (“Arranta”) was established as a CDMO dedicated to providing development and manufacturing services of live biotherapeutic products (LBPs) for microbiome-based diseases from early phase through commercialization.

Role of the Microbiome

The microbial population in the human body numbers in the trillions; estimates range from 10 to 100 trillion — well more than the number of cells that make up a person.¹ The genes within these microbes outnumber the genes in humans too — by a factor of 150 — and are sometimes referred to as the “second genome.”² Comprising the “human microbiome," most commensal, symbiotic and pathogenic microorganisms are found in the nose, mouth, skin and urogenital and gastrointestinal tracts.

Established at birth, the microbiome develops as humans grow and is affected by diet, the use of antibiotics, genetics and various environmental factors. Many (~80%) of the species in the microbiome are beneficial and contribute to the healthy functioning of human bodies.³ As a result, when the microbiome experiences a state of imbalance, or dysbiosis, proper functioning of many systems in the body can be affected. Dysbiosis can result from the use of antibiotics, viral infections and stress, among other factors.³

The Human Microbiome Project, conducted by the National Institutes of Health in the United States, characterized the microbial communities at five major body sites. Since then, there has been significant investment in research efforts to further elucidate the nature of the microbiome. Examples in the United States include the National Microbiome Initiative
established in 2016 and the five-year Interagency Strategic Plan for Microbiome Research launched in 2018 by 23 U.S. government agencies.⁴

Real Therapeutic Potential

All of this research has led to the development of evidence supporting a strong link between dysbiosis and disease. Since the initiation of the human microbiome project in 2007, the number of academic publications and active patent families around the microbiome has grown exponentially.⁵ Issues with the microbiome have been shown to contribute to the development of many different health problems, including not only the obvious, such as gastrointestinal disorders and food allergies, but everything from cardiovascular diseases to metabolic, autoimmune and neurological disorders, diabetes and cancer (Figure 1).⁴

Gut microbiota, in particular, have been shown to be important for proper development of the immune system.⁶ Animals raised without any gut microbes have significant local and systemic defects in their immune systems. On the flip side, the presence of certain types of bacteria have be shown to lead to increased risk of various types of cancer, effects that have also been linked to influences of the microbiome on the immune system. Cancer patients with a healthy gut microbiome have also been shown to respond better to anti–PD-1 immunotherapy.⁴

Evidence has also accumulated to support the causative role of gut bacteria in metabolic diseases, including obesity, insulin resistance and type 1 and type 2 diabetes.⁴ For instance, the well-established diabetes drug metformin has been shown to improve the tolerance of glucose by the gut microbiome. One study found that the reason that some diabetes treatments range in effectiveness from 50% to 90% can be linked in part to variations in the ability of a patient’s microbiome to influence the absorption and function of drugs.¹

The majority of microbiome-based therapies under development today target either diseases of the gastrointestinal tract, such as ulcerative colitis and irritable bowel syndrome, or conditions where a strong link between the gut microbiome and disease has been established, as is the case for psoriasis and diseases that involve the gut–brain axis, such as Parkinson’s and other neurological disorders. Others are targeting cancers that are potentially linked to gut health, such as colon cancer and other cancers localized in the gastrointestinal tract. The third main area of focus is infectious diseases.

Some patients are already receiving treatments targeting the gut microbiome. Fecal microbiota transplantation (FMT) has been successful in treating people with Clostridioides difficile (C. diff), a recurrent intestinal infection that was named a national health threat in the United States in 2013 by the Centers for Disease Control.³ These patients typically exhibit depleted native microbiomes, which creates an environment in which the opportunistic and dangerous C. diff can thrive, and treatment involves use of a healthy donor’s whole microbiome to reestablish a healthy microbiome in the patient.

