Le microbiome: une industrie en gestation (article en anglais)

Following our first paper called “The human microbiome: a promising research area with multiple applications”, this article is comparing the emergence of the human microbiome field with the rise of human genomics through a review on how academic research on microbiome has progressed in the last 10 years in the USA and Europe. We also investigate how life science investors and big pharma have started to pour significant amounts of money in the field, with the hope to turn some of this research into innovative drugs.

The emergence of human genome analysis can be divided into three waves. The first wave coincides with the initial discovery of human DNA by academic groups and is followed by a second phase initiated by private investors with the beginning of first clinical studies and the emergence of biotechs. The last phase corresponds to the commercialisation of products derived from genome analysis. The transition from academia to private projects occurred very quickly largely driven by the seek of patent protection of genes. Despite, the announcement of President Clinton in March 2000 that the genome sequence could not be patented, private investments continued leading to the first clinical trials mid 2000s on genetic diseases and oncology. In the meantime, private companies developed new technologies for faster and cheaper DNA sequencing (~$100M in 2000s versus $1k in 2015 per human genome) and all major central labs now have DNA sequencers.

The microbiome market is still emerging, but it has been following a similar trajectory as the human genome market. The microbiome field is currently at the beginning of the third wave with ongoing development of therapeutic solutions, an increasing number of products in clinical phases, and the creation of several CROs/microbiome platforms providing various dedicated services such as study design, sequencing, bioanalyses, and bioinformatics for clients from the Food, Pharma, and Cosmetics industries.

 

 A very active area for academic research, with Europe as a clear leader

 The first clinical trial mentioning the microbiome was launched in Europe as early as 2000, compared to 2006 for the USA and 2009 for China. Interestingly, after being a pioneer, Europe still leads the way in academic research (Figure 1). At the same time, China is quickly catching up with a growth rate of microbiome publications around +60% p.a. from 2008-16.

The picture is slightly different tough, when looking at large, academic research programs.

First of the series, the American Human Microbiome Project was launched in the 2000’s with around 160M€. 126M€ were allocated to the first part of the project over the period 2008-13. The objective was to characterize the microbiome of healthy volunteers, which led to the creation of a microbiome database and the definition of standardized protocols. It was immediately followed by a second phase running up to the end of 2018 with a budget of 34M€. It has been concentrating on understanding the microbiome evolution of three groups of persons: pregnant women and preterm birth, patients suffering from Irritable Bowel Diseases (IBD), and people at risk of type 2 diabetes.

Fig 1: Number of publications on microbiome (PubMed)

A second major American project, the National Microbiome Initiative, was launched in 2016 by the White House under the Obama administration. It is a consortium with the objectives of supporting interdisciplinary research, developing platform technologies, and expanding the microbiome workforce. Overall budget is near 420M€. While federal contributions to the project remain unclear due to the change of administration, 75% of the budget is from private institutions such as the Bill and Melinda Gates Foundation, the C3 Jian, the Jackson Laboratory, or the Gordon and Betty Moore Foundation.

In Europe, national research programs on microbiome are less ambitious. MetaHIT was the first European program, launched in 2008 and completed in 2012. The allocated budget was 21M€, order of magnitude smaller compared to the American equivalent: Human Microbiome Project. MyNewGut is the second major European project (2013-2018) with an estimated budget around 13M€ and it is focusing on the relation between gut microbiome, brain development, and diet-related disorders.

 

An emerging microbiome biotech ecosystem, dominated by the United States

Cumulated fundings raised by biotechs on microbiome-based therapeutics amounted to 1.2Bn€ from 2007 to May 2017. As shown in Figure 2, microbiome biotechs specialisation covers a wide range of therapeutic areas, the most important ones being gastrointestinal disorders, infectious diseases, and metabolic disorders. The USA concentrate 77% of these fundings followed by Europe with 21%. Moreover, the top 5 biotechs have cumulated around 50% of overall fundings raised by microbiome biotechs. They are: Seres Therapeutics, 4D Pharma, Synthetic Biologics, Synlogic, and C3J Therapeutics. Among them only 4D Pharma is a European biotech while the remaining four are all based in the USA. Microbiome biotechs creation and fund raising have reached a peak in 2014-2015.

