SER-109 well-tolerated, reduces recurrent C. difficile infection through 24 weeks

SER-109, an investigational oral microbiome therapeutic, was well-tolerated and durably reduced rates of recurrent Clostridioides difficile infection through 24 weeks, with benefits showing as early as week 2, data show.

SER-109 (Seres Therapeutics) is an oral capsule prepared from healthy donor stool containing dormant Firmicute spores that are activated in the lower GI tract. It received orphan drug and breakthrough therapy designations from the FDA in 2015, and appeared to prevent C. difficile infection (CDI) recurrence in a previous phase 1b trial, with 86.7% of patients achieving the primary endpoint.

In 2016, however, the drug unexpectedly failed to reduce the relative risk for recurrent CDI in a phase 2 trial, which the company determined may have been influenced by misdiagnosis of recurrent CDI and suboptimal dosing in some trial participants. In 2017, the FDA allowed Seres to conduct a new phase 2 trial. They agreed on a new trial design, in which investigators randomly assigned patients with multiple recurrent CDI to receive either SER-109 or placebo. Recurrent CDI diagnosis was confirmed by C. difficile cytotoxin assay to ensure accurate CDI measurement.

Earlier this year, data from a phase 3 trial that was published in The New England Journal of Medicine showed that SER-109 was superior to placebo in reducing the risk for recurrent CDI among patients with three or more episodes (12% vs. 40%; RR = 0.32; 95% CI, 0.18-0.58).

The current analysis evaluated prespecified secondary endpoints of adverse events and durability of response through 24 weeks.

For the trial, Stuart H. Cohen, MD, chief of the division of infectious diseases and director of Hospital Epidemiology and Infection Control at the University of California Davis Health, and colleagues randomly assigned 182 patients with recurrent CDI (3 CDI episodes within 12 months) to receive four capsules of SER-109 or placebo daily for 3 days. Comorbidities were common among patients, with a mean Charlson Comorbidity Index score of 4.1 in the SER-109 group and 4.2 in the placebo group, according to the researchers.

A significantly lower proportion of patients in the SER-109 group had recurrent CDI at weeks 4, 8, 12 and 24 compared with patients in the placebo group. Overall, 21.3% of patients in the SER-109 group had recurrent CDI during the study period vs. 47.3% in the placebo group.

Of those who had a recurrent CDI, 65.1% experienced recurrence by week 4. Only 6.3% of patients had a recurrence between weeks 12 and 24.

In terms of tolerability, treatment-emergent adverse events that occurred in at least 5% of patients — and more frequently in the SER-109 group — included abdominal distension, constipation, diarrhea and urinary tract infection, according to Cohen and colleagues.

Fifteen patients in the SER-109 group and 19 in the placebo group experienced serious adverse events, none of which were considered to be drug related, the researchers reported.

One patient in each group withdrew from the study due to serious treatment-emergent adverse events, and one patient in the SER-109 group and two in the placebo group discontinued the study “secondary to worsening of preexisting conditions,” Cohen and colleagues wrote. Three deaths occurred following the intervention, but none were drug related.

“The benefit of SER-109 was evident as early as week 2, highlighting the need for rapid microbiome repair after completing standard-of-care antibiotics,” Cohen and colleagues wrote. “One study limitation was the exclusion of patients with first recurrence, although this subgroup is similarly characterized by microbiome disruption. These data support a potential role for this investigational oral microbiome therapeutic in the treatment of patients with this debilitating infection.”