In a recent study published in JAMA Network Open, a team of researchers investigated the tolerability and safety of a microbiome therapy called SER-109 to treat recurrent infections of Clostridioides difficile in adults.
Clostridioides difficile infections are prevalent in elderly patients with comorbidities such as chronic kidney disease, malignant neoplasm, or immunocompromised. Previous broad-spectrum antibiotics exposure that could disrupt the gut microbiome balance is a prominent risk factor for C. difficile infections since the gut microbiota also plays an important role in protecting the body against pathogens. Recent trends reveal that younger patients without the traditional risk factors are also vulnerable to C. difficile infections.
While current antibiotic treatments with fidaxomicin and vancomycin have been effective against C. difficile, one of the properties that set C. difficile infections apart from other bacterial infections is the recurrence despite antibiotic treatment. About 15%–20% of the patients experience recurrent C. difficile infections after the completion of the antibiotic treatment due to the presence of persistent C. difficile spores and disruptions to the gut microflora. Although antibiotic treatment is important to eliminate C. difficile from the gut, re-establishing healthy gut microflora is essential to sustain the clinical response.
About the study
In the present study, the team conducted an open-label, single-arm, phase-3 trial involving adults aged 18 or above with a recurrent C. difficile infection diagnosed through stool testing. The trial consisted of two cohorts, one comprising ECOSPOR III trial rollover patients who experienced a C. difficile infection recurrence diagnosed using a toxin enzyme immunoassay (EIA) within eight weeks of receiving either SER-109 or a placebo, and the other cohort consisting of de novo patients with two or more C. difficile infections.
The recurrence of C. difficile infection was defined as having three or more unformed stools each day, for two days consecutively, a positive result for toxin production from a stool test or a positive polymerase chain reaction (PCR) test for the C. difficile toxin gene, and a response to antibiotic treatment for C. difficile infection lasting between 10 and 42 days for treatment with vancomycin or between 10 and 25 days for fidaxomicin treatment.
The primary objective was to assess the safety and tolerability of SER-109, a purified composition of Firmicutes spores, up to 24 weeks after initiation of treatment. The secondary objective was to evaluate C. difficile infection recurrence up to 24 weeks after initiation of treatment. All enrolled patients received one dose of SER-109 each day, each dose containing approximately 3 × 107 spore colony-forming units administered in four capsules over three days.
The trial was conducted at 72 sites across the United States and Canada between October 2017 and April 2022, according to approved guidelines and protocols. The race and ethnicity data were collected from the patients to determine whether outcomes differed according to race and ethnicity. Descriptive statistics were reported for all endpoints. The C. difficile infection recurrence rates were calculated for the intent-to-treat population, while the safety assessment was conducted among all the patients who were administered SER-109.
The results reported that out of the 263 patients enrolled in the study, 53.6% (141) experienced treatment-emergent adverse events (TEAEs) that were mostly gastrointestinal and ranged from mild to moderate. Although there were eight deaths and 12.5% (33) of the patients experienced serious TEAEs, none of these cases were thought to be related to the SER-109 treatment.
In the first cohort comprising of ECOSPOR III trial rollover patients, 13.8% of the patients (four out of 29), and in the second cohort consisting of de novo C. difficile infection patients, 19 out of 234 (8.1%) patients had a recurrence of C. difficile infections in the eighth week. The recurrence rates for C. difficile infections in both cohorts remained low till week 24.
Furthermore, when the recurrence rates were analyzed according to baseline characteristics, patients below the age of 65 had lower C. difficile infection recurrence rates than patients aged 65 or older. Similarly, patients who were enrolled based on positive results of the PCR test, which is highly sensitive, had a lower recurrence of C. difficile infections than patients who were enrolled based on a positive EIA result, which is highly specific for C. difficile toxin.
Overall, the recurrence rate in the entire study population was 8.7% at eight weeks, and 91.3% of the patients had sustained clinical response to the treatment at 24 weeks. The SER-109 treatment was well tolerated, and the findings indicated that early treatment with SER-109 around the first recurrent episode of C. difficile infection could reduce the morbidity of recurrent C. difficile infections.