Seres Sets Sights on FDA After C. Diff Microbiome Therapy Scores in Phase 3

[Updated 12:37 p.m.] An experimental Seres Therapeutics capsule of live bacteria has met the goals of a pivotal study evaluating it as a treatment for a type of recurrent gut infection, preliminary results the company says put it on track for an FDA submission—potentially the first-ever application for a microbiome therapy.

Seres (NASDAQ: [[ticker:MCRB]]) reported Monday that its therapy, SER-109, beat a placebo in treating Clostridioides difficile (C. diff) infection. The Cambridge, MA-based biotech said that the results so far exceed the benchmarks the FDA set for a regulatory filing. The next step is to seek a meeting to discuss the specific requirements for such a filing. Speaking on a conference call, Seres CEO Eric Shaff said that the data represent a “critical moment” for his company and for the field of microbiome research. [Story updated throughout with details from the call.]

“There have been stops and starts in the microbiome space,” he said. “To us, what we’ve been waiting for is late-stage data and line of sight to a [biologics license application]. I think that’s what we’re providing with these SER-109 results.”

Shares of Seres opened Monday at $20.13 apiece, up more than 333 percent from Friday’s closing stock price.

C. diff is a bacterium that causes diarrhea and inflammation of the colon. Infection by the bacteria can occur after a course of antibiotics. According to the Centers for Disease Control and Prevention, C. diff infection led to about 223,900 hospitalizations and 12,800 deaths in the US in 2017. Treatment includes vancomycin, an antibiotic. But C. diff can become resistant to antibiotics, leading to recurrence of the infection.

Rather than killing the gut-colonizing C. diff bacteria like an antibiotic intends, Seres aims to restore a patient’s gut microbiome. Each SER-109 capsule contains more than 50 species of bacteria from the stool of healthy donors. The company says its manufacturing process eliminates pathogens, such as potentially harmful bacteria, fungi, and viruses. The healthy mix of bacterial spores in the capsule are intended to help a patient’s gut return to the healthy balance of microbes that resists the proliferation of C. diff bacteria.

The clinical trial results announced Monday mark a recovery for a company that has had a roller coaster journey to date. In 2015, the company became the first microbiome therapies developer to complete an IPO. A year later, its C. diff therapy failed a mid-stage study. A reanalysis of the data found that some of the patients in the study did not actually have C. diff infection. In 2017, the FDA granted the company permission to conduct another clinical trial enrolling patients whose infection was confirmed with a diagnostic test. The study was also designed to test a higher dose over three days rather than two.

The Phase 3 study enrolled 182 patients. After standard antibiotic treatment, those patients were randomly assigned to receive either SER-109 or a placebo for three straight days. The study’s main goal was to measure the proportion of patients with recurrent C. diff infection at up to eight weeks after dosing.

At the eight-week mark, Seres says infection recurred in 11.1 percent of patients who were treated with its therapy. That rate was 41.3 percent in the placebo group. Looked at another way, Seres says the results showed a sustained clinical response in 88.9 percent of patients who were treated with SER-109.

The Seres therapy was well-tolerated by patients, with no serious adverse events observed in the treatment group—results that were comparable to the placebo arm, the company says. The most common side effects reported were flatulence, abdominal distension, and abdominal pain. Those effects were classified as mild to moderate, and they occurred at rate similar to what was seen in the placebo group, Seres says. The company says it plans to present the preliminary results at a future medical meeting and submit them for publication in a peer-reviewed journal.

The secondary goal was evaluating recurrence of the infection through the next 16 weeks. The company says it plans to present those results in the future. Speaking on the conference call, Chief Medical Officer Lisa von Moltke said that the company currently has data at 12 weeks after dosing that are “almost identical” to what the company is reporting after eight weeks. An open-label study testing SER-109 is continuing; Seres says the FDA has indicated that data from at least 300 patients would be needed to support a regulatory submission.

Recurrent C. diff infection is the target of other experimental approaches. Somerville, MA-based Finch Therapeutics reported encouraging Phase 2 data in June for its oral microbiome drug, CP101. Like the Seres therapy, Finch’s C. diff treatment is comprised of live microbes from healthy donors. The transfer of fecal bacteria from a healthy person, a procedure called a fecal microbiota transplant (FMT), has worked for some patients. But the treatment has not yet been approved by the FDA, which has issued warnings about the risk of serious infections.

Speaking on the call, Mark Wilcox, a professor of medical microbiology at the University of Leeds, said that FMT helped establish the concept that microbiome restoration can treat C. diff infection. But the procedure also left open possibility that this transfer of fecal material could introduce unknown risks that can’t be addressed by testing for pathogens and infectious diseases. Wilcox noted that before hepatitis C and the novel coronavirus were discovered, clinicians couldn’t screen for those viruses. “You can only screen for what you know,” he said.

The Seres data suggest that SER-109 is at least as effective as FMT, and possibly even more effective, Wilcox contends. In clinical trials that compared FMT to a placebo, results have shown that the procedure worked in about 60 percent of patients, he said. Though SER-109 has not been tested head-to-head against FMT, its 88.9 percent clinical response rate versus a placebo bests FMT’s performance.

“It’s not a direct comparison; I cannot prove a statistically significant difference,” Wilcox said. “But I take that 20-odd percent difference between those rates any day of the week.”

Seres declined to answer Xconomy’s question about whether Wilcox has research or financial ties to the company.

Shaff said on the call that the SER-109 results validate the company’s technology platform, which has spawned other therapeutic candidates. A potential treatment for mild-to-moderate ulcerative colitis, SER-287, is in Phase 2b testing. Another Seres therapy, SER-401, is in Phase 1b testing in patients with metastatic melanoma. Also in Phase 1b testing are SER-301 for ulcerative colitis, and SER-155, for preventing death from gastrointestinal infections, bacteria in the bloodstream, and graft-versus-host disease.

Public domain image by Janice Carr of the CDC