This article is more than 5 years old. Information may no longer be current.
CDI Microbiome Drug Trial Failure may be Explained by Misdiagnosis, Dosing
Click Here to Manage Email Alerts
Seres Therapeutics has revealed complete 24-week data from the phase 2 ECOSPOR trial of its investigational oral microbiome-based therapeutic SER-109, which failed to meet its primary endpoint of reducing the relative risk for recurrent Clostridium difficile infection at up to 8 weeks.
Seres also reported that an in-depth analysis of the data suggests that misdiagnosis of recurrent CDI and suboptimal dosing in some patients may have contributed to the “unexpected” negative results. The company has shared these conclusions with the FDA and is planning to design a new clinical trial for SER-109.
“Since obtaining the unexpected SER-109 clinical study results last summer, we have undertaken a comprehensive assessment of the program to understand the reasons for the results,” Roger J. Pomerantz, MD, president, CEO and chairman of Seres, said in a press release. “We have now identified specific factors that we believe contributed to the phase 2 results, including issues related to both the accurate diagnosis of C. difficile recurrent infection, and potential suboptimal dosing of certain subjects in the trial.”
As part of the analysis, the company evaluated whether CDI diagnostic testing correctly defined the study entry population and properly diagnosed CDI recurrences during the study.
Investigators reported that 72 of 89 participants (81%) were enrolled based on polymerase chain reaction (PCR) tests for C. difficile in addition to clinical evaluations, and noted that “a positive PCR test does not necessarily indicate that the organism is viable and producing disease causing cytotoxins, nor that C. difficile is the source of clinical symptoms.”
They also retested samples from 31 open label extension trial participants for the presence of the C. difficile cytotoxin and found only 44% of samples that tested positive by PCR also tested positive based on C. difficile cytotoxin assay, suggesting “that a substantial proportion of patients who entered the SER-109 phase 2 study may have been C. difficile carriers and, therefore, C. difficile infection may not have been the source of the clinical symptoms.”
Investigators also reanalyzed samples with cytotoxin assay from patients who were diagnosed with recurrent CDI in the trial, and found between one quarter and one half of these patients may not have been true CDIs. PCR may therefore have overestimated study recurrences in both treatment arms of the study, and complicated interpretation of results, they concluded.
“The company believes that misdiagnoses may have occurred both in some patients entering the SER-109 trial, as well as for recurrences diagnosed during the trial,” according to the press release.
Investigators also evaluated whether dosing affected the extent of changes to the microbiome, and found that participants in the open-label phase 1b study who received a higher dose experienced a significantly greater increase in diversity of commensal spore-former bacteria by 1 week after treatment, compared with participants in both the phase 1b and phase 2 trials who received lower doses. This finding suggests that some phase 2 trial participants may have received suboptimal dosing, according to the press release.
“The SER-109 analyses were recently shared with the FDA, and we are actively discussing the design of a new clinical trial for SER-109,” Pomerantz said in the press release. “There remains a compelling need for an effective, safe, and convenient FDA approved therapy for patients with recurrent C. difficile infection, and this investigation provides insights to guide further clinical development of SER-109.”
SER-109 is an oral capsule prepared from healthy donor stool containing the dormant spores of about 50 species of Firmicutes, which are activated in the lower GI tract. It received orphan drug and breakthrough therapy designations from the FDA in 2015, and appeared to safely and effectively prevent CDI recurrence in a previous phase 1b trial, with 86.7% of patients achieving the primary endpoint.
Disclosures: Pomerantz is employed by Seres Therapeutics.