Sander van Deventer, VectorY & Forbion | Pioneering gene therapy | E11

We’re in Amsterdam with Sander van Deventer, the CEO of VectorY. We will talk about VectorY and what’s missing in gene therapy.

Sander has an impressive track record, being a professor, operational biotech founder and a VC. In 1998, he co-founded uniQure, which brought the first gene therapy to the market. He also co-founded the leading VC Forbion as well as Dezima. He is now building a new venture VectorY, again in gene therapy. I interviewed him in 2017 back at Labiotech so it’s great to catch up with him again.


Transcript

Sander van Deventer: How large? And I said, well, probably a thousand square meters. They said, how many are you? I said, we are two. I’m pretty sure it will grow fast. 

Philip Hemme: It sounds amazing having the vector and then the antibody produced locally. How well does it work though? 

Sander van Deventer: You come from somebody in a wheelchair to somebody who can do top sports, and that is in one career.

Philip Hemme: How do you manage to just still keep going and then going again? Sander van Deventer: I’m the luckiest guy in the world.

[00:00:28] Welcome

Philip Hemme: Hi, I’m your host Philippe, and welcome to a new episode of the Flot.bio Show. Where I interview the best Europeans in biotech to help you grow. And today I’m in a very rainy, you know, Amsterdam. I had to talk with Sander van Deventer. And Sander has a really impressive track record, both as a professor, as an operational biotech founder, and also as a VC.

In 1998, he actually co founded what is now Unicure, and which actually brought the first gene therapy product. drug on the market. Then he went on Forbion, leading VC, and also a big success story, Dezima. And now he’s back at it again, founding a company, Vector E or Vector Y, again in the gene therapy space with some new technology.

We will talk about Vector E and also about the gene therapy field in general, especially what’s, what’s missing still to make it big. So let’s head upstairs and talk with Sanne. 

All

right. Welcome to the show, Sanne. 

Sander van Deventer: Well, nice to be here. 

Philip Hemme: It’s great that it worked out. I mean, I mentioned in the, in, I made a post about the Series A and I mentioned I will try to have you on the show and it’s great that it worked and we managed to get it just by the end of the year. Thanks for taking the time.

I mean, it’s a busy time before Christmas and all.

[00:01:54] The largest Series A ever

Philip Hemme: Yeah, I want to start with, with actually the Series A. I mean, 129 million euro, I think, let’s say 130. I mean, it’s, I think the largest series A this year. One of the largest ever, I mean, European standards as we been. But I’ve heard also, it took a bit longer to close than expected.

Can you maybe share what, what happened? 

Sander van Deventer: Yeah, so basically, I think there were two factors here. So the company started as a, a gene therapy company, advertising, basically it being a gene therapy company and. As we developed the technology it turned out that most of the value actually is in the ability to, to address difficult issues in proteostasis in neurons.

So, so actually from the delivery side of things, like we still like the delivery being a gene therapy because it’s a one off therapy that will work for a very long period of time, which is really nice when you do that. In the CNS, the focus shifted more and more to, to the business side of things, you know, what exactly we are expressing.

And so, you know if you look at the efforts here in the company by, by far the most effort actually is in the binary technology and the ability to distinguish between misfolded and non misfolded native proteins, natively folded proteins. And so we actually found in the TDP 43 ALS program that there were some unique features here.

That is, that at the same time you can address a gain of tox, problem, whereas you also have an important loss of function problem. And that put us on a really nice place. And so, yeah, some of the investors who looked at the company early looked at it like, there we have another gene therapy company doing a sort of orphan ALS approach or something like that.

to the newer, investors who came in later or looked at it later you know, deciding, wow, this is a neat technology and they can really do it. And if they can do it in ALS, they can do it in other CNS diseases. So that is basically the, the shift of perception that we got at Factory. 

Philip Hemme: And I guess with that shift also, means also the potential is 

Sander van Deventer: Yeah, because, you know, just to give you an example in ALS, of course you have you know, really good data for SOD1 now, and there’s academic data on FOS, but those are the genetic forms of ALS.

And together, all, you know, all, all the genetic forms of ALS together are maybe 7 percent of ALS. And the technology that we developed is for all sporadic, so sporadic. It seems like the more rare form, it actually is more than 95 percent of, 93 or 95 percent of ALS. So the market is enormously larger also for, for, for our product than it is for, for product targeting.

So one. 

[00:05:01] What’s coming for ALS

Philip Hemme: Actually, that’s good. I mean, I had some questions on ALS because I think, I mean, it’s a huge unmet medical need. I don’t think there’s anything really on the market right now. And I think that there were some failures, let’s say, or some things were blocked. I think, I don’t remember the exact name, but somewhere were blocked.

So can you expand a bit there of like, how, how will you position yourself compared to what’s in development at the moment? Or, yeah. 

Sander van Deventer: Yeah. Yeah, sure. So, first of all, the market has, so ALS people think about it as a sort of rare disease. Yeah. But the the, the odds of somebody in the Western world developing ALS are about one in 340.

Yeah. So I always tell people, you know, if you board a regular train, then somebody in that train will get ALS. So it’s not that uncommon, actually. So the market is pretty large so that’s one thing, but the other thing is that in the last probably five years or so, five, six years it has become apparent why actually motor neurons die in sporadic ALS.

And it turns out that it’s a, it’s a protein which is very much involved in the splicing of mRNAs in motor neurons. Now neurons splice RNAs in many more transcripts than other cells to to give you an example, we have done some of these analysis. And so of the 20,000 genes that you obviously have in, in a, in any cell, but certainly also in a motor room, you have like 150,000 transcripts.

