Drug developers have long pursued the elusive goal of safely increasing energy expenditure to treat metabolic conditions and obesity. Leiden-based Cantoni Therapeutics is hoping to achieve this goal with its novel small molecule inhibitors of nicotinamide N-methyltransferase (NNMT), which have the potential to treat obesity and improve metabolism without loss of muscle mass.
The promise of the technology and pathway is something that attracted Annegret Van der Aa, PhD, to take up the role of CEO and executive director of the company last year. With a long history of research and drug development at companies like Galapagos, where she helped bring the successful drug Jyseleca (filgotinib) to market for the treatment of rheumatoid arthritis and later, inflammatory bowel disease, Van der Aa is now diving into the ever more crowded obesity space with her colleagues at Cantoni.
Although she enjoyed her time at Galapagos, where she worked for a number of years, Van der Aa decided that she wanted to return to a startup atmosphere. Over the last seven years, she worked as chief operating officer at Octimet Oncology and chief scientific officer at Ermium Therapeutics before taking on her current role. She talked to Inside Precision Medicine senior editor Helen Albert about her motivations, her career, and what she hopes to achieve at Cantoni.
Q: What first inspired you to get into science?
Annegret Van der Aa: That goes quite a long way back. My father always was very involved with nature, and I think that also sparked my interest in biology. I was the one that was always doing small experiments with plants in my bedroom when I was a child.
Later on, my interest had more of a focus on human beings and medicine. When I had to choose what to study at university, there was quite some doubt [about] whether I would choose medicine or whether I would study some aspect of biology. At the university where I went, there was a new degree called biomedical sciences and that was, for me, the best of both worlds. Now it’s quite a popular degree, but at the time it was still novel, at least where I lived in Belgium.
When I started with those studies, it became clear I didn’t really want to treat patients, but I wanted to contribute, and I wanted to do something with science. And I think that combination for me was really nice. After doing my Masters, it was quite obvious that I didn’t want to stop there. I wanted to dig a bit deeper, and that’s why I did my PhD. After that, it was also immediately clear that I didn’t want to stay in academia.
Q: Why did you decide to go into industry?
Van der Aa: I know academia has evolved somewhat in the past few decades. But at that moment in time, it was still very solitary work, digging very deep into something and not really cooperating with other academic groups, and that was not the way that I wanted to work. I like working together with people, learning from each other, doing things together. That is why I immediately decided, after my PhD, to go into industry.
It was different there. There is indeed competition, you cannot disclose everything. But at least there, I found a much broader interaction with different people. Also, I think for me it was important to not just do basic research. I wanted to do something that could contribute to society, to patients, to help them. I was able to do that already during my PhD, because I worked on, at that time, a T-cell therapy for multiple sclerosis. That was quite close to patients but in an academic setting.
I liked that, and that is what I was looking for when I started in industry. That worked out very nicely after a few years in the first company I worked at. We were able to analyze some of the samples that came from clinical trials. There I could already be closer to what impact the therapy could have on patients. Then, after moving to the second company, I was a project lead of products that we brought from bench to bedside.
Q: I believe the next company you worked at was Galapagos, where you helped develop filgotinib. What was that experience like?
Van der Aa: When I started at Galapagos, I was hired there to bring their first asset ever to a Phase II study in rheumatoid arthritis patients—that was not filgotinib, that was another compound. So I set up the trial there, we did an interim analysis, and the compound failed, so the program was stopped.
At that moment, filgotinib was still in development with GSK (GlaxoSmithKline). GSK actually declined the compound and gave it back to Galapagos. Because I had set up that initial Phase II study with that first compound, they asked me to take on [the filgotinib] program because I was winding down the first one still, and the rest is history.
It was quite a big part of my time at Galapagos. We did a first study in patients in Moldova. I went there several times over a short period and got to know them. The rheumatologist there had a lot of patients available, so the study was run very quickly. One evening, she called me because we had a quite a close relationship, and she told me a story of a young lady that she knew with rheumatoid arthritis that was participating in the study. After a few weeks, [the patient] came back for a visit to the hospital. The lady told the principal investigator that finally, after several years struggling with disease, she was able to play the piano again, which was her passion. So just by taking that pill, she was able to return to doing what she liked. For me, that is one of the nicest moments that I recall, because you don’t get feedback very often from clinical trial investigators.
I worked on that compound, I think, for about five years in the clinic, and then some more years when we had Gilead as a partner, so for the Phase III programs and then all the other indications that we did together with them. It’s not always like that, let’s be clear! I also had a lot of compounds that failed, but filgotinib was quite special.
