Circio Holding ASA (CRNA) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to us at Circio and beautiful Oslo today. My name is Erik Digman Wiklund. I am the CEO of Circio. And I have with me today CTO, Dr. Thomas Hansen. In this webcast, we will provide an update on our R&D progress, including very exciting AAV data that we have recently generated, and we will also provide a corporate and general market update. So first, let's start with the market update. The circular RNA field is rapidly expanding, and it's an area of large interest in the biotech and pharmaceutical development space. And that is because of the intrinsic advantages of circular RNA, notably the ability to extend durability and expression level over what's possible with current mRNA technology. But it's a young field. It's really only existed commercially in the therapeutic space for the past 4 years. And we've shown this slide before and made updates. We want to point out that 2025 has so far been an exciting year for the circular RNA field. It started early in the year with a substantial licensing deal between Vertex and oRNA Therapeutics. I'll come back to that in a second. And back in April, the first patient was dosed with a circular RNA therapeutic by the Chinese biotech RiboX. And they're deploying a circular RNA that is LNP-formulated to treat dry mouth disease. It's an oral delivery. It's a big milestone for circular RNA. Now it's for the first time entered into the clinic. I'd like to briefly touch on this deal between Vertex and oRNA Therapeutics. This was a deal that triggered a $65 million upfront payment and substantial milestones. And it's for a really early-stage preclinical platform concept, whereby Vertex plans to deploy the oRNA technology in genetic blood diseases. Another interesting deal that we think is relevant to Circio is an acquisition by Novartis in the gene therapy space. So Novartis acquired a company called Kate Therapeutics late last year for just over $1 billion, and Kate was developing a novel AAV technology, so that's a gene therapy system for treating muscular genetic diseases. The lead program was in a disease called myotonic dystrophy. And incidentally, these are diseases we have also identified as particularly suitable for Circio. And again, this is a preclinical stage deal that triggered a substantial M&A transaction. So I think this illustrates the substantial commercial potential in the fields we are operating even at a relatively early preclinical stage. So Circio, we have a unique and differentiated technology platform. As I am sure most of you are aware, we are not directly competing with the other circular RNA companies and that we are not generating circular RNA that are in vitro transcribed and synthetic. We are building an expression system that takes the advantage of circular RNA into the field of gene and potentially also cell therapies. So our lead program is to enhance and create next-generation AAV gene therapy, whereby circVec can help make the AAV more potent and more durable. We have identified muscle and cardiac genetic diseases as particularly relevant to Circio in this -- and the circVec technology in this context, and Thomas will come back to that. And the diseases we are targeting have a patient population of more than 150,000 patients, which currently have no good treatment alternatives. So next-gen AAV, that's the lead focus. We have showed you earlier this year that we see a very interesting distribution and advantage of circVec in spleen. So spleen is the organ where immune cells reside, including T cells. And we see this as an opportunity to develop circVec for what's called in vivo CAR therapy, in the CAR cell therapy done directly on the patient, which is a field that is exploding at the moment and several programs are entering into the clinic. And this is what we view as our second leg, next step in our program, and we're really at the moment, trying to identify potential partnerships in this area. So with that introduction, I hand over to Thomas to take you through an R&D update.

