A look across the border at cancer research and drug discovery

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Jan Hoflack is chief scientific officer at the Dijon-based Oncodesign, a  drug discovery company and oncology service provider. Hoflack joined Oncodesign in 2009 and introduced the Nanocyclix drug discovery approach. He originally developed this next generation kinase inhibitor platform at Janssen Pharmaceutica, based on macrocylic medicinal chemistry. To fully exploit Nanocyclix, Janssen Pharmaceutica and Oncodesign signed a license agreement on the technology, aiming to expand it and create additional value by ensuring the necessary environment to further pursue these attractive molecules.

Serving cancer research with innovative tools

Oncodesign’s base technology, Predict, delivers conventional in vitro and in vivo tests for cancer research on a fee-for-service basis. Jan Hoflack comments: “These tests are relatively cheap and well-standardized, but they start to be somewhat outdated as they rely on cancer cell lines that have been cultured in artificial conditions for many generations. We now also offer more advanced and predictive technologies, which we call χ-mice (Chi-mice, for humanized mice). We are, for example, working with translational models, where cancer tissue of humans is implanted in mice, the so-called patient-derived xenografts (PDX). Every cancer can be different at a molecular level, therefore you need to hold dozens of models to represent the make-up of each of the major cancer types. We map DNA mutations and markers and look for the molecular reasons behind a cancer, directing us towards personalized medicine.”

Over the last couple of years, cancer immunotherapy has become of major importance. “Therefore, we are now developing cutting edge technologies using animal models that at least partially have the immune system of humans. We apply two strategies: on the one hand, we inject human immune cells in immune-compromised animals; on the other hand, we work with transgenic models. For the latter, we cooperate with CEIA, a Japanese institute that replaces entire animal organs with human tissue,” explains Hoflack.

“Next to cancer treatment, imaging is an important tool in the process of diagnosing and curing cancer,” adds Hoflack, “as it is a non-invasive technology already well established in a clinical setting. We focus on preclinical pharmaco-imaging: for us, imaging is a tool that allows a better understanding of the pharmacology of cancer. We develop new tracers in animal models and subsequently transfer them into clinical practice. Early 2016, we expect that our first product, a 18F-based PET tracer that specifically binds to a kinase-target, will enter the clinic. Imaging not only allows for mapping the size and location of a tumor, but also to follow-up the effectiveness of therapy. If a drug and tracer competitively bind to the same target, the tracer will be less visible if the drug works. In this respect, Oncodesign has initiated a multi-modality imaging campus in Dijon that combines preclinical and clinical researchers with direct access to a radiochemistry lab and a cyclotron, and all this within 1 square kilometer around our headquarter location”.

Drug discovery in reverse

“Where drug discovery is concerned, we do not limit ourselves to cancer,” says Hoflack.
In the human genome, genes for more than 500 different kinases have been identified. Kinases are enzymes that play an important role in signal transduction and cell regulation. The deregulation of kinases is linked with over 400 different diseases. Kinases are structurally very similar, so it is difficult to block one kinase without touching the others – leaving a major risk for unwanted side effects. “This is where the Nanocyclix technology comes into the picture. These are small macrocyclic molecules that are able to very specifically bind a certain kinase, due to their specific non-flexible 3-dimensional shape. They have very good physico-chemical drug properties and are able to cross the blood-brain barrier,” explains Hoflack. “We have a large and diverse collection of Nanocycles that we profile for activity against the available kinases. If we find a potent and specific match, we track down which disease this kinase might play a role in with extensive literature and patent searches, and then reach out to experts in the field. ”

“For example, we recently discovered a series of potent and specific RIPK2 (Receptor-interacting serine/threonine-protein kinase 2) inhibitors. Deregulation of RIPK2 is involved in Crohn’s disease and other autoimmune disorders. We contacted Prof. Derek Abbott, world expert of RIPK2, to test our Nanocycles in his in vitro and in vivo models, and we were able to rapidly demonstrate a solid proof of concept. We are now looking for a partner to further develop our lead compound,” continues Hoflack.

“Typically, the Pharma drug discovery process is target-based: it starts from the disease and looks for a suitable target, after which the search for a treatment can start. We identify the treatment early on and then find the disease. ”

“We also found Nanocycles that can counteract LRRK2 (Leucine-rich repeat kinase 2). Mutations in the gene that encode for this kinase are linked to Parkinsons. We are developing this program in cooperation with IPSEN. Another example of our internal drug discovery programs is on ALK2 inhibitors. ALK2 is a kinase that is at the origin of Stonemen’s disease (Fibrodysplasia Ossificans Progressiva), a condition that turns muscles and tendons into bone. It is a very rare but dreadful disease.”

Strong partnerships and big deals

“For our oncology discovery programs, we aim to develop our compounds as far as POC in men.  However, for other conditions we look for partners with a strong expertise in the field much earlier,” says Hoflack. “Our major partners are IPSEN, Sanofi and UCB. They typically fund our research and we receive success-based milestone payments. In total, this can yield us up to 350 million euros, and this does not even include royalties.”

Oncodesign’s share value remained stable since the IPO in early 2014, however last June, the share value tripled. “Yes, indeed,” confirms Hoflack, “at the start of 2015, UCB took a full license on a joint project of ours. This represented strong  validation of the Nanocyclix technology and great visibility for the company.” Hoflack concludes: “In a typical biotech company, the managers and founders typically only hold 10% of the shares. Risk capital investors hold the remaining part. This is not the case for Oncodesign, only 23% of the shares were offered during the IPO and the founders and management retain more than 50% of the shares, this self-reliance is really unique.”

Jan Hoflack obtained a PhD in Organic Chemistry at Ghent University in 1987, after which he started as a molecular modeller at Marion Merrell Dow (Strasbourg). He was appointed later as Head of Structural Biology and Molecular Modelling at Novartis (former Sandoz). He continued his career at Astra Zeneca, where he was responsible for setting up a new unit on structural chemistry, and became global head of enabling technologies in chemistry. In 2000, he became vice president of medicinal chemistry and enabling technologies at Janssen Pharmaceutica. Jan joined Oncodesign in 2009.