Seres’ pioneering science, paired with powerful drug development and manufacturing capabilities, underpins its unique therapeutics platform.
A robust body of research, which includes work by Seres and our collaborators, has revealed the integral role the gut microbiome plays in overall human health. Increasingly the gut microbiome is understood as a pillar of essential functions such as metabolism, immune and inflammatory responses, and protection against potential invaders. Bacteria, a major component of the gut microbiome, can affect these various functions by producing metabolites which interact with other microbes and the host. Scientific understanding of the role of the microbiome and microbe-associated metabolites has advanced tremendously and is allowing development of therapeutics to treat a variety of serious diseases.
Over the past decade, Seres has pioneered the translation of microbiome insights into an entirely new class of medicines, two of which are in late-stage clinical testing. Our microbiome therapeutics are consortia of bacteria in oral capsules that are designed to have specific functional pharmacological properties to modify the gut microbiome to treat and prevent disease.
Microbiome therapeutics can drive pharmacological effects across multiple pathways simultaneously.
Delivering a multifunctional
consortium of bacteria
The gastrointestinal (GI) microbiome consists of diverse bacteria which contribute to our metabolism and our immune function and have impacts throughout the body — protecting against numerous diseases, including serious infections, chronic inflammatory diseases like ulcerative colitis, and cancer.
A properly functioning GI microbiome has the following properties:
Disruption of the following microbiome-modulated functions can lead to and aggravate infectious diseases:
At Seres, we identify consortia of bacteria that modulate the functional properties of the microbiome. These bacteria can treat infectious disease via multiple effects including, for example, by changing the set of metabolites found in the gut to inhibit pathogen growth.
Loss of the following microbiome functions can lead to and aggravate inflammatory diseases:
At Seres, we identify consortia of bacteria that modulate functions of the microbiome. These bacteria produce changes leading to improved gut lining integrity, reduced gut inflammation and reduced local immune activation.
Disruption of the following microbiome-modulated functions can drive cancer progression or reduce a person’s response to cancer immunotherapy.
At Seres, we identify consortia of bacteria that modulate functions of the microbiome. These bacteria work with the body’s immune system to regulate anti-tumor responses, improving the effectiveness of cancer immunotherapy.
At the heart of our approach are multifunctional consortia of bacteria that are designed to functionally interact with host cells and tissues to treat disease.
We use data from clinical studies to discover the microbes and microbe-associated metabolites that functionally interact with human cells and tissues and can be targeted to treat diseases, such as ulcerative colitis and C. difficile infection, or to improve the response to disease treatments, such as cancer immunotherapy. We then utilize advanced computational tools and proprietary functional assays to design consortia of commensal bacteria that modulate these targets and act on multiple microbial and host functions.
Our focus on function reflects a key discovery from recent large-scale analyses of the gut microbiome: though microbiome composition can vary widely between healthy individuals, the functional outputs of a healthy microbiome are universal. In other words, good health and resistance to disease depend on the functions provided by the community of microbes, rather than on the presence or absence of any specific bacterial species.
Seres is harnessing defined consortia, or collections, of bacteria to modulate microbiome function. In contrast to conventional therapeutics, which target just one disease pathway, bacterial consortia are multifunctional. This means they can have multiple pharmacological effects and modulate numerous functional pathways within the body to achieve therapeutic impact.
Seres has built an unprecedented Microbiome Therapeutics Engine to design, test and manufacture multifunctional bacterial consortia.
Microbiome therapeutics engine
1. Microbiome biomarker discovery
As we begin development of a new therapeutic for a disease of interest, we gather insights from existing clinical studies and microbiome datasets. These datasets come from human subjects for the relevant patient population, a critical first step that is known as reverse translation. Starting with patient data allows us to identify and target drug development efforts on modulating microbiome functions that are clinically relevant to the disease. We deploy our proprietary, customized analytical tools to interrogate tissue samples, genomic and metabolomic data (revealing important bacterial functions and species), and findings from our own and others’ human studies to discern which microbes and microbiome functions are altered in disease or predict a poor clinical outcome. These microbiome biomarkers define disease-relevant functional pathways that become our drug targets.
2. Consortia design
Next, we design leads for development: unique consortia of bacteria that can modulate the target microbiome functions defined by the biomarkers. We draw upon our extensive proprietary strain library of commensal (resident) human gut bacteria. Bacterial strains are selected for consortia based on an expansive repository of genomic and functional screening information, with each strain addressing multiple target functions. We iteratively evaluate candidate consortia in computational models for specific functional characteristics, including interactions with human cells and tissues, other species in the gut microbiome, and impacts on specific disease-relevant functional pathways.
3. Pharmacological validation
Once we have assembled consortia with the desired functional effects, we test their pharmacological properties in the laboratory using in vitro assays and disease-relevant animal models. For disease states and functions that are challenging to study, we have developed proprietary human tissue cell assays, including organoids, to replicate key aspects of the disease and test the effects of individual bacterial strains and therapeutic consortia. We use insights from these experiments to iteratively refine and finalize the bacteria comprising therapeutic consortia to define the drug candidate.
4. Advanced manufacturing and oral formulation
Finally, we manufacture the bacterial consortia for evaluation in human clinical studies. Our in-house manufacturing organization integrates process development, current Good Manufacturing Practices (cGMP), Quality Control and Quality Assurance. These capabilities allow us to deliver effective, high-quality and consistent live microbiome therapeutics formulated for oral delivery.