Thank you, Erik. Thank you all for tuning in this morning, and good morning, everyone. My name is Thomas Hansen. I'm the CTO at Circio. And I'd like to give you an update on our most recent in vivo work, focusing mostly on AAV and nonviral delivery. So basically, as Erik said, at Circio, we are developing a DNA cassette that inside cells will express circular RNAs and circular RNAs are very stable and durable. So expression over time will accumulate to much higher levels than if you just express a conventional mRNA. And basically getting that DNA into cells, you can use 2 different approaches. You can use the AAV, as Erik just mentioned, or you can use a nonviral strategy typically with a lipid nanoparticle LNPs or some other formats similar to that. But I'll focus on AAVs first. So AAVs is probably most -- it's definitely the most popular vehicle or vector for gene therapy these days. Out of 8 approvals, 6 of them are using AAVs. So it's extremely powerful of getting that DNA into cells, and that has been shown preclinically numerous of times, and it's seen here with approved therapies as well. However, it has a few caveats. So in certain scenarios, gene expression levels from the AAV is not sufficiently high for a clinical benefit. You will require typically high dose levels to get the clinical benefit, which then in turn drives up costs and it drives up toxicities and you will have safety concerns occasionally, and then it's not repeat dosable. So you can only -- it's only one treatment that you can have. And if the effect wears off over time, there's no sort of repeat dosable option with an AAV. But we believe at Circio, with the circVec cassette, we can maybe mitigate or resolve some of these issues, driving expression up per viral particle with the circular RNA cassette, we can hopefully reduce dose levels or increase clinical benefit. So we still believe that the AAV is a very attractive format in gene therapy, particularly using circVec. So the approach is in a way, very simple. So this is the standard approach. Using an AAV, you have the AAV DNA genome within the AAV capsid. Inside cells, it will express mRNA, linear RNA that then in turn encodes a protein of interest. Of course, at Circio, we are manipulating the AAV genome in a manner. So once the AAV gets into cells, it will express a circular RNA instead of the linear RNA. And the circular RNA will have this enhanced durability. RNA level over time will increase to very high steady-state levels, and that will enhance expression of that same protein. So it encodes the same protein. So that's the same, but the intermediate RNA is different and much more stable using the circVec technology. And we envision that we can enhance expression by at least 3 to 5x using this technology compared to a messenger RNA and that would either translate into a better clinical benefit or a dose-bearing regime, so you can dose at 5x lower doses, leading to more safe therapeutics. In vitro, when we test this in cell lines, we do see a benefit from circVec here at the earlier time point after 2 days after you transduce cells with AAVs, we see a subtle increase using the circVec. But again, here, I just remind you that the stability of the circular RNA takes a while for that stability to kick in and you accumulate sufficient RNA quantities within cells to see the benefit. So if you wait a little while longer and look at expression after 4 days, you see here already a 2x improvement using circVec over mRNA or conventional AAV approaches. So that's in vitro. So we've been testing multiple different circVec designs in vivo. We have -- as Erik said, we are focusing on muscle and cardiac tissues. So we have devised an AAV that has a relatively good tropism for muscle. So it will mostly talk target muscle tissues. And then on top of that, we put a muscle-specific promoter that should drive mostly or predominantly gene expression in muscle and cardiac tissues in this case. So what we observe when we measure over time, expression of, in this case, [Firefly] luciferase in these mice that have been subjected to an AAV encoding mRNA, which we refer to as the mVec AAV or an AAV expressing circular RNA, which in this case is the circVec AAV in purple, you can see an increase, albeit not 5x higher, but a 50% increased expression here starting from day 60 roughly and then consisting sort of throughout the experiment here, which was terminated at 6 months after the single dose injection with 4 mice in each group here. So we do see an advantage, not as high as we may have hoped, but this is still work in progress. But definitely, when we then look a little bit more into detail postmortem with these mice. You can dissect the mice, take out individual organs and see expression from these individual organs. And here, we definitely see a higher on-target expression from circVec in different muscle type tissues here exemplified by the diaphragm and the heart showing higher circVec expression. But I think what is much more notable and interesting in this case is off-target or [DT] expression in unwanted tissues in this case, for instance, the liver, you see much more mVec expression suggesting that all this quantification that we are looking at in the whole body of the mice may mostly emanate from on-target muscle like or muscle-based expression using circVec. So I think there's -- already in this experiment, there's a lot of interesting conclusions to be reached, and we are, of course, following up with more advanced and next-generation circVec vectors to see if we can boost expression even further. However, what is even more exciting and some very, very recent data is when we then turn to a hard specific expression system. So what we've seen in the past is if you have low dose expression or low expression potency in your vector system, that is where circVec generally outperforms mVec the most. So in a low-dose setting, we see much higher full change between circVec and mVec compared to a high-dose setting. So similarly, if you turn to a system where you want very tight