And so they need to be correctly spliced and TD four three is, is, is, is the key component there that is in the splicers arm, the key protein. that binds to these RNAs and directs correct splicing. So we found that one third of that complete transcriptome, so we’re talking about 50, 000 or whatever transcripts are dysregulated when Tdp43 goes wrong.

So, so that gives you also the answer why it’s so difficult to develop something in, in ALS. Because we do know many of the downstream 

Philip Hemme: you’re hitting. Everything. 

Sander van Deventer: Right. So companies have tried to do like STATMIN2 or, or UNG13A or all these other genes that that are definitely dysregulated and definitely associated with pathology and ALS, but it’s only one of so many.

So we, we actually correct about 80 percent of that complete misplaced transcriptome just restoring nuclear TDP43. 

[00:07:50] Vectorized Antibodies

Philip Hemme: Wow.

And just to go on the technology, I mean, You say about vectorized, I mean, that’s where the name comes from, so vectorized antibodies. I’m curious on, on really how, how and how well it works. I mean, it sounds amazing, like having the vector and then the antibody produced locally or in the cell. I mean, that’s how, yeah, how well, how well does it work 

though, Eddie, how, on a.

Sander van Deventer: Yeah, so some companies that are also under the umbrella of factorized antibodies that they make, antibodies that are secreted and they work outside of the cell. So, 

Philip Hemme: Voyager and Yeah. Most of it, they are Exactly. Probably one of the leading ones, almost. 

Sander van Deventer: Yeah. They are in that business, basically.

We are developing antibodies, and actually some academic groups have done that, and Voyager has done that in the past also. that stay inside the cell. And so you can put them in different formats. So we have used single chain IVs. We have also worked with VHH, binars. And and, and, and those can be nicely expressed long term in, in animals.

I think, you know, the longest is a couple of months that we have now, but I expect these to express years after a single dose. And so that works nicely. Now, it comes to the part where what you bind and, and, and how you actually then get rid of it. So, in ALS, you have aggregates of Td43.

Normally, 80 percent of the Td43 is within the nucleus, and that’s where it mainly works, because the splicing aspect and, and so on and so forth is, it does more than that, but let’s focus on that. And, and then only 20 percent is in cytoplasm, and there’s a recirculation. Of TD four three from the cytoplasm to the nucleus.

So we know that process quite well. But if you have aggregation formation in the cytoplasm and you get mis, placed, so to say T four three, then you lose it in the nucleus. And also that circulation is then disturbed because the aggregates actually aggregate more and more. TD four three is like a gluey lump of TD four three that stays there.

And so that interferes with that recirculation. So, the, the, the, the, the binaries that we make need to get rid of those ag gats. In some, we, so we, we actually de, developed a whole lot of binaries targeting the complete protein. So there was a lot of work has been done there. And so we first, 

Philip Hemme: you said 

Sander van Deventer: that’s why most of the people work on the binaries.

Right. 

And so we, we, we first defined where actually to target that that protein. So then we came up with a binder that did it very well, and we actually found out why. Because it binds to a part of the protein that is not accessible in the normal forms. But it is accessible when you have aggregation.

And so, so that’s one part of it. And then, of course, binding alone is not enough. You need to get it somewhere. And so those large aggregates actually then need to get, degraded by autophagy. And if you have smaller misfolded proteins, it’s mainly through the proteasome. And then also one other pathway you can think about is the lysosome.

So at the same time we made what we made dagrons, so those are motifs that we can link. with our binders. And the dagrons actually instruct the whole complex to go somewhere. So it can be, you know, to autophagy, it can be to the proteasome. And we actually have binders now that we engineered to have a dual function.

Basically, it says if you bind to an aggregate autophagy, but if you bind to a misfolded protein, it needs to go to the proteasome. So all that work also was done in parallel. So we call the binders vectabs and these dagrons we call dagrons. And so the ones that are engineered with a dagron we call a vectron.

So it’s a little bit because otherwise we have to always explain. And that works amazingly well. So the, the binaries actually are expressed at the, the through levels, the trough levels or the, you know, the, the, the, the levels that we have in those cells are really low. They’re so low that you sometimes even have to go to technologies like, LC MS to, to basically even to show that they are there.

But they function like very, very well. So they almost completely or completely normalized the phenotype of ALS motor neurons. So, if you look at, you know electrophysiology, or you look at dendrite length, or you look at signaling, or you look at you know all kinds of aspects, survival, and all kinds of aspects of health, they’re completely too normal.

Philip Hemme: What’s the matter? 

Are you? Yeah, okay, so. If for instance, you have the, you have your, your Your vector, your, your gene cycle, your vector, you will insert the gene in a certain cells, which then express and make the, the, I mean, express some of your binders, intra, intracellular. And then you can, target the aggregates, bind them together, and then lead to the autophagy and, and restore the phenotype.

It’s crazy. Yeah, 

Sander van Deventer: but it’s not only autophagy, I think. All of it. Or, or we can run it to the proteasome or proteasomally. Degrade them. You can actually, we, we have a bin that’s neutral, and so if you put a different deagon on it, it’ll start doing different things. So if it’s neutral, so it binds through, an aggregate does nothing.

But if we engineer it with an autophagy, Deon, then it will instruct autophagy or proteasome more degradation. It will instruc that as well 

[00:14:03] Developing binars

Philip Hemme: and can really engineers the binders. I’m curious what, so you mentioned VH or what’s specific in the binders? I mean. Just coming from, I worked a bit with molecular partners with some, all right, alternative proteins and I know one of the big challenge with antibodies, it’s just usually too large, also a bit harder to, to re engineer precisely, especially when you talk intracellular, so how do you Yeah.

