These are glamourous times for the microbiome space. The microbiome has captured the heart of the media, and this red hot scientific area has spawned intense attention from researchers, courtship by investors and a myriad of unique business opportunities and partnerships among companies ranging in size from small start-ups to global pharmaceutical companies. Multiple companies with therapeutics in clinical trials are jockeying for position in a heated race to market, many with their lead candidate targeting Clostridium difficile (C. diff), and with a wide variety of other applications in the queue. Key players in both the scientific and business side of the microbiome space will be gathered together at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference, taking place in Boston, Massachusetts April 11th-13th 2017. Let’s capture an eagle eye view of that conference by looking at recent advances in the microbiome space, and some of the key topics represented at the conference.
Scientists are rapidly discovering the microbiome’s sophisticated and widespread network of interactions that affect human metabolism, neurology, the immune system and skin. The microbiome plays a role in radically different areas of health, such as nutrition, early childhood, hygiene, infectious disease and chronic health conditions. There is evidence that dysbiosis in the gut is a factor in an astounding array of conditions and diseases: inflammatory bowel disease (IBD), atopy, asthma, cancer, obesity, Type 2 Diabetes, fatty liver disease, and neurological disorders.
Hot Areas of Scientific Research
While investors, companies and the media are currently having a love affair with the microbiome (I decline to call it ‘hype’), arguably the science has yet to live up to the expectations. But the scientific foundation is gradually being constructed and is forthcoming with many recent studies. A January 2017 small scale clinical study of Autism Spectrum Disorder provided evidence of improved ASD symptoms resulting from Microbiota Transfer Therapy. A Dec 2016 Caltech study in a mouse model of Parkinson’s disease established that gut bacteria not only contribute to the disease, but apparently play a causal role. There are future market opportunities for treatment of anxiety, depression, and autism that may evolve from an understanding of the science behind gut-brain interactions. Emeran Meyer, MD and professor at UCLA, discusses these topics in his book “The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health.”
IBD has been linked for decades with dysbiosis in the gut microbiome, and more recently scientists have been gaining a deeper understanding. Laying a foundation for defining the mechanisms for this was a March 2014 study by Dirk Gevers of Janssen Human Microbiome Institute with a multi-cohort study comprehensively defining the microbiome diversity landscape of Crohn’s Disease and identification of potential biomarkers. A February 2017 study provided evidence that IBD can be distinguished as two subtypes with distinct microbial signatures, as Crohn’s Disease and Ulcerative Colitis. These microbiome signatures are critical in the development of therapeutic targets.
Another hot area is in the immunotherapy space: predicting patient response and modulating gut bacteria to optimize treatment. Research at MD Anderson Cancer Center in February of 2017 implicated gut bacteria in melanoma patients’ response to PD1 checkpoint inhibitor immunotherapy. Patients that responded to the immunotherapy had a greater diversity of gut bacteria and larger numbers of a specific bacteria than those who did not respond.
With a partnership that will translate microbiome research in immunotherapy into the commercial space, Bristol Myers-Squibb and Enterome entered into an immuno-oncology focused partnership in November of 2016 for the discovery and development of microbiome-derived drug targets and biomarkers to be used in cancer therapeutics and companion diagnostics.
We’ll hear more about these topics at the conference.
Areas with Great Market Potential
From a January 2017 review article by University of Chicago’s Jack Gilbert (conference keynote speaker) and Thomas Kuntz, a hot area in need of more research is in drug response and interaction, as there are already more than 60 drugs known to interact with the microbiome. Enhancement of personalized treatment in a clinical setting will involve a deeper understanding of bacteria’s role in drug metabolism and host variation to drug response, in particular as it corresponds to an individual’s microbiome (and host ‘omes’). For example, a March 2014 study found genes in the gut bacteria Eggerthella lenta that can be used as predictive microbial biomarkers for inactivation of the cardiac drug digoxin, with potential application in studying drug pharmacokinetics and clinical interventions.
Another area with large market potential according to Gilbert and Kuntz is in addressing alternatives to the widespread overuse of broad-spectrum antibiotics and the resulting health-endangering spread of bacterial resistance. One alternative involves targeting specific bacterial pathogens or enzymes with precision antibiotics and therapies. Multiple companies are focused in this area, including Eligo Bioscience, Second Genome, AvidBiotics, C3J Therapeutics, and EpiBiome, all of whom have platforms which selectively kill off harmful bacteria while protecting commensal bacteria.
Of course, precision prebiotics and probiotics are another hot focus area, which may involve a systems biology/bioinformatics approach such as used by Seres Therapeutics, Evelo BioSciences, Metabiomics and others.
