We'll get started here with the next session. I'm Steve Seedhouse on the biotech team here at Cantor. I'm really pleased to welcome ProQR. I'm joined, of course, by CEO Daniel de Boer. Looking forward to a great conversation. Even an update this morning from the company, which I'll ask about here momentarily. Thanks, everyone online and in the room, for joining us to listen in to the conversation. Daniel, why don't we start with just the press release you put out this morning. There's an event I think you're going to host at the end of September. Of course, you had an update on your novel and more potent RNA editing oligo that's in the clinic, so maybe you can remind folks that didn't have a chance to catch that press release what you announced and what to expect going forward. Yeah, absolutely. First of all, thank you for having us today. I'm happy to share some of the progress and the updates that we are having at ProQR. As you refer to this morning, we announced in a press release that our second RNA editing drug is now in the clinic. We've started dosing people in a clinical study of AX-0811, which is the fast follower improved molecule of AX-0810, for which we announced positive direct engagement data in June of this year. So really exciting to now have a second program into the clinic. It's the second of four that will enter the clinic in the near term. Over the next 12 months, we're going to have five different clinical trials reading out across those four programs. So a really exciting year ahead. To further educate people on what's coming up with our program for AX-0811, we are indeed hosting an investor event at the end of this month in which we are going to outline the expectations for the AX-0811 clinical study that we today have started. In that event, we'll have a key opinion leader, Gideon Hirschfield, that will walk us through the rationale of this therapeutic strategy. We will review the AX-0810 data that we announced last June, and then we'll also review on the basis of our now new learnings on these bioasset endpoints, the expectations for the 811 readout that we expect before the January J.P. Morgan Healthcare Conference. We expect to have two cohorts of PD data before that time point. So really exciting. Lots coming up. Okay. Yeah, and just in terms of setting expectations, I guess this is based on what you've learned from the preclinical to clinical translation and editing efficiency or predicted editing efficiency and all of that in terms of being able to project sort of what you actually, in fact, expect to see from- Yes, exactly. We will give expectations on what to see on the three different endpoints. Nice. We are measuring conjugated bile acids, which are the toxic ones that actually cause the disease. We are measuring TUDCA, which is a chemical bile acid that is not produced by the body, but we administer to measure the clearance rate thereof, and we are looking at total bile acids. Across those three, we are going to outline the priority order of how we rank them in terms of importance and also the threshold target that we are setting for each of those. Okay. For 810, is there going to be any new data relative to the prior update that you had, or will it just be a recap and sort of expansion on that? At this event, there will not be new data. Okay. We will present the remaining data from the AX-0810 study at a scientific or medical conference later this year. That will include cohort 3. So far, we have announced cohort 1 and 2, the 3 and the 6 milligram per kilogram doses respectively. Cohort 3 data will be announced together with the 12-week follow-up data of all 3 cohorts later over the course of this year. Very cool. Okay. All right, let us step back now that we have discussed that hot-off-the-press announcement that you made this morning. Always love to do this just because you are a leader in the field, just get a pulse check on RNA editing and where we are today as ProQR prosecutes this technology into the next stages of clinical development and then hopefully mid-stage clinical development sooner than later. Just where do things stand? I guess since the last time we spoke at the Cantor conference last year, what have we learned in the field about RNA editing that has moved the ball forward? I think it is really interesting times for RNA editing. This field, obviously, is a fairly young field. We only announced our initial programs in the pipeline just 3 years ago, and right now we are in the clinic with 2 of them and 2 more to follow very soon. There is a number of other players in the field that have progressed molecules into the clinic, some with more success than others. I think broadly as a field, we have learned a lot from all of those data points that have come out. I think most importantly, since the last time at the Cantor conference that we discussed this, we have now established that Axiomer RNA editing using ADAR with editing oligonucleotides is able to edit in a dose-dependent manner in a consistent way across different endpoints. We have seen across 3 different endpoints in human that there is, in a dose-dependent way, concordant responses after editing at the different dose levels. We also noticed that those are mimicking exactly what we have seen in the preclinical space, and that is really important from a platform perspective because it tells us that our preclinical models that we use, the primary human hepatocyte in vitro model, but also the humanized mouse model are predictive of what we can subsequently see in the clinic. That is relevant as it helps us to translate the next batch of programs and project where their editing will land once we are in the clinic. I think we've also learned that AX-0810 and