Investors are Banking on the Microbiome

The growing body of evidence supporting the role of the microbiome in disease has led to a proliferation of start-up companies developing microbiome-based therapies. Companies such as Finch Therapeutics, Enterome Bioscience, Rebiotix, Seres Therapeutics, Vedanta Biosciences, Microbiotica, Axial Biotherapeutics and Kaleido Biosciences have or are attracting significant venture capital funding. Firms like Assembly Biosciences and Evelo Biosciences, on the other hand, are opting to raise money through public markets.⁷

Big Pharma is active in the space as well, largely through licensing deals and development partnerships, such as Pfizer with Second Genome, J&J with Vedanta, Genentech with Microiotica⁷ and Takeda with Enterome, Finch Therapeutics and NuBiyota.⁴ Nestlé Health Science and Allergan have also made healthy upfront payments to microbiome therapy developers.⁴ J&J’s Janssen division is also active in the Human Microbiome Institute. Mergers and acquisitions are also taking place, with some of the older biotechs expanding their position by combining with newer start-ups making rapid advances, such as Ferring’s purchase of Rebiotix.⁷ Since 2015, more than $5.4 billion has been spent on partnerships and acquisitions in the therapeutic microbiome space.⁴

Other companies of note include 4D Pharma (collaboration with Merck), Biomica (bioinformatics platform), Biomx, Elligo Bioscience, Locus Biosciences, Maat Pharma, Symberix, Symbiotix and Symlogic.⁷

Multiple Approaches for Leveraging the Microbiome 

The use of whole-microbiome transplants, such as in FMT, is just one approach that companies are taking in their new therapy development efforts. Many companies are focused on isolating a single bacterium or consortia of bacteria determined to be important for a particular disease. These treatments are based on defined microbial cultures.⁶

Other companies are looking to create engineered bacteria that have improved capabilities compared with those identified in the human microbiome. In addition, bacteriophages, which are viruses that infect specific bacterial cells with genetic material, are being investigated as a way to alter the genetic code of microbiota to kill problematic bacteria or alter their behavior, such as their immune responses.²

Another group is focusing on the metabolites generated by the microbiome — small molecules or biologics that have been shown to be important in the mechanistic pathways in which the microbiome is involved. Yet others are attempting to engineer bacteria that will produce specific active drug substances in the gastrointestinal tract.² Vaccines are also being developed based on the idea of “molecular mimicry.”⁶

In 2018, the most common approaches used to develop microbiome-based therapies were small molecule therapies (31%), single-strain bacteria (26%) and microbial consortia (24%). Treatments based on genetically modified single-strain bacteria, phage cocktails and microbial ecosystems accounted for 12%, 4% and 3% of the approaches adopted for pipeline assets, respectively (Figure 2).⁴

Significant Market Opportunity

All of this activity is reflected in the high rate of growth predicted for the microbiome-based therapy market. The market research firm MarketsandMarkets predicts that the value of the global human microbiome market, including probiotics, prebiotics, foods, medical foods, diagnostic tests and drugs, will reach $1.7 billion in 2027 and will expand from $364 million in 2022 at CAGR of 22.5%.⁸ Prebiotics account for the largest share by product type. By disease indication, the value of the market for products targeting infectious diseases will grow at the fastest rate.

Other estimates peg the market as expanding at CAGRs ranging from near 20% (BrandEssence Market Research Company,⁹ estimated value in 2025 of $744.6 million; Mordor Intelligence¹⁰) to approximately 40% (The Business Research Company,¹¹ estimated value in 2022 of $1.28 billion) to slightly more than 60% (Persistence Market Research,¹² estimated value in 2025 of $890 million).

Hurdles to Overcome

Bringing microbiome-based drugs to market that have a true impact on disease control and reduction will not be easy. While there are many candidates in the pipeline, with a few in late-stage clinical trials, there is still much work to do.

More research must be conducted to fully understand the roles of the microbiome in maintaining health and dysbiosis in contributing to disease. It can be challenging to clearly establish that a change in the microbiome is a cause of disease and not a side effect.² The challenge is magnified given that each person’s microbiome is unique.