What, what are you actually using? 

Sander van Deventer: Well, there are a couple of things here. So there, the whole development of these binaries is very different from, from antibodies. I’ve worked with antibodies for a long time. And so to, to start with, how do you select binaries that specifically recognize misfolded proteins?

Because the moment you start making these proteins as an antigen, for example, They’re always misfolded and they’re in the, you know, they’re never in the correct configuration. So you really have to do this on a high throughput cell systems. And so here in the lab, we actually have a high throughput screening system in, in for example, U2R cells, but also in IPS striped human cells.

It could be motor neurons or, or immediate spiny striatal neurons or cortical neurons. We have all that here. And also glial cells, like we have astrocytes here and all that sort of, we have everything here. So muscle, we can do all that. So 

Philip Hemme: This floor, and 

the other floor, and the other 

building. 

Sander van Deventer: Right, right, right.

So it’s all there. So, so the screening is very different. But also the pharmacodynamics and pharmacokinetics totally different because, you know in, in, in, in the periphery, you would like to have you know, a sort of, you know, at least a significant trough level. But here you know, the turnover actually is pretty fast for these small binars.

Talk about hours or something like that, but within the cell it doesn’t matter. Actually, they’re extremely active. You can hardly measure them and they’re highly, highly potent. So the whole pharmacokinetic model is also totally different from, from what it is outside cells. 

Philip Hemme: And I guess they 

are produced constantly.

That’s the point. You don’t need a massive quantity because it’s over time. 

Sander van Deventer: Exactly. And then of course, how 

Philip Hemme: you tell me what, what, what specifically are those binders like? 

Sander van Deventer: Well, we do have them in different formats. So we do have a, for our TD43 program, it’s a single chain FV. And for our Huntington program, it’s a VHH engineered with a dagger on.

and all that sort of stuff. So it’s, it depends. There are some arguments why, why to choose one over the other for a certain program. But you know, there are also aspects you know, in what compartment do we want that binder to show up? So if it, if it, if we don’t want, for example, the binder to show up in the nucleus.

And clearly, for TD43, that would be, you know, not something that we want. Then then we, a single chain FE format, you know, doesn’t go to the nucleus. But the VIHH might. And so we do have some aggregates that are nuclear, and for that program, we would use a different binder. So these are just some considerations. 

Philip Hemme: Yeah, that’s good. And I’m curious just from also a bit comparing it to, to different technology. I mean When I, when I heard about it and looked over, I thought right away about mRNA delivery as well. I mean, you could deliver instruction to produce the other binder as well. But I guess then the window. to produce is way less long or less over time. So for ALS, you will not have this like ongoing production of binders, which will fix it really long term with a single injection, or you will need like several injections. That’s, yeah, 

yeah.

[00:17:57] AV technology

Sander van Deventer: So that’s why actually coming to the gene therapy aspect here. So we are open to any non viral delivery or even use the, the VAC taps as VAC taps, you know, engineer them in any way or format.

Right now for the brain programs, there are two things. First of all, in ALS, we really, really specifically need to target motor neurons. So we have a whole vector strategy to do that and and I’m pretty confident that with the vector we have now here in house we, we achieve that goal. And then it’s a single administration and there will be very long term expression based on what we have seen, for example, in Huntington Project that we developed at UniQR in years.

So that’s a good thing. With siRNAs, of course the specificity of the transduction will be, you know, more, you know, common. I’ve seen really good distribution data, by the way, with silencing RNAs now in the brain. But it would be a repeated dosing. And the problem with repeated dosing is that you know, a lot of the troubles that you now see in the Roche program, or with Spinraza, or other ACE whole programs, is really, you know, increases in NFL, ventricles and all that sort of stuff.

Which probably is related to, you know, it might be related to the repeated dosing of the, of the ASOS. So yeah, we really don’t want to get in those troubles. So for now, for these programs in the brain, we use AV technology but we are open to any other delivery technology 

Philip Hemme: because I, I mean, there’s a lot of also downsides to AV.

Yeah. It’s, I mean, in general, it is one of the bottlenecks. So yeah. Okay. 

Sander van Deventer: Yeah. But you know, to, to come back to that when we started this company, I’ve been producing AAV since 2004 and, you know, we did two commercial products, Clibira and Hemogenics, and so I’ve been scaling it up and and I’ve been, you know, involved quite a lot with the technology itself.

So here in this company, when we started, we said, well, we want to actually even the next gen. So we want to get to 90 percent full particles. We want to have the particles filled with the correct and intact genomes and all that. And then we want to produce this all the way to a 2, 000 liter scale. So that the cost of goods come down and that we can do hundreds and hundreds of patients from a single run.

And that’s, that’s the proc, the process we have. Yeah. So. 

Philip Hemme: I, I saw on the manufacturing you, you, you already claim on the 2, 000 liters already? 

Sander van Deventer: No, we haven’t done it but we are doing it now. Okay. So we are at the, at the process now to, to, here in, in, in the company we only go to 50 liters. Yeah. And so then we transfer it to CDMO.

Yeah. With, with exactly the same equipment. It uses our materials in our process, and then our people are there, and that’s how we’re scaling up now. Okay. 

Philip Hemme: And I was on the, what you mentioned also on the, on the AAV, I mean, I think it rapidly gets pretty technical as well, but what I’ve seen is one of your poster or paper on, you really can engineer the capside and have some like tissue specific peptides on the, on the side that you can.

basically targets certain type of tissue, I guess, in the brain. I guess, for us, this is super important. And at the same time, you also showed that, that the capsaicin can cross the blood, blood brain barrier. So you don’t even need to inject directly in the brain. 

