INDUSTRY LEADER INSIGHT
Early in my career, I did not anticipate that microbiome-targeted therapies would one day become such a major focus in drug development, nor that I would end up helping to drive these efforts. As an undergraduate at Benedictine College in my home state of Kansas, I pursued a bachelor’s degree in biochemistry. During my graduate studies at the University of Kansas, I studied the biophysical characteristics of metalloenzymes, mainly those containing heme. After receiving my Ph.D. in inorganic chemistry, I moved to the University of Georgia to complete post-doctoral studies involving the elucidation of enzyme structures using nuclear magnetic resonance (NMR) spectroscopy.
After concluding my post-doc studies, I was recruited by a former colleague to join OxThera in Gainesville, Florida, at a company focused on the development of an enzyme therapy that breaks down oxalate. Excess oxalate in the body can lead to kidney stone formation and has been linked to certain heart problems, kidney failure, and even death. After approximately two and a half years, my colleague and I realized that a better enzyme needed to be discovered or engineered to properly function within the acidic environment of the stomach.
We decided to start our own company to develop products that would have the highest possible chance of being successful in the clinic. Captozyme was founded on June 3, 2009, to develop enzyme-based therapies to treat a variety of conditions, with the first efforts directed at finding an oxalate-degrading enzyme that could survive and function in a low-pH environment.
Because the formation of kidney stones has also been associated with a lack of the beneficial bacterium Oxalobacter formigenes, research to support our enzyme development efforts at Captozyme ultimately led us to explore live biotherapeutics. Over time, we developed a reputation as a company with unique expertise in the cultivation of a range of bacterial species, particularly in the area of process development.
Our first major foray into providing development services for live biotherapeutic products (LBPs) involved a challenging phase III project. The client had spent millions of dollars validating a small-scale process that failed upon tech transfer to a new contract development and manufacturing organization (CDMO) for scale-up. After closely examining the characteristics of the resulting drug product and drug substance, we decided to redevelop the process, starting with the cell bank.
Colonies were seen to form at different days, indicating that the cell bank was inhomogeneous. In fact, we found multiple different cells within the cell bank, one of which exhibited 40 times greater activity than the others. By isolating this cell and using it for the process, we were able to produce a higher-quality product with increased viability and a shorter lag phase. That product is currently back in the clinic with a record of successful results.
What allowed Captozyme to find the source of the problem in this project — and to develop expertise in LBP processes and the ability to culture and harvest challenging species — is our unique perspective. Our knowledge base in microbiology is complemented by team members (like myself) with backgrounds in chemistry and other fields. As a result, we bring a different element to the table and can evaluate projects with a different set of eyes.
When working with live biotherapeutics, it is important to keep the organisms “happy.” That requires understanding and defining the space that will provide the optimum conditions for their survival and growth. Each organism is different and has different requirements. To develop successful manufacturing processes, it is thus essential to be “in tune” with each species’ unique characteristics. Doing so comes down to making observations about the cell structure during growth, the products the cells exude, and many other factors. Attention to even seemingly insignificant microbiological details is critical to determining the most efficient processes to cultivate and harvest these unique organisms.
Over the last 10 years, Captozyme has worked with 125 different isolates. Over that period, we have constructed a decision tree to determine the nature of each species and the various isolates associated with it. Because different isolates of the same species often each have different properties, it is necessary to start at the top of the decision tree for each project. The knowledge we have gained from other species and isolates may, in some cases, inform the decision process but in others may not be applicable.
One of the greatest challenges with LBPs is to develop processes that can be practically, efficiently and cost-effectively implemented when scaled. At Captozyme, we have always taken the time to understand what can be achieved at commercial scale, designed processes for the large-scale initially, and then scaled down to the lab scale for intensive development. In this way, we can ensure that the processes we are developing at small scale can be practically implemented for the production of clinical trial materials and commercial products.
The more LBP processes that we developed and attempted to transfer to other CDMOs, the more apparent it became that most contract manufacturers did not have the expertise, facilities, or physical equipment to properly work with anaerobic bacteria beyond the laboratory scale. Even firms with similar capabilities, such as those that conduct fermentations using Escherichia coli and other bacteria or produce plasmids for gene therapy, were very rigid and limited with regard to what products they could manufacture.
As a result, for each tech transfer project, we were spending several additional months training people at other CDMOs on how to set up their equipment and work with anaerobic bacteria. At the end of 2017, we made the decision to construct a Captozyme GMP facility dedicated to the production of LBPs. Construction began in February 2018 and was completed in August of that year. The facility has capabilities for the production of drug substance from fermentation through to freeze-drying.
The purpose-built GMP facility can produce LPBs up to the 400-L scale. An expertly designed cleanroom and manufacturing area were brought online in 2018 for any type of LBP, including aerobic, anaerobic, and spore-forming microorganisms. The cleanroom includes an ISO 8 fermentation room, an ISO 8 blending room, and ISO 7 lyophilization suites.
During the 10 years that our LBP process development services were growing, we continued to pursue new enzyme-based therapies. This effort resulted in the development of two promising candidates.
OX-1 is a novel oxalate decarboxylase (OxDC) enzyme developed to treat hyperoxaluria, a condition that cause recurrent stone disease, progressive chronic kidney disease and end-stage renal failure due to oxalate a nephrotoxin. With the support of four National Institute of Health (NIH) Small Business Innovation Research (SBIR) grants this enzyme was evaluated in pharmacology and toxicology studies. It demonstrates stability across a wide pH range including very acidic environments and can thus effectively degrade oxalate in the gastrointestinal tract, particularly in the stomach. More importantly, the catalytic efficiency, or its inherent affinity for oxalate, is superior compared to other enzymes in development allowing it to degrade oxalate even in low-substrate environments such as those where calcium or other chelators are present. Captozyme also developed another OxDC that in animal studies demonstrated encouraging effect in the gastrointestinal tract and effect on endogenously produced oxalate.
