While the microbiome therapeutics sector has yet to produce its first commercial success, it continues to draw interest across the industry, as evidenced by intensification of R&D efforts, expansion beyond the digestive system, and growing interest in the sector from big pharma. Manufacturing live biotherapeutic products (LBPs) to treat microbiome-associated diseases requires unique and dedicated facilities, but few contract manufacturers have focused on or even added on significant LBP manufacturing capabilities. List Labs is an exception. The company is investing early to build upon its existing capabilities and solidify a position as a leading contract development and manufacturing organization (CDMO) in the field of microbiome-based therapies.
The First Producer of a GMP LBP
Founded in 1978 by Linda Shoer, List Labs began operations as a producer of cholera toxin. It rapidly expanded, establishing a strong foothold in the toxin industry, and soon became recognized as a reliable supplier of reagent-grade bacterial products and toxins. Currently, List Labs offers over 100 high-quality, reagent-grade products used in the development of therapeutics, vaccines, and adjuvants.
List Lab’s expertise with botulinum toxins led to the formation of a relationship with the largest botulinum commercial manufacturer, which was developing a process for the commercial manufacture of botulinum toxin for aesthetic and therapeutic use. While working on this collaboration, the company developed extensive knowledge about the design and process requirements for optimal GMP manufacture of these types of organisms.
The construction of a facility for small-scale GMP production then followed, including containment and segregation capabilities for working with up to biosafety level (BSL) 3 organisms, as well as spore formers. In this first facility, List Labs has tackled development and manufacturing projects involving more than 60 different species of microorganisms and hundreds of different strains, including anaerobes, aerobes, and spore formers. In addition, List Labs manufactures a GMP lipopolysaccharide (LPS) product with a Drug Master File at the U.S. Food and Drug Administration (FDA), the only one of its kind on the market. This GMP LPS product is used globally in numerous clinical trials.
With such extensive expertise and experience in so many different organisms and a state-of-the-art facility designed for their safe development and manufacture, the natural next step for List Labs was to offer its services to companies focused on the development of microbiome-derived therapeutics. Many of these therapies are classified as live biotherapeutic products (LBPs), which comprise a specific strain or mixture (consortium) of strains grown, purified, freeze-dried, and then formulated into a final product that is typically filled into capsules or vials and may also be offered in a form for topical and vaginal applications. A significant number of them are based on anaerobes or spore formers. In fact, List Labs was one of the first companies to manufacture an LBP that progressed into clinical trials. Additionally, List Labs has developed several therapeutic proteins that are expressed in bacteria found exclusively in the microbiome.
Other differentiating capabilities developed by List Labs during its 40+ years of working with many types of organisms include the implementation of aseptic processing and the production of unique dosage forms. For example, the company has the ability to perform aseptic fill/finish of formulated products, as well as powder filling of vaginal applicators and vials.
Presently, while List Labs continues to support customers with the development and manufacture of various toxins, the bulk of the company’s contract services focus on LBPs: developing and scaling manufacturing processes and providing GMP material for phase I and phase II clinical trials.
State-of-the-Art Small-Scale CDMO Facility
List Lab’s facility in Campbell, California, is equipped with stainless-steel reactors with up to 100 liters working volume and a new 500-liter single-use stirred-tank reactor. The latter was installed to enable List Labs to support customers with higher volume requirements through their phase II studies. The facility and procedures were carefully designed to minimize the risk of cross-contamination, even for spore-forming organisms, through trained personnel, adequate air flows with pressurization, and material and personnel flows.
Another recent addition to List Labs’ capabilities at the California site is the ability to perform small-scale manual fill of capsules for phase I trials (programs that require larger-scale formulation and encapsulation are sent to expert partners).
Genome & Company Expands from R&D to CDMO Microbiome Services
With the microbiome sector expanding rapidly and numerous LBPs advancing through clinical trials, many of List Lab’s customers were looking for the company to expand its capabilities even further to include large-scale manufacturing in support of their upcoming phase III studies and future commercial product launches. Consequently, List Labs sought a means to establish large-scale production capacity.
