By Hui Cai, Vice President of Corporate Alliances and Head of Communications, WuXi AppTec

“We want to understand deeply not only the impact of engaging a target that forms a synthetic lethal pair within the framework of a single cell assay, but also how that translates to multiple cells that talk to each other in the tumor micro environment, and how such an approach can be targeted to always make sure you’re going to get a therapeutic effect, while at the same time measure markers that are metabolic and genomic going into the clinic.”

Harnessing a combination of science and business acumen, entrepreneurial experience, and a strong multicultural background, Simone Botti has developed a knack for leading seed and early stage life science companies through capital raising and partnership with top tier strategic investors.

The Weizmann Institute trained scientist is widely known for his work in Israel’s burgeoning life science sector, where he helped run business development at RAD Biomed Accelerator, one of Israel’s leading life science incubators, and was board member of IATI, the Israel Advanced Technology Industries Association, until last year.

In 2011, Botti joined MerckVentures, the corporate venture capital arm of Merck KGaA, as the head of its new Israel Bioincubtaor Fund, a strategic initiative designed to stimulate innovation by bridging the gap between academic research and the biotechnology industry in Israel. In July, he switched gears a bit to lend his business and biotech know-how as the new CEO of Israel cancer start-up Metabomed, whose focus is the discovery of small molecule drugs that inhibit targets that form a synthetic lethal gene pair with metabolic genes inactivated in cancer cells. The company – whose founders are leading experts in the systems biology of cancer metabolism – has recently attracted funding from big pharma, such as Merck KgaA, Boehringer Ingelheim and Pfizer, to the tune of an $18 million Series A.

I caught up with Botti during the recent IATI BIOMED in Israel, where he gave me a peek inside Metabomed’s strategy, as well as Israel’s changing life science landscape.

Hui Cai: Metabomed is an early spinout from Merck Ventures Israeli Bioincubator, one of the industry’s earliest big pharma-backed incubators of its kind.  How did the incubator evolve, especially in Israel, the Start-Up Nation?

Simone Botti: The history of Merck Serono in Israel is very long, dating back to the 1970’s through a collaboration with the Weitzmann Institute. This partnership led to the discovery and development of important biologics therapies, Rebif®, a blockbuster drug for the treatment of multiple sclerosis and  Erbitux®, the successful cancer medication licensed to Merck KGgA.  In 2009, the company set up MS Ventures, now Merck Ventures, particularly through the efforts of Roel Bulthius, who serves currently as senior vice president and managing director. The Israel Bioincubator Fund was started in 2011, through an initiative led by Jasper Bos, who leads the Healthcare practice of Merck Ventures. Today, Merck Ventures manages a €300 million Venture fund, of which €140 dedicated to healthcare, as well as €10 million Euro for the Israel Bioincubator Fund, which is focused on pre-seed and seed opportunities originating from Israel.

One of the differentiating features of this incubator versus others was to have the pharma company backing from the very beginning, the intent of which was for these new start-ups to understand how to partner with pharma. We started three companies: Metabomed, which concentrates on cancer metabolism; the Ion Channel-antibody-based Chanbio; and Neviah Genomics, which focuses on the discovery and development of novel biomarkers for the prediction of drug-induced toxicity as an approach to minimize attrition and mitigate risk of late-stage drug failure.

Hui Cai: How does the incubator fit into Israel’s bio ecosystem?

Simone Botti: Israel has a very dynamic entrepreneurial community. We see more than 150 proposals a year, and we pick about one. We hope to have up to six companies at a time in the incubator, and we’re always looking for new companies. By comparison, for the whole fund, we see about 1,000 or more a year. Yet, our strike rate for that is still no more than 1%-to-2%. Our goal is to incubate, start-up companies, and finance them with sufficient capital with expectations that milestones are achieved within three years.  In the case of Metabomed, the company recently completed an $18 million Series A financing that early investors Merck Ventures, Boehringer Ingelheim Venture Fund, Pontifax LLC and Technion Research and Development Foundation were joined by Pfizer and Arkin Holdings.

Hui Cai: Yes, and the company’s science holds tremendous promise – its unique approach to tackling cancer, the science behind the approach, and the caliber of its founding scientists. Can you walk me through that?

Simone Botti First, let me comment on the founders, and second, address the science behind Metabomed.

Eytan Ruppin is a professor at the University of Maryland, and director of the Center for Bioinformatics and Computational Biology. His computational systems biology approaches for genomic analysis and genome scale metabolic modeling (GSMM) of cancer led to the first GSMM models of metabolism of different human tissues, the first GSMM-based synthetic lethal drug targets to treat renal cancer, and the first to identify synthetic lethal networks in cancer in a genome-wide manner.