expression of your payload of interest, this typically also means that you want a less potent expression system. And in this case, where we have a heart specific expression system, expression overall is not particularly potent, but it should be very heart specific. Then we all of a sudden see a sort of a dramatic difference between mVec and circVec. Here, we trial different circVec designs and one mVec design. So here, you just see the overall in vivo images of the mice over time. So this has been going on for almost 2 months. And you can see a dramatic difference between circVec and mVec, where we paint signal from circVec but a broad and very potent signal from -- maybe I misspoke here, a very pain signal from mVec and a very broad and potent signal from circVec. And if you quantify the signal, you can see up to 35x higher expression from circVec in, again, the low-dose setting. So here again, we see much higher expression from circVec in low dose compared to mVec, and we see almost a 10x higher expression in the high dose. And just point to the fact that even here in the low dose, which is a tenfold reduced dose compared to the high dose, we actually see higher expression from circVec compared to the high-dose mVec. So at face value, you could imagine that you can actually reduce dosing here tenfold and get the same benefit. So this is exactly what we've been looking for. And this, I think, is a very encouraging results already there. However, we have been noting, we did notice that expression is not heart specific, particularly not at the early time point. So we tried computationally to look at expression profile sort of over the body of the mouse. So if you take a cross-section from the head to the tail and sort of monitor the profile of signal, you can see that there's a relatively broad distribution in the beginning here at day 10. But if you follow the expression profile over time, you can see that signal seems to be more and more concentrated around the middle here. So the gray area is the heart region, and you can see heart-specific expression from both circVec vectors here at the later time points. You can also see that on the images here that you have a more localized expression in the heart that also seems to be much higher than mVec. And if we quantify that signal specifically, we also see a significant increase from circVec in heart-specific expression. So here, 3x higher in the high dose and 10x higher in the low-dose setting from circVec and both of them highly significant improvements compared to mVec. So definitely, this is a scenario where we believe circVec will provide a tremendous improvement over conventional AAV expression vectors. So this leads me to sort of the first conclusion with our efforts to develop circVec in AAVs. So we clearly validated circVec, it works well in the AAV format, and we are moving on and testing multiple designs. And specifically in scenarios where we want very specific tissue expression. This is where we believe circVec has the highest value. But of course, we are -- we believe we can improve this even further. So this is not the end. And as I showed you here, in the heart, we can get up to a tenfold increased potency versus mVec in this heart-specific AAV scenario here. And we're looking into other tissue-specific AAVs. So I guess that's on the next step slide here. Further exploration, further enhancement of tissue-specific circVec expression that may open up new avenues for circVec in the AAV space. And of course, with our lead candidate focus on cardiac and muscular dystrophies, we are engineering AAVs now that will express therapeutic payloads, and we are aiming to set that up in relevant mouse disease models for the next step to get a better -- to see whether the clinical benefit may actually be even better than the luminescence that we're measuring due to the fact that we have more on-target expression with the muscle specific promoter. Business development-wise, we are collaborating and talking to a lot of AAV specialists to allow access and get access to better tissue-specific AAV targeting capsids. And we are also establishing collaborations to get circVec validated in other external settings. So this is all ongoing, and maybe Erik will touch upon that at the end as well. Okay. So that's the AAV part. So moving on with the nonviral-based delivery. So this is also a very active space, and I think this is something we are working a lot on at Circio. And I think everybody believes that this is the future. This would, at some point, replace AAV as your preferred gene therapy design, but there's still some work to be done. And of course, we are trying to do our bit at Circio. What happens normally when we do our R&D is that we are working on this DNA design that we just referred to as plasmid DNA. It's easy to work with. It's cheap. We can propagate it and we can manipulate it in-house. It's all very easy to work with. But of course, it's not unfortunately a clinically grade plasmid or DNA design. But there's been a lot of development here that you can improve on the DNA design itself. So these next-generation DNA formats that are smaller, in some cases, you can also make them linear. And this seems to be less toxic. It's easier to get into cells, and it's just much more effective from a clinical and gene therapy perspective. So we have been studying what next-gen DNA format works the best with our circVec cassette. So these 2 different, the circular and the linear next-generation DNA vectors. And we've done quite a lot of in vitro work, but what I'll share with you today is some recent in vivo work where we injected these vectors into the hind leg muscle of mice and then monitored expression over time. And we have trialed 3 different formats and compared it to our plasmid DNA, which we refer to here as pcDNA3. So when we compare these different formats to pcDNA3, you can see 2 of the formats here in green and red. They may have an early advantage, very rich in itself a little interesting observation. But overall, it seems to be roughly the