The Official Blog of the Annual Translational Microbiome Conference

The official blog of the Annual Translational Microbiome Conference provides readers with information, insight and analysis regarding the microbiome.

New Tools are Needed to Drive Microbiome Research to the Next Level

These microbiome insights are brought to you by Dr. Peter Christey of GALT, Inc., and Arrowhead Publishers. Dr. Christey will be presenting "Driving the Tidal Wave of Microbiome Discovery - a Next Generation Platform for Exploring the Microbiome" at Arrowhead's 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.

I so much enjoy microbiome meetings and continue to be blown away by the speed at which the field is developing and the innovative work being presented. However, there is a sense of frustration with many of the presentations and publications we see in the literature. You would have seen them - studies where samples are taken from healthy patients, samples are taken from diseased patients, next generation sequencing of the microbiome is performed and the results are compared. We get shown lots of charts showing that population x goes up, population y goes down. Then of course PCoA and other statistical charts are presented to demonstrate some point or other. All during the presentation I'm waiting for the punch-line, the insight that helps me understand what is going on. What is the microbiome doing? Who are the key actors? How are they impacting the disease state? What is the underlying biology, chemistry here? Data and insights that quench my curiosity. But no, the presentation ends once the sequencing data analysis is complete - we are left with that empty feeling that something is going on, but it is beyond our ability to understand.

Sequencing is an incredibly powerful tool that has helped illuminate the wonderful complexity and richness of the microbiome. It's one of the few, if not the only, research tools we currently have that scales to the complexity of the microbial systems we are studying. But is it enough? I feel we are doing the equivalent of trying to cure cancer solely by sequencing a million tumor samples. Cancer is being defeated by insights derived from multiple avenues of investigation, including clinical trials, epidemiological data, analysis of the underlying genetics and, critically, wet lab work dissecting the core biological mechanisms and pathways. Wet lab work is critical to test hypotheses and new ideas under controlled conditions - the path to getting from correlation to mechanism. Then we can seriously develop informed interventions to improve the human condition.

Microbiome wet lab work is constrained by the current toolset. Mainstream microbiology technologies were invented over 100 years ago. Core tasks, such as isolating target microbes, creating comprehensive strain collections or studying model ecosystems, are often difficult or impractical. We need new tools to drive microbiome research to the next level.

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Gut Bugs May Modulate the Efficacy of Anti-PD1 Immunotherapy

These microbiome insights are brought to you by Dr. Vancheswaran Gopalakrishnan and Dr. Jennifer Wargo of The University of Texas MD Anderson Cancer Center, and Arrowhead Publishers. Dr. Gopalakrishnan will be presenting MD Anderson’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.

Pioneering research performed at the MD Anderson Cancer Center1 suggests that the gut microbiome influences how cancer responds to immunotherapy; potentially creating new opportunities to improve treatment.

Cancer patients who saw no benefit from anti-PD1 checkpoint blockade immunotherapy lacked certain beneficial gut bacteria. On the other hand, cancer patients who responded to anti -PD1 immunotherapy possessed gut bacteria whose abundance in the gut correlated with the presence of cancer-killing T-cells. When the researchers transferred gut bacteria from human cancer patients into germ-free mice using fecal matter transplantation (FMT), the rodents mirrored the patient’s fates.

Anti-PD1 immunotherapy “unleashes the brakes on the immune system” by preventing programmed-death-1 (PD-1) binding to programmed-death ligand-1 (PD-L1) on cancer cells, allowing T-cells to attack. However, anti-PD1 immunotherapy is not effective for all cancer patients and responses are not always durable.

The Answer’s in the Poop!

To assess the impact of the microbiome, the MD Anderson team analysed oral and fecal samples of 112 metastatic melanoma patients undergoing anti-PD1 immunotherapy1. 16rRNA and whole genome sequencing was performed to determine diversity, composition and functional potential of the oral and fecal microbiomes. Baseline tumor and blood samples were also analysed.

While no differences in response or progression were found in connection with the oral samples; the 43 fecal samples told another story. Analysis of the fecal microbiome samples (30 of which were responders and 13 non-responders) found that patients with a greater diversity of bacteria in their gut microbiome at baseline had a longer median progression-free survival (PFS). While the high diversity group had not reached median PFS, intermediate and low diversity groups had median PFS of 232 and 188 days, respectively. 