Sander van Deventer: Yeah, there’s, there’s several companies that have shown that, so, in, and also in primates.

So we only showed it at Xvivo. So we don’t, don’t even have primate data. We are generating those data, but 

Philip Hemme: Wasn’t that on PICS, the data you poster you showed? 

Sander van Deventer: Yeah, but vivo, right? That was in a model. But you know, Capsogen and Dyno and Voyager and Dev, all these capsids that can do that. Okay.

So we are not unique there. But the one thing I think we’re unique at is the structural engineering part, right? So we basically choose the target, and then we make a peptide ligand, and then we screen that ligand in different formats. And that ligand we engineer in in the outer capsid directly in such a conformation that it retains that binding capacity.

So you can actually, if you work that way, you can work much more targeted than if you do a million or a billion, library with random mutations. And then you have to select back. And also the optimization is more straightforward. So, yeah, we’ve done that. And we’re, we have now. library that actually is being tested also with novel binding.

[00:22:55] The pipeline of VectorY

Philip Hemme: Okay. That’s nice. Yeah, I like that. On the, on the, you mentioned on the pipeline, so you have ALS, Huntington’s, Parkinson’s, but they’re all in preclinical slash in, in cells at the moment, so. Yeah. So where you found, where is it true, true then A and D and, and even which first human? 

Sander van Deventer: Well, for ALS, I mean, we’ve done the TDP43 mouse model and we’ve done multiple.

Models going from mouse to pig to, to primate. And we’re now at the stage that we are in, we’ll shortly discuss pre IND have a pre IND meeting with the FDA, and the plan is to to complete our primate top study this next year, end of next year, and to have an IND meeting and to start clinical trial in 2025, in Q1 and with ALS, of course, the point is that you know, fairly rapidly get to an end point, because the disease is rapidly progressive, and so we expect, and then there’s a whole biomarker strategy which is very much linked to the exact TD PFORT3 pathology, because the consequences of this misplacing as a consequence of loss of function of TD PFORT3.

Are that you also get peptides that shouldn’t be there, that are misplaced, actually the result of misplacing. And those peptides you can measure, you can measure them in CSF, you can measure them in patients. So if you then, if you restore splicing, you should get rid of those faulty peptides. So all that work is ongoing.

So I actually expect that if it all works well we will And, we do have a whole panel of those and, and then of course there are usual biomarkers like NFL. And, of course, there’s a motor score also that we are following that is rapidly progressive. And so 

Philip Hemme: I start to understand also what’s first, what’s behind the platform and also where is the potential and also where.

I mean, it sounds like you have pretty solid already knowledge slash data really on the cap side, on the, on the binders, on the, on the disease. on exactly where you, where you target, where the trial is going. You already have solid preclinical data. Because, I mean, my, my question, I mean, basically what’s, to, to explain the, the, the money raised, basically, at the preclinical stage, I mean, it’s, of course, I mean, you’re, you’re involved and everything.

You can, you can pull out a bit more, but still, there’s limits to a preclinical, let’s say, evaluation, or how much you can really raise. But now I start to really understand that seems like a lot of the pillars are basically very solid from the foundations and then it’s about executing on the clinical trial.

Sander van Deventer: Well, the other thing is, you know, we said, listen, I mean where are we going to finance towards? And the discussion we had with our investors and in the end, everybody was very much on the same page. You know, it only, you know, value you create here with clinical results. So we wanted this financing for sure to get to meaningful clinical results for our lead program, which is VTX2 is cheap for 3 in ALS.

But we were also bringing the Huntington program to IND. And two other programs in the same proteostasis paradigm towards DC. So, you know, if, if, if you, if you do have a product that succeeds in ALS, of course the upside is, you know, much larger than the investment now. And but also if the technology really functions like a platform technology because we have excellent data in Huntington models also.

So if that also translate into political effigy in Huntington’s, then, you know, and the program. It’s a multiplier. It’s a multiplier. 

Philip Hemme: Especially I mean, CNS still today. There’s still, I mean, there are lots of, let’s say, failures or big failures and, but the need is, is so, so high that, yeah, if you have something that works, I guess.

[00:27:22] Where the money is moving to

Sander van Deventer: But you know, if you, if you look at the, where investments are going now, then there’s a sharp drop in oncology and there’s a sharp rise in well, metabolic obesity, of course, but also in CNS. So it’s really where the money is going now. 

Philip Hemme: It’s interesting. 

And I saw LSP invested through what is one of the dementia fund, which they started maybe earlier, earlier than the trend, but there are there are some other VCs who have also dementia or dementia discovery fund in the UK, which I guess, I mean, I was watching it, I think, I don’t know when they started exactly, maybe four or five years ago, where was still at least to me, maybe a bit early or was not clear.

Okay. Is that now, but maybe now it’s, it’s the timing. And I mean, I guess it’s the goal of a VC to be a bit earlier than, than too late. 

Sander van Deventer: Yeah. They did very well, I think. And and also the ALS investment fund put quite some money in in this company as well. And I know them almost from the start because we were looking at ALS investments and at Unicure, we had a GDNF program that at some point in time was considered to be.

Potentially something we should try in a LS and so I in already in those days I was talking about that.

[00:28:50] Meet the team

Philip Hemme: I think that’s the, the last part I want talk about is more on the, on the team as well. I mean, obviously you, you have co-founded Unique and then you even went back in 2017 as acting CSO and I think then the, you now CSO is, was the head of m and DI don’t remember the exact title at, at also, I guess.

I mean, the team is definitely very solid, but I’m curious also how it’s like, what’s the story behind some of the team joining or what’s like, yeah, or what’s the, the relationship with, with 

Uniqueur? 

