Good morning, and welcome to the ProQR Investor Call. Today's conference call is being recorded. At this time, I'd like to turn the call over to Sarah Kiely, Vice President of Investor Relations and Corporate Affairs. Please go ahead.
Thank you, and good day everyone. We appreciate you joining our event today. Today we are pleased to highlight new preclinical proof-of-concept data for our AX-0810 program targeting NTCP, which was presented yesterday at the ASGCT annual meeting in Baltimore. On slide two, you'll find the agenda for our call and our speakers. From the management team are Daniel de Boer, our founder and CEO, who will provide a brief introduction, and then Gerard Platenburg, our Chief Scientific Officer, who will take us through the data presented at ASGCT. Following the presentation, we will have a Q&A session with covering analysts before we conclude the call. Today's event is being recorded, and we will have the replay available on our website following the event. You can also find our ASGCT poster under the Publications and Presentations section of our website. On slide three is our forward-looking statement.
During the call today, we will make forward-looking statements. There are risks and uncertainties associated with an investment in ProQR, which are described in detail in our SEC filings. I will now turn the call over to Daniel. Daniel?
Thank you, Sarah, and good morning, and good afternoon, everyone. Thank you for joining us today. We are pleased to share an update with you on the data that we shared at the ASGCT annual meeting. But first, I'll provide a brief overview of the company's strategy and our proprietary Axiomer RNA editing platform. Axiomer was invented at the ProQR Labs in 2014 and uses the well-proven modality of oligonucleotides to recruit a novel mechanism of action. Axiomer uses editing oligonucleotides, or EONs, to recruit endogenous ADAR to edit individual bases in the RNA. ADAR is present in all human cells, and RNA editing is a naturally occurring process. In fact, it's happening in all of us right now. Our proprietary Axiomer platform makes use of the ADAR mechanism that nature has developed and recruits it to edit specific nucleotides in a targeted way.
Preclinical platform data demonstrate that Axiomer is broadly validated across multiple genes, and today we'll focus on the preclinical proof of concept for our AX-0810 program targeting NTCP for cholestatic diseases. Our strategy includes both in-house development of pipeline programs, initially including AX-0810 as well as AX-1412 targeting the B4GALT1 gene for cardiovascular disease, and using the Axiomer technology for selective partnering and expertise in technology, like in our partnership with Eli Lilly, allowing us to capture the full value of this platform technology. ProQR has quite literally led the field of RNA editing since 2014, when ProQR scientists invented the RNA editing technology using endogenous ADAR and performed the first experiments using our editing oligonucleotides to recruit natural and endogenously expressed ADARs. These experiments also led to the first IP filings for this technology back in 2014, which laid the foundation for our leading IP estate today.
ProQR holds more than 10 platform patents protecting the use of oligonucleotides to recruit endogenous ADAR, broadly. Several of these patents have been granted and were subsequently opposed in several jurisdictions, where the patent courts ruled in favor of ProQR and upheld the patents. Our foundational IP estate is not only granted but also tested in opposition and survived that, which reaffirms the conviction in our leading IP estate. Finally, as we reported in our Q1 financials this morning, I also note our strong cash position, ending Q1 with approximately EUR 103 million, providing a runway into proper mid-2026. Now moving on to our pipeline on slide five. As you will see, our pipeline contains a variety of targets for rare and prevalent disease, as well as wholly owned and partnered programs. We plan to capture the value of our platform across two strategies.
First, through the development of an internal pipeline of high-impact medicines, and second, through selective partnering. We're initially prioritizing AX-0810 for cholestatic disease and targeting NTCP, and the AX-1412 program for cardiovascular disease, which targets the B4GALT1 gene. There are a number of earlier-stage programs as well, which we will share more about in due course. We've partnered with Eli Lilly on currently 10 targets on the Axiomer platform, where ProQR leads the discovery phase and Lilly all phases beyond that. This partnership so far brought in $125 million in upfront payments, and Lilly holds an option to expand the partnership from 10 -1 5 targets, for which they would pay an additional $50 million in opt-in fee. In addition to this, ProQR is eligible to receive $3.75 billion in milestone payments plus royalties.
