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Microbiome-based interventions – a labyrinth of modalities

Microbiome Futures Roadmap

Microbiome-based interventions, whether therapeutic or prophylactic, come in a broad spectrum of modalities, a consequence of the complexity of and possibilities afforded by the microbiome.

To help shed some clarity on this veritable labyrinth of possibilities, I have compiled a list of modalities represented in the microbiome R&D pipeline globally — from preclinical and clinical-stage programs to commercialized products. The list, which progresses from microbial consortia through single organism interventions to small molecule-based strategies, is by no means meant to be comprehensive but rather to provide a snapshot of the wide variety of possibilities being explored.

Natural microbial consortia as a therapeutic intervention set the space in motion based on early successes with fecal matter transplantation (FMT). Human stool has been classified as a biological agent by the US Food and Drug Administration (FDA) apt for the treatment of recurrent Clostridium difficile infection (rCDI) and other gastrointestinal (GI) conditions. FMTs are mostly administered in a clinical setting via colonoscopy, fecal enema or nasogastric infusion into the upper part of the GI tract.

More user-friendly delivery methods consisting of autologous fecal microbiota suspensions for oral administration are being developed by companies such as Lyon-based MaaT Pharma. MaaT Pharma has several clinical trials underway for indications including leukemia, and bone and joint infections.

Whether administered clinically or as a pill, FMTs represent the most basic approach to microbiome intervention and require little if any understanding of the actual mechanisms underlying the dysbiosis.

A substantial step up occurs when natural consortia are not simply harvested from humans for reinoculation but rather designed to contain specific functions to counter a particular dysbiotic state. Such rationally-defined bacterial consortia require an in-depth characterization of individual human microbiome-derived bacterial strains. Companies such as Vedanta Biosciences and Seres Therapeutics, both based in Cambridge, MA, are developing therapeutic strategies based on this principle.

Last month, Vedanta announced the initiation of a Phase 1a/1b clinical trial of VE303, an investigational drug consisting of a rationally-defined live bacterial consortium assembled to help shield against life-threatening infections, including rCDI. VE303 is administered in powder form.

Seres has SER-262, a rationally-designed, fermented microbiome therapeutic that does not require human donor material. SER-262 is in a Phase 1b clinical trial for patients with primary CDI. Seres is also developing two donor-derived oral formulations, SER-109 and SER-287, containing consortia of live bacterial spores. SER-109 is in a Phase 3 clinical trial for rCDI, and SER-287 completed a phase 1b study in patients with mild-to-moderate ulcerative colitis.

Natural microbiome-modulating consortia can also consist of other biological agents, namely bacteriophages, that target specific members of the microbiome.

San Diego-based AmpliPhi has AB-PA01, a drug candidate containing four specific bacteriophages that target Pseudomonas aeruginosa biofilms and is in development for the treatment of chronic rhinosinusitis patients with and without cystic fibrosis.

The next level of ‘simplification’ involves reducing the intervention to one biological agent that can single-handedly correct dysbiosis. The success of this approach hinges on the identification of keystone members of the microbiome community.

Cambridge-based Evelo is developing ‘monoclonal microbials’ to modulate biological systems and processes throughout the body. The company’s first push is in the search for single human-derived bacteria to develop immuno- oncology therapies.

And Evolve Biosystems, based in Davis, CA, has Evivo on the market, a probiotic powder consisting of activated Bifidobacterium infantis strain EVC001 that has been clinically proven to modulate the infant gut microbiome, resulting in the improved consumption of human milk oligosaccharides and overall intestinal fermentation. Recently published clinical results have also shown persistent colonization of the infant gut by B. infantis EVC001-limited colonization efficiency remains a challenge for many microbiome-based interventions.

Single biological agent strategies also open the possibility to engineering the microorganisms to optimize particular functions. I recently reviewed the synthetic biology microbiome subspace highlighting both companies developing single bacterial strains such as Synlogic, Inc. and Azitra Inc., and companies such as Eligo Bioscience developing non-bacterial synthetic agents.

Finally, the most reductionist approach in the microbiome space consists of completely bypassing the use of biological agents and instead translating our molecular understanding of the microbiome into strategies that use small molecules to affect microbiome-based functions and mechanisms.

C3J Therapeutics, based in Marina del Rey, CA, develops specifically targeted antimicrobial peptides (STAMPs). STAMPs consist of genome-targeting domains linked to antimicrobial peptides to treat specific pathogens within the microbiome. The company has C16G2 in Phase 2 clinical trials for the prevention of dental caries, and CD17 in preclinical development for CDI and rCDI.

San Francisco–based Second Genome develops small molecule inhibitors of key microbiome-mediated targets. The company’s lead candidate, SGM-1019, has completed a Phase 1 clinical trial in patients with inflammatory bowel disease (IBD)–related inflammation and pain.

And Paris-based Enterome is developing a number of microbiome-based small molecules for treating Crohn’s disease and IBD and for immuno-oncology applications. Enterome’s lead molecule is EB8018, a small molecule inhibitor of the bacterial adhesin FimH. Blocking FimH inhibits adhesion of Escherichia coli that cause intestinal inflammation in Crohn’s disease. EB8018 has successfully completed a Phase 1 clinical study.

These are but some of the ways in which microbiome insights are being translated into actual interventions. Our understanding of the interplay between the microbiome and the human body is constantly expanding and thus new ways of affecting these dynamics should be on the horizon as the space continues to evolve.

Microbiome Futures 2018-Global Engage
Gaspar Taroncher-Oldenburg
 is Consultant-in-Residence for Global Engage. He was previously Founding and Managing Editor of Nature’s SciBX: Science-Business eXchange (now BioCentury Innovations) and scientific editor of Nature Biotechnology.


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