The anticipated clinical effect from the superior characteristics of OX-1 were confirmed in a 2018 in a healthy volunteer study in which subjects were challenged with oxalate in their diet. This study showed excellent outcome in both safety and efficacy and a large improvement when compared to other enzymes in development. Data from recurrent kidney stone formers using one of Captozyme’s OxDC confirmed these results and significantly de-risks any further clinical development.
By early 2019, it became clear that, as a company, Captozyme was pursuing two disparate businesses and that, to provide maximum opportunity for growth in each area, those activities should be separated.
With the decision to split our drug development business from the LBP process development operations, we sought the right partner to help establish Captozyme as a CDMO that can meet this key market need. In early 2019, I contacted Mark Bamforth, who was completing the sale of his cell and gene therapy CDMO Brammer Bio to Thermo Fisher Scientific. As it turns out, for his next project, he was interested in building a CDMO in the microbiome space.
With many microbiome-based candidates in early-phase, preclinical, and clinical development, there is a growing demand for manufacturing capacity suitable for the production of LBPs. With very few CDMOs dedicated to the microbiome space, and none yet able to support the commercial launch of multiple products, many start-up product innovators have been forced to establish internal manufacturing capabilities, which is not the most effective use of their limited resources.
By May 2019, Arranta Bio was established to provide outsourced process development and scalable manufacturing of LBPs from preclinical phases to commercialization using a range of platform technologies. In October, Arranta Bio completed an $82 million funding round with Ampersand Capital Partners as the sole institutional investor and signed a strategic partnership agreement and strategic investment with Thermo Fisher Scientific. In November of that year, the services business of Captozyme became part of Arranta Bio, and I took on the role of Chief Scientific Officer.
Captozyme’s enzyme therapeutic assets were spun out as a newly formed biopharmaceutical company, Oxidien Pharmaceuticals, LLC, to continue clinical development under the leadership of Captozyme’s outgoing chief executive officer.
Arranta Bio will leverage the expertise at the Florida cGMP site, which will continue to provide process development and early clinical manufacturing support. Early-phase capacity will be expanded at this location with the addition of more process development and quality control labs and a second GMP manufacturing line, which will be online in 2020.
A new large-scale facility in Watertown, Massachusetts is also under construction to support late-stage clinical supply through to licensed, commercial manufacturing. The state-of-the-art commercial manufacturing facility will handle spore formers and anaerobic organisms and will include multiple suites with single-use fermenters up to 2000 L in capacity, as well as lyophilization and encapsulation capabilities.
Our goal at Arranta Bio, named for a Gaelic word meaning intrepid and daring, is to provide pioneering companies involved in the nascent field of microbiome-based therapies with the support they need to bring these novel treatments to the market.
As more and more researchers have investigated the link between the microbiome and diseases, evidence has been mounting regarding the role it plays in numerous health-related issues, including not only gastrointestinal disorders and allergies, but cardiovascular diseases and metabolic, autoimmune and neurological disorders, as well as diabetes and cancer.1
The list of diseases associated with the microbiome continues to grow. We are also gaining a better understanding of how the modification of the human diet over the last century and the use of antibiotics have influenced the nature of the human microbiome and in turn the rising prevalence of some diseases. Even the use of caesarian sections has been shown to have an impact on the microbiome, which is established at birth. The likelihood of the development of allergies is greater for babies delivered via C-section compared with those delivered naturally.
Not surprisingly, many of the microbiome-based therapies under development today target diseases of the intestinal tract, due to the presence of a large number of gut bacteria. Overall, there were approximately 2,400 clinical trials underway in 2018 of candidates developed using microbiome science and more than 200 firms active in the field.2 The market is estimated to be growing at a compound annual growth rate ranging from near 20%3 to as high as 60%.4
Going forward, we can expect our knowledge of the link between the microbiome and disease to be further expanded. For instance, diseases now considered to have genetic causes passed from mother to child may also be influenced by the microbiome colonized at birth.
The industry will also be challenged to develop more efficient manufacturing solutions for products comprising large sets of bacterial consortia.
The formulation of products that can be administered using various routes will also be a focused area of development. Currently, most products in clinical trials are designed to be administered orally or topically, but the ability to deliver LBPs via inhalation, vaginally, rectally, or via another route are also being explored and will provide additional opportunities for growth of the sector.
The turning point for the industry, however, will be the first approvals of LBPs. Once a couple of products reach the market and demonstrate that products based on live organisms can have clinical effectiveness, the market will be poised for significant growth.
Arranta Bio is positioning itself to help those first companies achieve those initial successes and also to support the further growth of the industry. We aim to be the go-to company for developers of microbiome-based therapies. As a dedicated CDMO focused solely on LBPs with extensive expertise in process development, we have the ability to develop processes that give live biotherapeutic candidates the best chance of success in the clinic.
Moodley, Thunicia and Erin Mistry. “Could the Gut Microbiome Revolutionize Medical Care? Current Status and Initial Considerations for Successful Development and Commercialization of Microbiome Therapies.” Syneos Health. Apr. 2019. Web.
Fernández, Clara Rodríguez. "No Guts, No Glory: How Microbiome Research is Changing Medicine.” Labbiotech. 22 Jan. 2019. Web.
Worldwide Human Microbiome Market Insights & Projections (2019-2027). Research and Markets. 9 Sep. 2019. Web.
Global Market Study on Microbiome Therapeutics: United States Projected to be the Dominant Regional Market During 2018-2025. Rep. Persistence Market Research. Jan. 2018. Web.
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