The PRI would like to thank Nina Vinot, Area Sales Manager at Probiotical, a PRI-member, for contributing this article.
The 2-day event focusing on the therapeutic potential of probiotics, Live Biotherapeutic Products (LBPs) and other Microbiome Modulators was held some weeks ago (14-15 March) by the Seine in Paris.
It covered different technologies, indications and regulatory questions, of which you can find a non-exhaustive sum-up below. The event also offered a partnering platform to alternate the presentations with one-to-one meetings. For this reason I can’t report on all talks.
Paul Cotter from the APC Microbiome Institute opened the event with a talk on bacteriocin production as an under-explored probiotic trait. Engineering bacteria can allow the creation of bacteriocin variants for ever more targeting of specific pathogens (such as Staph.) while preserving commensals (like Strep.). This work could bear particular importance to upgrade food preservatives, which are now “broad-spectrum”. Matrisys Biosciences, in the Innovation Showcase, is an example of company dealing with bacteriocins, through screening of bacteria from the skin of healthy people to make beneficial peptides antagonizing S. aureus (involved in physiopathology of atopic dermatitis), MRSA, etc.
Magali Cordaillat-Simmons, executive scientist from the Pharmabiotics Research Institute (PRI) did a quick regulatory review and explained the role of the association in educating the authorities and the industry. The PRI keeps working with the European Medicines Agency (EMA) and the European Directorate for the Quality of Medicines (EDQM) towards the creation of a legal framework in Europe that would be adapted for LBPs.
Here-under, a quick review of the health indications for which the therapeutic potential of probiotics was commented.
After some taxonomy information on Bifidobacteria and Lactobacilli, Marco Pane from Probiotical presented new results from a double-blind, placebo-controlled study showing potential for a selected blend of 3 live Lactobacilli and one Bifidobacterium strain to improve mood. Healthy students supplemented for 6 weeks showed a significant decrease in depressive mood, anger and fatigue as well as a significant improvement in acceptance and sleep quality in comparison to the placebo group. These are strong results, Marco highlights, because a healthy and young population is highly resilient, and such potential should be tested on depressive patients too.
This study is particularly innovative with the integration of 3 major novelties:
– The enumeration and stability of the probiotic blend done also with flow cytometry
– Reporting not only on mood but also personnality and sleep quality altogether
– Cell-phone app for real time monitoring
Wearable devices and apps as advanced tools for science and personalization are a new trend as highlighted by Nathan Gray at Probiota last month. Indeed they found their way in this clinical trial and in service like the ones provided by ACES Health, that intervenes to support trials with modern platforms in the digital health ecosystem.
Several speakers discussed the role of the microbiome in cancer, in particular as a screening tool to discriminate between responders and non responders. Marie Lindner from Novartis, who explained what Pharma wants (with a non-so-surprising enthusiasm towards metabolites produced by probiotics rather than probiotics themselves – a vision probably influenced by the regulation around drugs, adapted to molecules), believes cancer to be the most valid therapeutic area for microbiome modulation.
Jack Gilbert from the University of Chicago and Director at its Microbiome Center also gave insight on the role of microbes in cancer. For example, germ-free mice have two times less intestinal adenomas, while Fusobacterium nucleatum in humans is associated with colorectal carcinoma (CRC): there may be a transmissible, infective cause to cancer! Bifidobacteria can actively enhance the efficacy of immunotherapy, he says, and it would be possible to look for probiotics able, for instance, to antagonize a microorganism that can metabolize cycasin in carcinogen methylazoxylmethanol (MAM).
ACES Health developed the Rapid Oxidative Stress Analysis (ROSA) software and showed that the more oxidative stress, the highest prediction of autism and cancer on multiple distinct proprietary datasets. Such results give ground to the development of probiotic formules based on antioxidant properties. It is also a good example of another new trend: get value from company-developed algorithms that work as a black box and are applied on datasets and metagenomics (like ACES, Carbiotix, Bio-Me) to make sense of big data or cell banks (Optibiotix), to screen potential probiotics.
Professor Manimozhiyan Arumugam from University of Copenhagen presented great work of bioinformatics applied to the research of biomarkers in CRC from different databases. His team found a consensus for 4 markers in 4 cohorts (Chinese, Danish, Austrian and French), confirming in particular this strong association with that Fusobacterium nucleatum.
However, Ségolène Caboche, Bioinformatics researcher from Lille University, warned against the precision of the methods used. Trying to validate the repeatibility of results from Illumina and Ion Torrent on a reference dataset analyzed through different pipelines, she states “biological conclusions can only be as precise as the tool. It is completely unrealistic to reach the species level with these tools”. Is 16s metagenomics questioned? Jeroen Raes, Belgian bioinformatics expert who worked on the Flemish Gut Flora project, was more reassuring when he presented in Paris World Academic Colloquium on Microbiome and Permeability last October as he showed that the effect size of bioinformatics is much lower than the one of sampling procedures and handling. Should we understand that between the sample handling and the bioinformatics we should not go down to species levels in 16s metagenomics?