same level of expression you'll get compared to pcDNA3. This may still be okay because they're probably better from a clinical perspective. But what's quite interesting is actually one of these formats seem to actually boost expression from circVec. So there's something with this format that's particularly attractive for us. So we can actually turn out expression 6x just by replacing basically the backbone of our DNA vector. So the vector that we put in -- put on our cassettes into may also impact the expression yield that you get in the end. So of course, compared to AAVs, this is going nonviral has definitely some benefits such as you have a reduced cost. It's a much cheaper type of therapy. You can repeat dose. A nonviral gene therapy, as you may know, AAV has this upper limit that you can only put in 4.7 kb into the AAV genome. So that restrains what you're able to do, some genes are much longer than that, so that you cannot use AAV therapies for. And you get, of course -- but that's not an issue with nonviral-based delivery. There's -- I'm not sure there's any specific upper limit to how much you can express from a nonviral vector. And of course, compared to using nonviral RNA, DNA is much more long length and would have a much longer expression profile. So RNA is not really an approach for gene therapy where you basically are looking for lifelong therapies. So as mentioned, this is considered the future, but there's still some stuff that needs to be solved to get that -- to get effective delivery of DNA into cells using a nonviral approach. Here, viruses are, of course, evolved to do this very effectively. So we just -- we and others are working hard to get this solved. And we are, as mentioned, collaborating with other companies to enable delivery of our circVec cassette. So data that we may have showcased previously, but it's extremely exciting is when we collaborate -- here, we collaborated with a Spanish company, Certest to encapsulate our DNA vectors in LNPs through their proprietary LNPs. So on the left-hand side, you see plasmid DNA actually. So this is the old plasmid DNA format encapsulated in LNPs. And here, in this case, expressing mRNA. And then on the other hand, to the right here, you see the same LNP, plasmid DNA again, but this time, expressing circular RNA. So if you first look at the mRNA, you see already at day 2, very high expression in the liver that then is dramatically reduced already at day 7 and at day 23, hardly detectable anymore. And that seems to be then continuing all the way until the end of this experiment, which was 3 months after the injection roughly. However, in contrast, when we look at circVec, you can maybe imagine the distress we had at circVec when we looked at the mice after 2 weeks. No signal in the liver, nothing was appearing. However, we -- luckily, we were patient and we were waiting. And then at day 23, you see signal starts to appear and it accumulates and you actually see very high signal here, 1.5 months roughly after injection. And this signal we have validated is from the spleen. And as Erik mentioned, spleen is the organ where all the immune cells resides, including T cells. So this is, of course, a very interesting observation for 2 reasons, in particular, I would say. One is the more general circRNA biology that we're looking at here. As I mentioned, it's the same LNP. It's the same backbone vector. The only difference is whether it is expressing Firefly luciferase via a mRNA or via a circular RNA. And that in itself drives this dramatic difference. And these are -- this is exactly the scenarios that we are looking for at Circio that would differentiate our technology with conventional gene expression. And here, we're looking at the ability to actually drive high and prolonged spleen expression expressing using LNPs, which I believe is difficult and maybe impossible to achieve with a conventional gene expression cassette. Second of all, focusing on the spleen, this, of course, unlocks some therapeutic opportunities with circVec, specifically within the space of cell therapy and CAR-T therapies. So with that, that sort of concludes the nonviral part of the R&D session here. So we have identified a novel therapeutically relevant DNA format that actually seems in addition to be better and safer to a safer vector, it also drives up circRNA expression. So it has multiple benefits. And then we have confirmed that we get spleen expression from our circVec LNP, which is not observed with the mVec LNP that is specific to the circular RNA biology here. So ongoing work is trying to get a better idea of what cells in the spleen specifically are driving the expression of the circular RNA, which will, of course, also inform us what would be the best new next step and what would be the clinical avenues for this setup. And we are, of course, improving the LNP-mediated delivery. So we -- as you can imagine, we are now using this novel DNA format within the same LNP to hopefully drive up and get better expression in the spleen from circVec. So this is work ongoing, and we're also locating new and more advanced targeted LNPs and non-LNP delivery systems. And then, of course, we now will -- based on the spleen-specific expression, we are now establishing a platform for durable CAR-T therapies using our circVec DNA and the LNP delivery system as you see. So for business development, we have a lot of ongoing collaborations with delivery companies such as Certest, Entos,4basebio and actually also a couple of other companies with very interesting technologies that we are testing. And we're, of course, hoping to see something similar to what we've seen with the LNP, namely sort of tissue-specific expression of circVec that you would not -- that's not achievable with the conventional gene expression profile or gene expression technologies, and we are also seeking collaboration partners specifically in the in vivo cell therapy spaces. So yes, with that, hopefully, that made sense, and that was informative. And I'll now hand it over to Erik back again. Thanks.

