Circio Holding ASA (CRNA) Earnings Call Transcript & Summary

Welcome to Redeye. Today, we're happy to welcome Circio for a scientific update on the preclinical work with the circular RNA platform. We have with us today, CEO, Erik Digman Wiklund; Chief Technology Officer, Thomas Hansen; and also Chief Scientific Officer, Victor Levitsky. Please go ahead.

Thank you, Thomas. Before we get into the details here, and Thomas and Victor will tell you about the technical development and latest data at Circio, let me explain what the opportunities that we're trying to capture at Circio. So what we're trying to do at Circio is to improve on current gold standard gene therapy. You probably all heard about gene therapy, and this is one of the fastest-growing therapeutic areas today. And this is because of multiple reasons. Regulators are really starting to try to incentivize development of gene therapies for rare disease. Because of that, we're seeing heavy investments, and we're expecting rapid growth over the next decade. And the first gene therapies are now already becoming blockbusters. So it's a regulatory-wise clinical and commercially validated therapeutic area now. But there are only a few gene therapies that have actually been approved. You've heard of gene therapy for a long time, but the first one was approved only in 2017 for a rare genetic eye disease. And in the past 2, 3 years, we've had six more approvals. So today, there are 8 gene therapies on the market and available to patients. All of these are based on viral delivery systems. So you use a virus to deliver a gene. And the majority of these, 6 out of the 8 are using what is called the AAV vector or the adeno-associated virus. So you could say that the current gold standard in gene therapy is this AAV-based vector delivery of a gene that is malfunctioning in the patient. Now AAVs have been successful, but they have substantial caveats. And because of that, it's currently limited what diseases you can target with an AAV approach. The biggest problem with AAV is that it's really hard to get sufficient AAVs into patients to make enough protein to deal with a genetic disease. The low expression or the low potency, if you want to call it that, means that you need to give really high doses. Giving high doses gives you two problems. One is toxicity for patients. You can see liver toxicity, immunological toxicity and in some early trials, patients died simply because the dose was too high. And the high dose also complicates manufacturing and drives up the cost. So current AAV gene therapy, although it's been successful, suffers really from this challenge of low potency, low protein expression. Circular RNA has the potential to solve these issues by boosting the potency, thereby lowering toxicity, making it better for patients and reducing the cost, making gene therapy more available in general. So why can circular RNA fix this problem? And the reason is simple. Circular RNA is more durable than mRNA. You always have to use RNA route to express a protein. The mRNA is unstable and gets broken down very quickly inside a cell. A circular RNA is resistant to the standard [indiscernible] mechanisms for breakdown of RNA, and therefore, they have a much longer half-life. Typically, what we see is roughly 15x longer half-life of a circular versus a linear mRNA. And this leads to better protein production, higher expression levels and longer durability of the gene therapy. And this is why circular RNA is set to revolutionize gene therapy in the future. We have some of the key scientists in the field. It was actually myself and our Chief Technology Officer, Thomas Hansen, who did the early work on human circular RNAs and published the first papers and Thomas' Nature Paper that you see on this slide here is the most widely cited circular RNA paper. And many view this the paper that kind of status circular RNA field as we know it today. So we're uniquely positioned with the scientific expertise to really utilize the advantages of circular RNA in gene therapy. And now I hand over to Thomas and Victor to explain to you how we're doing this technically and what diseases we're going to target.

