Dario Neri: Co-Founder and CEO of Philogen

Dario Neri, co-founder and CEO of Philogen, shares his thoughts with BioBoss host John Simboli about leadership in biopharma and how Philogen is working to discover and develop targeted therapies to treat cancer and chronic inflammation.

Transcript

John Simboli: 0:00

Today I'm speaking with Dario Nari, co founder Chief Science Officer and CEO of Philogen, headquartered in Siena. Welcome to BioBoss. Dario,

Dario Neri: 0:11

thanks for the opportunity to discuss with you.

John Simboli: 0:14

Dario, what led you to your role as co founder, CFO and CEO at Philogen?.

Dario Neri: 0:20

This came only very late because I've actually been a professor all my life, at least for the last 27 years. I've spent my life doing biomedical research as Professor at the Swiss Federal Institute of Technology in Zurich. But 27 years ago, I made an important discovery, at least I think it's important. And together with my brothers, we decided to start a company, which is Philogen, which over time actually grew. And basically two, three years ago, we decided to list the company on the stock exchange, because we were in phase three clinical trials with products which were and are promising. And so at that stage, my passion for Philogen was so big that I decided to close my lab in Zurich, and move full time to the company. So actually, my history with the company is the history of 27 years. But my history as CEO and Chief Scientific Officer is only very recent

John Simboli: 1:26

How did you go about making that decision? Was it a difficult decision to shift over?

Dario Neri: 1:33

It was a difficult decision, because I really love my alma mater, my institution. I did my Ph.D. there. I was then in Cambridge, almost five years. And, as mentioned, I'm still a professor at the Swiss Federal Institute of Technology. I teach there. But at the same time, it was an easy decision, because I'm really passionate for drug development. That's what I've done all my life. And at some stage, if you're serious about it, you need an industrial dimension to execute your pivotal trials, and to hopefully show that we have drugs that can help patients and meet the endpoints in the trial. So it was difficult and easy, at the same time.

John Simboli: 2:19

Can you recall what your image of being a leader in an industrial organization was like prior to actually doing it, and then what your experience was, once you got into it?

Dario Neri: 2:30

My experience is very similar. I've led a group of about 30-35 persons at academia. And I was already associated with the company. So I've seen it growing from one employee to now 165 employees. And the leadership structure is similar. We try to maintain as much as we can, a biotech and also academic environment within the company. We are curiosity-driven, we publish a lot, but at the same time, we try to be diligent with goals, with timelines. And to be honest, there is not much of a difference. We strive for excellence in both environments. And with the listed company, we have maybe a couple of more duties to comply with, but it's not a completely different life.

John Simboli: 3:28

As Chief Science Officer, sometimes that's a position in which you are part of a team that chooses, that helps to choose the CEO that's going to run it. Sometimes the CSO becomes the CEO; sometimes one has dual roles as you do. Can you tell me anything about the decision, for you, was it straightforward? Was there something to weigh there whether for you to be the CEO or for you to hire a CEO?

Dario Neri: 3:53

Actually not. I tell you a little bit about the structure in our company, because as mentioned, the company was started by myself and my two brothers, and we have complementary skills. And we have really been around the company for all the past 27 years. So at this moment in time, I am the CEO, but one of my brothers, Duccio, is executive chairman. And we actually split executive roles based on our knowledge. And so you could actually say that the company has a dual CEO structure where Duccio takes care of certain duties, and I take care of other duties. And we have tried to have a structure where we do what we are competent at. And so my life may be a little bit easier because some of the executive roles are with my brother,

John Simboli: 4:48

What we're hoping to achieve that could be done at Philogen and not at another company?

Dario Neri: 4:53

For many, many years, by now, I've been really passionate in one particular scientific approach, which we call targeting, but you could call it targeted delivery. So, really, taking drugs which are already good and active, making them better because you deliver them to the site of disease, and you gain in therapeutic index. So, in principle, these drugs can be delivered, and can be developed in other companies. And sometimes we do in partnership with large pharmaceutical companies. But there is a special pleasure in doing it within your own company, often with collaborators with whom I've worked for the last 20 plus years. So things can be done in many different ways. But especially when many of my former Ph.D. students have decided to stay and actually joined the company, then it becomes even more of a team effort. And you have the feeling that this is like the last chapter of something that started, actually, a long time ago and soon will be judged the by the clinical results.