Professor Holger Bruggeman from AARHUS University challenged the notion of probiotic and pathogen in his presentation on acne. Propionibacterium acnes (which now changed name to Cutibacterium acnes) can be good or bad depending on its type and on the host. Acne-associated strains induce less IL-10 and more IFNγ and IL-17 compared to health-associated strains. On the other hand, S. epidermis can inhibit P. acnes, but ESS-deficient S. epidermis mutant induces an increase in IL-8 production in exposed keratinocytes. This is yet another argument in favour of a functional approach rather than species. In this sense Probiotical is developing probiotics for the management of acne thanks to their immunomodulation properties.
Catherine O’Neill from Skin Biotherapeutics harnesses the power of a probiotic lysate for skin health, through three activities: the improvement of skin barrier function, the inhibition of S. aureus, and the promotion of wound healing.
More on skinbiotics and on C. acnes to be followed with the Microbiome Congress in Rotterdam offering a dedicated room to talks on the skin microbiome.
Diabesity & diabiotics
Angela Horvath from the Mecical University of Graz reminded us that diabetes is characterized by a loss of butyrate producers (like F. prausnitzii) and an increase in opportunistic pathogens, as well as a loss in barrier function, allowing more bacterial translocation into the bloodstream. A recent meta-analysis on glucose and lipid metabolism further established that probiotics are able to increase HDL and decrease both total cholesterol and triglycerides. A clinical trial on 40 obese patients supplemented for 6 months with both probiotics and prebiotics is launched and we are looking forward to seeing the results.
Osteoarthritis & osteobiotics
Professor Yves Henrotin from the University of Liege and founder of the Osteoarthritis foundation gave one of the best talks, focused on the potential of probiotics in the management of osteoarthritis. Based on extensive work on the establishment of biomarkers, a preclinical study on guinea pigs showed promising results: an inactivated B. longum strain was able to stimulate collagen synthesis and prevent osteoarthritic cartilage lesions. Definitely hoping to see mechanisms detailed and human data soon.
Ulcerative colitis & colitobiotics
Thomas Tompkins, Research Director from Lallemand, presented results from a meta-analysis including 54 studies in Chinese population of a probiotic blend (Medilac-S) used against ulcerative colitis, and demonstrated 21% better results with the LBP associated to drug therapy as compared to the drug therapy alone. Could this data be strong enough to catch the attention of big pharma?
Other applications for microbes
David Berry from Flagship, investment fund pioneering microbiome innovations, mentioned thrilling other applications for microbes. In agriculture, they found a single bacterium in cotton that increases the yield by 11%, which is three times as much as the average yield increase in genetically modified crops. In the environment as well, there is current work on a bacterium able to extract cobalt with twice the efficacy of modern methods – with a shortage of cobalt expected by 2020, this is an important discovery!
Don’t hesitate to share, comment or contact me at email@example.com ! I’d be happy to share more info on Probiotical’s study on psychobiotics as well as other innovative therapeutic indications already backed by clinical trials or under investigation.
Following our successful travels in late 2017 and early 2018 Magali Cordaillat-Simmons and myself will be out and about again throughout the spring attending a variety of conferences related to the world of Microbiotic Medicinal Products.
Please feel free to get in touch with us to set up a meeting at any of the following events if you are interested in taking your products to market here in Europe.
- Next week we’ll be in Paris 14-15 March at Pharmabiotics 2018 which was created by the PRI over 3 years ago. We’re expecting in excess of 180 attendees this year and have a number of really interesting sessions on regulatory affairs globally; skin; Bioinformatics; Taxonomy; Innovation showcase; Biomarkers and so on!
- Immediately following that we fly off to Rotterdam to the Microbiome R&D & Business Collaboration Forum 21-22nd March! Probably the biggest conference around the Human Microbiome internationally, my colleague Magali Cordaillat-Simmons will be overseeing a round table on “the regulatory aspects around LBPs”
- The month of May at least one of us will be at Microbiome Invest in London to keep abreast of any new start-ups that might be interested in joining the PRI!
- June will see us in the US, in Boston to be precise, at the excellent Microbiome Drug Development Summit 19-22nd where we’ll be looking to continue to forge partnerships with US-based organisations looking to take their products to market in Europe.
The PRI is a non-profit European association with 4 major objectives to get Microbiotic Medicinal Products and therapies recognised as medicines and as such provide regulatory guidelines to our members when taking their products to market in Europe:
- to get Microbiotic Medicinal Products and therapies recognised as medicines and as such provide regulatory guidelines to our members when taking their products to market in Europe
- to offer our members value by operating Europe’s only network in the Human Microbiome supply chain!
