All right. Welcome, everybody, to day two of the Citizens Life Science Conference. My name is John Wolloben. I'm a biotech analyst here. We are pleased to have ProQR Therapeutics joining us and CEO Daniel de Boer. This is a story that we have been covering for quite some time. I think they have a very exciting technology and a very exciting 2025 with getting into clinic with your Axiomer platform, seeing the first clinical data in an area where I think investors are just starting to finally appreciate the potential here and trying to sort out how this modality could work and then how the different players are pursuing it. I think this is a great opportunity to kind of dig into all those things. Daniel, thanks again for joining us.
Excellent. Thank you, John, for having us here.
You know, I gave, you know, a quick sentence on it, but maybe tell us a little bit about what you're working on at ProQR, and then we can jump into some of the details.
Absolutely. At ProQR, we're working on the development of a novel RNA editing platform technology that's leveraging ADAR to modify individual bases in a messenger RNA. We discovered this platform more than 10 years ago, and we've been optimizing it since, really priming it for prime time and taking it into the clinic today. ADAR is a mechanism that's present in all human cells that is continuously editing our RNA right as we sit here. Our RNA is being edited. At ProQR, we discovered a way to use an oligonucleotide to recruit that process that's present in cells and make it edit the exact base where we want it to edit.
When we first came up with that idea, we believed that would be a really valuable potential new medicinal tool to develop drugs to treat genetic medicines without having to touch the DNA and modifying the RNA in a way that takes away the underlying defect of diseases. Over the years, we've optimized the technology. Right now, we are heading into the clinic with our first program. We have a number of fast-follower programs right behind that and other indications. That is in addition to a partnership that we have with Eli Lilly, in which we are developing 10 different targets on the platform technology as well.
Can you talk like big picture? You know, we hear CRISPR DNA editing. We have an approval, so I think there's precedent for safety. Still, I think you know a proposition that the risk-benefit really needs to be there. Can you talk about RNA editing versus DNA editing? Also, we've been hearing RNAi. We have siRNAs out there approved that will work great. What's different about RNA editing and benefits drawbacks?
Absolutely. RNA editing allows us to microsurgically edit an individual nucleotide in the messenger RNA. The messenger RNA is a string of building blocks, individual bases. We can change one base to, for example, change a genetic defect that leads to a genetic disease or to introduce a change that changes the function of a protein. This is a mechanism that's not achievable with RNAi, for example. RNAi knocks down RNA, so it breaks down certain RNA strands. We can modify them in a way that they get a new or restored function. I think for all of these technologies, there is a sweet spot. There is for CRISPR, gene replacement therapy, RNAi, and for RNA editing.
I think what we really like about the proposition of RNA editing is that it uses the well-known modality of oligonucleotides that have been studied for the last four decades. Multiple drugs are approved based on that modality of drugs, so chemically synthesized short strands of RNA that are called oligonucleotides. We design them in a way so that they engage this ADAR mechanism. We call them editing oligonucleotides. In addition to that, we know everything there is to know about manufacturing of these molecules, their safety profile, how they behave from a distribution perspective. That comes with a lot of de-risking for this novel approach as the modality as such is already known. The way that we use them is completely new. That is the invention that we made. I think that significantly differentiates it from other oligonucleotide approaches.
The trade-off versus especially DNA editing is temporal safety benefit that if something goes wrong, it does not go wrong forever. How does dosing work with RNA editing?
First of all, the delivery of these molecules is fairly straightforward. We do not need an AAV to deliver it. It is not encapsulated. It is a single-stranded naked oligonucleotide that is conjugated to a GalNAc sugar group to deliver it specifically to the hepatocytes in the liver. That means that delivery is relatively easy and de-risked to that extent. We also focus on a number of programs in the CNS, in the brain. There we dose them locally through intrathecal administration, also naked oligonucleotides without any conjugation. Both of those delivery routes are relatively de-risked in a way that there are oligonucleotides that are approved on the basis of these delivery routes.
Do you know frequency of administration, or does it depend on condition, dose? What does that look like?
Yeah, so it's somewhat dependent on the organ, so the tissue that you're targeting, and then also the specific target gene that we go after. But kind of as a rule of thumb, we anticipate that for liver delivery, we will be looking at quarterly dosing. And for CNS dosing, probably once every six to nine months.
OK. There are other companies using a similar technology, Wave and Korro, two publicly traded companies, and you guys. Is there anything different in the technology? That is, I think, what some people are trying to sort out, including myself, is how do we think about the different players in the space and the technology? Is there a difference in technology, or is it strategy and application?