John Simboli: 6:10

So it sounds like you probably did not actively consider taking your particular interest and and bringing it to a larger pharma company and trying to bring that in house as an aspect of that company. That probably didn't come into your plans. right?

Dario Neri: 6:27

We have some programs, which are partnered with pharmaceutical companies, and that's absolutely fine. A company of our dimension cannot do everything. So there are things that you do best in partnership. But there are some programs which have now reached phase three clinical trials, and we were very passionate about them for a long time. And at some stage, you're really curious to see the trials complete; that you want them run and designed the way you You were always hoping for. And so it came naturally. Of course, it takes money to run these programs. So the IPO was an important step. At the same time, we're quite efficient and also diligent in the use of money. And so at least we have the chance to follow our dreams,

John Simboli: 7:18

There is a special kind of quality of someone who is so in love, with connected to an idea. that they just have to see it through. Because I'm sure when you get to the stage three clinical trials, the expense of that is significant. That's probably not an easily made decision.

Dario Neri: 7:38

Yes, at the same time, first of all, you know, I've been greatly privileged to have really fantastic teachers. I did my Ph.D. with Kurt Wüthrich, who later won the Nobel Prize for Chemistry. I was then Postdoctoral Fellow with Sir Gregory winter, who also won the Nobel Prize for Chemistry and was, and is, a successful entrepreneur. So to a certain extent, I've seen it done before by very good people. And then when it comes to the cost and the execution of clinical trials, yes, it's significant. But it's still manageable in testing cancer, because clinical trials in cancer may have 100-200 patients. If you think that your drug is very active, you don't have to run clinical trials, as in other indications where you may need, I don't know, 15,000 patients. So it's still a dimension that can be managed, and where actually the molecules make the difference. So it is a challenge. It helps to have a well-capitalized company. But science drives everything. And so it's still managed, but there are, I'm sure, areas and indications which are much more challenging, but I have the feeling that the types of questions we are asking are feasible and doable.

John Simboli: 9:04

Can you recall at this point, can you recall a moment or a time when you were going from a general interest in science to a particular thing that really fired your imagination?

Dario Neri: 9:16

Yes, actually, I would like to mention two events, if possible. Actually, my family has a history in pharmaceutical science. My great-grandfather was the first man to treat patients with the anthrax antiserum. So in 1899, it treated anthrax patients with serum, antiserum, so with antibodies. If you want, something very similar to what we are still doing. And since I was a kid, my father was running a pharmaceutical company, which is now part of GSK Vaccine, but I've seen it from the very beginning. So the first event is actually remembering what my father used to do with the company, the people he brought home. At some stage, the company became Chiron vaccine, then Novartis and then GSK. But actually, I've seen it as a kid. And the second event, and this is more specific, I was at the end of my Ph.D. in Zurich, with Kurt Wüthrich. And actually my next mentor, Sir Gregory Winter, actually came to Zurich to give a lecture. And he presented the first case of a patient treated with a humanized antibody. You know, Sir Gregory invented antibody humanization and he won the Nobel Prize for it. And that was actually the first patient, a patient with a non-Hodgkins lymphoma, with a spleen of five kilograms, who was treated with a humanized antibody. And then you could see this huge spleen, the size of a football, shrinking to normal size in a matter of one month. And that was, for me, a very important moment, because at that time, I was solving protein structures. I was probably fascinated by drug discovery but I was not very specific. The moment you see a molecule that can turn a huge spleen into a normal organ, with exquisite specificity, then I thought, O.K. , this is what I want to do for the next 30 plus years of my life. And so this is a moment that I vividly remember,

John Simboli: 11:30

W.hat do you recall about being eight or nine or 10, as far as what your idea of what you might want to be when you got to be grown up? Do you recall that?

