Since the initiation of the Human Microbiome Project and the more recent National Microbiome Initiative (NMI) created in 2016 by the White House Office of Science and Technology Policy (OSTP), in collaboration with federal agencies and private-sector stakeholders, our understanding of the role that the microbiome plays in health and disease is steadily increasing. Although we are still a very long way from fully understanding its role, new research has indicated that the microbiome not only primarily affects the health and function of the gastrointestinal tract but also has a strong influence on general body health.

The implication of the microbiome in disease states has also been recognized. Findings that gut bacteria can affect patient responses to cancer immunotherapy has generated a great deal of excitement. For example, the results from researchers published in Science last November showed in preclinical mouse models that the gut microbiome could play a role in modulating the tumor response to checkpoint blockade immunotherapy. In addition, this study also demonstrated that the favorable microbiome properties found in checkpoint inhibitor responder patients are able to be transferred to mice.

Immuno-microbiome therapeutics

The expanding body of data relating to the impact of the microbiome on immunotherapies is stimulating further research and clinical trials.

Cambridge, Mass.-based Seres Therapeutics Inc. reported last November that it had established a collaboration with the University of Texas MD Anderson Cancer Center, and the Parker Institute for Cancer Immunotherapy to evaluate the potential of the company's microbiome therapies to improve the outcomes of cancer patients treated with currently-available immunotherapy.

The collaborators will work on a randomized, placebo-controlled clinical study at MD Anderson, sponsored by the Parker Institute, in patients with advanced metastatic melanoma. The clinical trial will evaluate the impact of an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy on patient outcomes. Seres is developing SER-401, a preclinical-stage oral microbiome therapy comprising a rationally designed consortium of live bacteria, to improve the efficacy and safety of immunotherapy.

Seres also received an exclusive option, with pre-defined financial terms, to license intellectual property rights from MD Anderson related to the use of bacteria in combination with checkpoint inhibitors.

Corresponding author of the Science paper Jennifer Wargo, associate professor of genomic medicine and surgical oncology at MD Anderson, noted that "modulation of the microbiome is a promising approach that may improve the therapeutic benefit of checkpoint therapy."

Cowen & Co. analyst Chris Shibutani commented that the phase Ib study "has a reasonable design, in our view. Three arms (rather than just one or two) will provide insight into the potential value of SER-401 vs. fecal microbiota (FM) or placebo. Twenty patients per arm will test safety and tolerability (the primary endpoint) and show any trends in efficacy that could justify further study."

At the beginning of this month, Cambridge, Mass.-based Vedanta Biosciences Inc. reported on preclinical data for VE800, an orally administered, live biotherapeutic product candidate in immuno-oncology at the Society for Immunotherapy of Cancer's (SITC) meeting.

The study showed that VE800 elicited an anti-tumor immune response as a monotherapy and also enhanced effects of immune checkpoint inhibitors. Specifically, VE800 enhanced the anti-tumor activity of both anti-PD-1 and anti-CTLA4 antibodies by increasing the level of tumor infiltrating CD8+ T cells. It also promoted induction of interferon-gamma producing CD8+ T cells via activation of intestinal dendritic cells and stimulation of interferon-gamma producing CD8+ T cells in a manner dependent on the transcription factor BATF3. The company hopes to begin clinical testing of the compound in the next few months.

4D Pharma plc, of Leeds, U.K., is working with a subsidiary of Merck & Co. Inc., of Kenilworth, N.J., to conduct a clinical trial evaluating the combination of Keytruda (pembrolizumab), an anti-PD-1 therapy, and 4D's live biotherapeutic candidate MRx0518 in patients with solid tumors. The company reported that it has demonstrated therapeutic potential in a variety of tumor types in preclinical models. The phase I study will evaluate safety, tolerability and preliminary clinical benefit of the combo treatment in patients who progressed on prior PD-1 inhibitor therapy with renal, bladder, melanoma and non-small-cell lung cancer.

Evelo Biosciences Inc., which raised $85 million in its IPO in May, is developing monoclonal microbials, which are orally delivered pharmaceutical compositions of strains of naturally occurring microbes, derived from a single clone, that are designed to act on the gut-body network. (See BioWorld, May 10, 2018.)

In its third quarter financial update the Cambridge, Mass.-based company reported that it expects the University of Chicago's investigator-sponsored open-label phase IIa trial of EDP1503 in combination with a checkpoint inhibitor in patients with metastatic melanoma to start in the fourth quarter. A company-sponsored phase IIa trial of EDP1503 in combination with a checkpoint inhibitor in patients with multiple cancer types will follow in the first half of next year.

Promising pipeline

Potential microbiome therapies are also being targeted toward a wide range of disease conditions with several that have advanced to late stage testing. (See BioWorld Insight, Sept. 24, 2018.)

Seres Therapeutics Inc., of Cambridge, Mass., for example, presented new data for SER-109, a microbiome candidate in phase III development for recurrent C. difficile infection, at the IDWeek 2018 conference in San Francisco.

In its third quarter financials the company reported that enrollment for the ECOSPOR III phase III study is ongoing. However, it noted that "study enrollment has been impacted by the widespread availability of unapproved fecal microbiota transplantation."

In view of this it is considering study design modification, to expedite the availability of clinical results.

In early November Ritter Pharmaceuticals Inc., of Los Angeles, a developer of therapeutic products that modulate the gut microbiome to treat gastrointestinal diseases, closed a private placement of series B convertible preferred stock and warrants for gross proceeds of about $6 million. Proceeds are expected to fund a Liberatus phase III trial of RP-G28 for lactose intolerance, which is expected to complete in the second half of next year. The product's mechanism of action is believed to be derived from colonic adaptation to increase beneficial bacteria in the colon.

The growing importance of the field continues to attract investor attention. Synthetic Biologics Inc. closed an underwritten public offering for total gross proceeds of approximately $18.6 million.

In September, the Rockville, Md.-based company entered an agreement with Cedars-Sinai Medical Center for an investigator-sponsored phase II clinical study of SYN-010, a modified-release reformulation of lovastatin lactone, to further evaluate its efficacy and safety. SYN-010 is designed to reduce methane production by certain microorganisms (M. smithii) in the gut to treat an underlying cause of irritable bowel syndrome with constipation.

Like several other companies, Synthetic Biologics is also targeting C. difficile infection Its SYN-004 (ribaxamase) is an oral biologic being developed to protect the gut microbiome from IV beta-lactam antibiotics that could cause CDI.

In its third quarter results it said at an end of phase II meeting the company had discussed with the FDA ways "to define a clear and achievable pathway forward for SYN-004."

Rebiotix Inc., which was acquired by Ferring Pharmaceuticals in April, is developing RBX2660, a non-antibiotic treatment currently in phase III development for the prevention of recurrent CDI. The product was developed using its Microbiota Restoration Therapy platform designed to deliver a broad consortium of spore and non-spore forming microbes into a patient's intestinal tract to restore a dysbiotic gut to a healthier state.

Indianapolis-based Scioto Biosciences Inc. reported on a study showing that its bacterial delivery platform, in which Lactobacillus reuteri is adhered to microspheres leading to increased biofilm formation, significantly reduced the incidence and severity of experimental Clostridium difficile infection.

The study evaluated the effect of Scioto's lead formulation SB-121 on the incidence and severity of CDI and showed an improved survival in mice using its live bacterial therapeutics delivery system. The results of the study were presented at the American Academy of Pediatrics National Conference in Orlando.

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