Additional analysis showed that responding patients with high levels of beneficial Clostridiales/Ruminococcaceae had greater presence of anti-tumor T-cells in their tumors, and higher levels of circulating T cells that kill abnormal cells. On the other hand, patients abundant with Bacteriodales had higher levels of circulating regulatory T cells, myeloid derived suppressor cells and a blunted cytokine response, resulting in diminished anti-tumor immunity.

To investigate causal mechanisms, the team transplanted fecal microbiomes from responding patients and non-responding patients into germ-free mice. Those receiving transplants from responding patients had significantly reduced tumor growth as well as higher densities of beneficial T cells in their gut and tumor sites and lower levels of immune suppressive cells. They also had better outcomes when treated with PD-1 axis blockade

Antibiotics May also Affect Anti-PD1 Immunotherapy  

Interestingly, the MD Anderson’s findings complement those of the Gustave Roussy Cancer Campus, France2. Lung, kidney or bladder cancer patients who received antibiotics to treat infection shortly before or after starting anti-PD1 immunotherapy, did not respond as well to treatment. The presence of Akkermansia muciniphila bacteria in both humans and mice was linked to improved responses to anti- PD1 immunotherapy.

Modulation of the Gut Microbiome Could Improve Cancer Prognosis

Although these findings are early, they suggest the connection between the gut microbiome and immune system could have major implications for cancer treatment and prognosis. Further work is needed to analyse the diversity and composition of the gut microbiome to predict response to anti-PD1 immunotherapy; and to modulate the gut microbiome to enhance treatment.

Research has shown that the human microbiome may be modulated by diet, exercise, probiotic or antibiotic use or FMT – however these need to be carefully studied in clinical trials. 

On that note, the MD Anderson team is now planning a clinical trial using strategies to modulate the gut microbiome in patients with metastatic melanoma going onto anti-PD1 (in collaboration with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics). The primary hypothesis of this trial will be that we can safely modulate the gut microbiome in metastatic melanoma patients going on to anti-PD1 therapy.

Tremendous promise but challenges ahead

These findings have important potential implications, though challenges are also evident.  Several issues have been raised by Dr Jennifer Wargo and Dr Vancehswaran Gopalakrishnan given these results.  “These findings have important implications, but we don’t know all the answers yet. Should we be profiling the gut microbiome of patients going onto immunotherapy? And should we tightly monitor antibiotic use in these patients? Furthermore, what other factors – including diet – may be influencing the microbiome? Should we also be profiling the gut microbiome in pre-clinical models where we are testing therapeutic strategies to fight cancer and other diseases? And finally, can we manipulate the microbiome to improve overall health and to facilitate cancer immunosurveillance?”

In addition to this, strategies such as FMT have their own inherent challenges. Although first documented in 4th century China as ‘yellow soup’; FMT has slowly gained popularity over the past years in the US for the treatment of inflammatory gastrointestinal disorders

FMT as a novel adjuvant cancer therapy could bring many rewards, though poses tough challenges. As a cutting-edge forefront therapy, FMT follows unique regulatory oversight. In May 2013, the FDA announced it would regulate FMT as an Investigational New Drug (IND) and Biologics. This classification restricted physicians to file an IND application to use FMT in a clinical trial. However, both patients and physicians raised concerns this would restrict patient access to FMT.

In June 2013, the FDA responded to these concerns and issued its Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies (http://fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm).

Under this ruling, qualified physicians can perform FMT for recurrent C. dfficile not responding to standard treatment outside clinical trials without filing for an IND application.

FMT also has other challenges, given variation between preparations. Ultimately, the MD Anderson team and their collaborators hope to identify a live bacterial product incorporating consortia of bacteria implicated in enhancing immunity and therapeutic responses. Though challenges exist, given the potential far-reaching rewards, these efforts are clearly worth pursuing.