South Korean drug developer Genome & Company, which has a robust pipeline of LBPs, had been working with different contract development and manufacturing organizations (CDMOs) in Europe and Australia providing LBP services but had not been satisfied with them. The firm identified an opportunity to address the need for high-quality CDMO services for this growing sector of the biopharma market. Genome & Company was introduced to List Labs through Scioto, now a sister company of List Labs, which had outsourced the early-phase production of a candidate LBP to List Labs.
A visit to List Labs’ state-of-the-art Campbell facility impressed Genome & Company leaders and ultimately led to Genome & Company’s acquisition of 60% of List Labs at the end of 2021. As part of this deal, a plan was initiated to create a new sister company — List Bio — to support the construction of a large-scale CDMO facility. Once certain milestones are reached at the new Indiana facility, List Bio will merge with List Labs to establish an end-to-end service provider in the microbiome space supporting projects seamlessly from preclinical studies to clinical development and all the way through phase III and commercial launch.
List Labs and List Bio are already working collaboratively, and in many areas the two organizations are operating as one company. For example, the basic processes and procedures, human resources, and quality systems at the two locations are the same. Achieving customer success is the focus of List Labs and lies at the core of our culture alongside a commitment to quality. That culture will be instilled at the List Bio large-scale facility as well.
State-of-the-Art Large-Scale CDMO Facility
The basis of the design of the new large-scale List Bio manufacturing facility is completed, and grading of the site and other pre-construction work has been finished. Establishing the detailed design is proceeding at a thoughtful pace, as it is important to ensure that all relevant factors are appropriately considered and questions resolved before moving on to the final stage of design. The 130,000-ft2 facility will start with four planned production lines, including upstream and downstream processing for drug substance manufacturing. Both 2000-L stainless-steel and single-use fermenters will be installed to allow for flexibility. Freeze drying will be performed in a 30-ft3 lyophilizer with the option to perform handling and filling under anaerobic conditions, a unique and industry-leading combination.
Advanced containment and segregation technology similar to that installed in the California facility is being deployed at the Indiana plant. Initial capabilities will focus on the production of both aerobic and anaerobic organisms through filling of bulk product and lyophilization. The ability to manufacture spore formers will be added as part of phase two of the project. List Labs excels at such processes on the small scale, and eventually having this technology at the large-scale GMP facility in Indiana will be a real differentiator. Final product manufacturing — encapsulation — will be added in the near future. In addition to replicating the clinical process trains at commercial scale, List Bio is also looking at the latest innovative technologies for preparation of these microbes, such as electrostatic spray drying and other new technologies, at each unit of operation.
The List Bio facility will also include the necessary components to support GMP manufacturing, including process validation and qualification, QC laboratories for incoming raw material and drug substance testing and release, cleaning validation testing, and environmental controls. The new facility will accommodate future growth and expanded production capacity, as well as custom-built-to-suit process trains to meet customers’ specific needs. Additional opportunities for adjacent business expansion also exist, such as adding a room for chromatographic purification to the facility for use in the production of plasmid DNA or microbiome-derived or recombinant proteins, leveraging List Labs’ decades of experience purifying native bacterial products.
Furthermore, in addition to tax incentives and access to local talent, the Fishers, Indiana, site was selected because of the available acreage — there is plenty of space for future greenfield expansion as well. List Labs welcomes collaborations on projects with unique needs for which the construction of dedicated commercial production facilities would be required. Relations with both customers and smaller CDMOs focused solely on clinical manufacturing that need a commercial-scale CDMO partner are currently being sought.
The groundbreaking ceremony for the List Bio facility in Indiana was held on June 8, 2022. The goal is to have the site completed by the end of 2024, with GMP production initiated in early 2025.
Microbiome Therapeutic Market: Strong Growth Projected
The first microbiome-based therapeutics to enter the clinic were based on fecal transplant technology using donor-derived material (donor-derived fecal microbiota transplantation (FMT). These initial products are now moving into phase III clinical studies, and two biologic license applications (BLAs) have been submitted. In the meantime, other companies have identified the actual organisms believed to cause the therapeutic effects resulting from fecal transplants.
LBPs based on these organisms (whether single strains or consortia), are not as far along as the fecal transplant products but are progressing through early-stage trials. Some companies are investigating single strains, while others are looking at consortia — some grown independently and then combined and others grown simultaneously, which reduces production complexity. Yet others are utilizing dextran microspheres as a vehicle or genetically modifying organisms to enable targeted delivery to a specific site or to insert a kill switch to readily eliminate them after they perform their desired function. Other biotechs seek to develop proteins expressed by the bacteria for use as therapeutic products that modulate the microbiome, impact the microbial population, and influence endocrine and immune responses.