Thank you very much, Thomas. So to summarize what Thomas just described, number one, AAV gene therapy. This is our lead program. We view this as the lowest technological hurdle, the quickest path to the clinic. AAV is a well-understood format. It has clear caveats that we can solve with circVec, and we believe we can faster more get into the clinic and demonstrate the advantage of circVec in a clinical proof-of-concept study. So right now, we've identified the specific advantage in heart tissue. We're exploring whether this also applies in other tissues. We see advantage in muscle, and then there are other areas where we expect to see the same type of difference. And this is really what we are after. As a next step, we seek to establish research collaborations with AAV companies, getting others to test circVec in their hands to see if it performs as we expect. Also, if we are able to identify multiple tissues where circVec has an advantage, it would not be possible for circVec developing everything in-house. So the strategy would then be to pick one or a couple of areas for focus in Circio and then we could partner in other tissues, other diseases or for other targets. And we're in constant dialogue with all the AAV companies, and we're now showing this exciting new data with the aim of moving forward to establish research collaborations. Second step, DNA cell therapy, whereas so AAV is the current gold standard. It's what worked best now. It's the fastest path to the clinic. DNA-based cell therapy or DNA-based gene therapy is the really exciting opportunity for the future. This is where the space is moving. But as Thomas described, there still are challenging -- challenges that need to be solved when it comes to delivery of the DNA vectors. And here, we're relying on partnership. We already established several partnerships to test delivery, and we have now identified a DNA format, which is superior to the plasmid DNA we use technically and which is something that can be brought into patients more easily than you can do with the plasmid DNA. So here, we are more relying on research collaborations. We provide one piece of the puzzle, and we need other companies to provide their complementary technologies and jointly, this can form therapeutic products that then we can develop forward together. And again, we have several collaborations ongoing. We expect these will read out data in the second half of the year that we will report as they become relevant. I'd like to stress here that absence of data for these collaborations does not mean they didn't work or failed. We also have a partner here to take into account. And sometimes, you simply need to redo experiments, you need to change the conditions and test multiple aspects of what you're doing before you have a clear answer. So that's simply the reason for that. And yes, just please be patient. We're taking one step at a time and progressing well. And as you can see here with the Certest collaboration, we already have some pretty encouraging results in spleen that really differentiates circVec and puts us in a different bucket that creates opportunities that are simply not doable with conventional mRNA-based systems today. I think that also summarized maybe the last point here, which is the delivery part. This is really the key aspect of the DNA and cell therapy and gene therapy. Getting your DNA cargo into the cell. We can make the DNA cargo better. Other companies are expert in the actual delivery part. So if we look ahead, here is a time line on some of the major milestones for the coming year to 1.5 years. We recently presented data at ASGCT 2025, which was last week in New Orleans. And that data has been summarized here plus some additional results. This incorporates now the upgraded AAV, our new DNA formats and delivery to specific tissues. I would say we received substantial interest at the meeting that triggered many discussions, which are now following up. So it's great to see that our data and results and progress with circVec is viewed as unique, creating unique opportunities and interesting to collaboration partners. Now as we look forward, we are exploring further the AAV tissue specificity, the new DNA format for spleen delivery, other delivery systems, as Thomas pointed out. So these will be important milestones. And another important milestone is going to be when we get this into more concrete disease models. Right now, our data is mainly with reported genes that allows us nicely to track expression, but we now want to switch this into demonstrating expression of relevant therapeutic genes and proteins in disease models. So if we go back at these collaboration deals and partnering deals we talked about before from at least what we see from the outside, having in vivo disease model feasibility data in addition to what we have now would look rather similar to what oRNA had available when the Vertex deal was done. So that package could illustrate that type of potential. Of course, we then we need to have that package and then discuss and then hopefully be able to enter into such deals. The Kate acquisition by Novartis for a muscular dystrophy AAV was probably a bit more advanced preclinical, still preclinical. That was following an in vivo disease model validation, so more robust data in, in vivo disease models. But with our current plan, that's somewhere we aim to be during first half of 2026 and then be in a position to potentially transact in a similar way. And I would like to stress that circVec is really a broad platform technology as we hopefully illustrated to you today. So here, there is not a single asset that you sell and then you're done. We can easily do one or multiple partnerships and still retain sufficient technology and carve-out aspects for ourselves to