References:

  • Gopalakrishnan V. et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan4236
  • Routy B. et al., Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan3706
  • Matson V. et al., The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018 Jan http://doi1126/science.aao3290

#microbiome #Arrowhead #cancer #melanoma   #PD-1 inhibitors #Gopalakrishnan #Wargo #MD Anderson Cancer Center #FMT #FDA #Seres Therapeutics #Parker Institute for Cancer Immunotherapy

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YUN Overcomes European Regulatory Issues Surrounding the Use of Live Probiotic Bacteria for Topical Skin Application

These microbiome insights are brought to you by Dr. Ingmar Claes, Chief Scientific Officer at YUN, and Arrowhead Publishers and Conferences. Dr Claes will be presenting YUN’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April 2018. (www.microbiomeconference.com).

We all know that the skin is critical for our health by serving as a protective layer against external factors, but we tend to overlook the importance of the skin microbiome. The skin microbiome, acid mantle and epidermal skin barrier functions as our first layer of defense against pathogens. Use of products with live beneficial bacteria, also known as probiotics, pharmabiotics, or live biotherapeutic products (LBPs), have the potential of improving dysbosis for a multitude of skin disorders. Such restoration of the microbiome using ‘live’ probiotic bacteria to treat disorders is known as probiotherapy.

YUN is a Belgian-based biotech company with a totally new vision on health and hygiene. YUN aims to take healthcare to the next level. YUN believes in maintaining and restoring the skin microbiome; and the importance of the microbiome for human health. Working closely with leading probiotherapy experts from the University of Antwerp over the past decade, YUN has developed a world premier range of skin products including treatments for pimples (ACN and ACN+) and athlete’s foot (FNG).

World Premier ACN and ACN+ Products
YUN’s ACN and ACN+ products are the first creams (oil in water cream) in the world that contain ‘live’ probiotic bacteria in a dose that will have an impact on the skin microbiome. This major breakthrough was made possible by the development of an innovative type of microcapsule. This new microcapsule contains the ‘live’ bacteria in a core suspension, surrounded by multiple layers to protect them from the water in the cream. Furthermore, YUN strains are ‘probiotic’ which are specifically selected lactobacilli strains. These have some shared mechanisms of action with other probiotic strains, but also have some very specific properties against a selection of pathogenic or problem-causing micro-organisms such as Propionibacteriuim acnes, Trichiphyton spp, Staphylococcus spp., Malassezia spp., Candida spp.

Tough Regulatory Approval Challenges
LBP products face tough regulatory hurdles. Unlike the US in which the FDA’s Center for Biologics Evaluation and Research (CBER) has issued LBP guidelines for industry, the EU lacks regulatory framework. Regulations are lagging behind the new innovations. As in all regulations, safety is considered the most important factor. Thus, safety should always be the first concern when using LBPs.

As a completely new field of products for topical application, YUN faced tough European regulatory approval challenges. YUN has been looking from the start to market its products outside the EU, and it is clear that there are differences in regulations between the US and Europe. Indeed, regarding the FDA LPB product guidelines, it is unclear whether YUN’s topical products fall under the FDA’s definition of LBPs.

Further complicating matters is there are major differences between the safety assessment of oral medical drugs and LBPs for topical use. Specifically, for topical application, the challenges regarding safety should not be neglected. Even though our epidermal skin barrier, the acid mantle layer and the skin microbiome seem to be protective for systemic problems, carefully selected safe ‘probiotic’ strains should be selected for topical application.

As YUN’s topical skin care LBP products are safe and work by restoring or maintaining the skin’s natural defense layer, namely the skin microbiome, they fall in the EU under the cosmetic regulations. These products must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use (cfr. Regulation (EC) N° 1223/2009) and data proving the safety of the probiotic strains being used must therefore be provided.
YUN specifically substantiated for the safety of all their topical products, both at the probiotic strain level and the final product itself. YUN goes even one step further as it wants to address the issues at hand of many of the current topical products which neglect safety on the skin microbiome.

Probiotic Strain Safety Research
YUN specifically performed research for the safety of the probiotic strains both in vitro and in vivo. Indeed, Dr Claes emphasized the importance of the safety of YUN’s probiotic strains particularly during the pre-clinical in vitro screening phase of development. Consequently, all the YUN’s strains were thoroughly characterized at the strain level. Mobile antibiotic resistance elements and virulence factors were investigated and excluded. Furthermore, interactions with human cells were also investigated.

Final Product Level Safety Research
At the final product level, aseptic filling, absence of contaminant pathogenic bacteria and amount of ‘live’ probiotic bacteria had to be proven by YUN. Additionally, the products with ’live’ probiotic strains were clinically evaluated by YUN to underline their level of safety for topical application on the skin.