5. Quality control and product safety
Our therapeutic candidates are comprised of highly purified consortia of targeted human commensal bacteria, which are manufactured under current Good Manufacturing Practices (cGMP) conditions and quality controlled using stringent standards to ensure product quality and consistency. In addition to conducting rigorous strain library and donor screening, Seres utilizes unique manufacturing processes that have been demonstrated to inactivate numerous potential pathogens. Seres believes that donor and product screening are necessary but insufficient to minimize infection risk for donor-derived microbiome and FMT products. Seres’ additional steps to inactivate potential pathogens represent a critical intervention to increase quality assurance and minimize the risk to patients.
Benefits of Seres' microbiome therapeutics over probiotics and fecal microbiota transplantation (FMT)
Seres’ microbiome therapeutics offer critical benefits over other live microbial treatments intended to modify the gut microbiome, including probiotics and fecal microbiota transplantation. Seres’ therapeutic candidates are being developed to be supported by a robust evidence base and are rigorously evaluated for both safety and efficacy.
Seres Microbiome Therapeutics vs. Probiotics
|Seres Microbiome Therapeutics||Probiotics|
|Species in Product||Multiple strains from the human gut, selected for their pharmacological functions||Single strain or a few strains from food or other sources|
|Demonstration of Medical Benefit||Benefit rigorously evaluated in clinical trials||Clinical trials not required; benefit unproven|
|FDA Regulation||Stringent FDA oversight as an investigational drug||Not subject to FDA rules on investigational drugs|
Seres’ microbiome therapeutics are multifunctional consortia of commensal bacteria empirically selected for their combined pharmacological effects, and their safety and efficacy are evaluated in human clinical trials registered with the U.S. Food and Drug Administration (FDA). Our manufacturing and quality teams rigorously demonstrate the viability of the bacteria in our therapeutics, and their ability to survive stomach acidity during delivery to the colon. Our clinical studies demonstrate that our therapeutic bacteria grow and populate in the gut and drive changes in the microbiome composition and modulate disease-relevant functions through the generation of microbe-associated metabolites.
Probiotics, by contrast, are typically sourced from food. Most probiotics do not survive stomach acidity, and some are not typically found in the gastrointestinal tract. Probiotic lots can have wide variability in content and quality because they do not have to meet regulatory requirements for therapeutics. Some studies have shown that probiotic capsules have dead bacteria or no contents at all. Probiotics can be sold under the claim of benefit for “digestive health,” but most high-quality, controlled clinical trials of probiotics in specific diseases have not demonstrated any benefit.
Seres’ Microbiome Therapeutics vs. FMT
|Seres’ Microbiome Therapeutics||FMT|
|Preparation||Purification and/or isolation of targeted bacteria; clearance of unwanted bacteria, fungi, parasites and viruses||Minimally processed human stool|
|Species in Product||Targeted bacterial species, selected for their pharmacological properties||All bacteria, fungi, parasites, viruses and other stool components|
|Demonstration of Medical Benefit||Benefit rigorously evaluated in clinical trials||Estimates of efficacy unclear due to few high-quality placebo-controlled trials|
|Safety||Favorable safety profile observed in clinical studies to date; inactivation of potential pathogens||FDA safety alerts on transmission of infections|
|FDA Regulation||Stringent FDA oversight as an investigational drug||Not currently subject to FDA rules on investigational drugs|
Seres’ microbiome therapeutics are being evaluated in rigorous, blinded, placebo-controlled clinical studies with FDA oversight. Each study is conducted under an Investigational New Drug application (IND) with rigorous safety monitoring and reporting procedures. Our microbiome therapeutics are comprised of highly purified consortia of bacteria manufactured under Good Manufacturing Practices (GMP) conditions and quality-controlled to stringent standards.
In contrast, fecal microbiota transplantation, or FMT, involves the transfer of minimally processed donor stool into the patient’s gastrointestinal tract. Few high-quality placebo-controlled clinical studies of FMT have been conducted, limiting the understanding of FMT efficacy and safety. Additionally, because the use of FMT for the treatment of recurrent C. difficile infection is proceeding under FDA Enforcement Discretion, it is not subject to the rigorous safety monitoring and oversight that are standard requirements for investigational drugs. Recent FDA safety alerts (including June 18, 2019 Alert and March 12, 2020 Alert) reporting hospitalizations and deaths following the administration of FMT containing pathogens such as drug-resistant E. coli have underscored the risk of transmission by FMT. Further, guidance from the FDA on the possible transmission of SARS-CoV-2 (the virus that leads to COVID-19) via FMT (March 23, 2020 Alert and April 9, 2020 Alert) highlights additional risks of transmission of unknown or emerging pathogens by minimally processed stool.
Seres’ manufacturing processes for purified spore-based products and fermented bacterial products limit safety risks to patients posed by FMT. While FMT is minimally-processed donor stool containing bacteria, fungi and viruses, Seres utilizes multiple processes in manufacturing to enhance safety. Seres manufactures by either fermentation of pure bacterial strains, which are then combined to produce the therapeutic (where only the therapeutic bacterial strains are present, for example SER-301 and SER-155), or a comprehensive purification process (SER-109, for example) which includes inactivation and clearance of non-spore bacteria, parasites and viruses, by which the risk of potential pathogens is eliminated or significantly mitigated. Seres’ processes minimize risks for patients, even for emerging infectious diseases where diagnostic assays may not yet be available.