Thank you, Erik. I will now go into more detail into the circVec technology that we are developing at Circio. So what's important to understand is that at Circio, we are developing a DNA cassette. So we start with the DNA material that we carefully engineer in a manner so that when that DNA gets into the cell, it will express circular RNAs, stable, durable circular RNA. That in turn then is designed in a manner so the circular RNA will encode proteins. So due to the stability of the circular RNA, this protein expression will be long, it will be enhanced and it will be durable. So that's the core of the technology. So basically, to sort of set the stage, you're probably all familiar with the COVID vaccine. This was a synthetic mRNA. The RNA is quite unstable within cell. So the expression profile from the Moderna and the BioNTech vaccines are at most 2 to 3 days, I would say. So that's quite convenient from a vaccine approach. So that's a good opportunity to develop vaccines. Recently, there's been some development within the synthetic RNA space. We now have Orna. We have [indiscernible]. We have other companies developing a synthetic circular RNA equivalent to the synthetic mRNA approach. This, of course, due to the stability of the circRNA will produce much longer expression and likely a much better vaccine platform than we have for the mRNA. So similarly, for our approach, we are also a circular RNA company, but we are quite different compared to the synthetic circRNA or IVT circRNA that is also referred to because we have the DNA starting point. So it's a vector-based expression. Consequently, we obtain month to years of expression. And as a result, this is a suitable gene therapy approach. In addition, we can deliver the cargo in an LNP similar to the mRNA vaccines, but we can also go into a viral-vector approach, which is, as Erik explained, is the current gold standard in gene therapy. Finally, there is existing CDMO opportunities for us because DNA manufacturing, viral vector manufacturing has been around for a while. So this is not as such a challenge in contrast to the synthetic circRNA, which is currently being developed. So basically, this slide captures the essence of the technology. So as you can see to the left-hand side, we have a 15x longer half-life for the circRNA compared to an mRNA, both of them derived from a vector-based expression system. So concretely, 135 hours we've measured for our circular RNA compared to 9-hour half-life for the mRNA. What that translates into, if we put that into cells, is basically an accumulation of expression. So if you take the mRNA first, the yellow line, you can see that peaks already at 48 hours after we introduced the vector system into cells and then it sort of declined from that time point. In contrast to the circVec vectors that are being tested here, you basically see the profile that we consistently observed namely an accumulation. So you should imagine that you have a stable RNA. It accumulates over time. It keeps getting replenished by the DNA system and then it ends up with much higher expression level. At this experiment, 8 days after introduction, we have 8.5x higher expression compared to the mRNA. What you can see additionally is sort of the evolution we've had at Circio from the vector system we had roughly a year ago, the circVec 1.0, still better than mRNA, if you look at the 192-hour time point, but was outperformed back then by mRNA. Now we have improved the sort of the vertical expression. We went up the Y-axis. We still have the same profile over time, but we've simply boosted the yield that we get per copy number of vectors. So now we have, as mentioned, almost 10x improvement over an mRNA at day 8. This, we have worked recently on reproducing in mouse models. So we've used a clever system here where we express a luciferase protein, so you can monitor the expression over time in the same mouse. So it's not -- so it's a very simple approach, and you can follow, as mentioned, longitudinal expression due to this luminescence that you get from the luciferase gene. So what we did is we inject in the left-hand -- in the left hind leg, we injected our circVec vector and then the right hind leg, we had the mRNA vector equivalent, both expressing the same protein. So what you see is at the early time point, mRNA builds up a little faster, but then you see at day 14, basically, and from that time point on, circRNA is on par. And then at the end at day 119, you basically have higher expression from the circVec design due to that circular RNA's stability that's critical for this technology. We've done a follow-up experiment, a larger cohort, basically the same experimental setup. Keep in mind here now we swapped the legs, so we put the circVec in the right hind leg and the mRNA in the left hind leg. And basically, we see the same readout that time point, not that much difference between the circVec and the mRNA, but at the later stages here at day 146, which is the latest time point we have. This experiment is still ongoing. Actually we have higher expression -- we basically have expression from the circVec and no detectable expression from the mRNA. So now we start to model this more statistically to get some of the uncertainties, get that captured and to better estimate the full [ change ] that we are serving from the circVec design. And what we see at this stage, between 3 and 4x better than the mRNA at this stage at day 146. Having this mathematical model also allows us to actually do sort of extrapolate into the future. So if we imagine a 2-year gene therapy time window, we would actually predict that we would be up to 20x the expression from the circVec compared to an mRNA-based expression. So that's a considerable improvement compared to existing gene expression systems in general. All right. So but -- we, of course, very focused. We don't think we've reached the limit yet. So we are consistently improving the vector system. So we are on the path now towards the circVec 3.0 generation that we believe would maybe boost expression 5 to 10x more. Now just show you some of the stuff that we've been working on recently. So there are basically two approaches to do this. One approach is to improve the biogenesis, basically the rate of circular RNA production from the DNA cassette template. Secondly, improve translation, and most often, there are two ways of doing this. Either you modify or optimize this little, not that you see in the middle of the circRNA which is referred to as the IRIs element, that's the sort of the initiating point for translation or for production. So that you can engineer in