We are very pleased with the partnership with Eli Lilly and continue to execute on that with high priority. We're also pleased to note that at ASGCT, we actually have a poster together with Lilly on some of the development work we were doing with Lilly. We also, earlier this year, announced a partnership with the Rett Syndrome Research Trust, which is focused on developing editing oligonucleotides targeting an underlying genetic variant that causes Rett Syndrome, a progressive neurodevelopmental disorder caused by genetic mutations in the MECP2 gene. Given the vast opportunity with the platform, we have appetite and capacities to selectively form additional multi-target discovery partnerships. Moving on to slide six. Building on our experience from the last 10+ years, we have designed a translational strategy that we believe gives a high probability of success for our first-in-human trials.
Our objectives are to generate a dataset in human studies where we are studying editing and disease-relevant biomarkers with proper sample sizing. To do so, we selected targets that introduce a variant in a wild-type sequence such that this allows us to study target engagement and biomarkers in healthy volunteers. The advantage is that in a healthy volunteer study, we can, in a much more efficient way, have appropriate sample sizing in each cohort, get a dataset without disease background noise, and get to a high-value dataset in a short amount of time. The targets are largely de-risked because we source these from human genetics research, from populations that carry these variants, which are associated with health benefits. In these trials, we can, in a cost-and-time-effective manner, demonstrate RNA editing or target engagement, disease-relevant biomarkers, proper PK and dose finding, in addition to safety and tolerability.
With that, I'm now pleased to hand over the call to Gerard Platenburg, who will take us through our data presented here at ASGCT.
Thank you, Daniel. On slide seven, I'm very happy and proud to share a little bit of the data that I presented yesterday at the ASGCT. I'll take you through the background of the ADAR technology as well as the experiments that we've done to come up with the poster that was presented. On slide eight, you actually see what ADAR editing is. It's an endogenous system where we use ADAR, adenosine deaminase acting on RNA to execute its natural function of RNA editing, and that is to convert adenosine into inosines, as you can see over here. ADAR binds double-stranded RNA, which you find in natural RNA. And on slide nine, I actually made a picture where on the left side you see the natural ADAR editing.
We studied that and provided by using oligonucleotides or editing oligonucleotides to bind to the target RNA, providing a docking for ADAR as an enzyme, and directing its action to a very specific adenosine that we would like to edit. So on slide 10, you can actually see that we are creating a new class of medicines with a broad potential. There's multiple ways to apply the technology. On that left side, you see the correction, where there's many, many G2A mutations that you find in monogenic diseases that we can correct. But on the right side, you see a vast opportunity to use in protein modulation. And for that, we can actually think about using ADAR to alter protein function or to include protective variants that, by genetic screens, we find protective variants and alter the function of specific proteins for their protective properties.
We can also use the technology to disrupt and change post-translational modifications such as phosphorylation, glycosylations, and many more that we can change. Lastly, we can change protein interactions, and that's being used to change localization of protein, folding, and protein function. So in the next slides, I will share data, obviously, that would bring us into altering a specific function of a protein. So on slide 11, you see that we are creating AX-0810 for cholestatic diseases, where the cholestatic diseases have a high medical need, where patients accumulate bile acid in liver, leading to fibrosis and ultimately liver failure. Bile acids are very essential molecules for absorption of certain nutrients and vitamins in the small intestine, but if they accumulate in the liver, that can lead to disease. So AX-0810 is a unique therapeutic approach, changing the cause of disease at the site of action at the hepatocytes.
So if you turn to slide 11 sorry, slide 12, you see that the actual mechanism uses the sodium taurocholate cotransporting polypeptide protein, which is encoded by the SLC10A1 gene, and it's expressed at the membrane of hepatocytes. And usually, it is there to when the bile acid is produced in the liver to actually reuptake the bile acids for more than 90% in the hepatocytes. And that's something that is taking place every day. So when the bile ducts are obstructed, you start to accumulate the toxic effects of bile acid in the liver. NTCP is the target for us to actually divert the reuptake of bile acids from the hepatocytes to the bloodstream. So in nature, we find variants that actually have that already, that property in them, and those variants specifically have altered properties that lower the reuptake of bile acid from the hepatocytes to the bloodstream.