Sander van Deventer: Yeah. Yeah. So, yeah, I mean, in general, of course, there are things like non compete and, I don’t think Unicure would like all their people to come here.

Actually they’re laying off people now like, like 130 or something like that. And I have a good relationship because actually they they’re actively helping people find new jobs, including here. So I have some people actually that worked at Unicure that work now here as of shortly.

The other thing is that yeah, I mean, listen, I mean, we started this company with two people, me and another and we, yeah, I, I quit Unicure and then I had a temporary job in China, as you probably know, when it was all about building an AAV manufacturing facility in Suzhou. And that all went very well was, you know, I wrote a little bit of a blog about it on LinkedIn being you know, in quarantine and what have you.

And then I came back and crazy. And we knocked here on the door where, where we are now to say, well, guy guys, do you have some lab for rent? And they said, well, yeah, how large? And I said, well, probably a thousand square meters or something like that. I said, how many are you? I said, we are two, but I’m pretty sure it will grow more fast.

So we didn’t get 1000 square meters, but, I think we started with maybe 300 or so. And but yeah, I mean, people just, we’re just like, and we were, we were like a magnet. People were calling us up spontaneously or. People really wanted to join. People left really good paying jobs to be in this company and and people actually, the founders invested their own money in the company and all that.

So that’s how it started.

Philip Hemme: I’m telling you, I guess you also, you also invested. 

Sander van Deventer: Yeah, of course. Yeah. And you know, the first thing actually I did is I went to the hardware store to to get some wrenches and stuff, you know, to, to put the the tables together and and and the wifi and what have you.

And so that’s literally how we started, but people really came here because there were so many people that, that we worked with in the past who knew us. They really want, the people like to work here. We have 15 nationalities here and we have about I think 65 FTEs or so, and the median age is 32 and we have 60 percent women.

It’s a, it’s a joyful group here, you know, with all these people coming from all over the place to actually do their best job here and that, that’s what, that’s how it works. 

Philip Hemme: I guess 

you’re hiring also actively, at least I’ve seen on your 

Sander van Deventer: Yeah, 

yeah, we just basically put out our, our vacancies, of course. 

Philip Hemme: I mean, people are listening to us.

[00:32:29] The Netherlands as a biotech cluster

Philip Hemme: But also, I mean, from what you said also, what’s pretty amazing also, Amsterdam or Netherlands in general, I mean, there’s a quite, I mean, quite a deep expertise in, in gene therapy in general. We are unique here, but also a lot of, of CDMO, manufacturers in, in the, in the space. Can you, can you expand a bit there, like on, yeah, on like how you, how you see, or like how you see that, or how it compares maybe to other clusters, let’s say, in Europe or?

Sander van Deventer: Yeah. Yeah. I think, you know, you have fantastic clusters all over the place. I mean, you, you talk about, Genepol, if you talk about a gene therapy but you know, all over the place and particularly also in, in UK, of course, enormous clusters of, of knowledge and know how. I think, you know, in the Benelux, actually, we’re, getting our act together, of course, with everything in Belgium going on, in Ghent and Leuven and what have you.

And, you know, Argenics, a company that we started with when there were five people at Forbion, we invested in it. And what is it now? It’s you know, now it’s 20, 20, 20 billion, market cap. So these are, these, these have become companies that are much larger than KLM Air France or Air France KLM more.

where companies like that, people just don’t know it, but you know, the cluster in Leiden is I was in the board there because I was a professor at Leiden also, I was in the, in the, in the board of the, of that cluster, and there’s more than a hundred companies there BMS is building a huge, cell therapy Cartisol factory there, Kite, of course here, so, yeah, there’s quite of that quite a lot of that and, but here in Amsterdam it started later, and, And it’s smaller, but we’re, we’re getting there.

I mean, we work with you know some companies here on, on site when it comes to promoter technology, for example and it’s growing fast. So yeah, I’m, I’m pretty optimistic about the, the environment. 

Philip Hemme: And I mean, also when you look at the map, Leiden, I mean. 

It’s nothing. 

I mean, far as you know, Paul, to the center of 

20 minutes here, 

I landed in Chippewa yesterday.

It’s crazy how close it is and the train, everything connected inside. That’s nice. Yeah, I was always surprised about this, like especially in the Netherlands. I mean, you had a few companies like unique here, but that’s a lot of like bigger pharma had their gene and cell therapy. here from a manufacturing or from development as always pretty like established trust me, 

Sander van Deventer: I was, well, J& J, Crusale, and of course we have GenMap and then, you know as I said, I mean, BMS, but big time now, Hostelos also in in in Leiden.

So yeah, there’s quite a lot. Yeah. 

[00:35:31] CRISPR approval and gene therapy

Philip Hemme: On the, maybe just on the, on the gene therapy field, if we, if we zoom out a bit, I’m curious what you think about the CRISPR approval, recently. 

Sander van Deventer: Yeah. So gene therapy I, I came to the conclusion that you know, the, the, you know, the, the promise of gene therapy. So people present you a slide deck and the first deck says, you know, there are 5, 000. genetic diseases and we can target them with with LALALALA virus you know, that doesn’t work, huh? So we already know that it’s difficult and you need to know what you’re doing. And so we are not doing gene replacement, for example, any longer. We’re just not doing that. So that’s not because it’s too complicated.