Over the last few years, big Pharma companies have joined the club following different strategies. Among the top 50 Pharma companies, 35 have explicitly expressed interests in microbiome research. Some of them are building partnerships with microbiome biotechs; for instance, Pfizer and Janssen have invested in Second Genome (USA) in 2013. Second Genome is currently developing two main products both in phase II on non-alcoholic steatohepatitis and IBD. Additionally, Enterome (FR) has established several strategic partnerships with Johnson & Johnson, Takeda and Abbvie in the inflammatory bowel diseases field or with Bristol-Myers Squibb regarding their research on immune-oncology. Nestlé Health Science and Enterome have also created a joint venture (Microbiome Diagnostics Partners) to develop innovative microbiome-based diagnostics.

Fig 2: Ecosystem of biotechs specialized in microbiome (TargEDys)

Big Pharma companies are also investing in R&D facilities. Janssen has created the Human Microbiome Institute in 2008 providing a favourable environment for microbiome biotechs with state-of-the-art R&D facilities. Merck opened the Cambridge Exploratory Science Center in 2016 to fuel early scientific exploration including the understanding of the role of microbiome in disease processes and, Ferring Pharmaceuticals is financing the Centre for Translational Microbiome Research in 2016 at the Karolinska Institute to explore the role of microbiome in pregnancy-related medical problems.

Investment funds are already very active in financing emerging microbiome biotechs. The two leaders are Seventure Partners based in Paris and Flagship Pioneering based in Cambridge, MA. Seventure has largely contributed to the creation of Enterome in 2011 but got also involved in many other European and non-European microbiome biotechs like MaaT Pharma, TargeDys, LNC, Eligo Bioscience, Vedanta Biosciences, etc. Moreover, Flagship’s investments cover a large spectrum of microbiome applications ranging from IBD and Clostridium Difficileinfection with its participations in Seres Therapeutics to plant microbiome with its investment in Indigo Agriculture.

 

The third microbiome wave is underway with the emergence of private microbiome platforms

 During clinical trials, biotechs are subcontracting several steps of their study to contract research organisations (CROs) such as the volunteers’ recruitment, the biological sampling, or the bioanalysis. CROs follow stringent protocols defined during the study design by biotechs as the outcome of a study relies heavily on their capacity to all perform precisely the same tests under the same conditions.

The standardisation of protocols remains a burning issue in the microbiome field. There are currently no universal standards for microbiome bioanalysis leading to a problem of replicability of the results. Indeed, risks of contamination are high and could occur at several stages. The highest risk appears during sampling procedures nonetheless samples integrity could be threatened during the transportation or the extraction of the DNA from complex matrices ahead of the sequencing. Long term storage stability of microbiome samples is also an open question. Institutes like the IBBL (Integrated BioBank of Luxembourg) are conducting research on finding the best way to process microbiome samples.

Additionally, there is a growing demand for microbiome biobanks. Theses biobanks will provide researchers access to data covering a large panel of the population. Big Pharma and biotechs would use biobanks for biomarkers discoveries through big data analysis or as providers of characterised faecal microbiota ahead of a faecal transplantation. For instance, OpenBiome, a US non-profit stool bank, is developing the FMT under the Investigational New Drug framework of the FDA and provides clinicians with ready to use faecal transplants.

Biotechs are currently subcontracting only a small part of their clinical studies to microbiome specialised CROs; mostly services around sequencing but there is a growing need for players able to offer a wider range of services from the study design and the kit preparation to data treatment and bioinformatics services. The development of these additional services is conditional on the emergence of standardised protocols.

Many public institutions are solicited as subcontractors in microbiome clinical trials like BioAster, TNO, or Metagenopolis, yet there is a growing number of private players. We distinguish three categories of private subcontractors: pure-player sequencers, bioinformatic companies, and microbiome service providers. Pure-player are equipped with several different sequencing technologies, like BGI or Fasteris, and provide Sanger and NGS sequencing services at competitive prices in short delays. On the other hand, some life science bioinformatics companies deliver data analytics services for various applications with an increase development of tools toward microbiome. Finally, dedicated microbiome platforms can either offer some partial services (uBiome, Microsynth, etc) while others are more diversified with a full-service offer from study design to report (Biofortis, Nizo, Atlantia).