Quality Control Issues
YUN guarantees the viability of its probiotic bacteria through patented breakthroughs in new galenic formulation and the development of microcapsules shielding its ‘live’ probiotics from water present in creams. Keeping the bacteria in a water-free core suspension ensures a minimal viable dose for up to six months at room temperature as the bacteria’s metabolical activity is minimal in the water-free suspension.

New Regulatory Framework is Needed
Dr Claes explains that by constructing the safety documentation and quality controls in the production of YUN’s products, they could be notified to EU authorities and placed safely on the market. It is therefore clear that safety is the most important aspect for LBPs and should always be addressed correctly. The added therapeutic benefits of these products for topical skin application might be the future for addressing specific skin disorders by using carefully selected probiotic strains.

Furthermore, YUN is a member of the Pharmabiotic Research Institute (PRI) and hopes to constructively interact with the European Medicine Agency (EMA). YUN believes that for some specific applications and products a completely new regulatory framework should be proposed for these new innovative products, which in the first place should always tackle safety before efficacy.

Clearly, approval regulation is lagging behind innovation. European drug authorities must tackle regulatory challenges to produce concise guidelines for industry in the development of LBPs. YUN deserves much credit for not only developing the world’s first ‘live’ probiotic creams in a dose to maintain and restore the skin microbiome, but overcoming tough European regulatory approval challenges.

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Analysis of the Human Microbiome Pipeline: Promising Opportunities to Develop Innovative Products

The human microbiome is an exciting revolutionary space which is captivating the interest of academia and industry alike. Consequently, the current human microbiome pipeline is emerging as a red- hot space with promising opportunities to develop innovative products.

The human microbiome pipeline can be divided into two major applications; therapeutics and diagnostic products. To date, no human microbiome therapeutic or diagnostic product has gained regulatory approval, leaving investors everything to play for. Pipeline therapeutics which modulate the human microbiome include fecal microbiota transplant (FMT), small molecules and live microbes. The human microbiome therapeutic pipeline encompasses a broad range of diseases including cancer, diabetes, asthma, atherosclerosis, nutrition, arthritis, neurological disorders and clostridium difficile infection (CDI). Currently, the human microbiome therapeutic pipeline involves a heated race-to-market for the treatment of CDI, featuring three late- stage products.

Rebiotix’s RBX2660 delivers live, human-derived microbes via enema into the Gl tract for treatment of recurrent CDI.  Rebiotix recently announced it has begun its Phase III trial. Rebiotix’s Phase II trial, known as PUNCH CD found overall efficacy of RBX2660 at treating recurrent CDI was 87%. The Phase IIb PUNCH-CD 2 trial found efficacy was 88%; while the open-label Phase II trial, PUNCH Open Label, showed efficacy was 79% compared with a historical control of 52% (p<0.000). RBX2660 was found to be safe and well tolerated. RBX2660 has been granted FDA Fast Track, Orphan Drug and Breakthrough Therapy designations.

Seres Therapeutics/Nestlé Health Science’s SER-109 is a single-dose oral capsule consisting of bacterial spores enriched and purified from stool samples of healthy, screened human donors. In June 2017, SER-109 commenced its Phase III trial (ECOSPOR III) for the prevention of recurrent CDI. Phase /II results at eight weeks found 97% of patients achieved a clinical cure. Additionally, 87% of patients achieved no diarrhea associated with a positive test for C. difficile. ECOSPOR results at 24 weeks found relatively little new efficacy data compared to eight weeks.  The Phase II open-label extension study ECOSPOR II found SER-109 led to a 32% recurrence rate.  SER-109 was found to be safe and well tolerated. SER-109 has been granted FDA Orphan Drug and Breakthrough Therapy designations.

Synthetic Biologic’s SYN-004 (ribaxamase) is an oral tablet in Phase II development for the prevention CDI and antibiotic-associated diarrhea (ADD). SYN-004 is designed to degrade certain IV beta-lactam antibiotics within the GI tract and maintain the natural balance of the gut microbiome for the prevention of CDI, pathogenic overgrowth and the emergence of antimicrobial resistance (AMR). Phase IIb results found SYN-004 significantly reduced the risk of CDI by 71% versus placebo (p=0.045). Furthermore, SYN-004 significantly reduced new colonization by vancomycin-resistant enterococci versus placebo (p=0.0002). SYN-004 received Breakthrough Therapy Designation from the FDA for the prevention of CDI.