Yeah, it’s often very complex and really, you know, not so easy to do, eh? So, yeah, at Unicure we started already a long time ago with silencing, and so there was actually a press release this morning from Unicure that had some positive news in the Huntington program. But I think, so gene therapy can be very useful for all kinds of things, and, and particularly now with the antibody.

technology that we have, we can tackle things that are very hard to tackle with small molecules or, or, or with sinusine technology. So, but yeah, I mean, the next new thing, of course, is gene editing or things like that. So yeah, with CRISPR technology, I mean, the, the, the hurdles are simple. So it’s delivery for many of the diseases that they’re targeting.

You need to have an even spread of the, of the repair. For example, if you look at cardiac indications, you cannot just repair one in 10 cardiomyocytes when it, when it goes to conductors because you will induce arrhythmias actually if you do that. So, delivery is a big one. And then of course with CRISPR, Gas based technologies, I mean the construct is very large.

So at at at, at, at Forbian, we’ve been looking at space quite extensively and we passed on many of those. But you know, with recombinases, you know, if this company’s seamless, with relatively small constructs that have no, guide DNAs or whatever. You can actually do the same. So, so we became interested in that.

So, I really believe that those technologies at some point in time will will, will you know, of course they work ex vivo, so we, that, that’s a big one, but in vivo that they will start to work in vivo. 

Philip Hemme: Nice. I mean, we had Roger Novak on, on the show and. One thing that, that struck me is how he said, CRISPR, of course, to put the, the, the potential and whatever you can do is basically a dream technology and you could do a lot, a lot of things, but they really focused on ex vivo, only ex vivo and something a bit more easier to, to do and to execute and to make trial versus some other CRISPR companies were tried in vivo wide away.

And it’s just way too complex. Yeah. So I, I like, I mean, I think it, it goes into what you are saying as well. 

Sander van Deventer: Yeah, no, there are proposals like we’re going to CRISPR all the HIV out of people and you know, this is crazy. 

Philip Hemme: Maybe in 20, 30, 50 years, I don’t know. And I’m curious what’s your view on the, let’s say from a commercial success, from a market point of view, from a, because gene therapy, I mean, so far.

There’s clinical trials, you have approvals, but then when it goes to commercial, I mean, in the U. S., maybe it’s a bit better. In Europe, I mean, I think it’s limited, but what 

Sander van Deventer: Yeah, yeah. We need to think about that better. So of course you know I think hemogenics, if you do a pharmacoeconomic model, it’s quite clear that if you treat somebody with hemophilia B early on, and it works like for 10 years, then even if you have a crazy price for the product, it’s You know, you, you, you win, so the, the, the healthcare system does win, because you know, these Yeah, 

Philip Hemme: but why is the healthcare system not buying it more than 

Sander van Deventer: Because people just are not thinking about it.

So you know, if I, if I say here in the Netherlands a gene therapy product will cost one or two million or anything like that, everybody says, that’s crazy. And, you know, the health care system cannot afford that. But if I just tell people that and, and what about some patients with hemophilia that cost 300, 000 a year just in product, and then I’m not even calculating.

That these people you know, cannot work and that that they’re, that they need surgery and all extra costs. And so, you know, 300, 000 every year, that you know, that is a lot of money over 10 years, it’s 3 million, right? So people just don’t do those basically calculations and since our healthcare system is not you know basically yeah, maybe in France now with the thalassemias, they actually calculated how much the thalassemia patient cost to the healthcare system in France.

There are quite a lot of them, of course, in France because of the Mediterranean migration. And so actually they came to the conclusion that it would be much, much, much better for them to go for gene therapy for that disorder than to pay for. All the, all the, you know, all the extra costs that these patients bring.

So we need to have healthcare systems and leaders that actually think about this in a much more relaxed manner and also in a much more informed manner. 

Philip Hemme: But I, yeah, but from what you say, I mean, the, and I heard that many times, I mean, the case is pretty clear as in like, I mean, 10 times 300, 000 versus one or two million, it’s not like super complicated math or whatever, like, but, so I’m curious, I mean, as a payer, they can also, I mean, it’s their job to understand it or like to, to do it.

So why, I don’t get where it’s like, really blocking and because I hear the same mess already, let’s say, five years ago, was already the same, let’s say, argument, but I don’t see necessarily payers, like, paying more, acting more. Yeah. Or is it, is it me? 

Sander van Deventer: No, yeah, you’re correct. I mean, the most frustrating part of it is the the lack of any vision.

And, you know, I’ve been here for a long time now. We did the first Remicade patient. It was infused in MCEM in 1991. So that’s a long time ago. And there we had exactly the same discussion. So people were saying, yeah, you know, you can treat Crohn’s disease with steroids and with azathioprine. And why are we now going for a treatment that at that point in time would cost like 35, 000 a year?

I mean, it’s now much cheaper, of course. But then you know, everybody started realizing that actually you know, we, we, with the old treatment, steroids and azathioprine, we never had complete remissions, actually. Never, ever. And so that’s a, a complete different, therapy had, had hit and, you know, everybody now is, is, of course treated with those kinds of drugs, the same holds true for, for, for when we started working on natalizumab or now with ocrelizumab.

If you have MS and you’re treated with the regular stuff, it’s basically waiting until you hit the wheelchair, that’s what you get. With ocrelizumab and ofatimumab, those new drugs. It’s, it’s, there’s zero relapse almost, almost nothing. And so, you know, these are completely different. Approaches.

And by the way, I can give you a little bit of an anecdote there. And, I, I was closely involved with Natalie’s map and I knew about OV2MU map because I was my friend is Winkel, who is basically first developed at, at GenMap and of course went to Novartis. But, my my wife basically got MS like six years ago.

Suddenly, and we are actually mountain biking in the Alps and stuff like that, you know, very fit and bang, you know, she went out actually and and had severe problems, couldn’t see and all that sort of stuff. And then we went here and then it’s like, yeah, you know, you can do this. You can do that. I said, no, no, no, no.