 

Conclusion

In microbiome academic research, Europe started earlier, and is still leading the way today, ahead of North America. China is quickly catching up with a significant increase in microbiome publications and state-funded programs.
Private investments however, are dominated by the USA. Besides well-funded biotechs, big pharma is also investing heavily in the field.
Private microbiome CROS/platforms are emerging both in the USA and Europe and the demand for microbiome subcontractors is expected to increase at a faster rate in the coming years. In the meantime, investments are needed to develop future standards of microbiome analyses.

 

Marc-Olivier Bévierre1, Etienne Casal2, Murielle Cazaubiel2, Françoise Le Vacon2, Alessandra De Martino2, Charles Savoie1

1 Cepton Strategies

2 Biofortis – Mérieux NutriSciences

 

References:

1 – PubMed as of January 2018

2 – Roots Analysis

3 – Clinicaltrials.gov as of January 2018

Les multiples applications du microbiome humain (article en anglais)

The microbiome is an ecosystem of microbes such as bacteria, fungi or viruses living in and on the human body. It plays an essential part in the functioning of our metabolism, our immune system and in our mental health. While the definition of a “healthy” microbiome remains to be defined, microbiome disruption is associated with numerous diseases, offering new therapeutic opportunities if causalities are demonstrated.
Characteristics of the human microbiome

 

Humans are colonized by trillions of bacteria, viruses, fungi and parasites. The recent decrease in price of DNA sequencing has allowed scientists to generalize their use of that method, and thus explore uncharted territories of our bodies. This emerging field is called metagenomics. Bacteria occupy not just the skin, but also many other parts of our bodies. The Human Microbiome Project, launched in 2008, has identified 48 body sites for microbiome sampling: among these, the top four are feces, the buccal mucosa, the vagina, and the rectum.

While bacteria account for just 1 to 3 percent of the body mass (~1.5 kg for an adult), the total number of genes is 10 to a 100 times the number of human genes, thus increasing the complexity of their analysis. Resulting from a long co-evolution, most of these microbes live in symbiosis and some of them are even essential to maintain our bodies healthy, such as those producing vitamin B12. The exact role of most of these organisms is nonetheless yet to be understood.

The microbiome is specific to both the regions of our bodies and to the different kinds of bodies themselves. As highlighted in Figure 1, the prevalence of bacteria is largely dependent on the region of interest. Moreover, there is no current definition of an “healthy” microbiome, as the distribution of bacteria across healthy individuals fluctuates largely. While it is increasingly admitted that a diversified microbiome is often correlated with a healthy body, growing number of articles on the subject also emphasize that changes in the composition of microbiomes correlates with numerous diseases.

Image 2
Fig 1: Prevalence of various classes of bacteria on different selected sites (www.genome.gov)

Among the ~2,100 microbiome clinical trials listed on the clinicaltrials.gov global database from 2000 to 2017, 35% of the studies are conducted in Europe, followed by 33% in the USA. China is third and far behind with only 5% of the overall number of studies. Nonetheless, the number of Chinese clinical studies is thought to be underestimated to be underestimated. Indeed, after merging the previous database with theChinese Clinical Trials Registry, the number of Chinese microbiome clinical studies is twice higher representing about 10% of the overall microbiome studies.

Europe was responsible for the initiative of the first trial mentioning microbiome in 2000, while the USA tackled the subject in 2006 and China in 2009. Moreover, Europe represents 32% of the publications on the microbiome listed on PubMed from 2006 to 2017, versus 23% for the USA and 9% for China. The USA is now taking the lead in number of microbiome trials. The number of trials in the USA is growing at +25% p.a. since 2014, compared to +17% p.a. in Europe. This gap is expected to further widen in the coming years. China is around 4-5 years behind Europe and the USA, yet the number of studies is growing at a fast pace (+39% p.a.).


