Mark Krul’s transition into venture capital was not entirely planned. In 2003, while presenting a proposal to use philanthropic capital to set up oncology companies based on Dutch academic research, an investor suggested a crucial structural change: ‘Can’t we create a fund?’. This redirection led Krul to co-found the Aglaia Oncology Funds, a first-time, single-sector, early-stage biotech fund.

Twenty years later, that conviction has been vindicated many times over. Several of the companies he helped to launch became successful with as best example Merus, which was started with just two people and €150,000 in 2005, and was recently acquired by Genmab for eight billion dollar. However, for Krul the financial returns were never the point.

‘’The mission is clear: How can we ensure that we get the best treatment for cancer patients in the fastest way? I’m a hardcore scientist by training, but that’s my general roadmap throughout all of my life. I love science, but I also like to see that science leads to something.’’

Now, as Chief Scientific Officer of Oncode Accelerator, he is tackling drug development’s most intractable problem: staggering inefficiency. Oncology drugs take fifteen to twenty years and up to two billion dollars to reach patients, yet only two per cent ever receive approval. The culprit is a fundamental disconnect: preclinical models are very poor at predicting human outcomes. Half of all cancer drugs fail in early trials due to unexpected toxicity and two-thirds of the remainder lack efficacy.

Coordinating cancer research

Mark Krul’s career began at the National Institute of Public Health’s Molecular Virology department shortly after Human Papillomavirus (HPV) was discovered. ‘’This was in the late 1980s. When I heard it was a cancer-causing virus, I immediately started thinking about therapy. I started a concerted action: an EU grant for coordinating research on HPV and vaccine development. This was also the final theme of my thesis: the immunology of HPV and vaccine development. I realised that coordinating research with an EU grant was more in line with my interests than simply running my own lab.’’

His next stop was Bob Pinedo’s European Cancer Centre in Amsterdam, which proved to be a transformative experience in terms of his understanding of the human dimensions of science. ‘’That was actually about coordinating cancer research and the idea of fully integrating the cancer research activities of The Netherlands Cancer Institute, the Vrije Universiteit Amsterdam and the University of Amsterdam and their respective hospitals.’’

What did you learn during that period?

‘’I realised that, although everyone supposedly has the same goal when it comes to coordinating cancer research, everyone also has their own initiatives, directions and agenda. It’s very difficult to get the people aligned in the same way. One of my main lessons learned over there is what I call ‘ego management’. You need to facilitate people and put them in a position where they can do their job to the best of their ability. Hopefully, you can also show them that collaborating is better than working alone.’’

Mark Krul moved over as a manager at the EORTC New Drug Development Office (NDDO) in Amsterdam, which was also set up by Bob Pinedo. In the mid-1990s, while working with compounds from biotech companies and collaborating with pharmaceutical giants such as Bristol-Myers Squibb to develop Taxol, Krul was confronted with a harsh reality: without quality assurance, brilliant science is just a wasted effort. ‘’At the NDDO, I learned the importance of including all quality measurements. I progressed from running a laboratory to coordinating cancer research and learning how to develop anti-cancer drugs and perform quality assurance.’’

Daring to take risk

By the late 1990s, an exasperating trend had become impossible to overlook. The Netherlands boasted world-class science in oncology and immunology. Dutch researchers could cure all the mice and publish in Nature alongside the best of them. But what then? Nobody was translating their research into clinically applicable products. The cultural barrier was profound. In the Netherlands, commercialisation was almost taboo. ‘’In the Netherlands, it really was like selling your soul to the devil if you were going to develop a drug, or be commercial, or have an involvement with pharma.’’

This conviction led directly to the founding premise of Aglaia: to team up with the best scientists in the Netherlands and remove every barrier between brilliant science and real patient benefit. This also marked the beginning of Krul’s transformation from a scientist to a venture capitalist, as he launched the Aglaia Oncology Funds at a time when the market was extremely negative. The internet bubble had recently collapsed, and investors viewed early-stage biotechnology as riskier than the digital ventures they had recently abandoned. The European Investment Fund politely told him and his co-founder, Karl Rothweiler, to return once they had built up a track record.

What did you learn about entrepreneurship from founding Aglaia?

‘’Family support is extremely important. I had a good job, we had a nice lease car, and everything was going smoothly. Then I got this crazy idea. Then our income disappeared and the car broke down. We had a second and third mortgage. You really get into debt. Throughout all that time, however, my family backed me, saying: ‘If this is your passion and your life, then please go for it’. Indeed, perseverance is key. You need to keep believing in every opportunity. We visited a number of people, of course, and got a lot of rejections. You need a tough skin to keep going. Believe in your story. If you don’t believe in your own story, forget about it.’’