We’re just doing what I think, you know, works. And we started immediately with Natalism app because that was available then. And and she, you know, she, she, she completely, almost completely normalized. And then when Oculism app came, I said, well, Oculism app clearly is better than Natalism app. You need to take that.

So that’s about, it’s about I think the cost is about 35, 000 a year or so for Oculism app here in the Netherlands. And I, I do this 

Philip Hemme: what’s the, the company’s behind? 

Sander van Deventer: It’s Roche. Roche. Yeah. 

Philip Hemme: And the other one? 

Sander van Deventer: Overture Memes, now partitioned. Yeah, of course, they’re finding their, they’re fighting their little Swiss battle, but, but they’re both good.

So probably Overture Memes might be a little better even than Opalism, but they’re both very, very good. And so I, I do these lectures and I had a meeting at health, the, the economy of the Ministry of Health here in in the Netherlands. I just showed them this. My, my wife is a professor of pediatric infectious diseases.

She has a big lab. She makes money. She pays tax and all that sort of stuff. So I did the, the, the commercial case of my wife. And I could, could actually calculate that it is much better for the Dutch. Taxpayer or for the Dutch government or whatever to have treated my wife for 35, 000. Then not to have treated her over because in six years in her case, she would have been in a wheelchair.

So I mean But, but it, you know, people just come to me and they say, wow, wow, you know, that’s really interesting what you said and blah, blah, blah. But nobody’s taking any action. So that’s really what worries me. 

Philip Hemme: Crazy, crazy story. Makes me think also about how beautiful and how life changing some of the biotech products developing are.

I mean, it’s The example of yours is crazy. 

Sander van Deventer: Philip, i, I, I became an internist in 1980, in 1987. And so I do have some slides, actually, that I made in those days about rheumatoid arthritis. There was a young woman, 30 years, in a wheelchair, completely, with all these deformations. I, you know, I have a slide about HIV, the HIV that we’re seeing.

I’ve just horrible. I have a slide of a patient with hemophilia in those days, with enormous swollen joints and whatever because of the bleeds. And if you, you know, I, I’m a, I’m a cyclist, I, I, I like to cycle and so a couple of years I was in, ago I was in Tuscany and there was a lady cycling with me really competitively.

Actually she was also, she had been in in the, in the, in the British squad I think actually for the coming out nationally. And she was on Remicade because of rheumatoid arthritis. And she was basically cycling like crazy. And then you come from somebody in a wheelchair to somebody who can do top sports, right?

And, and that’s in my, in my, it’s in one career. And so people just don’t realize how much, you know, things have improved. And then I’m thinking back, why have these things improved? Is it because we have better doctors? Is it because we have nicer hospitals or better ministries of health or ministers of health?

No, no, no. It’s a hundred percent because we have better medicines. A hundred percent. So, people need just to realize that. 

[00:48:15] Where Sander came from

Philip Hemme: Amazing. Yeah. Yeah. I like that. And it it’s, it’s great. It’s a perfect shift also to more, to yourself, to the personal story. I remember I asked you in 2017 that I think I, I wanna Get a bit into this again, and I think it connects exactly to what you’re saying as in, I mean, you’re, you’re really having these different hats as in like professor biotech founder, but not just scientific founder or, or professor, the founder, but also we executive and at the same time VC, I, can you, like, I guess from what you explained as well, you, you, you’ve seen I guess a lot of things that works in the lab, but it gets never translated and never really reaches the patient.

So I can imagine, I think that’s also a bit what you told me, that it’s pretty natural, it was pretty natural for you to push and go towards there. And even at some point you, you were raising money, but you wanted to see the other side. And also when you have the control of, or you have the bite of money and you can deploy it, it also makes you act differently.

Can you kind of maybe reflect on, on all of that? 

Sander van Deventer: Yeah. Yeah. So, yeah, to come back, you know, I’m the luckiest guy in the world, so I’ve done fundamental science. I was a scientist at Rockefeller University. And then I was trained as a, I’ve done a lot of virology in already in the early 80s. Basically doing molecular biology in the very early days that you have to do everything here.

You had to do everything yourself. You had to make your restriction enzymes yourself in the cold room and stuff like that. So, then I was trained as a doctor, internist, gastroenterologist and all that. And then I got involved in drug development and You know seen quite some success there in, on the antibody side the antisense oligonucleus nucleotide side, the gene therapy side, and then, you know, got the opportunity to become one of the founders of, And actually before that actually already founded of course Unicure and then afterwards some other companies.

So I’m, I’m, I really am very lucky because I’ve seen it from all sides. But in the end, you know, you have to think about, you know, what drives you? Why do you, why do you do the stuff you do? And so, I’ve seen, I’ve, for 20 years I’ve seen patients, okay, so patients that are very, very sick and for which we could do nothing particularly the worst probably was HIV because we had a lot of that in Amsterdam and I was in the smack in the middle of it.

And we could do absolutely nothing for these patients. And then later, you know rumored Crohn’s disease. You know 100 percent of patients almost with Crohn’s disease got surgery. And 25 percent of them almost, and always ended with a stoma. With, you know, with, you know, that’s really bad if you’re a young girl stoma.

That, that, I’ve seen that a lot. And then you know ALS and, and MS and all these diseases. So. I was seeing patients in the outpatient clinic and often couldn’t do a lot. And so that’s why in 2004 actually I made the decision to switch completely because until 2004 I was also in the clinic.

And I was thinking, you know, where can I contribute more to the health and, and, and the benefit of people, of patients being sitting here doing, you know, 20 patients in a shift in the outpatient department or developing something. And I thought, well, probably with developing stuff, it would be better.

