After FDA talks, Seres unveils potentially pivotal trial for once-failed C. difficile microbiome drug SER-109

C. diff
Clostridium difficile bacteria under a scanning electron microscope.

Seres Therapeutics has unveiled the design of a phase 2 trial it thinks could secure FDA approval for its once-failed treatment for recurrent Clostridium difficile infection. The microbiome pioneer emerged from talks with FDA saying the regulator agrees the study may qualify as a pivotal trial if it achieves a “persuasive clinical effect.”

Cambridge, Massachusetts-based Seres went into talks with FDA earlier this year armed with its analyses of what went wrong in the earlier phase 2—which missed its primary endpoint leaving a lasting dent in the company’s share price—and its proposals for designing a better follow-up study. At the time, Seres asserted the trial failed because it misdiagnosed the C. difficile infection status of patients entering and during the study and gave subjects a suboptimal dose of SER-109.

Now, Seres says FDA agrees with its analyses and plans to avoid the same pitfalls in the next study.

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“The FDA agreed with us virtually in toto. They agreed with our datasets from the root cause analyses. They agreed that it showed likely to be due with dose in certain patients and diagnostics, both coming into the trial ... as well as who might have recurred. And [they] agreed with our changing the dose to about 10-fold higher than we gave in last summer's readout, as well as changing the diagnoses ... from PCR to cytotoxin,” Pomerantz said.

Dosing and diagnostics are the headline changes to the study design.

Seres will enroll 320 patients with multiply recurrent C. difficile infection and randomize them to receive either SER-109 or a placebo. The last trial used PCR, the go-to approach for diagnosing C. difficile in modern medicine, to assess whether patients were eligible to join and whether their infections recurred after enrollment. Seres’ subsequent analysis suggested false positives resulted in patients who were free from infection joining the study and recurrences being misdiagnosed mid-trial.

PCR supplanted cytotoxin assays in routine care years ago. But as it looks for C. difficile genes, not the toxins that show the infection is active, Seres thinks it causes misdiagnoses. The hypothesis is backed up by independent research.

This time, Seres has plumped for the cytotoxin assay, an older test it thinks it can adopt without detrimentally affecting the smooth running of the study.

“Cytotoxin is still available. We are going to be able to get it to all our sites. We don't think there's going to be any problem with the cytotoxin assay at any of the sites,” Pomerantz said.

The other notable change to the study is the dose. Seres emerged from its dose escalation phase 1b with a belief—which Pomerantz says FDA shared—that there was no dose effect with SER-109.

That theory failed to survive an analysis Seres ran using a metagenomic sequencing approach designed to show which species of bacteria are present in a sample. By applying that approach, which wasn’t available to Seres at the time of the phase 1b, to samples from the dose escalation study, Pomerantz says researchers saw statistically significant differences in engraftment of SER-109 bugs into the microbiome and bacterial diversity between the different doses.

Seres has emerged from the analysis and tests in animals with a new model for what happens when a patient is cleared of a C. difficile infection—and what SER-109 needs to do to stop recurrences.

“There is a race between C. diff. trying to reset up a foothold in your microbiome so that you recur ... and the microbiome trying to become healthy again so that C. diff. cannot recur. It's not only how healthy you make the microbiome with a dose, it's how fast you do it,” Pomerantz said. “We think from the data we have that the kinetics show that the speed within the first week or two is very important, and that higher doses give a faster improvement. The FDA saw all of this, validated our data ... and is allowing us based on that data to increase the dose approximately 10-fold as we go into the new trial.”

Seres plans to start the study this year, but isn’t committing publicly to a date yet. And Pomerantz is holding off on predicting when the trial will readout until the study is up and running and the rate of enrollment is known. Whenever the data arrives will be a big moment, not just for Seres but for the nascent sector it leads and aspires to shape in the way Amgen and Genentech did their breakthrough fields.

If all the pieces fall into place, Seres thinks FDA could approve SER-109 on the basis of the data. Seres has developed the trial so the numbers, power, safety database and the CMC are consistent with a potentially pivotal trial. And it left talks with the regulator believing there is a path to approval.

"I take the FDA at what they said and wrote to us. And that is, you need persuasive data, launchable manufacturing process, good statistics, good safety database. None of this is any different from any trial. Even phase 3s are predicated on this. They didn't throw us any curve balls,” Pomerantz said.

The approval of drugs on the basis of phase 2 data has precedent, particularly in cancer. Given the scale of the C. difficile problem—CDC estimates there were 500,000 infections and 29,000 associated deaths in the U.S. in 2011—there is an argument for applying similar urgency to SER-109, if the trial delivers persuasive data. As for all drugs, particularly those with spotty R&D records, that is a big “if”.

If the data are good enough for approval, Pomerantz thinks a big, growing market awaits SER-109, despite the potential for its size to have been overestimated by the potential flaw in PCR Seres identified in the phase 2.

"Even if there are misdiagnoses, we think the expanding epidemic will give us a very rich market with lots of patients. [Misdiagnoses] are not a huge portion of it. They're enough to corrupt the dataset but still have a lot of patients,” Pomerantz said.