Other gastrointestinal Phase II pipeline candidates include Synthetic Biologics’ SYN-010 and Osel’s CBM588.

Synthetic Biologics’ SYN-010 is continuing to prepare for the initiation of pivotal Phase II/III clinical trials. SYN-010 is a modified-release formulation of lovastatin lactone designed to treat the underlying cause of irritable bowel syndrome with constipation (IBS-C).

Osel’s CBM588 is an oral Clostridium butyricum strain with a strong safety record undergoing development for antibiotic associated diarrhea and CDI. A Phase II study found CBM588 was safe. CBM588 has also been used safely in all age groups in Japan primarily for diarrheal disorders. Recent nonclinical studies support the use of CBM588 in treating IBS.

Other pipeline candidates to watch include:

  • Osel’s Lactin-V live biotherapeutic product for recurrent UTI and Bacterial Vaginosis in Phase II development
  • Microbiome Therapeutics’ NM504 for prediabetes and Type 2 diabetes; and NM505 for diabetes metformin gastrointestinal intolerance, both microbiome modulators in Phase I development
  • Ritter Pharmaceutical’s RP-G28 an oral galacto-oligosaccharide microbiome modulator for lactose intolerance undergoing Phase IIb/III development
  • Intrexon/Orgenics/Merck’s AG103 novel mouth rinse biotherapeutic for oral mucositis in Phase I development

The latest frontier of human microbiome research involves the development of diagnostic methods and tests that provide accurate assessment of the taxonomic compositions of microbiomes associated with complex samples.

Currently there is a head-to-head market race for two key colorectal cancer diagnostics; Metabiomic’s Colon Polyp and Colorectal Cancer Test and Origin Sciences’ Colorectal Cancer (CCR) Test. Metabiomics’ Colon Polyp and Colon Cancer Test is a non-invasive screening test for the detection of colon polyps and colorectal cancer. The Colon Polyp and Colon Cancer Test detects microbial biomarkers linked to dysbosis and colorectal cancer.

Origin Sciences’ CCR Test is under development for the detection of colorectal cancer in both asymptomatic and symptomatic patients. The CRC Test is designed to detect colorectal cancer using biomarker analysis of patient rectal mucosal samples collected using Origin Sciences’ proprietary OriCol device. A pilot study found that ELISA analysis of protein biomarkers collected with OriCol offers a pre-colonoscopy screening tool in patients referred under a two- week criteria rule. Data from the study suggests that a sensitivity of ≥95% can be achieved.

Although no human microbiome therapeutic or diagnostic product has gained FDA approval, promising new opportunities exist to develop novel therapeutics and diagnostic products across a wide range of diseases/therapeutic areas.

Join us to hear more on the human microbiome pipeline at Arrowhead’s 4th Annual Translational Microbiome Conference taking place in Boston, Massachusetts on April 18-20, 2018. (www.microbiomeconference.com)

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Key Innovations in Microbiome Therapeutics: Translating the Science into the Clinic

These microbiome insights brought to you by Dana Barberio, Principal at Edge BioScience Communications and Arrowhead Publishers and Conferences.

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 BioscienceSecond GenomeAvidBioticsC3J 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 TherapeuticsEvelo BioSciencesMetabiomics 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!

 

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The Mike Rowe of the Microbiome Space

By Martha Carlin, Chief Executive Revolutionary, The BioCollective

In every industry there are dirty jobs that must be done to fuel the business.  Business Insider recently published “Small World: 20+ Startups Targeting the Microbiome” a review of just some of the exciting new microbiome ventures that are primarily focused in four key areas - diagnostics, genomics, dietary supplements, and intestinal health/disease targeted therapies.[1] These ventures use convenient and available samples for their initial R&D obtained from relationships with universities, hospitals and friends and family. When a promising discovery is made from that initial research, it may be necessary to test it on a larger and more representative population and this is where the The BioCollective comes in. 

