Seres plots path back from phase 2 microbiome blowup

C. diff
Clostridium difficile bacteria under a scanning electron microscope

Seres Therapeutics has plotted a path forward for its Clostridium difficile infection (CDI) program after digging into the data to learn where it went wrong in phase 2. The analysis picked out suboptimal doses and misdiagnoses as potential causes of the phase 2 flop, giving Seres the encouragement to push ahead with a follow-up trial despite the weak data.

Six months have passed since the failure of SER-109 to outperform placebo in the CDI trial sent Seres’ stock spiralling down and raised doubts about the wider microbiome field. Seres has spent that time deconstructing the phase 2 trial to understand whether factors other than the failings of SER-109 could account for the weak data. Now, armed with a couple of red flags from the design of the trial, Seres has gone back to FDA for feedback ahead of taking another run in the clinic.

The design of the new trial will be informed by the two points Seres thinks could have affected the result of the earlier phase 2.

One potential explanation of the failure, as Seres sees it, is the use of PCR to test for C. difficile. Most subjects were diagnosed using PCR. But, having analyzed stool samples from an open-label using that test and a cytotoxin enzyme immunoassay, Seres thinks use of PCR may have resulted in people without recurrent C. difficile infection being enrolled in the trial. And, once the study was active, the test could have overestimated recurrences.

Seres has also taken a look at the dosing, specifically by comparing change in spore species richness in participants in different arms of its phase 1b and phase 2 trials. To Seres, the analysis suggests suboptimal dosing of some patients in the phase 2 could have contributed to the failure of SER-109 to best placebo.

Taken together, the misdiagnoses and dosing analyses amount to a “strong rationale” for taking SER-109 deeper into clinical development, according to Seres. The plan is to design a trial that uses the C. difficile cytotoxin assay to determine whether a patient is eligible to enroll and assess the recurrence endpoint. Seres wants to use a higher dose of SER-109, too.

Exactly what the next step in development looks like will depend on the outcome of talks with FDA. Seres has kicked off the process by sharing its analyses with FDA, but will only get a clear idea of the path forward once the agency has its say.