A Big Leap for Microbiome Therapeutics

Update: On April 26, 2023, the U.S. Food and Drug Administration approved VOWST™, previously known as SER-109, to prevent recurrence of C. difficile infection (CDI), making it the first and only orally available, FDA-approved microbiota-based therapeutic. Read the press release here.

Each of us is host to a vibrant ecosystem. Microbial communities reside within and upon each of our body’s surfaces — the product of millions of years of co-evolution that weaved together the biologies of humans and our passengers from other kingdoms of life. In On the Origin of Species, Charles Darwin’s macroscale observations of an “entangled bank” could also describe the microscale drama that has unfolded between human and microbial cells:

It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us.

We founded Seres Therapeutics in 2012 based on the hypothesis that we could tap into this evolutionary trove to discover specific populations of microbes to prevent and treat severe diseases. Through the progress of the scientific community and our work at Seres, the gut microbiome is now understood to be a pillar of functions such as metabolism, immune and inflammatory responses, and protection against potential invaders. As Seres enters its second decade of pioneering, we are deeply enthusiastic about the potential benefits that the first wave of microbiome therapies could offer to patients struggling to overcome Clostridioides difficile infections, as well as the many additional microbiome medicines that could follow.

The beginning of an era

Clostridioides difficile, or C. diff, is a type of bacteria that is ubiquitous in nature and can be found in the digestive system of healthy humans and animals. This common microbe, however, is classified as one of the greatest microbial threats to human health by the Centers for Disease Control and Prevention (CDC). It is responsible for about 170,000 infections annually in the U.S., causing the deaths of more than 20,000 Americans each year.

These potentially deadly bacteria are typically kept in check by other microbes that outcompete the bug for nutrients. The problem occurs when it is able to colonize a host and multiply out of control, producing toxins that cause diarrhea, abdominal pain, fatigue, fever, and potentially life-threatening inflammation of the colon. The underlying microbial dysbiosis is often due to antibiotic therapy that kills the favorable bacteria that typically keep C. diff at bay, and recent use of antibiotics is the primary risk factor for developing C. diff infection (CDI).

While C. diff can be acquired practically anywhere, it is a leading cause of hospital-acquired infections in the U.S, and hospitalized patients often have more trouble clearing the infection with higher rates of mortality. Hospitalized patients may be vulnerable due to advanced age, being immunocompromised, and/or antibiotic treatment. Patients may be isolated for extended periods of time, only able to interact with staff donning gowns and gloves. These precautions are necessary to reduce the spread of the sturdy C. diff spores that are not eradicated by common sanitary procedures, such as using alcohol-based hand sanitizers.

Perhaps paradoxical, antibiotics are the primary treatment for CDI. However, one in six patients have a recurrence of the infection in the subsequent two to eight weeks, called recurrent C. diff (rCDI). Patients with rCDI demonstrate severe microbial dysbiosis, characterized by a marked loss of microbial diversity. Symptoms are thought to recur because the dysfunctional microbiome facilitates germination of the C. diff spores, which are not affected by antibiotic treatment.

These CDI infections are a major clinical challenge in which the risk of recurrence increases with each successive episode. Guidelines for treating rCDI recommend a tapered and/or pulsed regime of the antibiotic vancomycin. The intent of pulsing and/or tapering the dosage over a prolonged course of at least six weeks is to provide more time for clearance of C. diff while allowing restoration of the healthy microbiome during antibiotic-free periods. However, this regime has shown only modest efficacy and does not reliably address the underlying microbiota disruption. The FDA has recently approved a fecal microbiota transplantation (FMT) product, which is aimed at restoring microbial diversity, but more options are desperately needed for patients.

Patient experience

Much of the focus on CDI is understandably on resolving the resulting diarrhea, preventing recurrence, and reducing mortality. But the impact goes beyond the gut, having a severe effect on patients’ perception of their quality of life both during and after the infection. In one study, researchers found that populations currently battling CDI and those with a history of the infection reported notable impacts to their physical, psychological, social, professional, and financial lives. As patients with active infections may have up to 15 bowel movements a day, it may be no surprise that this would leave them feeling isolated, but even about a third of patients with a history of CDI also reported that the condition still impacts their lives long after the infection had been cleared. Patients understand and fear the risk of recurrence, but therapies have thus far not adequately addressed this risk.

Modulating the microbiome

An efficacious, well-tolerated treatment that reduces the recurrence of CDI is a critical unmet need. Seres Therapeutics is focused on this need and is developing an approach to help prevent recurrence centered around modulating microbiome functions by altering the makeup of the microbial community. SER-109 is an investigational oral microbiome therapeutic composed of highly purified Firmicutes spores, which are bacterial spores that are naturally present in a healthy microbiome. The therapy is designed to restore the microbiome to a healthy state that resists C. diff colonization and growth, guarding against relapse of infection. Patients take capsules four times a day for three days following completion of a standard antimicrobial regime and a bowel wash.

The Phase 3 development for SER-109 included the ECOSPOR III and IV studies. In ECOSPOR III, 88% of subjects in the SER-109 group were free from C. difficile recurrence at eight weeks post-treatment (compared to 60% in the placebo group). In ECOSPOR IV, SER-109 was further observed to be well-tolerated and resulted in a 91% sustained clinical response at eight weeks in the overall population.

In October, the biologic license application (BLA) for SER-109 was accepted for priority review by the FDA with an expected review conclusion on April 26, 2023. Seres and Nestlé Health Science have teamed up with the aim of bringing SER-109 to rCDI patients, believing it has the potential to transform the current standard of care and provide much-needed support for patients.

What’s next?

Antimicrobial-resistant infections (AMRI), better known as superbugs, are a growing global health problem, and the same approach underlying SER-109 could be employed to go after this threat as well. With this proof of concept, Seres can look to other disease states in which infection is a complication of treating the disease. Seres is evaluating SER-155, an investigational microbiome therapeutic, in a Phase 1b study of immunocompromised patients receiving allogeneic hematopoietic stem cell transplantation to reduce incidences of gastrointestinal infections, bloodstream infections, and graft-versus-host disease. The success of these microbiome-based therapies would represent important progress in tackling AMRI, as well as increase the potential that microbiome therapeutics could be applied to prevent or treat many other pathogens affecting our guts.

From Seres’ inception, we believed we could identify key functional properties of the diverse microbial ecosystems within us that define states of health and disease, applying those findings to benefit human health. Faith in that premise and rigorous scientific inquiry has led us to this point, poised to dramatically improve the standard of care for a critical infection, and to extend this approach into a much broader category of therapeutics. What if this is only the beginning of the rich therapeutic potential evolution has sown into the “entangled bank” within us?