Faced with limited capital and unlimited risk, Krul and his team had to strike a balance between being selective and being bold. ‘’I believe that the initial selection of technology is crucial. Then, make sure you have all the right expertise around you.’’ One of the first investments was Merus, which was sold to Genmab for 8 billion dollars earlier this year. Krul and his team were the sole investors for the first four years, starting with an initial investment of €150,000. ‘’Ton Logtenberg founded Merus. He approached all the traditional investors with his plan. All the investors replied: ’That’s a nice plan, but you haven’t shown us anything yet. Please come back when you have’. There was no data, just a plan on paper. I believe he came to us as a last resort.’’

What made you believe in Ton Logtenberg and Merus?

‘’He had a very successful track record, so it surprised me that other investors didn’t join at such an early stage. Apparently, they didn’t believe in the novel concept he was aiming to develop. But everything looked right on paper, so we decided to go for it. Of course, many of the strategies changed as the company developed. In that sense, Ton is brilliant. He made all the right moves. We helped Merus financially and strategically during the first four years to mature. All the credit goes to the people who did the work. It’s very rewarding to see that you can really start from scratch and built a very successful company with a strong team and by providing the right support.’’

The math of drug development

When Oncode Accelerator approached Mark Krul about joining its mission to optimize and accelerate preclinical drug development, he responded immediately. ‘’Well, I must say this is exactly my goal in life, more or less: How can we develop faster and better drugs?’’ Although he was initially hesitant due to his commitments at Aglaia, discussions led to a creative solution. Krul became CSO for a few days a week. This opportunity was a perfect fit for Krul, who had spent decades frustrated by the inefficiency of drug development. As already mentioned, the numbers are staggering: developing an oncology drug takes 15–20 years and costs one to two billion dollars. Success rate? Less than 5%, with most estimates around 2%.

‘’The development of cancer drugs is a very inefficient process’’, Krul tells. ‘’From scratch, it takes five to seven years to develop a compound that’s ready for the first patients, in clinical trials. You have cured all the mice and shown that it is safe in animal models. You move on to human trials, but half of the drugs fail very early on because they appear to be too toxic. Half of the work is done for nothing. If we can make better predictions in the preclinical stage, such as how toxic and efficient the product will be, that will make a major difference. That’s exactly what Oncode Accelerator is all about: How can we ensure that the data we generate in preclinical research translates better to patients?’’

The way Oncode Accelerator helps

Oncode Accelerator now encompasses three innovation platforms designed to bridge the gap between preclinical and clinical research and speed up drug development. The first of the three platforms focuses on the use of organoids and Organ-on-a-Chip technologies. ‘’Hans Clevers is one of the founders of organoid technology, which involves creating tiny tissues from human cells. This can be done using cancer or healthy cells to respectively create mini-tumours, mini-organs or healthy tissue. These organoid technologies can be used to better predict whether your compound can specifically kill human tumours. This is one of the innovations that we are focusing on particularly closely. This technology is developing very quickly, and will definitely lead to better predictions. This has already been partially achieved, and the FDA has said that they can consider it for toxicity testing. We can already limit the use of animals in a number of studies because we now have better technologies available.’’

The second platform involves the development and use of artificial intelligence (AI). The contrast with approaches in the 1990s is stark. ‘’Nowadays, AI has enabled, for example, the development of tools like AlphaFold, an AI system that predicts proteins’ 3D structures from their amino acid sequence. Using AlphaFold and other AI-enabled tools, scientists can now say: ‘I would like to create a drug that targets one specific protein, which is overexpressed in cancer’. You can then design molecules on a computer that should fit and bind to that specific protein. AI can also help make compound screening more efficient, so rather than starting with two million compounds, you start with hundreds of potential products that you pre-selected in silico. This saves you a lot of time and money, and gives you more predictive power early on.’’

The third platform is based on patient cohorts. ‘’For instance, over 25,000 colorectal cancer patients have consented to participate in the Dutch Prospective National Colorectal Cancer Cohort, which is co-supported by Oncode Accelerator. We have data on these patients before and after treatment, as well as blood and genetic samples. This enables us to determine which patients responded to which therapy and which biomarkers could be used to predict responses. This information is extremely valuable, especially in combination with AI, and can allow us to shorten clinical trials by many years. In the past, a Phase 3 trial was always required. This involved treating a thousand patients with the new treatment and a thousand with the old treatment, both of which were administered blindly. Nowadays, however, we can use a synthetic control arm. For every patient receiving the new treatment, we search the database for an exact match: same age, same tumour characteristics, and so on. This means that you don’t have to treat another thousand patients with the old treatment and hence also significantly reduce time and cost.’’