Professor Eyal Gottlieb is a director at the Beatson Institute for Cancer Research in Glasgow Scotland, where he has established himself as one of the leading researchers in cancer metabolism. His laboratory combines metabolomics, cell biology, and biochemistry to study metabolic transformation in cancer.

Professor Tomer Shlomi is one of the youngest professors at the Technion.  His research focuses on understanding metabolic abnormality of cancer cells, tumorigenic potential, and underlying regulatory mechanisms which then can be exploited for finding new cancer therapeutics.

What brings these global research stars together at Metabomed is their Israeli roots and novel approaches to find tractable cancer metabolism targets based on synthetic lethality that could lead the way for innovative first-in- class therapies.

Hui Cai: This is a truly global team of academic stars coming together at Metabomed with strong Israeli connections and cutting edge research. On the science side, can you explain synthetic lethality in the context of cancer metabolism? What is its uniqueness?

Simone Botti: We concentrate on identifying synthetic lethal pairs that are driven by loss of particular metabolic genes. In some cases, these genes act as tumor suppressors, like FH and SDH. There is also a high occurrence of deletion of metabolic genes that are proximal to specific tumor suppressors lost in a number of cancers. This allows us to not only use genomic tools to identify synthetic lethal pairs, but to bring about the whole weight of modeling and measuring the metabolic event of the loss of the gene, of the inhibition of the target and how that translates from in vitro to in vivo, to the interplay between the single cells where we can see the effect of the division of the metabolic network, to then looking at the inhibition and the engagement of that target within the environment where the tumor is, and the interplay with, for example, the re-wiring of the immune system. This allows us, hopefully, to go into a potential therapeutic modality with our eyes a lot more open.

We’re gathering a lot more information about how we’re going to choose our patients, not only by the genomic signature of their tumor, but also informed by how most probably their tumor is going to behave metabolically when we go in and attack it. Thus, we are very focused on getting very deep knowledge about the biology of tinkering and attacking the tumor using synthetic lethality. Tumor metabolism is such a complex network that hitting one point most probably will not be enough to bring the system to collapse.

Although we are a platform, we want to understand deeply not only the impact of engaging a target that forms a synthetic lethal pair within the framework of a single cell assay. We also wish to examine how that translates to multiple cells that talk to each other in the tumor micro environment, and how that can be targeted to always make sure you’re going to get a therapeutic effect and how to then measure markers that are metabolic and genomic going into the clinic.

Hui Cai: Can you share Metabomed’s strategy on working with orphan indications within the cancer space?

Simone Botti: What we’re trying to do is first work on orphan diseases, where both the animal models and the patients have very well characterized pathology, for example, FH and SDH negative tumors. Those are systems that I think will allow us to translate very well in in vitro and in vivo to our patients, because we will be able to bring in biomarkers and knowledge about the biology that is going to be translatable to what happens to those particular patients. It’s an orphan disease, but I think it’s going to be probably something where the animal models have very high predictive power, and if we’re able to show that we can translate into the patient, then we will be strong enough to open it up to more general conditions.

Hui Cai: Are there particular challenges that Israeli start-ups face, and how may those affect your strategy?

Simone Botti: We are very fortunate to actually form a key part of the team with extremely talented biochemists. We are developing our core competencies that drive our competitive edge and leading position through the deep biology know-how, understanding and expertise we have and will be building, particularly through our advisors.

The piece that had been missing is a discovery partner, especially with medicinal chemistry expertise.  WuXi AppTec can be a significant discovery partner for Metabomed with its broad end-to-end small molecule discovery and manufacturing capabilities and expertise that perfectly complements our deep understanding of cancer metabolism. This balanced approach will take Metabomed from target to full proof-of-concept in an animal using a model that can deploy, as program advances, various resources that are typically found in large pharma, but on a service basis.

Hui Cai: Israel is widely regarded as the Start-Up Nation for its innovation and entrepreneurialism. Merck Ventures’ Bioincubator and Metabomed reinforce this global perception of the innovation occurring here. Can you share with our readers your perspectives about Israel as an innovation center?

Simone Botti: Israel has been a leading center of technology for many years. The fact that technology companies such as IBM, Cisco, and HP have had an R&D presence here is reflective of that view. There are several important contributing factors, for example, Israel is ranked number 1 in the world in terms of scientists and engineers per capita, and produces the third highest number of scientific articles per million population with equally impressive patenting in science and technology.  Healthcare is also a high priority – today we have probably 800-to-1,000 startup biotechs, including many early adopters in medtech and digital health technologies, strong institutional incentives for new technology development, and large commercialization outlets to the U.S., Europe and China. These are just a few of the reasons why Israel has emerged as a center of innovation. At Metabomed, we have an opportunity to be part of this ecosystem, and to translate the insights we have gleaned from our founders’ cutting edge science into meaningful benefits for cancer patients.