- to stimulate and exchange scientific discussion between our members. We will be holding scientific task groups next year in Paris with our members around the bioinformatics challenge and the microbiome.
- To create a link between academia and industry enabling industrials to learn about new science and academics to meet with potential investors.
Here are some videos of our members and staff talking about the PRI.
- Martha Carlin, CEO, TheBiocollective.
- Massimo Marzorati, Founder ProDigest
- Stanislas Desjonqueres, CEO, Biose
- Pierre Yves Mousset, CEO, Indigo Therapeutics
- Jaimé Lopez, Pharmabiotics Platform Manager, Ferring Pharmaceuticals.
- Magali Cordaillat-Simmons, Scientific & Regulatory Affairs Director of the PRI
We currently have members who are at stage III clinical trials with Microbiotic Medicinal Products in Europe.
Furthermore, as the impairment of microbial functions has been associated with numerous pathologies in humans, we now know that the composition of the microbiome could also affect the efficacy of other “regular drugs” (i.e. New Chemical Entities, Biotechnological products, etc…). One example of this inter-play is the influence of a microbiome’s composition on cancer therapy and on the responder/non-responder status.
As such, two important questions for European pharmaceutical regulators have now become evident, and if we as scientists and researchers are being honest with ourselves, unavoidable:
1. How do we clarify the regulatory framework so that the specific nature of Live Biotherapeutic Products is taken into account in the assessment, and the resulting adaptations are made to the regulatory framework?
Indeed, Live Biotherapeutic Products (LBPs, i.e. medicinal products containing live micro-organisms) are the only type of medicinal product which exert their action locally and through a modification of the local ecosystem and local microbial functions, which in turn exert an effect on the host homeostasis. The assessment of Pharmacokinetics, or dosage, works on a different paradigm. Moreover, safety of these products involves concerns not usually assessed for other types of drugs (i.e. antibiotic resistance, virulence). Consequently, as of today, assessment is done on a case-by-case basis and may vary on the reference member state’s own knowledge of this type of product.
Harmonization and European guidelines are thus sorely needed today as more and more products are in development (reaching clinical phases) and science has demonstrated the central role that the microbiome plays in human health. Future patients deserve assessment of the utmost quality; this will necessarily require harmonization at the EU level, as well as the drafting of relevant guidelines dedicated to this type of product, and not the usual application of the “spirit” of other existing guidelines, as is often recommended. Patients’ safety will be ensured by an assessment engineered for the specific nature of the products, and by harmonization of such assessments at the EU level through specific guidelines.
2. Can we continue to ignore the importance of the microbiome in designing and developing regular drugs (i.e. new Chemical entities, Biotech products, etc…)?
We know that drugs can have an influence on the microbiome, the obvious example being antimicrobials; but more importantly, the microbiome of patients may also have a strong influence on the efficacy and perhaps even safety of other types of drugs.
There are alterations of microbiomes that may look benign due to their resilience, but we now know that an alteration of the microbiome caused by antibiotic treatments during infancy is associated with a higher prevalence of chronic pathologies in adults. Microbiome alteration could therefore be a ticking time bomb with severe consequences later on in life, and this should no longer be ignored when designing new drugs.
On the other hand, it has been shown in cancer therapy that the composition of patients’ microbiome had an influence on the efficacy of their treatment (responders/non-responders). Characterizing the patient’s microbiome therefore seems to become a necessary factor in comprehending how to optimize drug efficacy. Administering drugs to non-responder patients is obviously a question of safety, and the understanding of the influence of the microbiome may indeed be critical in the development of safer and more efficacious drugs.
In conclusion, advancements in understanding the true nature of human microbiomes represent a paradigm shift for the pharmaceutical industry and regulators, and will require them to approach the human body in an entirely different way. We are not just human, we are a symbiosis, within which bacterial cells outnumber their host’s counterparts. Therefore each of us should be considered a symbiont going forward when we work on designing and assessing drugs: either drugs exerting their effect on the microbiome itself, i.e. LBPs, or drugs exerting their effect on the human side, but which may have a detrimental influence on its microbial counterpart.
We believe it is time the authorities tackle this issue head-on. Industry is generally ahead of regulator due to constant innovation, but it is unfortunate to hear such a deafening silence from European regulators on this issue, an issue which could all the same affect a large swath of new drug products coming to market in the near future. While the FDA has been working on this since 2010, Europe seems to be lagging behind; and as such, this revolution in medicine will come that much later to the care of European patients.