editing oligonucleotides broadly are safe and well-tolerated, and that they have a profile as was predicted preclinically from a PK and safety perspective. Those are really important from a broader pipeline view, as that will allow us to be more predictive as we take the next set of programs forward. For AX-0810, we have models that based on the PK we have observed in the clinic, we likely saw 10%-15% editing at the two lowest doses. For AX-0811, we can now, on the base of that modeling, project what we expect for the clinic, and we there now project between 40% and 65% editing, so significantly higher. I would say over the last year, we've gained so much data and insight that now allows us to make these projections with relatively high certainty that it puts us in a position to be much more in charge of the outcomes that are coming. Can I follow up on that point just because that's obviously a big step in editing efficiency improvement, and I think that's been one of the big questions investors have had about RNA editing is just can it be as potent as DNA editing, let's say? Can you get to the point where it's as potent as like siRNA, where we're talking about 80%, 90%, in that case, knockdown, in this case it would be editing. But where it's not even a question, right? You have a target you know you can design an oligo that can get you to call it max potency. Certainly sounds like with NTCP, you've made a big step in that direction. Is that a function of working on the same target for years and years and years, or are there generalizable learnings about chemistries and about ADAR enzymatic reaction or anything really, PK, that can sort of put you one step ahead for the next target that you go after? Yes. That is, I think, a really relevant and also timely question. I think this year for us was really a year in which we started to get a very strong grip on producing high-editing oligonucleotides. I do not think we are at the stage yet where siRNA is, where you consistently achieve 80%, 90%, 95% knockdown without having done the first experiment. I think for editing, we are still learning quite a bit about which of the factors are most determining of limiting factors of editing. Is it expression levels or secondary structure or sequence context? All of those we are separately, both in-house as well as together with academic partners, optimizing for. I think what really was the breakthrough for us this year was the AI model combined with the high-throughput screening methodology that we set up over the last two years. That has allowed us to learn from all the data we have generated, and obviously, we have been working on RNA editing since 2014. There has been quite a body of data that we could train our models on. With that, we have designed a process that, across a few iterations, allows us to go in a short three months from no editing to these high-editing oligonucleotides. NTCP we used as a learning program because we had so much data on it, so we trained our models on it, and then we found AX-0811, which was such a more potent molecule with a longer half-life that we decided to take it forward from both a platform as well as from a product perspective. I think this now also allows us to do that for all the other targets. We are rapidly progressing a wide variety of different molecules that are predicted by the AI for a range of different targets, but then test it in a high-throughput methodology that we have earlier this year announced together with Ginkgo Bioworks. We use their roboticized lab testing platform to very rapidly generate data points that go into the AI to further optimize EONs. I think we are getting a much stronger grip on the oligonucleotides. I think as part of that, we can start to extract portable learnings. It is not said that those hurdles are the same for each target. For one, it may be secondary structure, for the other one it may be something else. Yeah. The good thing about this AI high-throughput screen system that we have set up is that it does not care about what the hurdle is. It just optimizes throughout it. Mm-hmm. As you optimize something like editing efficiency, maybe using NTCP as an example, are there trade-offs? I am thinking about PK would be one obvious one. You have to make some changes, the editing efficiency is better, but then when you go into an animal or into human, maybe the PK is compromised. The model that you are using and the approach that you are using, are you able to sort of stabilize the variables as you go optimize the efficiency without compromising some other property? Yeah, no, that is a really fair point. Yes, it is always compromising. We know that more instable molecules are better editors. They are not necessarily better drugs. In our AI model optimization, we set a number of different variables to optimize for, which do include editing efficiency, of course, then its stability for half-life, its manufacturability, its safety, and then a bunch of other measures. We optimize for all of those, so the ultimate best EON that we take forward is always a compromise between optimizing for all of those factors. Got it. Before we turn to some specific questions on NTCP, obviously, which is the lead program, I suppose between the two oligos in the clinic. It sounded like you mentioned you have two others that we know about, and maybe you can highlight what those are that would be in the clinic shortly, maybe next year. I guess fast-forward 12 to 18 months, you are talking about four oligos in the clinic. How many would you have proof of concept data for, I guess, and maybe you can highlight those other two Yeah that we have to look forward to. Happy to. Within the NTCP franchise for cholestatic diseases, we