BOSTON – The gut microbiome and its prospects for drug development have been matters of debate for a while, sharpened by the high-profile phase II failure of Seres Therapeutics Inc.'s candidate, SER-109, in the summer of 2016. A panel at Biopharm America surveyed the space in light of developments since the stumble with that candidate, composed of about 50 species of firmicutes spores derived from stool specimens from healthy donors, against recurrent Clostridium difficile infection. (See BioWorld, Aug. 1, 2016.)

"I think [the fizzle] was a good thing for the field," said Sonia Timberlake, vice president of research and acting head of data science at Finch Therapeutics Group Inc., of Somerville, Mass., because it "tempered some of the hype and excitement about investing," though she allowed that such was "easy for me to say that since I'm not responsible for going out and raising money" in the risky research zone. "This is basically a new body organ that we didn't know existed 12 years ago, and now we're trying to drug it," she said. "I think we need to do that with the appropriate humility."

Finch last month pulled down a $53 million series C financing from new investors, including OCV Partners, Susquehanna International Group, Symbiosis LLC and the Trans-Pacific Technology Fund, as well as existing investors Avenir Growth Capital, Morgan Noble, Shumway Capital and Willett Advisors. The company said it will use the money to advance microbial therapies such as CP-101, from the Full-Spectrum Microbiota (FSM) platform, delivered in an oral capsule that is designed to contain a diverse community of microbiota and restore a balanced microbiome. CP-101 is under investigation to prevent recurrent C. difficile infections in Finch's potentially pivotal Prism3 trial.

"I don't think [the Seres failure] made us change our approach," said the other of two panelists, Erik Spek, vice president and legal affairs for Cambridge, Mass.-based Vedanta Therapeutics Inc., although it probably spooked investors. Vedanta is developing therapies for immune-mediated diseases based on rationally defined consortia of human microbiome-derived bacteria. In phase II for C. difficile Vedanta has VE-303, which consists of eight types of clonal human commensal bacteria strains selected for their ability to provide colonization resistance to the infection. The firm has earlier programs in inflammatory bowel disease (IBD), cancer immunotherapy, food allergy and multidrug-resistant organisms.

Not surprisingly, the panel also talked about the disheartening news in June when the FDA warned health care providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT), a procedure used to treat C. difficile. Two immunocompromised adults who received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. One died. The FMTs used in both people were prepared from stool obtained from the same donor. The donor stool and resulting FMT used in the two patients were not tested for ESBL-producing gram-negative organisms prior to use, and after the adverse events occurred, stored preparations of FMT from the stool donor were tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients. (See BioWorld, March 28, 2019.)

"That's one of the top five things you should screen for, and the fact that [researchers] were able to treat that patient under an IND with that kind of donor material is really tragic," Timberlake said, adding that her firm has developed rigorous screening methods. Only 2% of donors who apply are accepted. "We don't know many things about the microbiome," she said. "Could the microbiome transmit obesity or inflammatory disease or something like that? We don't know."

Spek noted that, although material for Vedanta's work comes from donors somewhere along the line, the clonal approach makes it much different.

Finch is working with Takeda Pharmaceutical Co. Ltd., of Tokyo, to develop new microbiome therapeutics for IBD, starting with FIN-524. The candidate is from Finch's Rationally-Selected Microbiota platform and targets ulcerative colitis (UC). For its part, Vedanta, in November of last year, collected $12 million from Janssen Research & Development LLC, a unit of New Brunswick, N.J.-based Johnson & Johnson, triggered by the start of a phase I trial of VE-202 in IBD, under the firms' ongoing collaboration.

'Make or break' for Seres?

One of the more intriguing applications of the microbiome approach lies in autism. In April, the FDA granted fast track status to Finch's FSM therapy for autism spectrum disorder (ASD) in pediatric patients. Studies have shown that people with ASD commonly suffer from gastrointestinal (GI) symptoms, such as constipation, diarrhea and abdominal pain. Research characterizing the gut microbiome of individuals with ASD has turned up an abnormal gut microbiome compared to healthy controls. Finch's collaborators at Arizona State University treated 18 children affected by ASD with FSM in an open-label study and found the treatment was well-tolerated and led to a 77% reduction of GI symptoms and a 24% reduction of core ASD symptoms at eight weeks post-treatment. A published study that followed the kids for two years after the first treatment reported sustained improvements in GI symptoms and core behavioral ASD symptoms. Finch is supporting a phase II investigator-initiated study testing the candidate in adults with ASD. The company also plans to conduct a randomized, placebo-controlled, phase II experiment in children with ASD. Both efforts will test an oral capsule designed to contain a diverse community of microbiota capable of restoring an unbalanced microbiome.

Timberlake's studies began in ocean bacteria, she said, but then "I looked out in the world and saw all of these inflammatory diseases increasing in association with antibiotic use, heavy red meat [consumption], smoking, the Western lifestyle, low-fiber diets, and then you see the microbiome going extinct in Western populations when you compare [habits in the West] to a more traditional lifestyle. The clock is ticking for all of us. How can we turn back that trend? Microbial therapeutics offers an opportunity to work in a field where you're targeting the root cause rather than a symptom of the illness. You can go at it with multiple mechanisms and intervene earlier in the disease course."

Cambridge, Mass.-based Seres isn't giving up with SER-109 in C. difficile, with a phase III trial underway called Ecospor III. In May, the size of the study was reduced to 188 patients from 320, "lowering our confidence that the trial could hit its primary endpoint and support a BLA filing," Oppenheimer analyst Mark Breidenbach wrote in an Aug. 6 report. "While management expects top-line data in the first quarter of 2020, we see the readout as a crapshoot," and he gave only 50-50 odds of a win. "Despite a recent FDA warning about the risk of infection from FMT, we believe FMT is still widely used and will likely limit uptake of SER-109," he added. "We believe Eco-Reset data in UC, expected in the third quarter of 2020 may be a make-it-or-break-it catalyst" for the company, he said. Eco-Reset is a phase IIb study testing microbiome drug SER-287 in patients with active mild to moderate UC. In January, Seres banked $40 million from partner Nestlé Health Science SA, of Lutry, Switzerland, in connection with the start of the study.

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