Q: Why did you decide to move on from Galapagos?
Van der Aa: Besides being the clinical lead for filgotinib, I also was the head of clinical operations. It took a lot of energy to build that group. We had, I think, over ten compounds that we brought from research to first-in-man studies. The program became quite big and complex, but being able to do that and putting Galapagos on the map for rheumatoid arthritis, I think that really was one of the biggest achievements that we did as a team. We also positioned the compound for Crohn’s disease.
When I left, the development department was around 500 people I think, it was huge. It’s exactly why I left, because for me, it was not the same company anymore. The culture changed. For me, it felt so far away from that early start period. An advantage of being small is that you can move fast, you don’t have a lot of structures and processes to go through. Ultimately, you need that if you go bigger, but it also changes the culture. I realized how much I like a startup environment, an environment where you can build not only a program, but also people around you and really have that impact on what you are doing. That’s the reason, when I got asked by a friend of mine to join a startup company, I found that I didn’t think too long about it!
Q: What attracted you to taking on the CEO position at Cantoni Therapeutics?
Van der Aa: I was not looking for a position of CEO. In fact, I turned down several offers from headhunters in the months before. Then I met somebody I knew at an event. He told me about a startup in the Netherlands. He said, “It’s very exciting and they are looking for a CEO.” I said I wasn’t looking for that, but he said, “Yes, but you should just go and talk to them.” I went there and when they showed me the data and I met the two founders, I was really impressed with what those two guys did at university.
I took up that position, and I’m still learning every day about some of the things I’m less experienced in. But in a year, we collected a whole team of senior experts I worked with in the past that are now consultants helping us. What we did in a year with a limited budget, I think it’s really amazing. I think we really are onto something. It’s a nice target. The compounds that Matthijs and Nathaniel, the two founders, have generated in their lab at the university in Leiden are extremely potent and nicely selective.
We also did a whole characterization of the compounds and have good proof of concept in vivo. We have nominated the candidate for development and are now starting the big work. It’s all going well, but now we are going for that next big step, and we need to get a big fundraise in to prepare for the clinic.
Q: What exactly are you trying to achieve at Cantoni?
Van der Aa: We know that the target we are after is a metabolic enzyme and it plays a role in several diseases. We decided at the end of last year to focus on a lead indication of obesity and its comorbidities, not because it’s a fancy, hot topic. The reason we decided to go for obesity is because we believe that with the package of data that we have, this target is important. It’s important not only for weight loss, which is intrinsically linked to obesity, but even more, to treat the comorbidities of obesity.
Our compounds do induce weight loss, but they do much more. They have a positive impact on diabetic parameters and lipids, which is linked to cardiovascular risk. We also see other beneficial effects.
The way that our compounds work is completely different to how a GLP-1 (glucagon-like peptide-1) agonist functions. What you typically see with the GLP-1 agonist is that they are reducing your food intake. If you eat less, you will lose weight. That is typically the way those compounds work. With our NNMT inhibitors, we have shown that in the obese mice, a typical model of obesity, these mice do not eat less. They keep on eating their high fat diet, as they did before treatment. But still, they are losing weight, and they are improving their metabolic health.
The way that that this is happening is by decreasing the activity of the enzyme called NNMT and thereby, stimulating their energy metabolism. It triggers them to burn that energy, rather than to store it. We know that in prehistoric times, this enzyme was critical for hunters because they didn’t have meals three times a day like we have today. By increasing NNMT levels when there was food available, they made sure that all the energy from the food was stored as fat. Today, we eat at least three times a day and NNMT still goes up, but it’s not useful anymore to keep on storing that energy because we just have too much. That is now driving us towards cardiometabolic diseases, including obesity.
We see potential for our candidate as a monotherapy, where you use it to boost your energy metabolism. Or we also see it as a potential combination treatment with GLP-1 agonists, where you actually try to improve your metabolic health from both angles—by taking less food in and combining that with better processing of foods and higher energy metabolism.
Q: I believe you don’t lower muscle mass with your approach, which I know is a problem with the GLP-1 receptor agonists. Have you seen any adverse events to date?
Van der Aa: That’s correct and is another big advantage. This is especially true in sarcopenic patients, because typically you don’t want to treat them with compounds that are also impacting their lean muscle mass.
We need to prove it, but we think [that] because we don’t have a centrally acting mechanism, we would not have a big gastrointestinal effect, which can be a problem with GLP-1 agonists. Obviously, this is something to be proven, because your animals don’t tell you that they are not feeling very well when taking medication. But theoretically, that could also be a differentiator for us.