So the strategy that we follow is a protein-sparing strategy, where the functions of the NTCP are saved, but the bile acid reuptake is changed from the hepatocytes. So on slide 13, you see actually that studying the NTCP protein based on genetic screens, but also in silico analysis, much is learned of the mechanism of bile acid transport. And as you can see over here, modeling in silico analysis shows that to be able to transport the bile acid to the central core, you need actually the binding of two sodium molecules at its core. That's something that is essential for its function, and that's been studied very well.
If you look at the conserved binding site of both sodium molecules, we focus on the binding site of the second sodium molecule, and that is to look at the conserved amino acids that were predicted in structural analysis. If you then turn to slide number 14, if you study the glutamate residue at position 68, it's very important that molecules over there to provide the context for the binding of sodium, which in itself is essential for the transport of bile acid. When changed to an arginine, you actually disrupt some of the hydrogen bonds that are there, and it's essential that that disruption no longer allows the binding of a sodium molecule.
That in itself led to the understanding that by avoiding the binding of sodium in that specific spot, you lead to an altered uptake, reuptake mechanism of bile acid, which is shown on the right side of the slide number in slide 14, this slide, where we studied the reuptake of bile acid in cells, where the cells express on the mid on the wild-type NTCP, where you see uptake of the bile acid, whereas the variant, the Q68R, is no longer able to take bile acid up to the cell. So the mechanism there is shown really that the interaction of sodium is impaired, and thereby we impair the uptake of bile acid.
So on slide number 15, we show data that actually indicates that there's no, that the Q68R variant only affects the bile acid uptake, but the presence of the RNA and the protein at the membrane in the middle panel, but also the localization of the protein on the right panel, as you can see in these expressed cells, is not impaired. So we only affect the NTCP-mediated bile acid reuptake function. And that is, of course, that we are after. So on slide 16, we then incubated cells with our EONs able to edit the target site in the NTCP RNA expressed in these hepatocytes. And as you can see, we see a very nice dose-dependent response for editing-mediated bile acid reuptake. So there's a nice decrease after the editing taking place in these cells, which was very relevant, as you can see over here.
So having now proven that we found variants that are no longer able to reuptake bile acid, but to maintain the function of the protein itself, we took that into in vivo, where we studied the concept in non-human primates on slide number 17. This experiment was done to actually show proof of concept, to show editing in vivo in the liver, but also to show correlation between editing and the bile acid uptake alteration. What you can see here is that an increased editing gives rise to a full increase of serum bile acid as we would expect it. With the EON, which is an early-generation EON, at around 30% editing, we see about an eightfold increase in serum, and that is exactly what we wanted to achieve.
Slide 18 is that in the next step toward development, we are now generating EONs with further optimized potency, as you can see over here, and leveraging the expertise that we have in EON design optimization, chemical optimization. We now are developing these molecules with greater effectivity, as you can see over here, and leading to at least threefold increase compared to the earlier generation of molecules. So on slide number 19, I can show you that there's translatability and clinical relevance of the serum bile acid changes in liver fibrosis. So the actual EONs that we have generated is confirmed by sequence homology, and we've developed the molecules that we've tested in human cells as well as in non-human primates that are able to execute the action of editing in human cells as well.
So the molecule that we've generated in these experiments will go through the next phases of development as well. As you can see over here, there's the serum bile acid of human volunteer plasma, plasma of monkeys. And at this editing experiment in non-human primates, you see a very nice increase of serum bile acid concentration at several days. And what is very encouraging is that we find in naturally occurring variants in humans, where these humans carry a variant that is actually no longer able to reuptake bile acid into the hepatocytes, that in the plasma with very high total bile acid levels, it's not harmful as evidenced by the data here. So we feel very much encouraged by the data that we now have and are looking forward to the next steps in development.
So summarizing on slide number 20, we see a first proof of concept to alter NTCP in non-human primates in vivo. For the first time, we show target engagement as well as biomarker change in the bloodstream using Axiomer EONs. We have a very specific targeted approach to specifically modify the NTCP protein, resulting in altered bile acid reuptake in cholestatic diseases. And this data supports our moving forward into a therapeutic application in cholestatic disease. So with that, I'd like to give the word back to Daniel.
