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Researchers, Drug Developers Discuss Progress on Therapies to Modify the Microbiome


NEW YORK (GenomeWeb) – Microbiome research may be turning a corner, according to some researchers and industry leaders at the Personalized Medicine World Conference in Silicon Valley. In a few short years, the field has gone from doing its best just to describe and dissect the immense diversity of microbial communities that inhabit the human body, to one where strategies are emerging for translating these discoveries into treatments for a variety of diseases.

In a panel session at the tail-end of the conference last week, Stanford researcher Ami Bhatt was joined by Second Genome's Peter DiLaura and David Cook of Seres Therapeutics to speak about how a growing understanding of the interplay between the microbiome and human disease has opened up new opportunities for therapeutic interventions aimed at modifying disrupted or dysfunctional microbiota.

Bhatt discussed her lab's work using shotgun metagenomic sequencing to study the effectiveness of fecal transplants in treating Clostridium difficile in immunocompromised cancer patients after stem cell transplant. Fecal transplants are not new, but microbiome sequencing efforts have provided important new evidence linking changes in microbial diversity to a variety of diseases — including C. diff — helping to rationalize and validate the effectiveness of this controversial treatment strategy in research like Bhatt's.

According to Bhatt, patients undergoing hematopoietic stem cell transplants are 10 times more likely to develop C. diff colitis than other hospitalized patients. In their study, she and her colleagues have been treating these patients with diluted, filtered, and capsulized feces from donors that they have been identified as optimal based on criteria like general health and lack of exposure to infectious agents. Subjects of her study are given 15 fecal capsules on each of two consecutive days, she said at the conference.

Overall, 70 percent of patients the group has treated have been effectively cured of C. diff after one round of treatment, Bhatt said. Over 92 percent respond after two tries.

"As a physician, this is an incredible," she said. "There is no other therapy I give any patient that is this effective."

Bhatt also shared some specific outcomes and sequencing data from a small group of patients treated with her group's protocol, in which they sequenced patients' gut microbiomes before, right after, and 21 days after treatment with their fecal transplant strategy.

Among nine patients, seven transplanted with donor feces were free of C. diff at 12 weeks, Bhatt said. One died of a relapse of their cancer unrelated to infection, while one suffered a C. diff relapse after three months.

In the researchers' sequencing data, they could also see that the fecal microbiome changed in patients who responded to the treatment to parallel that of the initial donor's, though there was also significant variability from person to person in the exact patterns of microbial species that ended up taking hold, even with the use of a single common donor.

According to Second Genome's DiLaura, fecal transplants are only a first generation approach to modifying the microbiome, and could soon be the crude older brother of a new generation of more targeted, specific therapies. For that to happen, he argued, the field needs to continue shifting its attention from genomic studies focused only on characterizing microbial diversity to more complex, pathway-based, and computational analyses of the causal relationship between dysbiosis and human disease.

"If you look at literature, for every indication imaginable, as long as you can get [a] comparison in a MiSeq, you can establish a difference in the microbiome between disease and health, but that hasn’t gotten us to drug discovery," DiLaura said. "That's where companies like ours and others are really putting resources to get to that causal understanding of how the host and microbiome are working together in disease."

One way to do this is to try to narrow a person's overall micriobiome down to specific bacterial species that can be shown to have the same effect as a fecal transplant, and can be isolated and advanced as therapies.

According to Seres Therapeutics' Cook, his company is mainly engaged in this type of drug development, with its two lead candidates targeting recurrent C. diff infection and inflammatory bowel disease (IBD).

The company's program that is furthest along is SER-109, an oral microbiome therapeutic now in a Phase 2 trial for the prevention of C. diff in adults who have had three or more episodes within the previous nine months. The firm is also in preclinical development for something it calls a "ecobiotic" drug — a follow-on C. diff drug called SER-262 based on bacteria cultured in a lab, rather than isolated from donor feces. Seres also has a microbiome therapeutic for IBD called SER-287 in Phase I trials, but also has plans to move forward with an ecobiotic in that space as well.

Beyond translating the success of fecal transplants into curated therapeutic bacterial cocktails, DiLaura said there is also a second step, which is mining microbial genomic and other downstream data to identify small molecule therapeutic candidates.

Second Genome's efforts are focused more in this vein, DiLaura said, mainly to advance drug candidates to treat IBD. The company has completed a Phase I trial for its lead candidate, SGM-1019 — a small molecule inhibitor of what DiLaura called a "key microbiome-mediated target to address inflammation and pain in IBD," but which also has potential in a range of other indications.

"Over the last several years, we've built a platform that allows us to go from a knowledge base of microbiome samples across a range of diseases — a very robust genomic platform, metagenomics, transcriptomics, post-gene expression — to get at the bioactives actually having an effect … to advance [them] as drug candidates," DiLaura added.

He also highlighted a few other promising recent advances in the scientific literature pushing microbiome studies in new directions. In one study, published in Science late last year, a team from the University of Chicago demonstrated that the microbiome may play a role in the effectiveness of drug therapy, specifically PDL-1 checkpoint blockade.

Investigators observed that genetically identical mice from two different labs had different rates of tumor growth when induced to develop melanoma. Hypothesizing that the different microbiomes of these two mouse populations might explain their differing cancer susceptibility, the group showed that by transplanting feces between the mice they were able to replicate the relative cancer resistance and improved prognosis of one group in the other, improving upon the benefit of PD-L1 therapy alone in reducing disease.

More importantly, DiLaura said, the researchers took one important further step, analyzing the differences between the microbiomes of the two mouse populations to identify a specific bacterial strain that they showed had the same effect as a broad fecal transplant.

According to DiLaura, other new discoveries are also showing that the microbiome could serve as a biomarker to subtype patient populations into responders or non-responders to specific therapies. For example, he said, Second Genome is involved in research with a pharmaceutical company in which it was able to identify a potential microbiome-based signature that could predict response to a candidate therapy before other clinical endpoints.

Second Genome has also announced a number of partnerships over the last few years, including with the Mayo Clinic, Pfizer, and Janssen, to conduct microbiome research.