have AX-0810 and AX-0811. They both target the same target, but AX-0811 is an improved version of AX-0810. AX-0811 will have initial two cohorts of human data in early January, and on the base of that, we will select either 810 or 811 to progress into a first inpatient study in biliary atresia. That will run into the first half of next year. It is an IIT. That will be in pediatrics that have biliary atresia. We expect the first data read from that in the first half of next year, and then we will continue for probably a longer period of time, maybe years. We are also progressing AX-0422, which is a program that we are developing for MPS I or Hurler syndrome. This program is entering the clinic in the next few months, and we will then have an initial data readout in the first half of next year in patients where we are looking at very well-established biomarkers of GAG reduction in circulation as well as in urine. This is a lysosomal storage disease affecting both the periphery as well as the CNS. Our fourth program is called AX-2911, targeting PNPLA3, which is a gene that when mutated, is involved in MASH, in particular in lean MASH. More than 90% of the patients with lean MASH carry this variant. By editing, we can restore a normally functional protein that takes away the toxic elements of the mutation. We have shown preclinically that that has a really good read-through into steatosis, so fat reduction in the liver, and this will enter in IIT as well, and we will have first data in the first half of next year. So in the next 12 months, we expect five clinical data readouts across four different therapeutic molecules. Fantastic. Let's drill down on NTCP then for a few minutes here at least. Just recap, I guess, what you learned from the initial phase I readout for AX-0810. You had a couple doses. There is one more still to come, so maybe if there is anything you wanted to forecast in terms of what we could learn from that third cohort, presumably you might get sort of some incremental editing efficiency benefit even from that third dose. But yeah, what gives you confidence that you have a sort of therapeutic on hand in either AX-0810 or AX-0811, same target? Yeah, good question. The therapeutic strategy here is to ensure that the body is enabled to excrete the toxic bile acids from the circulation. We do that by preventing reuptake, by modulating NTCP, therefore more of the bile acids stay in circulation, and then the kidney starts filtering them out and excreting them. We have seen that in our AX-0810 health volunteer data, that there was indeed an increase in circulation and subsequently an increase in excretion. That exactly is what you want to achieve, because with every cycle, you reduce the overall load of the system, and with that overall load that goes into the liver, and ultimately brings it below a point that leads to the inflammation and the fibrosis and the ultimate trigger for liver failure. That process is probably quicker with AX-0811 than it is with AX-0810, but likely both will arrive in the same place by excreting some of the bile acids over time. We have learned that that has been now correlated and translated from the preclinical space to the clinic, and we think that with that finding, we can go into patients and see how that affects liver health biomarkers and subsequently liver imaging, where we can measure that in patients with BA. The ultimate objective is to prevent that these patients progress so far that they need to get a liver transplantation. In biliary atresia, that is a very common ultimate outcome of the disease. 75% of the patients goes on to get a liver transplantation in the first two years of life. That is obviously a very severe outcome. With AX-0811, we expect to see higher editing, and likely that will lead to a higher target engagement biomarker effect, and ultimately in patients that may lead to a quicker clearance of the bile acids. We think with cohort 3 of AX-0810, there is likely also a potential to increase further. The cohort 3 dose is relatively high, though. It is 9 mg per kg, so that is higher than where we normally go with oligonucleotides, and it is really for us to learn about the dynamic range for editing and the biomarkers. We are curious to see what is in there. Also, we are curious to see what the 12-week data will show. After the four weeks treatment period, there is 12 weeks of follow-up, and in these 12 weeks, we are going to look at what happens over time, and that will help us to inform the design of the phase II as well. Including dose interval, maybe is something important? Dose interval. Durability of the effect, dose interval, PK, et cetera. Okay. Whether we are talking about an 8-fold increase or even something less than that, or as we talk about AX-0811, maybe even something more than that in terms of serum bile acid increase as a measure of activity, what gives you confidence as you look to the literature, as you talk to doctors, that sort of that level of bile acid modulation will ultimately affect, maybe not liver. I doubt you can measure sort of outcomes in liver transplant in an early stage biliary atresia study, but certainly the imaging and the liver function test measures that you are going to be looking at. How confident are you that it is going to be correlated? Yes. No, great question. I would say we are going to learn more about that and have data to prove that from the IIT study that we are running next year. But what is most important is to realize that we are excreting the toxic bile acids from the system through the urine. By excreting them, they can no longer harm the liver, so they can no longer be absorbed into the liver to harm them. With every cycle where the bile acids