Pivoting To RNA With Circio's Dr. Erik Digman Wiklund

No wonder that so many biotech builders pivot begrudgingly only when they have no other choice , their hand perhaps forced by a board . Better , in my opinion , to be a proactive and optimistic pivoter , one who embraces the pivot and who pivots not in the direction of the path of least resistance , but in the direction of the path of most opportunity .

I'm Matt Pillar and I'm Anna Rose Welch , and on this yet another RNA-centric episode of the Business of Biotech , we're talking with a renaissance man who's been busy perfecting the pivot . Dr Eric Digman-Wiklund is CEO at Circio , a circular RNA developer .

That's the product of a recent pivot that we'll learn about today , but we'll also learn about some of Eric's preceding pivots and those he sees coming next , as RNA and the circular variety of RNA continue to make waves in the space . Anna Rose, I don't know if I've ever , if you count all the times that I said pivot in my life .

I don't think I've said it as many times as I have I'm not going to lie , there were moments there that felt almost Shakespearean .

And , as you know , I kind of like to start these conversations off with sort of some background for context on the perspectives of my guests . So I want to rewind a little bit and start with you . It's not uncommon for me to interview biotech builders who began their careers at McKinsey .

In fact , just a couple of weeks ago I was at a conference having a conversation with Udit Batra , who's the CEO at Waters , former CEO at Millipore Sigma . He started McKinsey .

There are probably I could probably count like a dozen guests that I've had on the podcast who started their careers at McKinsey and it's interesting to hear about how that perspective , that early perspective , kind of shaped the worldview and the next steps for the biotech builders that have started there . So tell us about that experience from your perspective .

You need to get all the details right , and once you step out of that and go into management consulting in a place like McKinsey it's the opposite in many ways . You need to quickly figure something out and you need to move from one topic to the next .

So I think you learn to structure and analyze information in a quicker way and get up to speed more quickly , and you need to be willing to do some hands-on work yourself . I think that drives very well with being a biotech executive and CEO , because because one , you need to be strategic . You need to understand a lot of different areas .

You need to understand everything from manufacturing , regulatory , pre-clinical development , clinical trial , design you're involved in absolutely everything and you also need to roll up your sleeves and do a lot of the the actual hands-on work yourself , and that's probably more lost in a larger corporation .

You probably stick more to your department , and when you're at a strategic level , you may no longer actually do so much hands-on work yourself . So maybe that's why a lot of McKinsey people like the biotech world because it gives you this opportunity to be involved in everything . Wear many hats .

Because when I look at your resume , so to speak , right like your LinkedIn profile , when I look at your resume , so to speak , right like your LinkedIn profile you left McKinsey to lead post-acquisition integration of Algida into Bayer and it seems like , okay , well , this guy is solidly on track to be a dealmaker in biotech .

But your next position after that was in product development with a krill-based nutrition supplement company . After that was in product development with a krill-based nutrition supplement company . You did that while simultaneously founding and launching a dinner kit cooking concept .

Which is amazing , that's just awesome All the while running a successful of all things photography business . So it begs the question , like anyone looking at your CV is going to go like well , what was this departure on Dr Digman-Wicklund's trajectory ?

I went to Algeta , as you said , after McKinsey and my role there was initially in strategic planning of manufacturing for the future and then quickly the Bayer acquisition came up and I spent significant time at Bayer during my consulting year so I knew that organization well .

So I think that's why I was selected to do this integration project between the two organizations . Now I also learned from from my time as a consultant that I'm much more of an entrepreneurial person than a big corporation person . So I also kind of knew that I didn't want to stick around there .

So I could say I integrated myself out of the resulting merged entity in Norway . But overall that merger was very successful and to this day Bayer retains a substantial I think two thirds of the team in Elgeta . They've put their radiopharma research hub in Norway .

So we were able to make sure that a lot of the team in Elgeta they put their radiopharma research hub in Norway . So we were able to make sure that a lot of the value was retained in Norway . The manufacturing is still retained in Norway . But I then went on to other things , as you said , and my plan actually was to not have a boss again .

