With new science and true innovation, reimbursement should "take care of itself," Seres Therapeutics Inc.'s chief scientific officer (CSO) David Cook told BioWorld Today, on the brink of phase IIb data with SER-109 for recurrent Clostridium difficile infection (CDI).

An FDA advisory panel vote on Merck & Co. Inc.'s bezlotoxumab for CDI and Summit Therapeutics plc's phase II data with ridinilazole sharpened investor appetite for the Seres results. Oral SER-109, described as an ecology of bacterial spores enriched and purified from healthy, screened human donors, fixes the biome disruption that leads to CDI. It's been awarded breakthrough status by U.S. regulators.

Somewhat skeptical FDA panel members voted 10-5 in favor of recommending the treatment from Kenilworth, N.J.-based Merck, a fully human monoclonal IgG1/kappa antibody. Summit, of Oxford, U.K., offered further results from the Codify trial with its antibiotic during ASM Microbe 2016 in Boston. Specifically, ridinilazole outperformed the standard of care, vancomycin, in the preservation of the gut microbiome of patients during treatment for CDI, Summit said. (See BioWorld Today, June 10, 2016.)

Unlike Merck's, the candidate from Cambridge, Mass.-based Seres targets patients with multiple CDI recurrences, Cook said. So few of such patients were enrolled in the Merck experiments that "they don't even break [the numbers] out," he said. "This is a setting where antibiotics simply don't work," with at least 60 percent of patients given antibiotics recurring within eight weeks. "There literally are patients who have been kept on antibiotics on a long-term basis in order to avoid a re-infection," he said. In fact, the number one risk factor for CDI is prior exposure to antibiotics, even as long as months earlier. "Once you get on that slippery slope, the rate of recurrence increases until it's 60, 70, 80 percent," he said.

Summit's approach is "not at all the same" as SER-109's, Cook said. "What Summit and a few others have claimed is that they have an antibiotic that's more sparing of the microbiome. To be honest, I have not seen any published data."

Powerful and inexpensive sequencing technology has made it possible to sort through the gut, and a handful of biome-focused firms have arisen. "I believe a lot them have keyed off our early success," he said, noting that Seres has another program in ulcerative colitis and has pledged to launch a third later this year. "We have a really talented group of people out of the vaccine industry" who know how to leverage the findings, he said.

Doctors now will either prescribe Flagyl (metronidazole, Pfizer Inc.) for CDI, "which tends to be somewhat inferior," with a one in three chance of recurrence, Cook said, or the "slightly more expensive but still generic vancomycin. There, 25 - 28 percent of the time, you're going to recur. I guess you can call that success, but when you have a bacterial infection, you expect antibiotics to work, unless you have a resistant organism. The fact that standard of care fails at least one out of four times is because it perpetuates dysbiosis – it doesn't treat the root cause. We feel this is exactly the right environment for doing what we're doing," given that treatment either doesn't exist (for recurrent CDI) or isn't effective (for primary disease), he said.

COLLABORATIONS APLENTY

Still garnering deals is Merck's macrocyclic antibiotic Dificid (fidaxomicin), which is used to treat CDI-associated diarrhea. Taipei-based OBI Pharma Inc. last October entered a deal with Merck for the development and commercialization, with OBI getting an up-front payment of $3 million. Undisclosed royalty and other payments could come as milestones are reached. Merck is responsible for all future costs associated with commercialization, development, and manufacturing of Dificid in Taiwan. (See BioWorld Today, Oct. 7, 2015.)

Dificid was originally developed by Optimer Pharmaceuticals Inc., of Jersey City, N.J., parent company of OBI when it was known as Optimer Biotechnology, before becoming an independently owned company in 2013 and changing its name to OBI. In the U.S., Dificid was marketed by Cubist Pharmaceuticals Inc., of Lexington, Mass., after its $535 million acquisition of Optimer in late 2013. Cubist was in turn acquired by Merck in December 2014 for $8.4 billion. (See BioWorld Today, Dec. 9, 2014.)

In phase III trials, Dificid chalked up a 10 percent benefit "at most" compared to vancomycin, Cook said – "certainly not worth paying 30 to 50 times the amount of the generic. I think Merck may have the same problem with their antibody, which is going to be more expensive and require an intravenous infusion by patients who are actually feeling well. It's hard to figure out how you get paid for innovation, if that's the level of benefit you're providing." Seres' phase II is powered to show a doubling in response rate from 40 percent in placebo to 80 percent in the test, he said, though the company hopes for better.

Cowen and Co. analyst Ritu Baral said her firm is "very optimistic [about] these data, given strong previous SER-109 pilot data and good phase IIb powering." Seres also is developing a fully synthetic follow-on for prevention of primary CDI, SER-262, due to enter the clinic shortly, as well as SER-287 for active ulcerative colitis, she noted. "We think SER-287 has encouraging proof-of-concept findings and look forward to phase Ib data in 2017," Baral wrote in a research report. "Based on discussions with key opinion leaders and [a] trial investigator's careful review of individual pilot patient data, we think the pilot trial relapse rate using the refined phase II primary endpoint was 7 percent (2/30)," which bodes well for SER-109 in the data to come. She estimated peak sales at $525 million.

Leerink analyst Joseph Schwartz said his "gut feeling" is that the phase IIb results will contain "no surprises." He wrote in a report that his firm "look[s] forward to a high response rate (80 percent-plus) being duplicated when data are reported in mid-2016." He found SER-109 "poised to be first-in-class among fecal microbiota transplant-derived drugs, and we are intrigued by the other programs" that Seres is pursuing by way of its approach, which deploys systems biology and comparative genomics.

CSO Cook said the firm has collaborations with Memorial-Sloan Kettering Cancer Center in immuno-oncology, with the University of Pennsylvania in inflammatory bowel disease and with Massachusetts General Hospital in obesity and metabolic disorders.