This is particularly difficult to grasp, as Europe has been a leader in microbiome research, and is in point of fact well-positioned worldwide when it comes to understanding the mechanism of actions by which microbiomes influence human health. Once again, biotechnology companies are being created in staggering numbers in the US, while in Europe the lack of a regulatory framework impede their financing and growth.
We urge European member states to comprehend the significance of this transformative shift in the field of medicine, and address this need so that Europe may start to regulate and harmonize in order to enable the emergence of this new industry; but above all, to ensure the safety and benefit of future patients.
– Dr. Magali Cordaillat-Simmons, Scientific and Regulatory Affairs Director, PRI: Microbiotic Medicinal Products
Part 2 of our new member update – more and more companies our joining the PRI, not only from all corners of Europe, but a new wave of North American companies as well, each looking to get a foothold in the European Microbiota & Human Health Industry. We are anticipating the first marketing authorization in Europe for a Microbiotic Medicinal Product! Join the PRI and be a part of this new medicinal future.
Here 6 of our newest members at a glance –
Matrisys Bioscience – “Re-Balancing the Skin Microbiome & Innate Immune System – MatriSys Bioscience is a Clinical Stage Specialty Biopharmaceutical Company for the post antibiotic era. Our company focuses on dermatology and skin care and develops therapeutics at the interface of the microbiome revolution and the innate immune system. Historically bacteria have been considered as natural enemies that must be fought. However, recent advances in skin microbiome research have led to a better understanding of the mutualistic beneficial relationships that exist between the highly diverse skin microbial community and skin health.”Visit the Matrisys Bioscience website here.
The human microbiome has emerged as a key driver of immune dysfunction. At Siolta Therapeutics, we leverage multi-scale next-generation microbiome analyses to develop and test microbial-based therapeutics for induction and maintenance of immune tolerance.
At Siolta Therapeutics, we harness information from human microbiome studies to design next-generation microbial therapeutics that re-engineer the human microbiome to prevent or reduce inflammatory processes.
Understanding and leveraging the microbiome to influence human health, represents one of the most exciting areas of therapeutic development in the modern era – Founder, Susan Lynch.”
“With a global vision, 5QBD-Biotech brings efficient & pragmatic solutions, included a simple, clear & flexible documentation and quality system, suitable for any company in a fast-evolving environment.”
Contact : Frederique Vieville
Dr in Pharmacy – Industrial & Biomedical –
Engineer in Biotechnology
+33 6 08 63 74 39
“Established in 2002 by Professor Mike Rubinstein, Quay Pharma is an independent, privately owned company with the scientific expertise to respond flexibly to each new challenge, and give every project the best possible chance of a successful clinical trial.
…Over the past decade we have successfully developed safe, robust and effective new products for more than 100 clients, across a spectrum of projects that range from hard-to-deliver New Chemical Entities to reformulations of established drugs, many of them now either successfully licensed or in the latter stages of clinical development. We have also helped with the successful development of a wide range of generic products, medical devices and veterinary products. Significantly, we have often devised successful formulations where other companies have failed.
Already recognised for our innovative and successful work in developing highly effective drug delivery mechanisms for the pharmaceutical and biotech industries, our aim is to establish ourselves as recognised world leaders in early stage drug development…”
Synlogic – A novel class of living medecines.
“Synthetic BioticTM medicines to perform and deliver critical therapeutic functions to treat diseases throughout the body. At Synlogic, we are dedicated to bringing innovative living medicines to patients by using the tools and principles of synthetic biology to genetically re-program beneficial bacteria.
Using our Synthetic Biotic platform, we are engineering probiotic bacteria to perform specific therapeutic functions with established links to disease. We can deliver these living, Synthetic Biotic medicines orally, where they act from the gut microbiome to correct missing or dysfunctional metabolic activities throughout the body. We also aim to deliver Synthetic Biotic medicines at the site of disease in cases where local activity is critical, as in stimulation of immune effectors to combat certain tumors.
SkinBio Therapeutics PLC – Protect. Restore. Manage. Harnessing the power of the microbiome for skin health.
“SkinBio Therapeutics is a life science company focused on skin health. The Company’s proprietary platform technology, SkinBiotix®, is based upon discoveries made by CEO Dr. Catherine O’Neill and Professor Andrew McBain at The University of Manchester.
The SkinBio Therapeutics’ platform applies research discoveries made on the activities of lysates derived from probiotic bacteria when applied to skin. The Company has shown that the SkinBiotix® platform can improve the barrier effect of skin models, improve repair and reduce bacterial load.
SkinBio Therapeutics is targeting three specific skin healthcare sectors; cosmetics, infection control and eczema. In each of these areas SkinBio Therapeutics plans to exemplify its technology in human studies. The most advanced programme is focused on the application of the Skinbiotix® platform in managing sensitive skin in the cosmetics industry. The business strategy is to partner and outlicense its programmes at proof of concept.