So I decided look , I'll try and start some projects on on my own . I can work when , uh , when I feel like it , instead of having a boss . And I had the six months garden leave and and uh salary anyway from later . So then I I started a few things off . I I'd always been the keen photographer and and worked on that . So I and the professionalized .

That was a way to earn some revenue fast because I can take sort of wedding photography jobs and these kinds of things . I do that with my wife , so it's a fun thing we do together . And I started this dinner kit concept simply because actually the selection in grocery stores in Norway is terrible .

So we wanted to make a food concept suitable for people who want to eat good food and busy lifestyles with , with , with kids . So so we we started that with uh , with four of my friends and that's still a thriving business and I'm not no longer operationally involved but I chaired a board and help out in fundraising and the company is doing well .

And I set up also a consulting business to do projects and that consulting business is what led me into the krill arena . Some former McKinsey colleagues worked in an Omega 3 company in Norway . So in Norway pharma and biotech is a really tiny , tiny industry . Energy , seafood these are the large industries in Norway .

So I also thought maybe it makes sense to position myself a bit more towards seafood and nutrition , simply because it's a bigger market , more jobs available in in norway .

So I started off taking some projects and that eventually evolved into uh , into a full-time role with the , with the , with the company actually to make protein powder like for sports nutrition from from krill . That was the . That was the project we're working on yeah , yeah , no , that's really cool .

And in 2017 , he was looking for a CFO and contacted me .

So then basically that was too difficult to turn down Some of my old colleagues at that time immunotherapy was super hot , we were developing an oncolytic virus , which was also in vogue , and even though I've been doing a bunch of different things , I've always , since I was a research scientist , I envisaged that at one point in my career I'd want to be a biotech

ceo . Seemed like a really fun thing to do and I've kind of kept that in mind , sort of make make career decisions that could move me in that direction . So when a cfo role came around , I I thought that was a great opportunity to to learn some more , the , the finance ropes , plus . Plus , I knew the CEO well .

He had been the CFO of Algeta , but a non-scientist , so we had this kind of symbiosis where we could learn from each other . He was a mentor in terms of the finance and fundraising aspects , and I could be supportive on the science side for him as a discussion partner .

So that's how I ended up coming back to biotech and oncology in the end after all , even though I purposely tried to get out of it for a while .

They fundraised , got off to a pretty good start and ran a an exploratory trial , phase one two trial program , which had been that was starting when I joined , and so the first part of the time at TargoVax was to execute these clinical studies , get the readouts and then move the company on .

Now I think what happened is that both cancer vaccines and oncolytic virus , which is what we were developing , went a bit out of favor . Cancer vaccines are maybe having a bit of a renaissance now , but unfortunately several clinical failures made it very difficult to finance . So it's difficult to excite investors even though we had good data .

And then in the middle of the development we were focusing that cancer vaccine , that's a vaccine targeting KRAS mutations in the resected pancreatic cancer setting . And right in the middle , when we were planning our phase two program , the standard of care changed dramatically , extending the expected survival .

So we were then looking at having to do a survival trial where expected median survival would be between four and five years , and that was just impossible to you to fundraise for . So we would just put our vaccine on top of whatever was the standard of care .

But you can't get an investor to put money into such a program where it's going to take six , seven years before you have a definitive readout . So that's going to pull the rug under that program a little and we had to step back and as we did that sort of realized we need to pick a new indication and restart phase one .

In many ways we also decided to upgrade the product itself . So we took two years to modify both the formulation , the adjuvant we used , as well as find other combination strategies and then put it back into patients last year . So now that program is actually returned and I think cancer vaccines are a bit more in favor these days . So that's been resurrected .

So that's been resurrected . The other program , the oncolytic virus program that was really when we started a field that was very much involved . People were quite excited about oncolytic viruses but then slowly there were readouts that were negative . Tvec from Amgen hasn't performed commercially as well as was anticipated and people became really skeptical .

So I think what happens is the burden of evidence required to move on or get fundraising or a partner , changes or becomes more substantial . So when the program was started , this was hot stuff . So people , let's just do a quick trial , 20 patients get a signal , then we can partner out the program . That was the thinking .

But when that work was done , people wanted to see 100 patient data , preferably randomized data , to be able to make a decision , because a small trial simply didn't cut it .