Dario Neri: 11:37

Yes. And honestly, I didn't have plans. I don't know whether to be proud of or ashamed of, but actually, my dad actually decided for all the three songs. So he decided I would be a chemist like him, my brother would study business, which he did. And the third one has a Ph.D. in biotechnology and takes care of IP. So I don't know whether this is lack of leadership, or whether this is just following the advice of a good father, but he had planned it for us. And we actually followed his advice. Maybe it's very Italian. I don't know. But that's the way it went.

John Simboli: 12:17

If you look back over the last week, say, and pick a day, how much of that day is storytelling to investors? How much of it is communicating with the team about science? How much of it is dealing with exigencies of production of a pilot plant? How does it all fit?

Dario Neri: 12:35

We spend a lot of time on executing our industrial Does it tend to be shoulde-to-shoulder, plan. Maybe we don't spend enough time in communication, but we spend a lot of time in science and development. So most of my hours are devoted either to the discovery part, or to the execution part. And that certainly addresses over 80-90% person-to-person? Does it tend to be remote? of my time. No, it's often remote, also, because we have two locations, we have chosen to have Zurich in Switzerland as our discovery site. We do discovery entirely in Switzerland. In Italy, we do GMP manufacturing. And we run clinical trials globally, s o in the US, and in 13, European countries. So I would say 50-50, 50%, really, in the same room, and 50% via Zoom communication. With these two locations, I commute a lot. I spent maybe two thirds of my time in Italy and 1/3 of my time in Switzerland. And if there is one good thing that COVID brought, you know, alongside the many bad things of COVID was that I think we have learned to work more efficiently remotely. We ran actually our IPO completely remotely, so we didn't have to travel, we could communicate. And I think we all learn how to become more efficient with these tools.

John Simboli: 14:09

When someone says who is Philogen, what's the simplest, most basic answer that you'd like to give?

Dario Neri: 14:15

It's a company that innovates targeting. And to be more specific, it's a company, which I think is good at taking medications and making them even better, because we deliver them to the site of disease. We take this delivery very seriously. We image patients, so we really make sure that the drugs reach the site of disease. And believe it or not, very, very often, drugs go everywhere in our body, except where they're supposed to be. And doing this job right, actually can be a very good exercise.

John Simboli: 14:53

What is it that distinguishes Philogen and makes it a different way of approaching that problem?

Dario Neri: 14:59

This strategy is an old strategy. Paul Ehrlich spoke about zuberkugel, magic bullets, these molecules that would find their way to the disease. I think one of our strengths, we have always been very rigorous in using nuclear medicine techniques, and also bio-distributions in animal models. Because it's easy to claim, yes, my molecule goes to the site of disease, but to actually show it, it takes a lot of diligence. And we have started really hundreds and hundreds of patients using radiolabeled preparations of our drugs, really checking that we achieved in patients the selectivity that we claim. So we are not the only one, not the only company that does it. But one of the very few companies that do it that actually go and actually quantify the selectivity. And we build on the selectivity. So if there is one distinguishing factor, I think, is that when we say we target disease, we actually show this with nuclear medicine imaging techniques, I think I've seen and you have seen it often enough in science that we often give for granted things that are not grounded. And I think a lot of persons give, for example, targeting for granted—that it's easy to you know, make a molecule maybe couple something to an antibody, and it will go to the tumor or to a site of arthritis. I think this is something which many scientists even do not appreciate how difficult it is to do it, and to do it with the selectivity that you need. So if there is one aspect that often is probably not addressed with the rigor that it deserves, is to really measure this and to really try to optimize your molecule so that you offer to the patients the best you can. Because you hear about targeted drug, and you hear about selectivity and specificity all the time. But one thing is claiming something, one thing is to prove it experimentally,

John Simboli: 17:11

Do people sometimes think that you're developing an idea that's not necessarily part of developing a therapy? Sounds to me, like you're most definitely involved in the research that you hope will lead to a therapy. Do people understand that?