Yeah, that's a great question. First of all, it's great to see this age of RNA editing beginning. Ten years ago, we invented this technology. We were the only one in the space pioneering this technology, advancing it, optimizing it to the point that it's now ready for clinical studies. Over the last three, four years, we've seen a number of other players coming into the space, which is fantastic because it means that there's a lot of data being generated, a lot of scientific advancements. It gets a lot of exposure. It means that the field itself is really validated, starting to get validated and maturing by so many parties involved and so many eyes on the science. At ProQR, we discovered this. We invented this. We patented this with dozens of different patents.
We believe that we control all the foundational IP underlying ADAR editing. We think that's a really important and valuable tool that we hold that over time will in itself create value and gives us exposure to the entire RNA editing field. I think between the different players in the field, there are some differences. Some deliver with LNP, others with GalNAc to deliver. There are maybe some minor design rules of how the oligonucleotides are designed. They're all in a fairly confined space. There's no one completely out there with a very different approach. The technologies are similar, if not the same. Yeah, I think strategy is different. At ProQR, we've chosen to pursue targets that have been validated by human genetics research.
Where naturally occurring variants that have been found in the general population that are associated with certain features actually help to treat a certain disease. On the basis of that proof of concept, we are developing medicines that introduce those variants. In addition to that, we focus on both CNS and liver, which are, I think, both very attractive therapeutic areas. We focus on both kind of more common diseases as well as rare genetically caused diseases.
Can you talk a little bit about your lead program in cholestatic diseases? The data you've generated preclinically looks very interesting. Talk about what you've shown and where you are in development today.
In our development pipeline, we have a whole range of different programs across liver and CNS. There are four that are most advanced, of which the lead program is called AX-0810. It is targeting cholestatic diseases with a specific focus on PSC and biliary atresia. These are both very severe cholestatic diseases with no proof therapy that are ultimately lethal for patients. In these indications, the main problem is the concentration of bile acid in liver that leads to inflammation, liver fibrosis, and ultimately liver failure. The main contributor to having this bile acid in your liver is the NTCP channel, which is a channel that lives on the hepatocytes that takes up bile acid from the blood into the liver. It accumulates there because of the disease. It cannot really exit the liver. That is why the high concentration leads to inflammation.
What we have found in human genetics research is that there is a group of people in the general population that are healthy individuals that live with a variant in their NTCP channel that leads to a reduced uptake of bile acid from the blood into the liver. These people are completely healthy. They were found to have a very high bile acid concentration in blood because it is less taken up into the liver. We are, with AX-0810, essentially introducing that variant that gives this reduced uptake of bile acid in patients that have too much uptake of this bile acid into the liver. That is a completely novel therapeutic strategy, which could potentially be disease-modifying for these indications that, between the two combined, affect about 100,000 patients between the U.S. and Europe.
For this program, we've presented a proof of concept across human cells, across mice, humanized mouse, and non-human primates that shows that AX-0810 can edit the target, that it can generate a restoration, or it can generate an increase of the bile acids in serum, showing that there is a decrease of uptake into the liver. That's exactly the next step for this program to show exactly that outcome, but now in humans. For that, we are planning to submit a CTA later this quarter. That is a clinical trial application such that we can start a clinical study that we would then have read-out initial data towards the end of the year, and then a more complete data set next year.
Will the first study be, where do you plan on conducting the study?
We're a Dutch company. We're conducting the study in the Netherlands.
OK. Healthy volunteers, patients, who are you going to enroll?
Yeah, so the interesting aspect of our strategy is that we have picked targets where we introduce a variant in a wild-type sequence. That means that anyone here in the room could be a participant in the study. We can actually measure if there's target engagement of the oligonucleotide. That means we're going to do this study in healthy volunteers. That allows us to rapidly enroll, rapidly execute, have sufficient subjects in each of the cohorts to really understand and power the outcome in this study. After that, we'll go into a patient trial.
What are you going to be able to measure in healthy volunteers to show the target engagement that you want? Is it serum bile acid increase, any other markers?
Yeah, so primarily, it will be serum bile acid levels that should indeed increase. We target a twofold increase in serum as that's associated with a reduction or a stop in the fibrosis. In addition to that, we're going to look at bile acid profile, so the ratio between conjugated and unconjugated bile acids. We'll be looking at some more exploratory endpoints like circulating RNA in exosomes, et cetera.