a manner so that will recruit the machine involved in translating more effectively or you can basically also modify the whole region of the circRNA that basically encodes the circular RNA, the so-called the codon composition. So this is what I'm just going to show you now. We've done quite some work trying to understand what codon composition is important in the context of circular RNA-based expression. So the way we did this was very state-of-art I would say, we assembled almost all possible codon composition that you can imagine in this in-dimensional space of possibilities and then selected the most informative variants that we then tested experimentally, and from that, we were able to build a machine or a model that could not only infer the most predictive parameters in this scenario, but could also predict basically what would be the expected performance of given design. So we use that model basically in a completely unrelated protein that we then expressed as a validation. And as you can see here in this plot, the expected -- based on the model, the expected performance of that codon composition correlates quite nicely with the observed performance of that codon composition. And just to give you an idea of how this works, if we encoded that protein using the circVec 2.1 or basically the wild-type protein sequence, we get a certain level of expression. If we used commercially available tools to do this trick, which of course not -- they have not been developed for circular RNA-based expression, so they may work better in an mRNA context. They did not perform well. But our model, as you can see, actually provided a 2 to 4x protein boost compared to the 2.1 design. So we now have a model that actually allows us to boost protein expression specifically from circRNA vector systems. So that's sort of the end of the data update, and I would like to hand over to Victor Levitsky, our CSO, for the therapeutic applications of circVec.

Let me then discuss with you how exactly we are planning to bring circVec technology into the clinic in the space of genetic diseases. So to do that, we have chosen one particular genetic disease, which is called alpha-1 antitrypsin deficiency or AATD. And this disease has several interesting features, which we believe allows us to exploit fully the potential of the circVec platform. So first of all, this disease is characterized by pathology developing in two different sites. So when mutation happening in the genome leads to inactivation of the wild-type protein, these inactivation results primarily in pathological changes, inflammatory processes developing in the lungs, and eventually could lead to the death of the patient. At the same time, which is not very characteristic for other diseases, genetic diseases, a very common type of mutation in the same gene leads to a change in the confirmation of the protein, and this protein starts making aggregates and accumulate in the liver, which could also lead to pathological changes in that organ resulting in two tasks that have to be resolved for this disease. One is that we have to reconstitute the expression of the wild-type protein to deal with the pathology in lung, but at the same time, ideally, an optimal therapy should also suppress the expression of the mutated protein that accumulation of these aggregates, abnormal aggregates and deliver does not take place. And to do that, our platform allows us, first express the protein from circular RNA and produce the corrected well type normal version of the protein. At the same time, we can incorporate into our cassette an inhibitory RNA sequence which will bind to the -- specifically to the mutated version of the RNA message and use its degradation without affecting the wild-type sequence. As you can see now on the right side of the slide, this approach allows us to express high levels of the wild-type protein while the inhibitory component incorporated in the cassette results in almost elimination of the mutated variant. And to do this in the clinic, we are planning to deliver the circVec cassette through an adeno-associated virus, which, as Erik has already explained in his introduction, is the primary platform -- technological platform currently used in different forms of gene therapy. And the standard approach assumes expression of proteins using conventional RNA messages. As you see on this slide, in our case, we'll be using circular RNA expressed from our circVec cassette incorporated into the genome adenovirus, and then the expression of the protein will be driven by the stable circular RNA, resulting in much higher levels of expression and more stable levels of expression in patients. We have done already preliminary experiments in vitro showing the same tendency already described by Thomas to you in great details that when we observe expression kinetics over time driven by mRNA versus circular RNA, the protein RNA messages from the circular RNA cassette accumulate over time. And here on the slide, you can see the difference already popping up during a relatively short observation period of 4 days. We have also already tested adeno-associated viruses, expressing circular RNA from the circVec cassette in two different sites. On the top of the slide, you see expression of circular RNA encoding luciferase gene, which allows monitoring -- to easily monitor the expressions of protein through a special machine recording light -- developing in these animals if they are injected. And on the upper panel, you see expression of this protein driven by circVec cassette from the AAV vector in the muscle. While at the bottom slide, you see expression in the liver after injection into the vein. So after we inject the virus into the vein and it goes into the liver and drives the expression of luciferase, which we can monitor as shown on this slide. So essentially demonstrating that we can achieve expression of desired protein from the adeno-associated virus carrying our circVec cassette in different organs and tissues. And this characterization is ongoing, and we are planning then to apply this technology for the treatment of alpha-1 antitrypsin deficiency. But I have to stress that analysis of circVec performance in different tissue types and cell types is ongoing. And of course, if we discover that circVec technology performs particularly well in the specific tissue type or cell type, this could drive further ideas, further thinking on where this technology can be applied best to the benefit of patients with different forms of pathology, including genetic diseases. And with this, I conclude and give it back to Erik to round up our presentation.