Dario Neri: 17:28

I think, yes, when we can show images. So if you really go through the process, and you say, Look, this is how we develop the molecule. This is how it works in animal models, and you show pictures. This is how this targeting works in patients. And these are the clinical results. If you can guide people through the process, it's actually much easier because you're showing pictures, you're not showing graphs or strange chemical symbols, you are showing something that intuitively, we are very familiar with—the concept of targeting, of selectivity, becomes very visual, the moment you give imaging data.

John Simboli: 18:09

Did your background lead you to see the advantage of imaging right from the beginning? Or is that something that you discovered along the way?

Dario Neri: 18:17

It took me some time. I have done many things in my life, I've started as a synthetic organic chemists, so I was doing synthesis. I then thought, O.K., you need to know about proteins, because a drug is something that binds to a protein. So I've spent almost five years solving protein structures. And then I started using proteins as therapeutics, antibodies, before going back to small organic molecules. And actually, there were two moments where, really, imaging became very important in my life. The first was that I was in Cambridge, and we were the first, together with Sir Gregory Winter, we were the first to actually have molecules, antibodies in that case, that selectively recognized tumored blood vessels, but not not normal blood vessels. So we had antibodies that could really home to the tumoral vasculature and spare the rest of the body. So once you have it, you want to show it. And so that was the first moment that we said, O.K.,, we need to image it, we need to show it microscopically and macroscopically. So that was a need. And then also, again, I go back to my family, my uncle was Professor of nuclear medicine in Rome. And actually he always insisted on the importance of nuclear medicine and it took me some time but at some stage, I actually realized it was true because that's the way to show non-invasively where your molecule really goes where it's supposed to go. Of course, radioactivity needs infrastructure because you don't do it in the kitchen of your home. So you need specialized facilities, but actually it pays off because the information you get is invaluable.

John Simboli: 20:09

So let's talk about partnership. Earlier in our conversation, when I was asking about have you considered taking your idea to a large pharma company and trying to build from within? And you'd said, No, but there certainly is a place for partnerships. What makes a good partner to Philogen?

Dario Neri: 20:29

We collaborate with many companies. And if I can name three attributes that we value very much, the first one is being very honest and direct about the results. So data first. The second one is this desire, the sense of urgency to get the job done. And the third one, if I may say that the goal may be even more important than the procedure, and it's important to be correct from a procedure perspective, but this passion for achieving a goal, which may be success, it may be actually showing that the molecule doesn't work. But actually this passion of getting an answer, a clear answer, a yes or no answer, is very important.

John Simboli: 21:23

And I'm guessing that those qualities are also ones you look for when you're hiring. It sounds like you have a considerable number of people at Philogen. How do you filter to make sure that you're getting the people who fit for you?

Dario Neri: 21:38

Obviously, it's the most difficult part of any job. But I was lucky because I've trained 85 Ph.D. students in my career. And now at Philogen, actually, we are continuing; we have industrial Ph.D programs. Recently Chem, one of the leading journals in chemistry, actually dedicated and editorial to our industrial Ph.D. programs as a possible way to go. So what we have tried to do is to actually recreate within the industrial environment, Ph.D. programs, so that actually people can work three, four years full time on a project. And very often they are the ones who then transition to leadership roles because they want to see their molecules moving through the development path. So I believe very, very much in this process of training, getting people when they are young, and actually letting people who are successful at what they do grow within the company.

John Simboli: 22:42

Is that unusual?

Dario Neri: 22:43

I think it is. I've heard from one of my colleagues in a very large pharmaceutical company, and he was also a professor at a very famous university and late in his career, transitioned to industry. He told me that actually what he was missing most in the new environment was not working with Ph.D. students. They had great postdocs, great scientists, but this contact with the very young, talented students is often missing in industry. We have tried to do it as much as possible to really have the discovery start with young people and Ph.D. students. I'm very proud of it. I think it's actually a very good model. And you need also institutions to work along, of course, because you don't issue degrees so you need partner universities who see it the same way.

John Simboli: 23:38

How does the pipeline express your vision for the company?