are excreted from the liver, go into the circulation, and then are back taken up into the liver, with every cycle, we lighten that load. We reduce and reduce and reduce. Ultimately, the only cause of the disease in biliary atresia is the high concentration of bile acids intrahepatic in the liver. By lightening that load, you are essentially removing the underlying cause of the disease. and with that, preventing the inflammation that leads to the liver disease. Yes, we expect that to translate into improvement in liver health biomarkers and improvement in imaging through liver stiffness. What is your current understanding at ProQR about the pivotal trial/regulatory approval pathway in biliary atresia, both in terms of where it is today versus, if we are talking about 811, by the time you establish some proof of mechanism in your early studies, is there any way that this could evolve in the coming years? Yes. We plan to start a phase II program mid-next year. It could potentially be pivotal depending on our discussions with the regulators. Obviously, as you can imagine, we are now doing a lot of work to design that trial to get the information to and from the regulators. Once we have our plans finalized, we will update people on that. We have some time to do that. There is a lot we will learn in the meantime on 810, 811, and also on the IIT. Yeah. We plan to start that study mid-next year with potentially an interim readout in mid 2028. That would give us confirmation that the study is on track. I think we believe that in biliary atresia, especially as there is nothing else in development for these patients, and there is a very high unmet medical need with this rapid progression to liver transplantation. We think there is a strong rationale for an accelerated development path. We also know the disease moves very quick, so we expect the onset of the effect of treatment to be relatively quick. Therefore, we would aspire to at least discuss with the regulators to have an accelerated development path that would be based on a combination of biomarkers and imaging for the accelerated approval, followed by an outcomes data set that likely would look at time to liver transplantation. Okay. Now, since the vast majority of the liver transplantations occur in the first 2 years of life, there's a good chance that we will have quite a bit of data on that as well in the initial phase II study. If the drug is as potent and as functional in this indication as we think it is, there may be a rapid path to patients. Okay. Speaking of potency, you've already basically surpassed, matched or surpassed, I would argue, like what Bulevirtide, the NTCP small molecule inhibitor, which is of course approved for HDV, it's not used in cholestatic disease. But what that shows on the biomarker. There are other NTCP inhibitors in development. I'm thinking specifically of Assembly's molecule, and I believe they've actually indicated they will test it in cholestatic disease, so it's a competitive program now, I guess. Do you think RNA editing with AX-0811, certainly, if you get up to 50%-60% editing, do you think that can be as potent as what you've seen from the small molecules? Is there anything pre-clinically that gives you insight into that? Do you think you need to be as potent as the small molecules? What are your thoughts on that competitive dynamic? Yeah, I think that's a good question. To the extent I know, Assembly Bio has announced they are going into PSC, not into biliary atresia. So we're not directly competing in the same indication, but likely down the line, there will be a comparison, which I think is good. We're going to learn a lot in the field of NTCP about how this therapeutic mechanism is helpful in cholestatic disease. I think the editing approach is significantly differentiated from inhibitors. Steric blockers like the peptides from Gilead, Bulevirtide, but also the small molecule from Assembly Bio, they block the entire protein altogether. The NTCP protein has a range of different functions. In addition to bile acid transport, it's also involved in hormonal regulation as well as in drug uptake. If you block the hormonal regulation, you will likely see a significant reduction in T4, which, especially in children, but it remains to be seen what that will do in adults, would be concerning as that may lead to growth deficiencies and CNS issues. We think that this editing approach that we're taking is, to a certain extent, validated as nature has already done the safety experiment for us. There's a number of people that live with these variants in the natural population. They're completely healthy. They for sure do not suffer from effects of hormonal regulation or drug uptake. Just for context that I think although we're both targeting NTCP, it's very differentiated approaches, and there may be pros and cons to those. On the amount of editing and biomarker effect, I think a lot of people are focused on total bile acids as a biomarker, but the total bile acids are, in our view, not the key driver of disease. The disease is driven by the conjugated bile acids, and those conjugated ones are specifically regulated through NTCP. Those I think are more interesting and probably also more precise to measure. In our study, we will also measure TUDCA, and TUDCA is a very clean measure, as you've seen in our data earlier this year, as TUDCA is not produced by the body itself. It's a chemical form of bile acid that we administer and then can in a very controlled way measure the clearance thereof. I think those are probably endpoints that we will be looking at. We'll talk more about this at our event later this month. But I think there's clear differentiation. And to your question, do we