Everybody poops.[2] But nobody wants to have to “deal with it.” One of the biggest barriers to accelerating microbiome research is getting a sample from everyone doing their duty! (or dooty depending on the age of your audience!) So we approached the problem from the Pooper’s perspective. We created a kit that is easy to use in the comfort of your home, ick-free and even a little bit fun. There is no scooping, probing, dipping or mixing needed. There are no messy plastic “hats,” bowls or containers to be disposed of. The process is seamless with nothing left behind, so to speak. Our BioCollector patent-pending design collects the entire sample, keeping it viable and ready to leverage into any number of research pipelines. Once the live sample reaches our lab, it is divided into smaller portions and cryopreserved enabling many types of research on the same sample. One sample can generate data from phage to fungi and culture. We are much more than DNA! 

Subject recruitment and sample collection is one of the top five cost drivers in research, but when we do the “dirty job” of providing samples to support microbiome research we can save thousands of dollars from the process. The BioCollective has made pooping a fun and profitable way to participate in microbiome research. We use engaging and innovative ways to get people of all ages and walks of life to become members of The BioCollective with the goal of building a microbiome resource full of samples that are actually representative of the US population. We go beyond the narrow and limited population of WEIRD (white, educated, industrialized, rich and democrat)!

In exchange for providing a sample to aid in research members receive a share of revenue from sample sales and feedback on where their sample is being used. We also provide the member with options for learning what’s in their gut from a basic 16S analysis to whole genome sequencing.  For the super curious, we can provide specialty analysis such as metabolomics, 18S and transcriptomics through our sequencing partners.  

Learn more about what we do and how you can become an active participant in the field of microbiome research at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA.

 

[1] https://www.cbinsights.com/blog/microbiome-startups-market-map-company-list/

[2] This is fact, and for an excellent read on this subject, may we suggest “Everyone Poops,” by Taro Gomi, https://www.amazon.com/Everyone-Turtleback-School-Library-Binding/dp/0613685725

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Tailoring Microbiome Interventions: The Intersection of Precision Medicine and the Microbiome

By Carrie Brodmerkel, Senior Director, Systems Pharmacology & Biomarkers, Janssen R&D

The microbiome gets a lot of press these days, from leading scientific journals such as Science publishing a special issue “Microbiota at Work” in April, 1 to articles about fecal microbiome transplants in major newspapers like the Washington Post.2 Many articles tout the need for a healthy gut microbiome and that the diversity of the gut microbiome is what maintains not just gut health but overall health. But for all of the hype, what do we really know about what a healthy microbiome looks like? What do we really know about the impact of the microbiome on health and disease? Is there a universal definition of a healthy microbiome or is it more likely that the each person has his or her own unique healthy gut microbiome?

A study published in 2015 in Science Advances studied the fecal, oral and skin microbiome of an Amerindian tribe, the Yanomami, who were completely isolated from the Western world.3 The researchers found that the Yanomami had the highest levels of human microbial diversity ever reported. They also don’t suffer from Western diseases like cardiovascular and metabolic disease or autoimmune and inflammatory diseases. Does this infer that gut microbial diversity equates to better health and less disease? That has not yet been proven and it may be that the microbiome in this tribe works in conjunction with a far different lifestyle and lack of chemical and pharmaceutical impacts and interventions to support a lack of disease. Still it drives the question of whether personalized cocktails of microbes will be needed to achieve optimal gut health for a given individual or group of individuals with similar microbiomes?

This collision of microbiome research and the precision medicine space, and the potential need for patient selection and personalization of microbiome therapies, will play out as microbial based therapeutics begin to hit the clinic. Evidence supporting this need already exists from fecal microbial transplant studies in C. difficile and inflammatory bowel disease where the response rates in an unselected population of patients leaves opportunity for improvement. Efforts to understand the functional effects of the microbes that inhabit the human gut and determining which promote health and which promote disease will be essential in unraveling the microbial communities necessary to promote health at the population or cohort level.

Hear more about Janssen’s efforts to define patient stratification strategies and personalized medicine in the age of microbial-based therapeutics at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA. For more information, visit: http://www.microbiomeconference.com

1 Science Magazine April 2016 http://science.sciencemag.org/content/352/6285

2 https://www.washingtonpost.com/news/speaking-of-science/wp/2016/04/28/scientists-think-theyve-found-the-secret-to-better-poop-transplants/?utm_term=.91f00d298c91

3 http://advances.sciencemag.org/content/1/3/e1500183.