I'm guessing it's going to be a single-senting dose to start. Given the dose duration, even with one dose, we should be able to see some sort of effect. How are you thinking about the data that will be available later this year?
Yeah, so it will be an integrated single-ascend and multiple-dose design, which means that we're going to dose subjects and then use those same subjects for the multiple-dose part of the study. We're doing five doses over the course of four weeks to accumulate drug. The intended use of the drug once it's developed is once a quarter. For this study, we're doing five doses over the course of four weeks. After those five doses, we want to see the increase in bile acids. We're then going to follow the patients or the subjects in the trial for another 12 weeks to see when the effect starts to wane off, such that that will inform what the dosing frequency will be in our future clinical trials.
How do you think about the opportunities in PSC and biliary atresia? Both you mentioned fairly large rare diseases, high unmet need, nothing approved for either. Is this something you want to do for both, or is there something you're going to see in the data that decides, hey, this is better for one or the other?
Yeah, so as we speak, we're going through our indication selection process, which will determine if we're pursuing PSC or BA in our first patient study or potentially both. Biliary atresia is more of a pediatric indication, which has some pros and cons from a development perspective. PSC is more of an adult population. Both are really high on the medical needs. Ultimately, the goal is to develop this for both, the order of which we haven't decided yet.
You mentioned you have three other lead programs. Can you talk a little bit at a high level? Then maybe we can talk in more detail about the other three.
Yeah, so we have our second program targets the B4GALT1 gene, which is a gene that's associated when mutated in a certain way to reduce the chance of cardiovascular disease by 36%. It is similar to what PCSK9 was when that was discovered. This is B4GALT1. It happens to be that the variant that was discovered is exactly the type of mutation that we can introduce with the Axiomer technology. What that essentially means is that we can give people potentially protective variants against the development of cardiovascular disease, for which the mechanism is different from PCSK9. It can be used either instead of or in addition to. That's a really interesting program for which we have presented in vivo proof of concept studies in a very relevant disease model.
We're further optimizing that program and plan to give an update on that over the course of the summer. Our third program is our first CNS program targeting Rett syndrome, which is a neurodevelopmental disease. It's caused by mutations in the MECP2 gene. It's a very, very severe disease affecting girls. Boys are not born that carry this variant. These girls live a very, very disabled life because of this variant. We are potentially able to restore normal function of this protein. That's what the preclinical data shows. It's not just us who are excited about that. Also, the patient organization, the Rett Syndrome Research Trust, they decided to award us $9 million to help us develop this program.
Yeah, how did that come about? Were you guys working on this? They became aware? Or did they contract you to say, hey, can you do this? Can you talk a little bit about that partnership? Because again, there are other options out there. The leading patient organization came to you guys.
Yeah, so first of all, the MECP2 gene has a very specific feature, which means that you have to express it in a very precise band. If you express too little, you get the disease. If you express too much, you also induce the disease. With many technologies, it's really hard to control the expression level. With RNA editing, you're essentially restoring the RNA that's there. Therefore, you leave the cell's regulatory system in place. Therefore, you can never overexpress. That's a really attractive proposition for this indication specifically. We did some work on that. We got in touch with the Rett Syndrome Research Trust. They're really excited about RNA editing as a whole and in particular this approach. We started with a small collaboration to get to know each other.
Six months ago, we expanded that to a broader collaboration to now take it into the clinic.
The other program that I have particular interest in because it overlaps with some of my other coverage is in MASH. Can you talk a little bit about their target there?
Absolutely. Our fourth program is targeting the PNPLA3 mutation that is a factor in MASH. There are about 8 million homozygous people, so people that have two copies of this mutation. These people develop very severe forms of MASH. We can restore MASH to a wild-type-like protein that has the same function. That is really attractive because it is such a significant market. The target itself has some validation from other approaches. We think that with this approach, we can really restore a wild-type functioning PNPLA3 protein, which could potentially make a big change to this disease.
How do we think about the platform and the technology? If the lead NTCP targeting program works, does it become plug and play? Are we in the early innings of an Ionis or an Arrowhead or an Alnylam-type platform here? How difficult is it to go from one program to the next?
Yeah, no, we're certainly modeling our business plan to what Alnylam did about 15 years ago when they really pursued the siRNA strategy for liver. John Maraganore was the CEO at the time at Alnylam, is on our board. That gives us a lot of access to some of those insights. I think it's indeed a really good analog for what we're doing here. When this works for one target, you can extrapolate many of those findings to other targets. There are some specifics to each target, like expression levels and sequence context and secondary structure. There are some other things that are related to that. Generally, when we invest sufficient time, most of the targets are very much editable. We can go after.