Even though we had strong data , I would say it wasn't a large enough data set or robust enough that we could get sufficient interest to pursue it and then , unfortunately , we just had to pull the plug on that program .

We were able to fundraise maybe a third or half of that , but then we decided , look it's uh , doing another sort of half-baked , not properly sized program . We know it's going to be hard to partner this out . It's only worthwhile if you really do it .

We still had some , some funding left and at that time I I , of course I worked on circular rna back when I was a researcher and published some of the very early circular RNA papers , together with a very talented colleague of mine , thomas Hansen , and we published an initial paper in 2011 . And after that it became this big thing .

So this evolved into big fields . So I sort of tracked over the years , big fields . So I sort of tracked over the years . And then in in 2019 , it was shown that you could use circular rna to to make express proteins in vivo .

And then in 2021 , which is just a few months before we were in this situation , orna had launched , yeah , with their synthetic circular rna program , followed closely thereafter with a massive financing round . So suddenly circular RNA was this ultra hot thing , yeah , which I naturally wanted to get into . So I pitched this to the board .

I said , look , I know circular RNA , I can recruit Thomas , who is our founding scientist of this field and is very knowledgeable , and we can build a circular company instead of of pursuing these legacy immunotherapy assets , and the initial thinking was that we could use the viral vector we had .

So for the , the oncolytic virus program is based on an adenovirus , so we had substantial adenovirus knowledge in-house . We had access to a clinically validated vector , and the initial idea was to make that adenovirus express circular RNA , and circular RNA has the advantage of being more durable . It'll hang around in a cell for longer and it makes more protein .

So we thought this would be an interesting tool to to use to to make a virus for cancer that can express a therapeutic payload at higher levels for longer . Yeah , and that was .

I had two conditions to to take the job uh , in 2021 , and that was one that we move in this circular RNA direction and two , that I could recruit Thomas to the company , because it would be impossible without having someone with deep scientific knowledge .

The second one that Anna Rose joined me on , that was RNA focused with radar therapeutics and I didn't give you like for listeners who are like maybe missed the first time you recorded with me . I never gave them an opportunity to like understand why you're here .

But we also do cater to and are always looking for content on the non-coding side of the industry as well .

You wanted to kind of continue the research in that with Thomas , but it also sounds like you saw a lot of benefits to sort of integrating it into the viral vector space , gene therapy space , right . So I'd I'd be curious to understand a little bit more of you know your interest in jumping into the gene therapy space .

Where were some of the biggest limitations that you were seeing ? Where did you really find that there was a good window for you guys as a circular RNA company to start playing in the AAV right gene therapy world ?

Yeah , so largely a virgin territory . So first of all , what you need is to build an expression construct that makes circular RNA and , of course , you start from linear DNA . So the viral genome is linear DNA and you need to put the recipe inside of that DNA so that the RNA that is transcribed circularizes .

So that's where we needed to start and in nature this is quite an inefficient process . I think it's been estimated that in a natural circular RNA locus in a human cell , for example , only about 5% of the RNA will actually circularize . The other 95% gets degraded or have some other function .

So in order to make sufficient circular RNA , it took quite substantial work to optimize the structure , design sequences , and over time we've improved this at least tenfold . So we built what we call CircVec .

This is a genetic cassette , double-stranded DNA that you can put into anything that is a DNA or viral DNA format and it will make circular RNA inside of a cell . So that's the fundamental technology that we developed . Now that's sort of independent of where you utilize it .

So the story we first told was that we were going to use this when we went to investors and partners .

Now we're going to use this circular RNA expression technology to make better oncolytic viruses , because we were an oncolytic virus company but I think we underestimated the negativity of the oncolytic virus company , but I think we underestimated the negativity of the oncolytic virus modality .

And then people saw us as oh so you're not a circular RNA company , you're just a turbocharged oncolytic virus company . I thought still , that would be pretty cool .

And then the more data we generated and demonstrated expression advantage , longer durability compared to expressing from mRNA , higher expression level , expression level I mean we get about 10 times higher protein outputs simply by switching from linear mRNA to circular mRNA when expressing a reporter or whatever , and in mouse models we see several months of longer duration .