Interestingly, despite their isolation and no known exposure to antibiotics, it was found that the tribe harbored bacteria that carried functional antibiotic resistance genes, including those that confer resistance to synthetic antibiotics and are syntenic with mobilization elements.

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Interview with Mollie Roth: Executive Director of The Microbiome Coalition (TMBC)

 

Interview with Mollie Roth, JD

Executive Director of The Microbiome Coalition (TMBC)

 

What is The Microbiome Coalition and what’s its goal?

The Microbiome Coalition (TMBC) represents a variety of commercial entities working toward commercial success in the microbiome field, united by their desire to promote greater public understanding of the role of the microbiome in human health and wellness, and the desire to advance appropriate regulation, needed investment and required infrastructure.

Recognizing that a shift in how microbiome based medicine and research is implemented will not happen simply because a body of scientific evidence suggests it should, TMBC has identified key goals to support and advance the industry, including: Education, Regulatory Engagement and Standards. You can learn more about what we are doing on all three fronts at http://www.themicrobiomecoalition.com/

 

How did TMBC come to be formed? 

Although I started my career as a litigator for the pharmaceutical industry, I have always had an affinity for making business run better. I spent 10 years working with a precision medicine consulting company helping pharma drug development teams understand how to co-develop and launch companion diagnostics.

In early 2013, I started working as a consultant in the microbiome space and became interested not only in the vast body of research that was happening across multiple industries – pharmaceutical, diagnostic, consumer products and nutrition – but in the challenges for companies to become a commercial success. Many of the hurdles and challenges this industry faces mirror exactly the experience in the precision medicine field – an unclear regulatory path, unclear business models, a lack of standards, differing reference databases among others.

It was my opinion, based on my experience in the precision medicine field, that a coalition of companies in this space could better address and overcome these challenges than any one company could. Thankfully the founding companies agreed with me and TMBC was born.

 

You said one of TMBC's goals pertains to standards, is there a problem with standards in the microbiome space?

In scientific research, standards allow for and ensure quality in research and the generation of quality evidence that can be compared across researchers and companies. Absent uniform standards, the quality of scientific research can be uneven and lacking in credibility, making it difficult to make confident, concrete assertions or predictions regarding evidence for improving practice or consumer outcomes.

For example, in the precision medicine space, we saw the lack of standards cause issues when it became apparent that there were no standardized practices for how samples being used to generate clinical data for diagnostic tests were handled. There are a number of groups already hard at work on two distinct standards issues in the microbiome space – how samples are handled and sequenced as well as how the vast volume of information generated in this space is processed. 

TMBC will serve as a clearinghouse for these activities already underway and will bring these disparate groups to the table to ensure they are engaging with each other so the industry ends up with a set of conformed standards, rather than numerous sets of non-interoperable standards.

 

What companies formed TMBC?

The founding companies are a visionary set of innovators who quickly understood the need for a coalition of companies working toward commercial success in the microbiome space and have provided seed support and substantial resources to get the coalition off the ground. They include AOBiome, Whole Biome, CosmosID, Abbott Nutrition, The Mayo Clinic, Diversigen and Second Genome.

 

How important are collaborations in the microbiome space?

 As incredibly important as they are in any area of new scientific research!

There are literally hundreds of small startup companies making incredibly exciting discoveries with regard to the microbiome, but without the resources or global reach to complete their research or get products approved and launched. Collaborations with larger companies, carefully crafted to ensure a win-win, are not only vital but imperative to move this space forward.

Further, now that we are a few years into the “age of the microbiome” we are starting to see a convergence between microbiome therapies and precision medicine, as companies consider how patients might need to be stratified based on their microbiome to determine who best to treat. The business models of how pharma and diagnostic companies can best collaborate and work together will continue to be vitally important as these two spaces continue to merge.

 

Is membership in TMBC open and to whom?

Membership in TMBC is open and we welcome any company, association or individual with an interest in advancing the commercial viability of microbiome based therapies, diagnostics, consumer or nutrition products to address and improve human health and wellness. You can learn more about membership options at http://www.themicrobiomecoalition.com/become-a-member/

 

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