Strategically, how do you think about these opportunities? What plays into what moves forward and what you hold back on? We hear rare liver but fairly large, rare CNS, but then MASH. How do you figure out what to work on?
Yeah, so at this stage, there is a number of different objectives with development choices that we're making. First of all, to validate the platform and show that across different targets and across different organs, we can use this as a new platform for drug development. That is why we are differentiating across different organs and about genetic variants and de novo mutations. Strategy-wise, we plan to commercialize the rare disease products independently and seek a partner for co-development or otherwise further development of our large indication programs. I think a cardiovascular disease program will probably be a bit too much for us to develop independently. Nevertheless, they are potentially really valuable programs to further validate the platform. Also, once they have generated clinical data, they could become really valuable partnership assets for us to transact on.
Speaking of that, in the last few minutes, I wanted to make sure we save some time to talk about the Lilly partnership. Can you talk about the history there, where you guys are today, and what you're both working on?
Yeah, absolutely. Our initial partnership with Lilly was forged back in 2021. We partnered on five targets. In 2022, Lilly came back. They wanted to expand the partnership to 10 targets. They gave us $125 million in upfront payments for that. There is $3.75 billion in milestones to be earned, plus royalties. Lilly also recently participated in an offering that we did towards the end of last year, which I think signals their excitement about the ongoing partnership. The Lilly partnership is predominantly focused on central and peripheral nervous system applications, where Lilly is essentially doing all the development activities. ProQR does the discovery up to kind of hit selection. We hand over to Lilly. They do all the development and commercialization activities.
Really good structure for us that is not distracting us too much from our internal pipeline, but gives us a lot of insights in application of this technology across other targets. We also learn a lot from the partnership through the data that gets generated there.
When do you think we'd start seeing the fruits of that partnership? They expanded the target list. I don't think I've seen something as far as a disclosure from them about something getting to the clinic or progress there. Anything you tell us about how things are moving behind the scenes or when we could get some updates that give us even more confidence in Axiomer?
Yeah, Lilly is a great partner. Unfortunately, they are in the driver's seat around communication about the progress in the partnership. They so far have decided to not talk about these programs publicly. We have to honor that. The partnership itself is going very well. There is real progress being made. We earned five or six different milestones last year. We'll earn several milestones this year and probably many more next year. Obviously, as the programs progress and get to later stages, the size of the milestone payments also will increase. Those milestone payments we announce. That is what people can look at. Beyond that, I think we have to be a bit patient for Lilly to decide to publish and present around these programs.
They've selected, what, 10-15 targets? Is there anything that kind of crosses your wires too that you guys wanted to? Or what are you excluded from working on that's under Lilly's purview?
Lilly has exclusivity on the targets that are in the partnership. That is it. Any new target that they choose, we get to decide if that is going to be part of the partnership or not. That works really well. I think the target universe for RNA editing is so significantly large that we have not been in each other's way so far. That is going really well.
In the last minute or so, you talked a little bit about kind of the payments from Lilly. Can you remind us of your cash position? We also talked about a lot of updates coming. If we could put a button, like, what to look forward to in the next kind of 12 months and then the cash position you guys have today.
Yeah, so our cash is about EUR 134 million that funds us into mid-2027. That is, I think, a comfortable runway for where the company is today. We are pursuing for this year a clinical candidate selection for up to three different programs. The follower programs that I mentioned for Rett, for MASH, and for cardiovascular. We plan to submit a CTA for our lead program, AX-0810, this quarter, then have that enter the clinic and have initial data towards the end of the year. This year is going to be fairly newsflow rich. Next year, we may see several other programs entering the clinic and drive to initial data.
If everything goes well this year with the candidate selection, we could have at least three candidates entering the clinic next year. We have eight, ten moving forward into probably patients next year as well. Then continuing backfilling depending on how you guys prioritize the next best thing.
Exactly.
What is the next best thing?
That's a great question. I think we're still in the early days of ADAR editing. I think there's still so much to be discovered about how we can use this. That's really exciting. We live in a really exciting time for ADAR editing. We're going to see it unfold over the next few years.
We look forward to tracking the progress. Daniel, thanks so much for joining us today and giving us the rundown.
Excellent. Thank you.