In addition, drug developers must be sure to take into account the importance of factors beyond the microbiome that influence disease development and progression. It may be that combination therapies involving microbiome-based drugs and other more conventional treatments will achieve the best results.¹³

Translating research results into commercial therapies won’t be easy, either. Reliable and cost-effective in vitro/ex vivo models for the microbiome in the gut and other parts of the body are needed for both relevant diseases and healthy states to facilitate drug development.¹³

Greater insight is also needed in determining how to choose the right patients for enrollment in clinical trials. The complexity of the microbiome and its changing nature can make not only drug development difficult; diagnosis can be equally challenging.⁴

There are manufacturing issues as well. First, for any treatments involving live organisms, some level of standardization must be established so that regulatory authorities can have confidence in the reliability and reproducibility of manufacturing processes.⁴

In addition, improvements are needed in the manufacturing methods used to produce small quantities of clinical trials materials. Practical solutions are needed for selecting and developing the optimized media and process conditions that will afford efficient growth of the desired bacteria to ensure the production of sufficient quantities of a given isolate for clinical trials without the need to
construct large manufacturing facilities at an early stage of development.

Many of the live bacteria candidates in development are anaerobic microbes and must be handled in oxygen-free atmospheres throughout the manufacturing process. Practical and scalable downstream processing solutions are needed to enable cost-effective and efficient manufacture of commercial products. Unlike conventional biologics, processing must be achieved without impacting the viability of the live microbes, and they must be formulated to ensure release in the right place so they can effectively recolonize the gut or relevant area. Furthermore, patient-friendly and safe delivery solutions that are also manufacturable at scale are needed. Most clinical trial materials today are lyophilized to stabilize the bacteria and then encapsulated.

Facilities must be designed taking into consideration that some of the microbiome-based products are spore formers, which are hard to detect and difficult to contain. Unidirectional flow, segregation of suites to protect people and products, proper air handling and sterilization – many of the same conditions required for viral vector manufacturing facilities –must be applied, with added capabilities for maintaining low oxygen/low moisture conditions during drying, milling, encapsulation and packaging.

Uncertainty with respect to the regulatory approval process for novel microbiome-based drugs is another issue that ultimately must be managed.⁶ One question the U.S. FDA is addressing is when bacteria should be considered a probiotic and when they should be classified as a drug. For these drugs, the question then becomes whether they can be approved following the process and requirements established for conventional biologics.

Guidelines for handling spore formers do exist and are applicable. In addition, the FDA has issued draft guidances and, as in the case with other novel treatment fields such as cell and gene therapy, is willing to work with industry to provide accelerated approval pathways.¹⁴

Developers of microbiome-based drugs are also faced with intellectual property and patent protection challenges.⁴ For instance, existing patent law prohibits patenting live organisms and naturally occurring materials. Questions have also been raised about claims regarding beneficial functions versus claims for specific microbes.

What’s Next for Microbiome Therapeutics?

The number of microbiome-based therapies in the clinic is astounding. One source identified 2,400 clinical trials underway in 2018 involving candidates developed using microbiome science.² That number was up from 1,600 in 2017, reflecting the rapid growth of the field. Today, there are investment funds dedicated solely to companies developing microbiome-based therapies, and around 200 firms are actively working on different aspects of the microbiome.

A few products are in phase III clinical studies, more have reached phase II and even greater numbers are in early stages of development. The first products likely to receive approval will be treatments for C. diff. infections. Candidates targeting diseases of the GI tract — ulcerative colitis and others — also look to have good prospects based on published early clinical data.

Not too long ago, the focus in medicine had largely been on “bad” microbes and the need for sterility, the lasting impact of the transformative “germ theory of disease.” There has been a huge shift in thinking, and just in the last 10 years, tremendous advances in our understanding of the microbiome have been made. But we are just scratching the surface at this point. We are starting to peel back the outer layers of the onion and have no knowledge yet of how many layers there are in total.

Crucial clinical work needs to be done to demonstrate the safety of microbiome-based therapies, establish the existence of relevant cause-and-effect relationships and clearly show how these novel treatments can address unmet medical needs.

This work is being done today by companies located around the world. Microbiome-based therapy development has become a truly global phenomenon, and there is a high level of interest and engagement in all of the possible approaches and for many disease targets.

All of these efforts have the potential to lead to products that can treat and/or possibly prevent significant and widespread diseases and disorders, such as obesity, diabetes and Parkinson’s. As a result, they could eventually have a tremendous impact on human health.

Arranta to Provide Early Phase to Commercial CDMO Services

With many microbiome-based candidates in early-phase, preclinical and clinical development, there is growing demand for manufacturing capacity suitable for these products, many of which comprise live biotherapeutic products (LBPs).