So once we start showing this data to people , they say forget about cancer here , this you should deploy for gene therapy . Forget about cancer here , this you should deploy for gene therapy .

So our pivot to gene therapy was to a large degree driven by demand from companies and investors we spoke to just telling us that look guys , this is something I would really like to see being deployed in the gene therapy setting . And of course it makes sense .

The biggest hurdle in gene therapy is , besides the delivery aspect , is getting sufficient protein expression for good enough durability . So anything you could do to boost that expression is going to be an advantage .

And I know Tom Barnes , the former CEO of Aura Therapeutics you had on the podcast and he said that he was convinced that everyone over time is going to switch from in vitro transcribed mRNA to circular RNA , lmp package , circular RNA because it's simpler to make , it's cheaper to make it's more durable .

It's going to make more protein it's at least so far there is . There is no evidence that should suggest that you would . Once this is firmly established technology , why would ? You would stay with mrna . Everyone's going to switch , seems obvious , and I think you can extend that to any virus or dna-based therapeutic .

In the future , everyone will switch from linear mRNA to circular mRNA . Everyone is going to switch from mRNA-expressing vectors to circular mRNA-expressing vectors because they will make more protein with better durability .

Now , manufacturing cost and complexity . Now , if you simply make the switch where , instead of expressing your genetic payload of the AAV from mRNA , express it from circular RNA and that helps you boost the protein output , that would be a massive advantage and our data suggests that we can get to 10 , 20 , maybe 100-fold better protein outputs from an AAV .

If you can reduce the dose of AAV gene therapy by 10-fold , that would be a big thing . That would mean lower cost , more accessible to patients and suddenly you can treat more diseases .

We know that data drives confidence in the investor community , in the scientific community , in your own internal community , but when you made the decision to make this change , this circle or pivot , it was pre-data .

So I'm curious , from a business leadership standpoint , what other resistance you may have faced and had to work through prior to having that data that kind of generated the direction right , that created the impetus for like okay , well , this is where we're going to go with this . What other resistance did you have to overcome and how did you overcome it ?

So it had been on the stock exchange for a long time and , of of course , there were many tired investors because they had invested in clinical stage programs and these had kind of I wouldn't say failed data-wise , but not sort of materialized into later stage development and the share price had fallen .

And there's not a lot of sophisticated biotech investors in Norway , norway . It's hard enough to understand the clinical stage program .

But when we come then , suddenly now we're a company working on early rna platform , uh , that generated , I think , a disconnect with uh , with the , the shareholders we had we had at the time , and also when you're listed I think most listed companies , at least when you've been listed for a while you really need to be in the clinic .

That's the right time of development . So it's not ideal to be an early preclinical stage company and listed .

So we were grappling with how to square the circle where the investors we have are not really that interested in investing into this type of early stage technology or platform , and then that's much more attractive to VCs to come in early Seed investors and VCs that's what we're really after , but they don't buy listed shares .

So from the get-go , when we set this up , we built it as a privately held subsidiary and , for a variety of reasons , we set that up in Sweden via a lab at the Karolinska Institute , so we already , from the start , incorporated this as a standalone entity within the group .

It's still fully owned by the parent company and then you could view the listed parent company as the seed investor . So the listed parent provided the funding to set the company up , generate that first data Because , as you rightly point out , it's difficult to fundraise on a slide deck . It was maybe doable 2020 , 2021 .

So I think we're kind of building this as a private company which we will eventually finance and spin out when the data package is mature enough , when the parent is no longer suitable or capable of funding it to its full potential . I think that's time to let that ship loose from the group . And then the group holding company continues to run this .

Kras cancer vaccine clinical development .

When there is plenty of US , they don't even have time to review all the opportunities that are available . So it's certainly been trickier . The last thing since the COVID bubble burst , it's been harder for the Nordic or the European companies to get a lot of meetings and interest in the US .

I'm not saying it's zero , but it's less than it was before , whereas in Europe I sense the opposite . It's zero , but it's less than it was before , whereas in europe I sense the opposite . And now you you tend to see higher valuations in the us .