Empowering Deep Level Understanding with Big Data
If you consider the complexity of genomic and environmental factors such as lifestyle, diet, toxins, polypharmacy, metabolomics, and the gut microbiome, it’s clear that we need some high level bioinformatics to interpret the enormous amount of data for translation into the clinic.
Microbiome-based precision medicine will stem from a deep level understanding of the mechanisms involved in the complexities of host-microbiome interactions. The ultimate level of analysis may come through a systems biology paradigm, which uses mathematical/computational models to analyze large datasets and simulate system behavior with network-based analyses of the interactions between different types of ‘omics’ data (such as genomics, transcriptomics, proteomics and metabolomics), providing novel insight into complex biological systems, new biomarkers and enhanced drug discovery and development. For example, a March 2017 article proposes an ‘omics’-based precision medicine approach for elucidating genomic and metabolic interactions in the microbiome-gut-liver axis. These Big Data practices are expected to transform clinical practice.
Jack Gilbert, one of the keynote speakers at the conference, has a brand-new startup, Gusto, which produces formulations of probiotics. They use a computational modeling platform, GUST+, which predicts bacterial interactions and their effect on the immune system and human health by compiling data from human studies and running thousands of simulations.
One technical hurdle faced in the microbiome therapeutics space is in securing precise taxonomic assignments for bacteria based on sequence alignments, which is a computational challenge for both 16S and shotgun libraries, due to the short Next Gen Sequencing read lengths. This creates an obstacle for identification of reliable clinical biomarkers and hinders follow-up experiments. James White of Resphera BioSciences, at the conference, will discuss a novel approach for high-resolution microbiome profiling of 16S sequence data, which provides accurate species-level characterization.
Databases and Specimen Collection
In the case of Fecal Microbiota Transplantation, the rapid entry into clinical practice preceded the science. The FMT National Registry, a public-private collaboration, was established as a database of clinical and patient-reported outcomes intended to establish the short- and long-term safety and efficacy of FMT.
Another organization, The BioCollective, provides a resource for obtaining human fecal specimens paired with data for use in microbiome research and development, eliminating the need for researchers to recruit individuals for studies.
Frontrunners in Clinical Trials
As leaders in the field rapidly uncover the mechanisms driving the microbiome’s role in disease, the foundation is being established for capitalizing on the science in order to decrease disease and improve health. Farthest along in clinical trials is Rebiotix, with a drug candidate, RBX2660, for recurrent Clostridium difficile in Phase 3 trials. Their Microbiota Restoration Therapy (MRT) platform, which targets other diseases as well, delivers a broad spectrum of live microbes into a patient’s intestinal tract for rehabilitation of the microbiome.
At the conference, we will hear first-hand from a few of the companies in the trenches of clinical trials - Rebiotix, Seres Therapeutics and Vedanta Biosciences - on regulatory considerations, customer expectations, messaging implications, and other critical factors involved in developing and launching microbiome therapeutics.
Partnerships and Regulation
While the scientific and technical resources are critical, we will also hear about the equally critical business side - the role of partnerships as well as regulatory and patent issues.
Since probiotics have widespread acceptance by clinicians and the general population, microbiome therapeutics is at an enviable jumping off point for some microbiome companies. However, the FDA is of course involved in prescription products. The criteria for FDA approval involve defining bacterial colonization, what effect colonization has and how fast it occurs, and the pharmacokinetics/ pharmacodynamics, among other factors. This is for live bacteria. The addition of genetic manipulation adds another level of complexity in gaining approval.
Big Pharma has taken a huge interest in the microbiome space, with numerous partnerships. Among those leading the way was a partnership in 2014 between Second Genome and Pfizer, in which the two companies engaged in a large observational study with the goal of gaining a better understanding of the connection between obesity, metabolic disorders and the microbiome. Three major pharma investment funds have invested in Second Genome. Second Genome is partnering with Monsanto in applying big data science, bioinformatics and machine learning to drive discovery of microbiome-based solutions that can help farmers better manage on-farm challenges.
In 2015, Janssen and Vedanta Biosciences struck a deal involving Vedanta’s out-license of its most advanced clinical candidate VE202: a mix of bacteria from the Clostridia subspecies that are a potential treatment for several IBD disorders: Crohn’s disease and ulcerative colitis.
Most recently, in November of 2016, the aforementioned Bristol Meyers-Squibb and Enterome established an immuno-oncology focused partnership.
Join us to hear more on all of these topics and the many exciting opportunities and challenges in the microbiome space at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference. We will see you there!