Building an ecosystem

Oncode Accelerator’s physical co-location in the building in Utrecht is no coincidence. They share the building with several programs funded by the Dutch government’s National Growth Fund, such as Biotech Booster, RegMed XB in addition to Oncode Institute. ‘’We are not on the same floor of this building by accident. We have close interactions with Biotech Booster. They are setting up new companies and we are developing cancer drugs. We expect to see a number of companies in our fields working with both of us. The same applies to Oncode Institute, which funds many talented researchers who could benefit from our infrastructure.’’

‘’Deep in my heart, I would like to establish Oncode Accelerator, and our partners, as a long-term ecosystem’’, Mark Krul continues ‘’Even after the National Growth Fund is closed, I would like to see that we can continue with the Dutch ecosystem. We have some good examples in other countries, like Cancer Research Horizons in the UK, who are working in that way already for many decades. In Belgium, we have the VIB. With all the power we have generated now, and the network we are creating, we should be able to also establish such a system for the longer run in the Netherlands as well.’’

How can researchers and companies collaborate with Oncode Accelerator?

‘’At Oncode Accelerator, we have chosen the three innovation platforms I mentioned. We have also set up networks of experts and facilities focused on specific types of cancer therapies, known as workstreams. For example, there are a lot of experts from all over the Netherlands joining efforts on how we can develop therapeutic vaccines, together with Oncode Accelerator. We have similar workstreams for biologics, cell and gene therapy, and small molecules. We are now open to any investigator or biotech or pharma company in the world who wants to work with us. Those involved in preclinical drug development can apply for a Demonstrator Project with Oncode Accelerator to use these expert networks and our innovations.’’

What are the benefits for those who join Oncode Accelerator?

‘’It’s very attractive because they gain access to a lot of expertise and facilities. For us, it’s attractive because we want to demonstrate that our organoid models are more predictive than other models, that AI can accelerate drug development pipelines, and using data from well-defined patient cohorts can lead to development of better drugs. To achieve this, we need to work on a lot of drug development projects. We’ve created an attractive system to encourage people to join us. We can even match investments. For example, if a project costs two million, we can contribute one million.’’

What’s the structure of this investment?

‘’It’s neither a loan nor a grant. It’s a way of reducing risk for a company. If you are a start-up company, you can validate and develop your compound together with us. If it turns out well, you will essentially need to repay our contribution, but you will have the data and reach your next value inflection point, as it’s called in the world of venture capital. This means you can raise more money because you have better data. If it fails, Oncode Accelerator loses its money and there’s no repayment. It’s a way of reducing risk and gaining access to facilities and technologies.’’

When asked to define success, Mark Krul highlights a few key points. ‘’We have already achieved a great deal with the launch of Oncode Accelerator, the establishment of these expert networks and collaborations, and the development of these innovations. We are a knowledge economy. If we can establish Oncode Accelerator to be a leading player and thriving ecosystem, pharmaceutical companies will come here. We also expect many companies to be inspired by our initiative.’’

As Oncode Accelerator continues to build this ecosystem, you are invited to stay connected with the latest developments. Follow Oncode Accelerator on LinkedIn to stay updated on the progress from innovation to impact.

Mark Krul has a strong track record in anticancer drug development with over 30 years of experience in the field of oncology, and a background in molecular biology and immunology. Currently, he is the Director of Oncode Impact Foundation. Earlier he was the Chief Scientific Officer of the Oncode Accelerator Foundation. Oncode Accelerator is a public-private partnership partially funded by the Dutch National Growth Fund (350 million euros), which aims to innovate and accelerate the preclinical development of new cancer therapies by placing cancer patients at the core. Furthermore, Mark is founder and Director of Aglaia Oncology funds, co-founder of several biotech companies, and an active board member in several of Aglaia’s portfolio companies.

In his early career, Mark was Program Director of the NDDO Research Foundation. He held several positions with NDDO Oncology BV (formerly the EORTC New Drug Development Office) with respect to oncology drug development strategies. Mark was Research Manager of the European Cancer Center and prior to his oncology days, he headed the Department of Molecular Virology at the National Institute of Public Health and Environmental Protection in the Netherlands.

This article is part of a partnership between BiotechNews and BioPitch. See here for the original article on BioPitch.