Microbiome Matters: Spotlight on Israeli Innovation

The Bulletin by the BE ForumBioExecutive Forum Logo

September 2016

Microbiome Matters: Spotlight on Israeli Innovation

By: Joe Straus, MD, MBA, Editor

If you have not yet heard the words “human microbiome”, you will…! The term refers to (the genetic material of) all the micro-organisms that collectively live on, and in the human body. These symbiotic microbes reside in our intestines, on our skin and mucous membranes and in our lungs, but typically the term microbiome refers more specifically to our gut flora. The microbiome is often called “the forgotten organ” and we could not survive without it. Scientists are only just beginning to understand the impact of the microbiome on a host of circumstances, conditions and therapeutics, and microbiome science is one of the most interesting and important developing disciplines in medicine today. Pharma companies are also becoming very interested in this field, not only because of the intended or unintended impact pharmaceuticals can have on the microbiome of patients, but also because, conversely, the microbiome can seriously impact the absorption and metabolism of drugs in ways that we have yet to elucidate.

“The microbiome is still in its diapers” said Nitsan Maharshak, MD tongue in cheek. Maharshak, Assistant Professor and Head of the Bacteriotherapy Clinic at the Tel Aviv University Faculty of Medicine chaired the microbiome track at the IATI – Biomed conference in May. The presentations and the panel discussion focused on “moving beyond hype and hope to happening” as panel member Michael Berman, MD, put it.

In this article we will review 5 Israeli companies that presented at the microbiome session, and that are on the forefront of this exciting new field. 3 of the 5 companies were established as a result of research conducted at the Weizmann Institute of Science. Professors Eran Segal and Eran Elinav, both at Weizmann, are leading much of the microbiome related science in Israel today.

Though the challenges are many, and microbiomics is indeed still in its infancy, it is becoming increasingly clear that the microbiome plays a major role in the pathophysiological processes related to various diseases. Maharshak points to the exponential growth in related publications over the last 15 years. Much of this research was facilitated by the tools derived from the human genome project, he says.

While today, Fecal Microbial Transplant (FMT – the transplantation of fecal material from a healthy donor into the digestive tract of a patient) is approved as a therapy only for recurrent, therapy resistant Clostridium difficile (C. diff) infections and is expected to be approved as first-line therapy in this condition in the near future, various other initiatives based on microbiome science are in development here in Israel.

RondinX Ltd. is a technology-driven biotechnology company founded in 2015 and located in Tel Aviv. The company has licensed a family of algorithms from YEDA, the TTO of the Weizmann Institute, with which it is building a platform for the discovery of microbiome related targets, drugs and companion diagnostics. Using algorithms developed at Eran Segal’s lab and machine learning, the company’s proprietary, cloud based Peak-to-Trough (PTR) technology can harness raw meta-genomics to determine which bacterial strains in an individual’s microbiome are proliferating most actively. This can provide insights into the pathogenesis of specific diseases. According to CEO Guy Harmelin, MD, the company is now seeking collaborations with major pharma in order to further develop and commercialize its computational pipeline.

Another company, Day Two Ltd. based in Moshav Adanim also licensed its technology from the Weizmann Institute and is built on a collaboration between Segal and Elinav. As reported in their article published in Cell in November 2015, blood glucose (BG) levels in healthy subjects vary sharply in response to the same foods based on differences in their colonic flora. Proper BG regulation is significantly influenced by an individual’s microbiome, a “new” factor which deserves careful consideration in diabetes management.

Building on these findings, Day Two has developed clinical applications of algorithms which can predict a person’s individual glycemic response to various foods and individualize optimized nutrition. The company plans to help patients and consumers understand which foods are best for them, by gathering their personal metrics by means of an online questionnaire, as well as by collecting and analyzing samples of their microbiome. Using their proprietary algorithms, the company will then provide personalized nutrition recommendations and meal plans, customized for different weight loss, BG management, athletic and other goals. CEO Lihi Segal said that the company is scheduled to launch in the US towards the end of the year, and will allow its users to better maintain normal BG levels and live healthier lives.

Meanwhile, Segal and Elinav are now conducting a new study in pre-diabetics and Type II diabetics. The trial will seek to determine the effectiveness in these populations of personalized diets based on their algorithm which integrates both clinical and microbiome data. One arm of the study will test the hypothesis that a personalized, high fiber, low fat diet can optimize the establishment of donor bacteria in the colon of recipients of FMT from lean, non-diabetic donors. On a related note, in September 2014 the Journal Nature published a widely acclaimed article by the Weizmann scientists about the microbiome mediated diabetogenic effect of artificial sweeteners.

MBcure Ltd. is a biopharmaceutical company, which is part of the FutuRx biotech incubator in Ness Ziona. The company is developing new therapeutics for diseases that result from microbiome dysbiosis, using bacteria-specific bacteriophage cocktails.