Thank you, Gerard, for walking us through the data. On slide 22, with this preclinical proof of concept dataset in hand, we are moving this program forward towards an entry into the clinic around the end of this year or early next year. As part of our platform clinical validation plan, we are designing our initial trials in healthy volunteers to benefit from a clean dataset with no disease background noise, proper sample sizing, and rapid execution. With these programs, we can as well measure RNA editing, target engagement, and disease-relevant biomarkers. This trial will have a typical single ascending dose, multiple ascending dose design, allowing us to generate a valuable translational dataset for the development of AX-0810 in cholestatic diseases. Further details about the trials we will share in the second half of the year.
On slide 23, with this exciting data presented at ASGCT and on the call today, we look forward to sharing the translational data on our clinical candidate for AX-0810 with you in the second half of the year as we prepare for our entry into the clinic around late 2024, early 2025. Over the course of this year, we will also share with you preclinical proof of concept and translational data on our second clinical program, AX-1412, targeting cardiovascular disease via the B4GALT1 gene. We will also provide further platform updates and potentially additional pipeline programs. We are progressing with our Rett program, which is in partnership with the Rett Syndrome Research Trust, and we will share more information on this program as we progress.
As we announced in our quarterly release this morning, we have achieved the first milestone in our Lilly partnership and anticipate many more to follow, including this year. We do anticipate to potentially enter into an additional multi-target discovery partnership. On the IP front, we will continue to file additional IP and continue to enforce our leading IP estate. With our cash on hand, we are funded into mid-2026, well beyond all the key value inflection points, and with ample opportunity to extend the runway from non-dilutive sources. With that, Operator, we are now ready to take questions.
Thank you. If you wish to ask a question, please press star one and one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. We will take our first question, and your first question comes from the line of Jon Wolleben from Citizens JMP. Please go ahead. Your line is open.
Hey, everybody. Congrats on the data and progress, and thanks for taking the question. Wondering if you could talk a little bit about the translatability between the in vitro and the in vivo editing because you gave us a nice increase in the optimized EONs versus the poster, which is the first generation. So just wondering what you would expect to see with in vivo editing with the optimized EONs.
Hey, Jon. Thank you for the question. I'm going to pass this on to Gerard.
Yeah. Hi, Jon. Thanks for the question. I would anticipate that the more improved editors would give us higher editing in vivo as well. I think the improved, let's say, version of the molecules not only give us a higher absolute level of editing, but also the, let's say, we need less molecules to create that editing, basically. So I would expect the molecules that we are developing will give rise to higher editing in the subsequent animal studies.
You've talked a little bit about a target editing range in the past. Is that across the board what you'd want to see? You could remind us or if this is target or disease area-specific. And then last one for me, is this GalNAc delivered, and is there any difference between delivery on what you did in these non-human primates and what you expect in your clinical candidate? And then I'll jump back in the queue. Thanks.
Yeah. So thanks again. I think important is to note that we feel that the full increase that we see and also the absolute levels that we see bring us in a range of clinical applicability is known from literature. It's expected that a change of a twofold in serum bile acids could lead to a clinically meaningful improvement. So obviously, we need to show that, but that's something that is in the realm of possibilities. So on your second questions, clearly, this was to show proof of concept of the AX-0810, but we are testing different modalities in our IND-enabling studies, and we'll announce the development candidate later this year. So for your information, we are looking at GalNAc and LNP formulations, amongst others.
Very helpful. Thanks again.
Thank you. We will take our next question. Your next question comes from the line of Steve Seedhouse from Raymond James. Please go ahead. Your line is open.
Great. Good morning. Thanks so much for taking the questions. First, just wanted to ask about bile acid synthesis with this mechanism. Is it increased to compensate for the reduced reuptake, and what do you think chronic treatment would do ultimately to the bile acid pool as a monotherapy? And then is this something that you maybe want to combine with an IBAT or think about managing the serum bile acid pool long-term, holistically?
Hey, Steve. Thank you for the question. This is Daniel. So we know that in nature, this variant occurs. There's people that have this variant in NTCP. That's how we came across this approach. Those people represent themselves without any disease manifestations. So they have high concentration of bile acid in blood but do not represent any clinical symptoms as a negative downside of that. So in many ways, nature has already done the experiment for us to show that this variant in NTCP will not give you negative side effects of the increased bile acid. We also know from literature that this variant increases the excretion of bile acid from blood through both feces and urine. So there is also a regulation of eliminating the bile acid from blood.