develop. So we really aim to do in-house development, get into the clinic, our own programs at the same time as out-licensing the use of the circVec technology in suitable settings. Finally, I'd like to touch on the AGM notice. Our AGM is scheduled for 5th of June. That's next Thursday. You may have seen yesterday that we had initially proposed a capital reduction and reverse split. So this was to deal with the share price having fallen below NOK 1, and there is a regulation that mandates the Board needs to take action to bring the share price over NOK 1. We -- in light of the situation we are in and the strong data that we have generated, we see strong interest for the company in general. We, together with the Board evaluated the situation and believe that the moment is better to withdraw these proposals. We are, of course, currently exploring all alternatives. We're closely monitoring the situation. So this will be revisited and dealt with as we move forward. We have also proposed a mandate to the Board to issue 40% new shares. And I'd like to provide a little bit more color for that around that. Many shareholders see some concern in this. They prefer it to be lower. I would like to stress that this is important flexibility for the Board and the company to be able to attract financing. As an example, back in December, we had substantial demand to participate in our warrant exercise period and we executed a small private placement on the side. There was actually substantially more capital available at that point, which we were not able to take because we exhausted our mandate for 2024 in full. So had we had a larger mandate at that point, we would have been able to raise more capital and rely less on the Atlas financing facility. Therefore, we believe it's in the company's and the shareholders' interest that the Board has more flexibility to issue shares to be able to capitalize when the market may open. Right now, conditions are tough. That may change. The quicker we can move, the more flexible we are, the better the chances of securing strong financing that helps us move on beyond the current convertible bond facility. I'd also like to stress that we are working hard to secure international and specialist investors to come into the company. Now in many cases, such investors are skeptical to wait for a general meeting in order to receive their shares. If we have a larger mandate, it would mean we could accommodate that concern by directed quick issue and get them in. Again, we believe this would strengthen the cap table and be an advantage both for shareholders and the company. So it's the Board and my strong view that it's in everyone's interest that this proposal for a 40% mandate is passed. Finally, we received some questions around our RSU and option mandates. The RSU and option programs are integral parts of the compensation policy for early-stage companies. It's particularly important these days when the industry in general is undergoing some turmoil and substantial layoffs and companies shutting down. So this is a tool we really need to be able to attract and retain our key employees. And this also aligns the shareholders with the employees' long-term goals. So again, important for the company to attract and retain talent. It also reduces cash expenditure for the company as we can keep salaries lower. So this is important for us to be able to work with. If we don't have a mandate to fulfill our obligations under RSU and option programs, this also means that any conversions here triggers just a cash need instead. So having this mandate enables the company to decide whether such compensation is issued either in form of the shares or converting the options or cash. So again, this is important for the company to have available as a tool. I would also like to stress that the current options are mostly out of the money, meaning they have a strike that is over the current share price and many of these options only vest in the future. So the risk here in terms of the dilution is minimal at the moment and only plays through in the mid- to long term following success where the share price has increased. So they only really have value in a situation where things have gone really well. So hopefully, this clarifies these items in the AGM. Don't hesitate to reach out if you have more questions around this. We did receive multiple questions beforehand, and we've tried to address this during the presentation and now in this summary of the AGM notice. So with that, we can move to the Q&A session. There it's possible to submit questions in the chat. We also received several questions beforehand, and we've tried to group these in buckets and cover them that way.

The first question to cover follows what we just discussed, and that's around financing. As you are aware, we have a firm financing commitment from Atlas that was entered during the rights issue last summer. And that's guaranteed the company funding until end of June 2025. As previously communicated earlier this year, Atlas has agreed to extend that financing facility. So that does exist and has been extended beyond June 2025. If you combine that with our current cash resources, the company now has secured funding well into Q4 2025. And then how we proceed, how we fundraise, et cetera, that will inform and decide how much of that available financing facility from Atlas we end up using. So yes, the financing is secured beyond June 2025. I think then we can move to a couple of more R&D-related questions for Thomas. The first question, Thomas, and I think this is an interesting one, is this tissue distribution and the specific expression of circVec in certain areas of the mouse in vivo, how can this be explained? Why is there such a difference between mRNA and circular RNA-based expression?

