A virtual event held earlier this year, Microbiome Movement – Drug Development Europe 2022, provided a chance to bring together the microbiome drug development community to share updates and discuss current challenges in the field. This brief report covers some of the take-homes from the event. Interestingly, scale-up and manufacturing were identified as key challenges for microbiome-focused companies at present as they advance live biotherapeutic product (LBP) candidates.
An overview of the field
The event program kicked off with a panel hosted by Denise Kelly, Investment Advisor at Seventure, that focused on the current successes and challenges in the microbiome drug development field. The panelists agreed there has been continued progress in the field overall, although they acknowledged some approaches have not proved successful. Duncan Peyton, CEO of 4D Pharma PLC said different companies are taking widely different approaches to LBP development, so inevitably not every product will succeed; however, across the field there are strong safety signals, underpinning the long-term potential of LBPs. Hervé Affagard, CEO of MaaT Pharma, said the entire industry tends to ride on a few high-visibility companies such as Seres, but beyond the ups and downs of those companies, the situation is generally positive, with new data being generated and more Phase 3 trials commencing. Mike Ramonas, CEO of Microbiotica emphasized that companies should focus on clinical efficacy, adding that investors tend to look for drug candidates with multi-therapeutic potential.
Declan Jones, VP Head of External Innovation & Scientific Licensing at Ferring Pharmaceuticals highlighted the importance of designing LBP clinical trials to be as close to the current standard of care as possible. Peyton backed this point, adding that manufacturing is important because it determines what the finished product looks like for patients; this in turn affects how it’s received clinically. Affagard recommended working with key opinion leaders who are already well familiar with the indication of interest.
Panelists also discussed the spectrum of approaches to microbiome modulation, from delivering precise single microbial strains on the one hand, to full ‘ecologies’ of microorganisms on the other hand. Petyon made the case for single strain products, saying manufacturing can be more straightforward. Affagard’s company, however, has shown success with ecological principles by delivering a mix of 450 species that ‘reset’ the microbiome with clinically positive effects in graft-versus-host disease.
A microbiome initiative for pharma
Bernard Walther, Director of Drug Safety and Pharmacokinetics at Servier, spoke about the work of Medicen Initiative: “Towards integration of the microbiome in the drug development process”. He gave an overview of this initiative, which brings together private and public organizations around the challenges of drug innovation to develop therapeutic solutions for the future. The initiative serves as a network of excellence to explore the two-way relationship between drugs & microbiome: both drug-induced microbiome changes and drug-related microbiome changes. A key question for the working groups of the initiative to address is whether the gut microbiota is able to modify the benefit/risk ratio of a drug candidate. This would impact the design of clinical studies and perhaps inform the time points for patient follow-up.
Novel approaches to drug discovery and delivery
Interesting approaches to drug discovery were presented at the event: one was from BioGaia, a well-known probiotic dietary supplement company. BioGaia’s CEO, Nigel Titford, covered “From Probiotic Research to Drug Development Candidate”. He explained that the parent company founded BioGaia Pharma AB in 2017 to explore research opportunities in drug development. Their approach is to look for a combination of existing preclinical and clinical work that show promising results. For example, their scientists might seek to understand a strain’s mechanism of action, then select a related strain that’s better at that mechanism before embarking on pre-clinical work to bridge to an indication relevant to the strain. The company is currently advancing candidates for adult ulcerative colitis and for opioid-induced constipation.
Drug delivery is also a continual challenge in the field. Edward Green, CEO of CHAIN Biotechnology LTD explained how his company focuses on Clostridium for oral drug delivery to the lower gastrointestinal tract. Green called clostridia a “fantastic chassis” for engineering and drug delivery. Not only are they easy to manufacture and scale, but also their strict anaerobic status allows targeting of the lower gastrointestinal tract. Since they are spore-forming, the therapeutic payload is produced during cell growth, where it impacts the gut mucosa and gut microbiome. The clostridia are also non-colonizing, which provides tight control over dosage.
Manufacturing and scale-up
Manufacturing challenges were a hot topic at the event. Richard Ellis of Biose Industrie presented on “Choosing the right CDMO for your LBP project”. Ellis explained that the company has longtime experience with live microorganism development and manufacturing. Founded in 1951 to manufacture bacterial ingredients, the company shifted to became a CDMO in 2016. Ellis described the development and manufacturing sides of the business: (1) product development and clinical manufacturing up to Phase 3 trials, and (2) manufacturing registered products on the market. The company is one of the best-equipped in the world, and is developing over 100 different strains at present.
Yvonne Naylor, Principal Scientist at Boston Analytical, spoke on “Overcoming challenges associated with performing bioburden and other purity tests for microbiome based therapeutics.” Naylor emphasized that cGMP considerations impact every part of the LBP manufacturing process: the equipment, the environmental monitoring program design, disinfectant efficacy, release and stability testing. Some methods are harmonized while others are not, so the expertise of the testing lab is crucial. Naylor said microbiome products are diverse, and characterization relies on guidance documents but also on biologics expertise.
A panel on the second day of the conference focused on “Effectively scaling up microbial therapeutic manufacturing”. The moderator was Shahram Lavasani, founder & CEO of ImmuneBiotech AB. The panelists started by talking about the biggest challenges in scaling LBP candidates. Christophe Clarite, CMO at 4D Pharma PLC emphasized the time aspect, encouraging teams to think through the time required for each manufacturing step as early as possible. David Ege, EVP Bioprocess & Manufacturing and CTO at Seres Therapeutics added that raw materials are also critical, since they must be capable of going into a GMP facility.
Ege noted that what attracts many to the microbiome field is the use of organisms that would historically never have been imagined to be effective therapeutics. The end goal of manufacturing is high productivity and maintaining viability over time, but to achieve this you need to understand the science and troubleshoot, adapting or building on techniques that have been used in the past.
When Lavasani asked the panelists what they should consider when choosing a contract manufacturing organization, they said that the equipment was important, followed by the competency of the team. Ege added that companies should have some internal expertise, however, to augment external capability. A partnership approach is needed, particularly in an industry that is constantly tackling new challenges. The best situation is when a company and its CMO can maintain a strong collaboration over time as both organizations learn. The panelists emphasized a partnership approach so those in the field can build on each other’s expertise and move as quickly as possible to bring new therapeutic options to patients.