Seres Dissects Failed Microbiome Drug Trial, Suggests Changes to FDA

Xconomy Boston — 

The workings of the trillions of microbes that colonize our bodies—known collectively as the human microbiome—are still very much a mystery to scientists. Seres Therapeutics found that out firsthand when its first experimental microbiome drug, for a dangerous bacterial infection, failed a clinical trial last year, sending its shares into a freefall.

Since that time, Cambridge, MA-based Seres (NASDAQ: MCRB) has been digging through the data, hoping to find why a drug that showed promise treating Clostridium difficile infection, or C. diff., in a Phase 1b study came up woefully short in Phase 2. The company has come up with a hypothesis: CEO Roger Pomerantz says Seres didn’t test a high enough dose of its SER-109, and additionally, some patients who got the drug in its trial didn’t actually have C. diff infection. Seres is discussing its findings with the FDA, hoping to agree on the framework for a new study.

Pomerantz says addressing those two factors should lead to different results in a future trial, though at this point it’s unclear when Seres will get the chance to prove it.

Seres broke ground in June 2015 when it became the first microbiome drug developer to go public. The company raised $134 million in its IPO, in part because of SER-109’s promising Phase 1 data. Seres’ goal was to fight bacterial infections with bacteria—good bacteria that could take root in a patient’s gut and bloom, making it harder for the bad bacteria to proliferate. SER-109 is a capsule containing a mix of bacterial spores from healthy human donors.

Seres shares plummeted more than 70 percent when SER-109 failed a Phase 2 study in June 2016 and have hovered at around $10 per share ever since. Pomerantz says Seres examined all aspects of the clinical trial, from how the drug was made and supplied to trial sites, to how the drug performed when ingested by patients. The company concluded that the polymerase chain reaction, or PCR test it used to diagnose patients with C. diff was providing inaccurate results.

Before PCR testing, the standard for diagnosing C. diff. was to get results from a cell culture cytotoxin test, says Pomerantz. PCR tests have gained favor in recent years because of their ease, speed, and sensitivity, he says, but they might not be the best way to diagnose a recurrent C. diff. infection. Some patients may carry genes for the bacteria—visible on a PCR test—without actually having C. diff infection, he says. That means that patients treated with the Seres drug could have been inaccurately diagnosed. Seres plans to ask the FDA for permission to use older cytotoxin tests that test for the infection in a stool sample.

Seres will also discuss testing a different dose of SER-109. The Phase 1b trial cured nearly all of the 30 patients with C. diff infections, but it included a wide range of doses of the Seres drug. Seres used only one dose in Phase 2, and Pomerantz says that the company’s analysis suggests it was not high enough.

That analysis came with new tools that allow Seres to sequence all of the bacteria from a sample and categorize them—a capability that the company did not have at the time of the Phase 2 trial. Pomerantz says this technology helped the company better understand how SER-109 was working at different doses.

“This is a new ability we have to look at the species level, look at the kinetics in more detail, and figure it out,” he says.

Seres still needs to get the FDA’s permission before it proceeds with another clinical trial. With those discussions ongoing, Pomerantz says it’s too early to discuss when another trial might start. But he says that, at minimum, the autopsy of the failed SER-109 study will help Seres with the rest of the drugs in its pipeline. Besides the drug for recurrent C. diff. infection, Seres has microbiome drug candidates for primary C. diff. infection and ulcerative colitis. Both, however, are only in Phase 1 testing.

Public domain image of C. diff. by Janice Carr of the CDC.