Interesting. Okay. So in the poster, the increase in serum bile acids corresponding to editing, in a clinical study, I guess, where reduction in serum bile acids has been an endpoint in cholestatic diseases, for instance, could you still use that with chronic treatment, or would you expect an increase? And how will this sort of feature of the mechanism affect the way you think about clinical development and trial design and regulatory strategy in various cholestatic diseases?
So the IBAT approach is obviously a very different therapeutic strategy. I think with NTCP targets, we can go to the core of the problem, which is the concentration of the bile acid in hepatocytes and prevent that concentration getting too high to prevent liver fibrosis. I think with this different therapeutic strategy, we will likely be looking at different endpoints and measuring different things. That also depends a little bit on the indication of choice that we will choose once we go into patients. And we have a little bit of time to determine how to go about that. The first objective here of these trials is to prove RNA editing in human in a clean dataset in a robust way with proper sample sizing to set us up for proper patient trials after that.
Okay. And then just on one of the details of the trial design that you pointed out, looking to detect RNA editing in circulating exosomes, what's your confidence in just the precision and the accuracy with which you'll be able to and just the sensitivity of that test to be able to measure RNA editing? Do you have some evidence or some reasons for sort of high confidence that you'll be able to detect editing pretty readily in those exosomes?
Yeah. I'll take that question, Daniel. Thank you. So the actual test has been pioneered by folks at Alnylam. So the accuracy of the test itself is highly dependable and feasible, so to speak. So we have a different mode of action, obviously. So we're determining the sensitivity and the reliability of the assay as we speak right now. But it will be the idea of that, similar to what they found, that they can measure the effect target engagement at the RNA level as what they have published.
Okay. Last question if I could. Just the delivery methods you're thinking about for the human clinical programs, just in the RNA editing field, I mean, there's some work with LNPs, GalNAcs, AAV. How are you thinking about the sort of near and long-term optimal approach to delivery of the editing oligonucleotides? Thanks so much for the questions.
Yeah. Thank you, Steve. So we're exploring both LNPs and GalNAcs and some other things. We're not exploring viral delivery. And for this program in particular, we have kept our options open. So in our IND-enabling, there's different delivery moieties that allow us to make a data-driven decision later on in the preclinical development before we enter the clinic around the end of this year or early next year. So yeah, we are tapping into proof and delivery moieties, in this case, GalNAc and LNP. And we make our decision later on in the process.
Thanks so much, Steve.
Thank you. We will take our next question. Your next question comes from the line of Yigal Nochomovitz from Citi. Please go ahead. Your line is open.
Hi. This is Amin on for Yigal. Thank you for taking our questions. We had a couple. First, just looking at the slide 17 graph, which shows the serum bile acid versus the editing levels, we see meaningful increases in the serum bile acid above 25% editing. Is there a minimum threshold of editing that you believe you need to see that could result into a meaningful improvement in the disease condition? That's the first one. And then on the second one, what can you tell us about the safety signals that you have seen in the NHP models that you studied?
Yes. Thank you for the questions. So we're happy to address those. So these experiments were not done to explore the highest editing or really study safety. But really, what we've done here is we collected data from a number of experiments where we used different doses and different delivery moieties to study the correlation between editing percentage and total bile acid in serum. And that's the data you see here. So this essentially is the proof of concept. If you edit the NTCP, you will get a disease-relevant biomarker change in total bile acid. We do anticipate that these levels will be sufficient. We've been saying somewhere around 25% editing should be enough to have a meaningful clinical effect. And it seems that we have quite some wiggle room there from the data that we have generated. Sorry. Your second question was?
On safety.
So this study was not on safety. This study was not specifically designed to study safety. But obviously, we're monitoring that, and we've not seen anything out of the ordinary. Typically, LNP delivers single-stranded EONs, and they have all similar profiles. We've not seen anything out of the ordinary. We are now in IND-enabling studies. That's obviously where we will further validate and confirm that. But no surprises so far.
Okay. Got it. Great. Thank you very much for taking our questions.
Thank you.
Thank you. Once again, if you wish to ask a question, please press star one and one on your telephone.
There seems to be no further questions at this time. I would now like to conclude today's conference call. Thank you all for participating. You may now disconnect.