In general, the field of microbiome-based therapeutics is developing rapidly. Knowledge about the role that the microbiome plays in disease is expanding exponentially. Most LBPs target gut-related indications, but many are targeting diseases that manifest elsewhere but are still impacted by the gut microbiome, such as various forms of cancer, autism, kidney stones, dermatology, infectious diseases, and Alzheimer’s and Parkinson’s diseases. All are conditions that have historically been difficult to treat. Additionally, many LBPs in development target patient quality of life and as such seek to improve compliance to harsh, traditional small molecule treatments, such as chemotherapies.
Presently, there are 46 preclinical or early development LBP programs and 43 candidates (excluding those based on donor-derived materials) being investigated in clinical trials, with 44% in phase I, 53% in phase II, and 2% in phase III.1 The current volume demand for LBP production via CDMOs across all development and commercial phases is estimated to be slightly greater than 50,000 liters and is projected to increase to nearly 14 million liters by 2031. This expansion will be reflected in an increase in market value from $90 million in 2022 to $7.98 billion by 2031.
Supporting a Maturing Microbiome Industry
The science in the microbiome space is strong and diverse. It incorporates live organisms and bacterial therapeutic proteins, formulated not just as oral products but also as injectables and in other dosage forms. Throughout our history, List Labs has developed considerable experience across a broad range of scientific areas that will be essential to supporting innovation in the microbiome space, including purification of native bacterial expressed proteins and polysaccharides; cultivation and handling of anaerobic and spore-forming organisms; powder filling of unique dosage forms, including vaginal applicators and vials; aseptic manufacturing of dextran microspheres as delivery vehicles; aseptic fill/finish; lyophilization of bacteria; and many others. We are further committed to exploring and cultivating expertise in any other methods or processes needed to help the sector achieve its full potential.
List Labs' heritage as a producer of reagent-grade materials focused on supporting the research market means that the scientists at List Labs continue to think like process scientists and go the extra mile to offer the highest-quality products, solve problems, develop innovative solutions, and continuously improve our processes. Collaboration and transparency are also foundational for List Labs — we feel that maintaining integrity in all interactions with our valued clients is just as important as our scientific expertise in driving success for our clients’ programs.
List Labs' flexibility at small scale will also benefit efforts at large scale. While there will be a drive to develop platform processes, the nature of LBPs will make that challenging and not always possible. In such cases, access to a flexible mindset will be a true strength. List Labs does not need to force projects to fit into a specific process, platform, or format. We view each project as unique and collaborate with customers to find appropriate bespoke solutions that lead to the success of the program.
Taking Action Today to Meet Customer Needs Well into the Future
The first microbiome-derived therapies to be approved are likely to be FMT products, but they will soon be followed by LBPs. Proven clinical success will drive more money into the sector, leading to further breakthroughs, which will entice more investors into becoming active in the space.
With the construction of the large-scale List Bio LBP production facility, List Labs is already taking action to solidify its position as a leading CDMO in the field of microbiome-based therapies. The company is also exploring other acquisition opportunities as a means for quickly expanding into parallel technologies and/or capacity, such as those required to enable final drug product manufacturing.
These developments will take place alongside continued support of customers developing toxins for aesthetic or therapeutic applications. Expanding capacity for the production of recombinant proteins expressed in Escherichia coli and various Pichia species or plasmid DNA presents additional growth opportunities. As a result, within the next few years, List Labs will be viewed as a leading CDMO, with our name synonymous with our full range of capabilities.
Our extensive experience as a leader in the field of microbiome bacteria and LBPs, combined with the extensive capabilities of our forthcoming state-of-the-art manufacturing facility, position List Labs strongly as a leading provider of reliable, high-quality end-to-end solutions for customers developing products in the space, regardless of indication, bacterial species, or dosage form. We are excited about the opportunity to play such a key role in driving and accelerating innovation in what we anticipate will be among the most dynamic sectors in biopharma across the coming decade and beyond.
Reference
1. Microbiome CDMO Market: Opportunity Evaluation Interim Report. Frost & Sullivan. Oct. 2022.