Joining us at the Cantor Global Healthcare Conference. I'm Jennifer Kim, one of the biotech analysts here, and I'm excited to be joined by Daniel de Boer, CEO of ProQR, for this fireside chat. Daniel, thanks for joining us.
Thank you for having us. Good morning.
Maybe to kick things off, can you introduce yourself and give a quick overview of ProQR?
I'm happy to. So, ProQR Therapeutics is a leading company in the RNA editing field. We are developing medicines based on a proprietary platform that recruits a natural process in human cells to edit human messenger RNA in vivo. This allows us to develop medicines that change genetic sequences at the RNA level, and with that, we are building a pipeline of medicines for rare and common indications, both wholly owned in our own pipeline as well as through partnerships.
Okay, maybe we can start with the platform, Axiomer. Can you talk about sort of the development of that technology and sort of the role you've had since 2014, the IP portfolio you've built, and sort of what the advantages of that approach could be in your view?
Yeah, I think this is a really exciting time. So as you mentioned, ten years ago, at the ProQR labs, scientists invented ADAR as a mechanism to edit human messenger RNA, and we were able to develop and design oligonucleotides that we can deliver as medicines that recruit endogenous ADAR that's present in human cells, guide it to a place in the messenger RNA to make the edit exactly where we want it to edit. ADAR is a process that is continuously editing our RNA. So everyone here in the room, as we sit here, our RNA is being edited by ADAR, and what we invented is how we can guide this ADAR to a place in the message where we want it to edit.
So back in 2014, we conceived of this idea, and we started working on that in the lab as a side project. We incubated that over the years, and while we made inventions along the way, we filed patents that protect this platform in a broader sense, so we now have more than twelve different platform-oriented patents that protect the use of oligonucleotides to recruit ADAR to develop medicines. These patents have been granted, they've been opposed by others, and these patents survived opposition, so we believe that this patent estate appropriately represents our leadership in the invention of this technology over the last ten years. I think this is a really exciting time because over the last ten years, the science has really matured.
We've been able to develop medicines, molecules that have drug-like properties that allow us to dose infrequently, dose in a manner that is convenient for people, and that will lead to high editing in targeted organs. This high editing subsequently translates in a change in protein function, restoration of protein function, upregulation of protein, whatever we decide to design the oligonucleotides to do. With that, we can develop medicines for a whole range of different diseases, and right now, I think we're seeing that translation happening as we speak. At ProQR, we are developing currently two medicines that are entering the clinic in the near term. Then we also have a partnership with Eli Lilly, where we have ten targets in that partnership that are moving forward as well.
So let's talk about those internal programs. I think you announced the initial targets last year. You've guided to advancing both programs into the clinic late 2024, early 2025. Maybe to start, can you give a quick overview of those programs and sort of your rationale for starting with these targets?
Absolutely. So Axiomer, our RNA editing platform, is really broadly applicable. It can be applied to potentially hundreds of different targets, if not more. These are targets in the rare disease space, where we reverse a genetic defect back to a wild type sequence, but it can also be used in a more common disease space, where we, for example, introduce protective variants, or we can modify wild type sequences to give the protein different properties. When we started designing our pipeline two years ago, when we announced our initial programs, we focused on targets that would carry the validation of human genetics research. So in population research, a lot of variants have been found that have certain properties, that have been found to be safe and come with certain characteristics in humans.
We've inspired our pipeline on this human genetics research and have found certain variants that have health benefits when applied in certain diseases. Our lead program, based on this philosophy, is for cholestatic diseases. Cholestatic diseases are diseases that have high concentration of bile acids in liver, in hepatocytes, that lead to liver fibrosis and ultimately liver failure. We have identified a variant that we can introduce with Axiomer that reduces the uptake of bile acid into hepatocytes, and with that, you lower the concentration of bile acid in the liver with the objective to take away the underlying cause of the inflammation, and with that, avoid liver failure. That's our lead program. For this program, we've made really good progress.
We have at ASGCT, just a couple of months ago, presented data where we've shown that in vivo, in non-human primates, editing leads to a meaningful change in the biomarker, the total bile acid in serum, and this data was presented at ASGCT, which I think constitutes a world first, where in non-human primates, editing leads to a change in a disease-relevant biomarker, so we're very pleased to announce that. This program is currently in IND-enabling studies and will then enter the clinic. Our second program is called QR-1412 for cardiovascular diseases, and it's based on a similar philosophy. There is a population identified in the world that has a genetic variant, due to which they have a lower chance of developing cardiovascular disease.
And with our Axiomer technology, we can actually introduce this variant in people that don't carry the protective variant. This allows us to give people that don't have this variant, the protection that that variant provides. And it's known from research and literature that this variant targets two independent risk factors in cardiovascular disease. So through this mechanism, we can introduce that and potentially reduce the chance of cardiovascular disease by 30%. This program, we have not presented any data on yet. That is due for the second half of this year. So for the second half of this year, you can expect from us some meaningful data updates on both the lead program, QR, sorry, AX-0810 for cardiovascular disease, as well as AX-1412 for cardiovascular disease.