Thank you, Thomas, and Victor for explaining the technology and how we're planning to use circVec therapeutically in the future. Now let me summarize what you have just seen. So at Circio, we developed a circVec platform. And we're currently at the circVec 2.1 generation, which actually outperforms mRNA expression by almost tenfold. And this is a big deal. This can really improve on gene therapy as we know it today. I mentioned at the beginning the challenges with AAV gene therapy, we believe that we will be able to reduce the dose by AAV gene therapy according to current data by potentially tenfold or even more. That means you could treat more diseases, you can make gene therapy cheaper, but we don't believe this is the ceiling or the threshold. And as Thomas showed you, we're already well on our way to the next generation of circVec designs, and we're already at the circVec 2.2 being tested in the lab, and that will be brought forward and into the in vivo testing in the future. We've validated circVec in a variety of settings. We expressed almost 20 different proteins of various size ranges. So we believe the technology is very versatile and we already filed 3 patent applications, we have more coming. Next, we're starting now to really get evidence that circVec performs as well in vivo in animals as it does in vitro. And we've shown you that we now have expression data up to day 146. So that's well over 4 months in mouse models. And clearly, the circVec is doing better than mRNA, especially over time. We hardly see any mRNA expression from week 4 onwards, and circVec just keeps going. So we're really seeing this durability advantage translating in the clinic. Now we're going to test this in multiple settings, other tissues, where in the mouse, what organ or what cell type does it perform the best. And this will inform us what type of diseases we should be aiming at into the future. Right now, we're focusing on AATD as the primary format, and we are focusing on the AAV delivery vector. And we validated now that the AAV circVec viruses are functional. This is important. It shows it can be done. And now we need to optimize and understand it further and then move into disease models. So the next step now is, one, to start tracking how the circVec AAVs are performing against classic mRNA AAVs over time. Remember, with the early experiments we've done, we started seeing the advantage after roughly 4 weeks. And currently, our AAV experiments are around that time. So now it will be really exciting to track during summer how the AAV expression develops for circVec versus the mRNA variants. And then following that, we will start moving into AATD disease models and we should be able to show you in the second half of the year, how that looks when it comes into the mouse models. In parallel, we're testing multiple different delivery strategies and vector types. So we are expanding the platform and enabling a broad applications. And we also think this will be important for entering future business development deals. In terms of timeline, we summarize here on the slide we're trying to achieve at Circio over the next 12 months. So you can see the important milestones we achieved already this year. It's a technical in vivo proof of concept. This was shown by Thomas earlier. And as Victor showed you, the AAV gene therapies are also being validated now, and we know functionally that they work. Next step we'll be tracking of the AAV performance versus mRNA. And then circVec 3.0 generation we expect to establish sometime during second half of the year, followed by AATD disease model data. So these are important milestones that are coming up. These data points will all help us move towards a business development deal. So we're talking to a lot of companies at the moment, especially now the AAV companies, and our aim is to enter into a strategic R&D-based partnership during first half of next year based on this circVec AAV platform we're developing at Circio. And as most of you probably are aware, we're currently working on the financing of up to NOK 50 million, and this funding shall be sufficient to take us through this important milestone, get us in position to develop and get to a business development deal. Following that, we aim to select a lead candidate sometime during the middle of next year. That would be a lead candidate. We currently believe that will be in the AATD disease and then take that forward towards clinical studies. So with that, I wrap up the presentation. I hope this was informative, and gave you a flavor of where we currently stand and the big steps forward we have made with the circVec platform today. So with that, I round off from Circio.