Yes. Thank you for that question. I think that is indeed very interesting. So I think what we are looking at here is basically the core of circular RNA versus mRNA biology. So what we've seen at Circio and what we hear from other companies is that in the liver, there tend to be a higher RNA turnover. Maybe there's another set of destabilizing enzyme being expressed in the liver. So I think as a consequence, because the stability of the circular RNA is critical to our expression profile, if you do not have that stability, which seems to be the case in the liver, we don't see much expression. In contrast, in the spleen, it seems that this is not the case. This is a scenario where circular RNA are really thriving and they will accumulate to very high levels. So this is a context that really supports the accumulation of circular RNA. So I think what we're looking at is basically you have similar distribution of the DNA, the DNA cassette would go equally -- the mRNA cassette and the circular RNA cassette would go to the liver with equal efficiency and they will go to the spleen with equal efficiency. So what we're looking at is basically how the stability of the circular RNA differentiate the expression profile. So in this liver, you see that accumulation. It takes 3 weeks. That should be noted. It takes 3 weeks for that accumulation to actually become detectable. But then you'll get to that steady state level after 1.5 months where you really see high and durable expression. So I think this is what explains the difference. Of course, we are still studying these things, as Erik said in the beginning, I mean, circular RNA is still relatively a young space. So a lot of stuff still needs to be figured out. What is actually driving circular RNA turnover is not well understood in general. But I think this is what is -- this is our current working hypothesis, I would say, as to why we see this spleen-specific accumulation, mainly that circular RNAs are particularly stable in the spleen, which allows them to, over time, accumulate to very high levels.

And I can maybe add that this expression pattern we see, it's consistent between different vector types, and it seems to be also consistent when you switch to the AAV. So this looks like fundamental biology. And I think we're learning from other circular RNA companies out there when they present data that they observe similar patterns also with their synthetic circular RNA approaches. So following up on that, there was a report just now recently in the last few days that there had been a death associated with a heart gene therapy program in the U.S.A. This was an AAV in a cardiac genetic disease. And there has been concern and FDA has called a clinical hold on that AAV gene therapy in the heart. Thomas, how does this impact the development of circular AAV?

Yes, of course, this is, of course, unfortunate news for the AAV space. Of course, we will -- this is -- we don't have much information currently. So I guess -- but what would likely be the case is they are -- they seem to be dosing relatively high levels of AAV in this trial. And I would maybe sort of a little jump to the conclusion, even though this is maybe a little premature that if Rocket Pharmaceutical had the option of going tenfold down in dose levels, likely this therapy would have been much safer for the patient. And this is, of course, what we believe we can do at circVec with the circVec technology at Circio, namely develop AAV vectors that are showing the same clinical benefit, but at a much reduced and much safer dose level.

Yes, I agree. I think this is an extremely important point to show that reducing the dose is potentially very important for these AAV gene therapies, which are costly and have high toxicity and they require treatment with parallel immunosuppressants. And like we've shown from at least in our in vivo data, we can reduce the tenfold -- the dose by tenfold. And this is obviously extremely interesting for the space if we can validate that now in more situations and in other species. We also have received many questions about the TG01 program. So this is our legacy program, the cancer vaccine targeting mutant KRAS and NRAS in several cancers. What I can say about that, the clinical trials that are ongoing are externally managed and funded. There is one trial at Oslo University in multiple myeloma. It's a single monotherapy trial, single arm. That trial, there will be data presented at an upcoming conference in June, the EHA, European Hematology Association. So there will be a poster there, and we will come back with an update when that poster has been presented in the middle of June. So shortly some clinical data from the TG01 program. When it comes to our partner in China, IOVaxis, many people ask whether we still have a dialogue? And I can confirm we're still in dialogue with IOVaxis. They remain interested in developing TG01 in China. They do have an IND. Their bottleneck is fundraising. It's challenging there like everywhere else. And they are currently still working with investors to try and finance. And potentially, if they are successful, we would expect that they might come back and want to start clinical development in China. So difficult to predict what the likelihood is, but it certainly is a dialogue that remains active, and we support them where we can. So with that, I think we've covered the areas of questions that we have received. As always, don't hesitate to contact us offline. We're happy to jump on the phone call or respond to your questions by e-mail. Thank you all for joining and listening in and your continued support for Circio. And thank you, Thomas, for a very engaging and interesting update on our circVec progress.