I think many european vcs are to some degree preferring local investments because they see it as an opportunity to to get the better valuations are you sorry ? yeah , so all the investors we speak to , I'd say about about 70 80 percent are european .

Where is some of that resistance , do you think , coming from ? What are some of the biggest challenges you're facing in engaging the investor community today , particularly as you're working with circular RNA and potential viral delivery right ?

When you come with a circular earning program , everyone wants to listen . This is just something everyone is really curious about these days .

I would say the biggest difference from a couple of years back to now and challenged to some degree , is it's much harder to sell a platform now or to get investments into a platform , and that's , in its essence , what we're developing . Our tool is Circular RNA Expression is a genetic cassette that you could put anywhere .

It can be used to whatever you want to express from a DNA or a virus or even in a VLP context . So it has a lot of versatility and I don't think we've come to the point where we reached its maximum potential and we still think it can get more potent than it is . And at the same time , we're still testing where does it work ?

Which vectors are the best ? What tissues are the best ? So this we still need to figure out , but investors these days want the therapeutic candidate . You need to have a lead program . It's coming with a platform place is difficult to get money out of the bag for .

So we need to have two thoughts in our head , because it's crucial to keep expanding , building understanding , developing the platform , but , at the same time , having a therapeutic lead spearhead which clearly says this is the direction we're going . This is how we're going to get to a clinical proof of concept .

It's the lowest technological risk , it already works , clinically validated , manufacturing is understood , it's approved for several and it has a lot of caveats . So we can improve on this . So let's , let's see if we can simply is improve on existing aav technology . You take aav express a payload by a circle and use an mRNA . That's the only difference .

Everything else can be the same . So you could then develop something . Just go head-to-head against an existing gene therapy . Take an AAV gene therapy and switch to our expression system , reduce the dose . If you could do that , then show just in a non-inferiority trial . I think that's something that could be approvable . So this is where we started out .

Then the question is , what is the best disease to pick ?

And do you either go that direction where you try and go head-to-head against something that's already existing and reduce the dose , or do you pick something where AVs weren't sufficiently effective in the past and then switching to a CERC RNA could get you over the threshold to make it clinically relevant , right .

So that's something we debated back and forth and I think both options are still in play , but in the end we opted for the latter because once you start to go head to head against something else , you need to do randomized trials and gene therapy .

It's often diseases with very few patients available , so we prefer to go to something that is still virgin territory . So we decided okay , let's pick a disease where A-avials have been tried but didn't make enough protein so we can boost the expression level and have a successful therapeutic product that way . And from there on we were all oncologists .

Mainly the cancer is there , we knew . So we had to sit down and learn about genetic disease . So we screened the genetic diseases you'd never heard of two great study parties we had we had a very talented analyst at the time was it was excellent at compiling this information in true mckinsey styles , a perfect mckinsey project .

Right coming back to that quickly , sort of making five pagers for each disease and have a good heat map where you can score what is the better and worse options , and then in the end , we settled on a short list of disease targets , all the while working on the platform in the background .

I envision , like all these oncologists , anyone who's watching the podcast right now on the website can see that Eric is in his summer home near a fjord in northern Norway . Is that where ?

We built a super team over the years and then we had very little science . The labs had been shut down earlier because when you're in clinical development you have less need for that than the clinical data analysis was outsourced .

So we only had one or two scientists really and the CMC and clinical team team and that obviously that's not what you need when you're building a pre-clinical research organization . So very important , though it is important we built out one part of the company and built up another part .

So the , the clinical development and cmc group , is down to just one person in each . That's it . So that that's been .

That's been tough , but everyone right , I have a very sort of open dialogue and and never hide anything and tell people the truth and I think people , people understood the rationale and this is what has to be done , and then it's just the way things are . So there has never been any any grudges , or it's . It's sad , but it's . That's just the way it is .

And then in parallel we've built up a new science team in stockholm . So we've both been downsizing and recruiting at the the same time yeah , yeah , managing the balancing the demand right , yes .

We've added scientists and we have one more now and actually an American lady coming in after summer joining us in Stockholm to manage the lab there we're just moving into a new lab and so that side is growing . And in Oslo we're down to .