Some established biopharmaceutical contract development and manufacturing organizations (CDMOs) offer limited services in this area, but there are concerns about containment of spore formers in most biologic manufacturing facilities. Very few CDMOs are dedicated to supplying therapeutic products for the microbiome space, and none are yet positioned to support the commercial launch of multiple products. Some start-ups have elected, as a result, to build internal manufacturing capabilities — not an ideal use of their limited resources.

Arranta was established in May 2019 to meet this important market need; however, our roots go back a decade. We are building a business that will serve the pioneers at the frontier of these exciting developments, providing outsourced process development and scalable manufacturing all the way to commercialization, using a suite of platform technologies.

After completing our fundraising of $82 million in October 2019, our next step, in November 2019, was the acquisition of the early-phase development and clinical manufacturing business of Captozyme (Gainesville, Florida), which has focused on LBPs and enzyme development since 2009. The products business of Captozyme was separately spun out under the control of the former CEO.

Captozyme has built expertise in process development and the production of LBPs for over a decade. The company has worked with more than 125 different isolates and established a purpose-built GMP facility with the capability to produce LBPs up to the 400-L scale, including obligate, facultative and microaerophilic organisms. The cleanroom includes an ISO 8 fermentation room, an ISO 8 blending room and ISO 7 lyophilization suites.

Arranta will leverage the expertise at the Florida cGMP site, which will continue to provide process development and early clinical manufacturing support. Plans are already underway to expand early-phase capacity at this location with additional PD and QC labs and a second GMP manufacturing line that will be online in 2020.

A new large-scale facility in Watertown, Massachusetts will support clients through late-stage clinical supply to licensed, commercial manufacturing of their products. Arranta has purchased a site with high ceiling space ideal for fitting out with clean rooms and additional room for laboratories and offices. We will begin conversion of the building into a state-of-the art commercial manufacturing facility that can handle spore formers and anaerobic organisms in early December 2019. Once completed, the site will include multiple suites with single-use fermenters up to 2000 L in capacity, as well as lyophilization and encapsulation capabilities.

Both facilities are designed to be fully compliant for microbiome products under the FDA Code of Federal Regulations (Part 21) and the European Advanced Therapy Medicinal Products’ regulations.

Arranta has also been successful in the fundraising arena, garnering $82 million to support the launch of the business and the build-out of our early-phase and commercial capacity. We have a main institutional investor (Ampersand Capital), as well as a strategic investor, Thermo Fisher Scientific, whom Arranta is partnering with to access processing, analytical and material technologies that can be used to manufacture LBPs. In addition, Arranta will use its bacterial fermentation platform to manufacture plasmid DNA for Thermo Fisher’s gene therapy clients.

We are led by a strong management team with many years of experience in the biopharmaceutical industry and a team of technical experts with a proven track record in both process development and contract manufacturing from fermentation to lyophilization and encapsulation of live biopharmaceuticals. I bring my experience as the founder of Gallus Biopharmaceuticals, a CDMO providing biologics development and manufacturing services, and Brammer Bio, a viral vector CDMO supporting cell and gene therapy companies, to now lead the growth of Arranta.

As our Chief Technology Officer, Captozyme founder Arron Cowley brings a wealth of expertise and relationships in the field of microbiome-based therapies. Our CFO Steve Favaloro and Chief Legal Officer and General Counsel Lana Gladstein came with me from Brammer Bio and also bring with them extensive experience in the successful start-up and operation of companies focused on novel therapeutics. Our new COO will be joining the company in early December and has deep knowledge of contract manufacturing operations.

We are currently interviewing people for positions in technical, engineering, manufacturing, quality and support operations and expect by the end of 2020 to employ over 100 people in total.

Arranta is a Gaelic word that means “intrepid and daring,” which reflects how we view Arranta. We are embarking on a new CDMO business to lead the supply of product development and manufacturing services to pioneering companies that are discovering novel therapies to tackle serious gut health and microbiome-related diseases based on LBPs. Arranta is excited to support the growth of this burgeoning field and enable new, effective treatments to reach patients in need.

References

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