Bacteriophages are viruses that destroy bacteria by invading them. They are effective in low doses, as they replicate within the bacteria. Their amplification is self-limiting since it requires the presence of the target bacteria. For these reasons, and because phage cannot infect human cells, phage-based therapeutics are expected to be non-toxic.

Phage technology is used in various settings, including the treatment of foods to prevent spoilage. Phage drugs can target and suppress specific disease- associated bacteria. Most importantly, as designed, it is anticipated that target bacteria will be unable to develop resistance to MBcure’s advanced phage therapy.

CEO Naomi Zak, PhD explained that phages are another tool with which to carry out directed modulation of the microbiome. MBcure is preparing for its first in man study in a dermatological indication and is working towards an IND by the end of Q3, 2017 and proof of activity by mid 2018.

Looking ahead, MBcure is also pursuing several oncological indications and is eying metabolic and autoimmune diseases, as well as infections with antibiotic resistant bacterial strains. In addition to natural phage, the company is also creating designer phage equipped with robust lytic abilities through synthetic biology approaches. MBcure’s technology is licensed from the Weizmann Institute as well and its team includes founders Prof. Rotem Sorek, a renowned phage expert and CrispR researcher, and Prof. Elinav.

Ness Ziona based MyBiotics Pharma Ltd. is also a microbiome therapeutics company, and is at the forefront of the newly emerging field of pharmabiotics. The company is manufacturing (instead of harvesting) fecal microbes and then deploying the live bacteria as a drug.

The team is developing a line of these products; “probiotics version 2.0”. The company’s MyCrobeTM is a platform to culture single bacteria and multi-bacterial communities on a specific medium. This includes bacteria that could not be successfully cultured previously. In a targeted treatment setting the bacteria are administered to colonize and thrive in the colon. The bacteria will compete with the resident pathological population and re-establish a well balanced, healthy microbiome.

Taking this concept much further, MyBiotics developed its SuperDonorTM technology, a feces-free FMT product line, cultured in-vitro, as an alternative to donor FMT therapy. According to CEO David (Didi) Dabush, complete microbiome replacement with an artificial product that closely resembles human feces, and subsequent colonization and maintenance in vivo is a technological breakthrough.

“The ability, unlike with other probiotic products, to overcome the body’s natural resistance and to colonize the gut with an appropriate, essential manufactured bacterial population represents an important, novel therapeutic alternative for patients with a variety of medical indications”, said Dabush.

The first indication for SuperDonorTM will be the treatment of C. diff infections with intent to cure. Subsequently, MyBiotics will focus on antibiotic side effect reduction and post-antibiotic microbiome restoration, and on the treatment of other microbiome related indications.

MyBiotics has completed 3 successful pre-clinical experiments with the MyCrobeTM product which demonstrated effective bacterial delivery and colonization. First in man trials with MyCrobeTM in a post antibiotic treatment setting are scheduled to begin at the end of this year, and first in man studies with SuperDonorTM in C. diff. infections will be initiated in Q2 2017.

Founded in 1974 in Rehovot, Hy Laboratories Ltd. (Hylabs) provides a full range of microbiology and molecular biology products and services. In 2015 the company initiated Project Obediome in collaboration with New Jersey based Genewiz, a privately held global CRO specializing in genomics services. The project is funded by the BIRD foundation.
In addition to deep expertise in designing microbiology and toxicity testing and in molecular genomic services, Hylabs has a strong relationships with HMOs, hospitals and other providers and thus has access to a large network of patients. The company also has extensive experience with international regulatory compliance. Genewiz brings its genomics development pipeline and sophisticated sequencing methodologies to the table, with which it can identify increased sequence diversity with a very high level of sensitivity and specificity.

Currently, the Obediome project is conducting a multi-center clinical trial in Israel, designed to detect and determine the relative presence of bacterial and archaeal species in the microbiome of obese and diabetic patients undergoing bariatric surgery. This will be accomplished using the 16S MetaVx™ patent pending assay and medical metadata.
Stool samples are recovered with a unique stool collector, and the proprietary assay allows for enhanced data analysis with increased sensitivity and specificity, yielding a better display of microbial diversity. The project aims to accelerate the development of novel diagnostic panels for the characterization of the microbiome in obesity and diabetes. Both conditions are strongly associated with the makeup and function of the gut microbiome and the project is expected to lead to alternative treatment options for these patients. Additionally, the study also aims to improve stratification for bariatric surgical intervention.??
According to Liora Madar-Shapiro, PhD, MSM, Director of the Molecular and Cell Biology Division at Hy Laboratories, the trial will enroll 100 patients and is scheduled to be completed by the end of 2016. The first diagnostic panel should be released in 2017.

Another version of this article by the same author was published previously in BioWorld Today and Medical Device Daily.

The Bulletin welcomes your feedback. Please send your comments to dorischneider @ gmail.com