It's just me and finance , two finance people and myself , so we're just three people left in Oslo managing at least the company . So it becomes pretty complex , and then the rest of the team is scattered with the bulk in Stockholm . Yeah .

I think it's not until 2013 , so about 10 years ago , where it became obvious to everyone that this is a real , biologically relevant and functional class of non-coding RNA . And from 2013 onwards it's started growing .

Initially it was kind of an academic corner of people , a few people working on this until Alex Veselov out of the Dan Anderson Lab , which became the foundation for RNA , showed that you could use it to express protein in mouse , and then from there it kind of exploded a a bit .

But the point I'm getting it as that it's only 10 years since it started and I think for the first five of those , very few people worked on it . So it's extremely hard to find any experts . There are very few scientists around who understand the , the biology of of circular rna , and and come with with experience in in the space .

So that's maybe what's holding back most the . The development is just kind of we're still playing catch up in in uh , but building down understanding and and also getting learning the scientific techniques to manufacturing and having enough people who are knowledgeable about it .

Obviously there can't be even in a small but hot industry , there can't be three or four or five people doing the exact same thing who know what they're doing in general , circular RNA , and then you've got to teach the platform , you've got to teach the differentiator .

So let's talk about that a little bit and that'll tee you up , anna Rose , to ask more questions about what Maybe what Circio is doing . We'll find out . But is it the in-situ production approach at Circio that is sort of the cornerstone of the differentiator there , or is there more to that story ?

And once you figure out that manufacturing it's a sensible thing to do because it's likely to be cheaper and better , that's what everyone jumped on first . And still , when I talk to even people I've had two or three meetings with and explain our technology , they still think we do that .

No one had just made that simple effort of making an expression system using circular RNA instead of mRNA from a vector , and we saw it as an opportunity , a virgin territory in many ways . And we're a small company , we're based in the Nordics , we're much less capitalized than these other companies .

Why go head-to-head against them when you can sort of have this niche that no one's taken and and rather be the the the big player in a in another area of of circular rna ? so we don't view these other companies like orna and sale and and now uh , orbital , as well as editors . This is complementary technology .

We are simply using circular RNA advantages for different purposes , and I'm only aware of one or two other companies and groups really working on the same approach as we are doing .

gave pause , right , I was like what is this ? How does this work ? So you know , I think that it is a really interesting and a competitive angle . But I also love this concept because I think in the RNA space in general , we're all talking about how we can create a pretty well rounded toolbox , right , it's not just one modality , one method of development .

I think having this version as well could be a really interesting addition to that .

Yeah , when you're talking gene therapy , you need something that can express a payload for years , at least months . So we're just solving different problems here and I think we are enabling circular RNA to be utilized for new things .

You know , I'm curious , as you guys are working to sort of develop these products and position your science , you know , where are some of the biggest groundbreaking foundational research elements to CERC RNA that you really need , we need to see , or that you're hoping to make as well , to help , I'd say , you know , kind of heighten the way that you're using circular

RNA at Circio .

It will express the gene there for a long period of time .

So that means you can deliver stuff to the liver . So obviously that's where you start . First , the therapies . You pick diseases where , like either muscle or liver , which you can easily access .

But the moment you start being able to get these into brain art , other areas , you can start dealing with other diseases and inevitably that's where we're going to get to in the future . But we can't solve everything . I think you need to focus right on what you're an expert in . Some companies are vector companies .

They make the best vectors , like AAV engineering and having the AAV go where you want it to . Others are delivery companies making chemical compositions that enable packaging and targeting of molecules and therapeutics .

That way and we are the molecular biology we create genetic constructs and we are relying on partnerships to solve these other challenges are relying on , on partnerships to solve these other uh challenges .

So I'd be curious if you could share a bit more about how you're approaching partnerships today and in the the circ rna space , in that AAV realm . What are some of the most important questions that you've been asking your potential partners ? You Wasn't we asking ?

You can't really redose them , at least not as it is now . But if you could deliver a synthetic DNA construct efficiently , that should be much more durable than an RNA-based therapeutic and also it should be redosable .