Dario Neri: 23:41

The pipeline is the company. So we develop targeted drugs in oncology and beyond. So if I start with oncology, we have two branches of the pipeline. In some cases, we use antibodies to deliver protein payloads, especially cytokine payloads. So it's a simple concept. We have cytokines which are proteins which modulate the activity of the immune system and we deliver them to the site of disease. And we have part of the pipeline where the payloads are small molecules, maybe a drug, maybe a radionuclide and then we use small organic ligands to deliver them to the site of disease. So let's start with the most advanced products. We have one product called NidlegyTM which is a dermato-oncology drug. And basically we deliver two cytokines, interleukin 2 and tumor necrosis factor to the tumor. So it's quite intuitive—if you bring these strong pro-inflammatory cytokines to the tumor, you should be doing something good. Now, dermato- oncology, to us, means that we started with stage three melanoma. This means there Is metastatic disease in the skin and in lymph nodes but has not yet spread to visceral organs. So you want to stop the disease there, you don't want the patient becomes a stage four disease, which in spite of progress is still difficult to cure. And when we have published that actually these melanomas go away, then we thought, O.K.,, let's start treating other types of skin conditions. For example, high risk basal cell carcinomas that often are disfiguring the face. They can be very, very nasty.And we have really been surprised, pleasantly, to see that the same approach that worked in melanoma seems to be very efficient also, in in non-melanoma skin cancer. So, for this particular product the vision was take payloads, interleukin 2 and TNF that were already products on the market, make them more selective, and try to achieve the benefit in their dermato- oncology. A second program, which is also in phase three clinical trials is Fibromun. In that case, we deliver only tumor necrosis factor, as the name says it's a cytokine, which has the potential to kill tumors. And we have focused in two main indications. One is soft tissue sarcoma, and the other one is glioblastoma. So why these indications? Because we were able to cure mice, with really aggressive tumors that could not be cured with any alternative medications. We were curing 100% of the mice. And so of course, the natural transition was to the clinic, hopefully, providing a benefit in these two indications, which are really very nasty—soft tissue sarcoma and glioblastoma multi format are tough indications were really nothing has worked so far. And we have communicated promising results in the clinic. And so you'll see two most advanced products at phase three clinical trials stage, and you'll see our desire to actually complete the trials and then every trial is a binary event—can be yes, or can be no, but we work with passion. Then when I look at the younger part of the pipeline, we try to do the same with small molecules. And we have been, I think, successful at targeting different types of tumors with small organic molecules. For example, ligands of a protein called FAP, fibroblast activation protein. You see that these ligands actually, selectively image many, many different types of tumors. And it's always the same desire to translate selective targeting into selective therapy.

John Simboli: 28:00

When you describe that, do people ask you the question are you a platform company? Is that a question that you'd have to face and try to answer?

Dario Neri: 28:12

Yes, in the sense, we use platforms to discover our

John Simboli: 28:14

Several of these, as you pointed out, are advanced vehicles. So our antibodies are our small organic molecules, we have been building very, very large libraries of antibodies or libraries of small molecules for 20 plus years. I think we have innovated the field. So the platform is important because any drug, to begin with is, a binding molecule. So you have to be good at discovering the binding molecules. But then, of course, it's the product that matters. So I don't really see a difference. You need the platform for the discovery and for the strategy, maybe. But then you need the development, because any drug, in the end, has to go through its trials. phase three candidates. Do you allow yourself at this point to imagine how it would change patients lives if they were to be approved? Or is that something that, as a scientist, you say, one step at a time?