need as much? I think probably more editing is better, but our view is that more editing will lead to a quicker clearance, not to a better absolute clearance of the bile acids. Got it. You'll have imaging and liver function tests. Is there any need or desire to collect liver biopsies in the biliary atresia study, or is it sort of unwarranted, unfeasible? Yeah, it's unwarranted. Okay. Especially since it's in pediatrics that have severe liver disease, so we're not doing that. Okay. Maybe you can talk a little bit about these other programs. I'm thinking of Hurler in particular. This is a program that was at one point licensed. It's back in your hands now, therefore it's very close to the clinic. Yep. It's sort of among the more advanced programs you have as a result of all the collaboration work that had been ongoing. What are the development plans for that once it gets into the clinic, and is it sort of multiple products with multiple different modes of delivery, and how are you going to mesh all that together as it unfolds? Really fair question. MPS I affects CNS and the systemic part of the body. We are currently in IND-enabling activities with this program. We plan to start a clinical study around the end of the year, so maybe late this year or early next year. Then we will have one cohort of data in the first half of next year in patients. This will be in the subcutaneous study, where we dose systemically to target the liver and increase the enzymes that lead to then the very well-established measure of GAG reduction in circulation and in urine. That is what we will do for systemic circulation. We will then, on the basis of that, expand it to higher dose subcutaneous dosing, but also start working on the intrathecal administration to treat the CNS elements of the disease. There is currently not much going on for that part of the disease. Current standard of care is weekly IV administration of systemic enzyme replacement therapy. We plan to replace that with probably every five or six months subcutaneous administration for the liver, so very low burden to patients, and probably once every nine to 12 months intrathecal administration for the CNS. We think there is a high benefit for patients with this approach, as it treats a part of their disease that is currently untreated and also it reduces the burden on administration. Okay. Is it the same oligo just without GalNAc, or is there any optimization that needs to be done? It is the same oligonucleotide that we use for both tissues. Okay. And I guess what you will learn from that intrathecal administration and the activity in Hurler could or would be an entree into broader CNS discovery and development at ProQR. Is that fair? Absolutely. Okay. Yes. We think CNS is very interesting as a tissue for ADAR editing. Editing is very efficient there. Half-lives are very long. I think MPS I allows us to test the same molecule first in liver, which is an organ that we have a lot of data on, also in human, and then expand into CNS, which is a novel tissue in human, at least, with editing oligonucleotides. That is a perfect bridge for us to go into that tissue. Right. Okay. And I guess what is the update then on. You have the Rett program in development, which looked interesting pre-clinically as well, and that could leverage some of the learnings you would have from the intrathecal delivery, I would imagine. Absolutely. For that reason, we are staging the Rett program behind the IDUA program- Okay the Hurler program, so that we can take the learnings into account and really de-risk the Rett program in the clinic. Okay. In MASH then, quickly, with PNPLA3, this is a target that has been pursued before with mixed results, because when you are not editing it, if you are, let us say, knocking it down, it is just different, right? It has potentially a sort of complex relationship in people that are carriers of that. We are all familiar, I guess, with just sort of myriad MASH programs, and there are some very typical measures that you can look at, liver fat and liver function tests. For this target and this sort of selected population, is it the same type of clinical endpoints that would be interesting early on? Is there anything unique about the trial design or measures in those patients that- Yeah. I think PNPLA3 is a really nice example where RNA editing is much more appropriate than knockdown, because if you knock it down, you also lose the function of PNPLA3, which has its own metabolic function in the liver, and that leads to actually worsening of the disease. We think where editing, you both get rid of the toxic element of it, but also maintain the function of the protein. We think the trial designs will likely be very similar on an endpoints basis to what you are used to, as the disease manifestations are very similar. I think there is a high correlation in Lean MASH with this mutation. Right. That is right. More than 90% of the lean MASH patients carry this variant. There will be some specifics to the lean MASH population from an endpoints perspective. For the upcoming trial, we will look at broadly patients that carry this variant, not just lean MASH. Okay, great. Well, Daniel, congrats obviously on the clinical progress with AX-0811 and the update, and we will look forward to hearing more about that program and the corresponding update on AX-0810 later this month, I suppose. Looking forward to what is going to be a number of programs in the clinic this time next year. There will be a lot to talk about, of course, at the conference next year from a data standpoint as well. Thanks for being here and great conversation, and look forward to following all the progress going forward. Excellent. Thanks for having us. Terrific