So that's sort of our long-term goal to make DNA format gene therapies expressing the gene that we're delivering from our circular RNA CERCVEC technology . So in terms of partnering , that's , of course , something we're very interested in meeting up and and collaborating with dna vector companies that have these technologies are starting to develop them .

Not not none of these have moved into the clinic yet , so this is all kind of early stuff , uh , but , uh but . But that's a high focus for us , in parallel with other delivery technologies , like I described before .

And and this is maybe more kind of a long-term goal , of course we need to keep in mind , like I said before , what's our lead therapeutic candidates , and there we're still prioritizing aav because it's something we believe that we can fix fast . It's much more straightforward and you don't need all these other moving parts to work together .

You can sort of make a simple switch to an AAV and have it work . So there we're looking to partner with any AAV company . Really , I think once we show this works and we can improve on the protein output from an AAV , every single AAV company should be interested in this technology . Why would you want to from an AAV ?

Every single AAV company should be interested in this technology . Why would you want to make an AAV expressing for mRNA if you can do it via circRNA and get more bang for your buck ?

So there , I think we're trying to make ourselves attractive for AAV companies and we're looking for collaborations in that space and , of course , in parallel , advancing our own AAVs .

It's a disease that gives symptoms similar to COPD you get breathing issues and also it has a liver aspect to it and it's a unique genetic disease because you have a mutation and that mutation results in a misfolded protein and that misfolded protein one it accumulates in the liver . So over time you get liver toxicity and it can be very serious .

Patients need a transplant in the end and then the lack of the functional protein causes these problems in the lung , like the COPD-like symptoms . So it's a unique genetic disease where you need to deal with two problems . You need to both remove the toxic form of the mutant protein and you need to replace the functional one .

Because we use circular RNA in our expression , we can do this trick where we're able to knock down in the patient the mutant form and replace from circular RNA the functional variant , and it's only a single nucleotide difference between the two . So these are extremely similar .

But because we use a circular RNA for the replacement of the functional protein and naturally in the body there will be an mRNA making the mutant form in the patient , we can distinguish the two very cleanly knock down one , replace the other .

So I think that's where we established a unique selling point USP , and with our CERCVIC we can do what we call remove and replace , so we can have dual functional gene therapy , where we shut something off at the same time as replacing the wild type , and therefore we purposely looked for these type of diseases where you need to solve both of these problems , and

that would be really hard to do with any classic mainstream AV or gene therapy . The only other technology that could deal with this in a similar way would be gene editing , which is exciting but also very early . So in that regard , maybe gene editing is our real competitor , not another circRNA company .

Long story , but remove and replace gene therapy for AETD and beyond . That's where we're heading .

Cystic fibrosis is another one where you both want to remove and replace at the same time , and we're looking at several other candidates that we haven't disclosed yet .

You could pick other targets as well , where you're able to here modulate pathways to boost the potency of your therapeutic yeah we're running a little bit tight on time here at rose , but I don't want to .

I mean you , you've mentioned , uh , there's a lot on the agenda , right , You've mentioned , uh , there , there's a lot going on there , uh , in in terms of what , uh , what Eric's going to do next , like what's the next immediate challenge that you , as the leader of Cirqueo , uh , are compelled to wrestle to the ground ?

As the leader of Cirque are compelled to wrestle to the ground .

Here we should use it with this type of vector . So I think it's important to balance here the platform versus the product candidates and , like we pivoted before , I think we need to be ready to pivot in the future . If we come across something that looks more promising .

We need to be ready to switch because we still don't fully understand the potential and the best applications . We have a pretty good idea , I would say , we know which direction we're going in , but we're certainly not married to that and ready to switch when the time is or when the data calls for it .

So , having having lived through this and being that guy who , who does it optimistically and proactively , embraces it and who lives it , too right .

Being too focused for too long can get boring , but some people are more like that and then maybe biotech is less an ideal organization or industry to be in .

I think you need to kind of love this fast-paced , dynamic aspect , see new opportunities when stuff inevitably fails and other things work and unexpected things happen and you need to be able to quickly adapt to that and let it guide you and don't roll over and die .

We'll let you get on with your day , but I appreciate you coming on and spending some time with us . Yes , thank you .

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