Dario Neri: 29:16

You bet on success. When you design a phase three clinical trials, you set statistical goals, you have to prove a certain superiority with a certain statistical strength. So the moment we start our people trials, we make a promise. That is we want to reach that particular endpoint. And so then, of course, at the end of the trial, you open the book. And you see. We have not yet completed the readout of our, let's say, most advanced product but we have completed recruitment for example of of our most advanced phase three clinical trials. So our pivotal trials will read out. For some trials you are at phase three, and you are blinded. So you will not know until the end, you typically run interim analysis that would kill the product, if there was futility, and what products have actually survived the interim analysis. Other programs for very nasty indications may give you registration after phase two. So you don't need to go to phase three, because if you are really solving a very nasty medical problem, and you have strong data, you may apply for registration after phase two. And this actually happens quite often in oncology. And so at that level, you actually see results in real time. And so you have a pretty good idea whether your drug works or not. And we run webinars every two months, in which we show pictures, and we try to be very transparent about our success and our failures so that whatever we do, we have a transparent communication with the market. For us, it's still work in progress. We are proud of what we have achieved. But we don't have a product on the market yet. So this is not the time for celebration, this is time for work. We are addressing big unmet medical needs. If you go one by one, melanoma is a killer, even though there has been, luckily, a lot of progress in the field. If you go for high-risk basal cell carcinoma, the complete response rate of available drugs is still anything like 10%-20%, at best. So there is a lot of margin for improvement in a very disfiguring disease. And glioblastoma, unfortunately, is still almost always fatal. And so unfortunately, for these conditions, these are tough conditions, but at the same time, these are conditions where you have room for improvement. So the strategies that I've done this, I'm absolutely certain. The easiest way to build selectivity, when you have a good drug is to make it even better, and to make sure it concentrates where you need it, which is at the site of disease.

John Simboli: 32:18

Is working in Siena is different or the same as it is in other biopharma areas in Europe?

Dario Neri: 32:38

Well, I've been out of Italy for so many years, I came back only about couple of years ago, I was 35 years abroad. As you mentioned, Switzerland, UK is back in Switzerland. Siena is a special place because it's a small university town, 50,000 inhabitants. But we have about 3000 persons that work in biotech in Siena. So it's a little bit . . . people speak about pharma Tuscany, because there is actually a lot of biotech and Pharma in Tuscany. We have operations in Siena because myself and my brothers are from Siena. My brothers were always based in Siena and they've run the operations in Siena. As mentioned, I've spent so many years of my life in Zurich that we really established the discovery activities in Zurich. There are excellent infrastructures and also excellent universities in Zurich. And so it made sense to actually keep discovery in Zurich, where we also have access to an animal house and other facilities. And in Siena, we do other things, including manufacturing. Most of our partners are American partners, I travel almost every month to the US. And I admire the quality, for example. And actually the transparency, the directness of FDA, for example, I think it's a great authority. But I think in the US, I get this feeling it each time I come back, I come back full of energy, because I feel that there is this pride of getting the job done and also this commitment to work, which I think is very refreshing. And, of course, you know the science in the United States is great. Also, science in Europe is not bad. But what I'm trying to say I think it's an international community. And we meet regularly either in person or via Zoom. One of the things I'm proud of, I was among the first that work in an area which has become very important. It's called DNA encoded chemical libraries. That means you use DNA bar codes to identify molecules and you can build and screen libraries with billions of compounds. You know, previously, you had to screen one molecule at a time. And maybe you would screen, I don't know, 1 million. And that's it. And now you can screen billions of molecules. And, for example, we have now built a community. And we have this DEL symposium, DNA encoded chemical ABI symposium, once a year. Last year, it was in Boston this year, it will be in Zurich. So it's actually a community and it doesn't really matter so much where you work as long as you work at a given standard.

John Simboli: 35:43

Dario, had you not become a scientist,. what other forms of work or inquiry might have been interesting to you?

Dario Neri: 35:50

I mean, if I had more time, music. That's something I really like. I like to play. I like to sing. I like to record music. So I'm very happy as a scientist, I think I could be equally happy with music. They're both creative jobs. My father used to work with Ernst Chain, Nobel Prize winner for penicillin. And he was an immigrant from Nazi Germany. He was Jewish. So he actually fled to the UK and he was almost a professional piano player and he told my father that he actually managed to find a position in academia because of his piano skills. So you never know when they can be useful in your life.

John Simboli: 36:30

Thanks for speaking with me today, Dario.

Dario Neri: 36:32

Thanks a lot, John. It was a pleasure.