Therapeutic applications and areas of interests

 Historically, microbiome therapeutic areas of interest have been gastrointestinal diseases (irritable bowel syndrome, inflammatory bowel disease, and Crohn’s disease) and metabolic diseases (obesity and diabetes). They respectively represent 20% and 15% of the overall number of microbiome trials performed in Europe and the USA.

In recent years, the potential applications for microbiome have extended to other therapeutic areas. Based on the number of clinical trials, the therapeutics areas that progress the fastest are central nervous system diseases, infectious diseases, and oncology. The number of clinical trials in oncology, including a microbiome analysis, is growing at a fast pace in Europe with +41% p.a. since 2011, but it is still behind the USA in volume. Indeed, microbiome trials in oncology already represent 7% of the overall number of trials conducted since 2000 in the USA while it represents just 2% in Europe.

First therapeutic treatments are already emerging, such as the fecal microbiota transplantation (FMT). The intervention consists of introducing the microbiota from a healthy donor into a patient. The FMT could be used to treat Clostridium difficileinfections (CDI) but it could also be applied to fight gut dysbiosis following heavy treatments like chemotherapy. For instance, Maat Pharma, OpenBiome, or Rebiotix are biotechs developing FMT solutions. It requires the access to a biobank with characterized feces from healthy donors. However, the legislation around FMT is still to be defined. In the USA, it is classified as a biologic product and a drug only for CDI affections. In Canada, it is registered as a new biologic drug and its use is restricted to clinical trial. There is no regulation at the European level but countries are setting their own rules instead. In France, it is considered to be a drug and aside from exceptional circumstances, FMT should only be administrated under a clinical trial. However, in the UK, the National Institute for Health and Care Excellence (NICE) allows the use of FMT in the NHS for patients with recurrent CDI who are not responding to traditional therapies.

 

The microbiome is not limited to the Pharma industry but is also of interest to the Food industry

The interest of microbiome is not limited to the scope of the Pharma industry and the Food industry is actively contributing to the research on microbiome. Indeed, the Food industry holds a significant part in the emerging of microbiome clinical trials. Among the 15 clinical trials mentioning “microbiome” in Europe in 2008, 14 were related to the Food industry and in Europe, 57% of overall studies related to microbiome from 2000-17 come from the Food industry. Yet in the USA the cumulated number of food microbiome trials represents 43% of the total. In both the USA and Europe, microbiome clinical trials related to the Food industry accounts for about 50% of the studies in 2017.

The interest of the Food industry in the microbiome relies mostly on the development of probiotics and prebiotics. Probiotics are live bacteria positively acting for health, while prebiotics are molecules that selectively favor some commensal bacteria, enhancing their growth. Moreover, clinical trials investigate the role of different diets like Mediterranean diets, vegan diets, or gluten free diets on microbiome. However, since the reinforcement of the European Food Safety Authority (EFSA) regulation on health claims in 2012, the number of food clinical studies is stagnating. Yet some Food companies such as PiLeJe are developing their products as a drug and therefore follow the same path as Pharma companies with clinical studies to prove the efficiency of their products.

 

Conclusion

Thanks to metagenomics development, the understanding of the human microbiome has opened the door for multiple applications. They are already spreading from nutrition to diverse therapeutic areas such as gastrointestinal and metabolic diseases, infections, neurologic diseases and oncology.
While associations have been found between microbiome dysbiosis and pathologies, causality and mechanisms still represent an important scientific challenge. Our study shows that Europe is at the forefront of the human microbiome research, as it promotes the emergence of new biotech companies developing microbiome-based products.

 

Marc-Olivier Bévierre1, Etienne Casal2, Murielle Cazaubiel2, Françoise Le Vacon2, Alessandra De Martino2, Charles Savoie1

1 Cepton Strategies

2 Biofortis – Mérieux NutriSciences

 

References:

1 – Human Microbiome Project website

2 – Kumar A, Chordia N (2017) Role of Microbes in Human Health. Appli Microbiol Open Access 3:131. doi:10.4172/2471-9315.1000131

3 – Clinicaltrials.gov as of January 2018

4 – Chinese Clinical Trial Registry as of January 2018

5 – PubMed as of January 2018