Microbiome Therapies Beyond Fecal Microbiota Transplantation (FMT)

Microbiome research is one of the most rapidly growing fields of biology. Spurred by advancement in genomic and metabolomic sequencing, microbiome is a young field of research that has generated a surge of enthusiasm among investors and industry. The promise of microbiome therapeutics has extended from Fecal Microbiota Transplantation (FMT) to treat gastrointestinal (GI) track related opportunistic infections to a myriad of therapeutics areas including oncology, autoimmunity, inflammation and depression (Image 1).

Image 1. The microbiome-based therapies are targeting different organs systems and pathways

This enthusiasm is exemplified by the increase in investments in microbiome space every year since 2010. Though helmed by small biotech, big pharma has shown interest in the field and is collaborating with small biotech in different ways to progress the space (Table 1).

Table 1. Big pharma has made significant investments in microbiome therapies in the last decade

The microbiome-based therapies can broadly be categorized into two main classes – microbiome modulators and live biotherapeutics. Microbiome modulators are interventions (small molecules, proteins, oligo etc.) that either affect microbial population in the body or molecules that are secreted or degraded by the microbiome and act directly on the host. Live biotherapeutics are interventions (bacterial strains) selectively delivered that interact with the patient to exert therapeutic effects. Halloran has helped biotech clients to understand the layout of the field within these categories including market assessment, commercial opportunity and clinical development landscape. Both categories have interesting candidates in development, exploring different diseases and mechanism of actions.

Live biotherapeutics are enamored with their own unique set of challenges. On one hand, it is an extraordinary feat that researchers and startups helming this space are combining precise metagenomic studies with big data and artificial intelligence to identify microbial composition that can potentially alter the progression of a disease. On the other hand, the microbiome field is marred by new challenges. Startups and academia are tasked with identifying the underlying mechanism of action, developing reliable animal models, and determining the appropriate dosing regimens for adequate engraftment to achieve meaningful clinical benefit. Manufacturers face challenges in developing the formulation technology for live bacteria and upscaling of strict anaerobic gut commensals. In addition, uncertainty regarding regulatory authority expectations due to the lack of approved microbiome products on this frontier have further accentuated the hurdles for product development.

Stakeholders, including academia, industry and CROs are working together to create unique solutions to address these challenges and progress the field. Some of the unique solutions worth noticing are:

1. Development of new humanized mice models where gut of a caged mice is manipulated to resemble the human gut. In addition, organ-on-chip microfluidic system have been developed that mimic human gut-used to determine engraftment variations with different conditions (pH, temperature and metabolites variation). These tools have helped in generating toxicology data, pk-pd assessment and identify right dose for treatment.
2. Biocontainment of genetically modified bacteria is a concern that researchers are addressing by making the strains incorporate ‘kill switch’ or depend on the supply of an extraneous nutrition supply to embed and grow.
3. Generating anaerobic fermenters in combination with assays that can inform on potency, activity and reconstitution of microbial strains in the gut have contributed to mitigating challenges associated with manufacturing, scaling and packing the therapy.
4. INTERACT and Pre-IND meetings provide opportunities to get regulatory agency feedback that can be valuable in novel microbiome-based therapy. Companies are using these sessions to get feedback on the consortium strains, validity of their animal models, proposed first in human studies, CMC and quality assurance methodology etc.

Live biotherapeutics based drug development is different from development of small molecules or antibodies and therefore has its own set of unique challenges. Unique solutions are being created every day to address these challenges. As the first live biotherapeutic will hopefully gain approval from regulatory agency in next 1-2 years, it would pave the way for other therapies to follow a similar regulatory pathway which will certainly help in getting more therapies approved in the next decade.