So. And then, you know, we did Clibira, we did Amgenix, we did this program, of course, in Huntington’s and and of course, New Amsterdam Pharma with CTP inhibitors and you know, many different things that we did, I think will benefit patients quite a lot. And if you think back and you think, you know, how many patients now have been treated with MTT?

TNF in one way or the other, it’s a lot, right? More than I ever could have seen in the outpatient clinic. So, so that is the good thing about, I think, where I am now. 

Philip Hemme: Yeah. And you, I was about to ask you when you, if you look back, if you do the math, it’s always also I guess you. Yeah, I mean, you have impact, but when you are treating a patient, you have also, you know, a direct impact and you need also people to treat patients and you need doctors as well to deliver the drugs and to do all the following, but I guess for you, it’s really clear that you had more impact.

Developing the drugs didn’t, but 

Sander van Deventer: I think so. Yeah. 

Philip Hemme: At the same time, you also got, I guess, I mean, there’s always some luck involved in, in biotech, as in like, I mean, the failure rate is just so high in, in, in your case, it’s, it’s not only luck of course, but No, no, we , yeah. 

Involved. And it’s amazing that you managed to.

be involved in two or three, four approved drugs within not even 20 years. It’s, it’s very rare, actually. I can’t. 

Sander van Deventer: Yeah. And, you know, there, you know, you always think back and you think, you know, what actually was really, a career you know, changing or, you know, what were the big things. So one was actually that I was lucky to run into, you know, a promoter you know, for my PhD project.

who was really a visionary. So he was, for all his PhDs actually, there was a like, you know, you really have to go here or there and that usually would be the United States or whatever or, or other places. But you know, he had more than a hundred PhDs and he, he has died. But I think his offspring is like, I think we had a sort of, gathering reunion or, and there were like, 30 or 40 professors who came out of this one man.

And so for, he said you need to go to the United States and you know, I, I did my PhD on bacterial endotoxins and it was when, cytokines became you know, and discovered. Ah, and so Charles Dinorello and and and Sarammi and Bruce Boyler and whatever. And so I, I became there and then, then I came in the United States and I was actually accustomed to the European sort of thing like you know, you said, well, it would be really neat if we would do this or that.

And everybody would say, yeah, but you know, you know, the risk or who says it will succeed or you cannot do that or whatever. And then I came in New York at Rockefeller and it was like. Okay so yeah, this sounds like a good, a nice idea, you know, we are, we, you know, new, and what can we do, you know, what do we need?

And that’s how it went there, you know, there were also struggles to get into the lab, you know, we had to fight for a bench, but on the other hand, you know, people were really supportive in, in, in, in basically saying, yeah, you know. Sounds like a really interesting idea. How, how, how could it be done? And so that changed my mind and I never forgot about that.

Philip Hemme: How could it work versus how can it not? 

Sander van Deventer: Exactly. Why it would not work. Yeah. Oh, 

Philip Hemme: that’s, that’s nice. And I guess you, you kept some of this mindset even though you returned to Europe. 

Sander van Deventer: Absolutely. Absolutely. 

Philip Hemme: Yeah. I like it. I can second this. And I mean, I went, I was one year in, in, in Boston to finish my masters and say my, Especially in Boston, especially like it was 2013, 2014 was an amazing energy, vibe, everything.

And I learned also a lot from there. 

[00:56:14] How to have the energy to be a serial entrepreneur

Philip Hemme: Maybe just from the last, last point, which also fascinates me as an entrepreneur as well, is that you still have like crazy amount of energy to go again and to build again a company. It’s, I mean, it’s so difficult in any kind of company, but in biotech it’s so complicated.

I guess from what you said, there is impact behind and there’s a lot of motivation, but can you explain a bit there, like how, yeah, how do you manage to just still keep going and then going again? 

Sander van Deventer: Well, I do not really have an answer for that, but you know, there’s a couple of things I have very rapidly get bored.

And you know, also here at the universities in the Netherlands, you would get a compulsory retirement. Yeah. So I was just basically. Yeah. Yeah. Very, in a very, very friendly manner, actually told to, to not to show up any longer. They were really kind. I mean they were really, you know, they were, but they have to do that sort of stuff.

But yeah, I mean, listen I, I, I, I had a good friend dying from ALS. Then two other people I knew also died from ALS. So at some point in time it came. Yeah, I, I realized that particularly also because this pathology became apparent in the last five years, I think, wow, if this is the case, then, then, then I, I think I know what, what to do about it.

And so then I thought, yeah, if I know what to do about it and we have the ability to do it and almost obliged to do that. And it’s great fun. I mean, it’s just great fun.

Philip Hemme: Amazing, Sander. We could continue, but I think you are pretty packed schedule, so it’s 4. 00. 

Sander van Deventer: Okay, well, great. 

Philip Hemme: Thanks a lot for joining again. Thank you.

[00:58:15] Thanks for listening

Philip Hemme: Wow. Wow. Crazy, crazy discussion. It’s amazing what he has achieved and what’s behind. I loved how he’s really super focused on the patients, but the clarity to develop it and really focus on impact. Really, really inspiring. I mean, we need. Well, Sanders for Europe and for humanity. Super inspiring. Thanks for staying until the end I hope you enjoyed it as well.

If you did, please hit the like Subscribe button if you’re on Apple podcast or Spotify You can also leave us a five star review Any of these actions would help us a lot and I would also be curious to hear what you think So if you’re on on YouTube or Spotify, you can comment directly or you can send me an email at philip at Alright, catch you in the next episode.

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