One of the things we are focusing on as part of a possible combination approach is using lower doses of a GLP-1 agonist, because the GI (gastrointestinal) effects we know are dose-dependent. If you took a lower dose of GLP-1 agonist and an NNMT inhibitor, you would still be able to have beneficial effects on your body weight, on your diabetic parameters, on your lipids, but you would not have an impact on your lean mass, and you would also have the least gastrointestinal effects as well.
At this stage, we haven’t seen any significant safety signals with the NNMT inhibitors in rodents, but we have yet to test them in humans.
Q: How is fundraising for Cantoni going so far?
Van der Aa: Everything is dependent on the fundraising at this moment in time. We did a small financing round over the summer to bridge towards a bigger Series A next year. If that is successful then we should be able to get into the clinic about a year later, in 2027.
I think so far, we have been lucky because we worked very hard on it. We have been able to secure additional financing, both through grants and an angel that invested in Cantoni. We have another VC (venture capitalist) that came in over the summer. So I think there is quite some appetite, from VCs but even more from pharma.
At this moment in time, we are in conversation with nearly all the big players that have a franchise in obesity. Each of them is looking for candidates with novel modes of action to combine with their incretins. They are all looking for it, and I think it’s mainly a matter of finding a partner that wants to get involved at the right time for us.
It’s good to learn from that, and to hear what they want. If we can keep on delivering as we did over the past one and a half years, I think there will be a time [when] all the pieces come together. I’m a strong believer that we will find the right partners to progress.
I think we are not doing too badly, but obviously now we have moved into development activities we come into another area when it comes to budgets that you need. That is really where the bigger money comes in. Therefore, we need to secure that Series A and find the right partners.
Q: This is the first time you’ve been the CEO of a company. What have your learning experiences been so far?
Van der Aa: I’ve always been somebody who likes to have an impact and who likes to build things, but really from an R&D (research and development) perspective. I always thought being a CEO was not for me. I’m not a seller. I’m very scientifically driven and I always want things to be solid. But in the end, and that’s what I learned as well, if you just try to sell something that isn’t true, people will find out and then you lose your credibility. In the end, doing it with a scientific backing is not a bad thing.
I like being a CEO so far, but it’s tough. It’s not easy. I think it’s good that there is now a kind of an atmosphere [in which] you can say that. For example, on some days, if things are not going well or I don’t feel well, I think the time is over that you always have to be strong. I think you can show that vulnerability now.
For me, it helps having a network of people that are close to me that I know, that I can call for advice or just to reflect on things. I’m very happy with my board today. They are really supportive. I told them before I started that I am not a CEO that has done this 10 times. I’m very comfortable with the R&D part, but I told them upfront that I would need their support with the whole corporate thing and that is exactly what they are doing.
They are using their networks to introduce me to VCs. They try to get me talking to people and that helps. It helps if you have people who know people, then you get into systems and networks and that’s what you need.
It’s not easy every day. But I think overall, what we did in 15 months with so little resources—I think it’s quite remarkable that we have been able to get there and I’m proud of that already. Now getting to that next step would be, again, a big thing to do.
Q: What do you personally bring to the role?
Van der Aa: The advantage for me, I think, is that I’ve been in this biotech scene now for 25 years. I’ve seen a lot. I know where the hurdles are. I know that failure is normal. I know how to approach a development plan and I know where I need to look for money.
I think it helps to be a bit more experienced in biotech as a whole. That’s also where I see my contribution to Cantoni. Our founders are extremely smart guys. They know everything about the compounds, they know the target, and they worked on it for 10 years, but they have never done drug development.
They are really willing to get those compounds into the patients. They are really willing to learn and they want to take those molecules to the clinic. That for me made the difference and it made me want to help them. I don’t regret that I took the decision. It was probably the right company at the right time to do it.
Q: Do you have any advice for somebody thinking about taking their first CEO position?
Van der Aa: Talk to a lot of people and make sure that you are surrounded by a good network, so that you have people to go to with problems and you don’t struggle with things for too long.
Try to give something back as well. I will always try to help anyone who asks me something. I see if there is something I can do or somebody I know that can do something to help. Then if you have a question yourself, it helps, because these things go back and forth.
Not everyone has that attitude, but that’s what I see from people in my network. We are all the same type of people when it comes to stepping up for each other or helping each other. And for me, that’s how it should be.
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Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.