Okay, great. That's a great setup. I would love to ask more on the ASGCT presentation. Maybe to start more broadly, for people who are less familiar with the cholestatic disease space, can you walk through sort of the unmet needs in PSC and BA, and what are the goals of treatment and what the development pathway would generally look like?
Right. Cholestatic diseases is a group of diseases that's characterized by a high concentration of bile acids in the liver. This can be caused by many different ways, bile duct obstruction or other reasons, but the commonality is that they all have high concentration of bile acids in the liver. The majority of the bile acid in liver gets there through a membrane channel that's called NTCP. This channel lives on the membrane of the hepatocytes, and it essentially absorbs bile acids from the blood into the hepatocytes. 95% gets there through this channel. We have identified a variant in the NTCP channel that preserves the protein, that leaves the protein there, but reduces the function of bile acid uptake from blood into the liver.
With that, you reduce the amount of bile acid in liver, which has the objective to then lead to a reduction in the inflammation and the liver fibrosis. This is the hypothesis we're testing in our first human studies. We have recently, as mentioned, at the ASGCT, presented this data in a non-human primate study. We're essentially going to repeat that study, but now in humans, with the advantage that this is a variant that we introduce in a wild-type sequence, which means that we can test this hypothesis in healthy volunteers. We don't need patients to actually measure disease-relevant biomarker changes because we can make the change in healthy volunteers, and there we can measure the change in bile acids levels in serum, which is directly related to the function of the NTCP channel.
So our first step is to validate this in healthy volunteers. That will give significant de-risking, proof of mechanism data, showing editing, as well as changes in the bile acid levels, as well as the bile acid profile. From there on, we will move forward into patients. We are currently doing the work to decide which indication we're going to lead with. I think both BA and PSC have very significant high unmet medical needs. BA is more of a pediatric population. Kids with biliary atresia typically develop this disease in the first months and typically don't grow older than two years.
The only current standard of care is a Kasai surgical procedure, which opens them up from one side to the other, and, yeah, comes with a very heavy surgery that does lead to a delay in the liver fibrosis, but ultimately does not prevent the need of liver transplantation. There's currently nothing approved for this population, so very high unmet medical need. The second indication we're looking at is PSC, where there is a somewhat slower progression of the disease, but ultimately, all patients require a liver transplantation, which comes with a lot of challenges, and it's not always successful, and typically is only a temporary solution. So, for both, there's a really important unmet medical need that we think we can potentially solve with this approach.
There's other cholestatic diseases, but initially, we're gonna focus on these two, and while we execute our first in-human studies, we're doing parallel additional work to make up our mind what our first indication is going to be, where we develop this.
Okay, and then, going back to the ASGCT data, I guess one question I had is the, the NHP data you presented was based on an earlier generation, ion, and I think you showed, 29% editing, and then there was, like, eightfold change in certain bile acids. But you've developed later generations of ions that have sort of optimized the potency. Have you run NHP experiments with those more optimized ions, and is there anything you can say about the expectations there?
Yeah. So what we presented at the ASGCT was a dataset where we looked at a number of different data points that were generated in non-human primates, where we actually correlated editing level to the amount of bile acid serum levels, so the amount of bile acid in blood, which you would expect to go up if you increase the editing of NTCP. We saw a pretty good correlation there, showing that when editing goes up, the bile acid serum levels go up as well, and that was encouraging. This was indeed generated with an earlier generation of our molecules, so I think we are continuously innovating and improving the molecules that we develop.
We have indeed at ASGCT also presented some in vitro data where we show that we have now multifold better molecules at the RNA editing level in human primary hepatocytes. A really representative model for a human situation. Later this year, we will present additional data where we will actually show data on our development candidate, where I think it's fair to assume that higher editing does lead to higher bile acid levels in serum. Yeah, there's not much we can say about it at this moment, but later in the year when we present this data, I think there's a lot for people to dig into.
Okay, great! You should present it here. Just kidding. I think you've also pointed to something in the ballpark of 25% as a minimum threshold, at least, and getting to a twofold increase in serum bile acids for it to be clinically meaningful. Can you just talk through what that goalpost is based on? Where does that come from?
Yeah. Yeah, so there's a number of different biomarkers that can be explored in cholestatic diseases. They're all related to measuring bile acids or the profile of bile acids. There's different forms of bile acids, and that, the profile of the bile acid is also really relevant to get an impression of what's happening in the human body. We are so far looking at total bile acids in serum as an interesting biomarker, although when we come out with our clinical plans, we will give people the full picture of what to expect from the trial. In total bile acid levels, we expect that a twofold increase will reduce the inflammation, and with that, reduce or stop the liver fibrosis, in human. And this is based on other clinical trials that have been done with NTCP targeting molecules in other indications.
This helps us to get a steer of what the cutoff is for where, inflammation levels start to drop, and we think at the twofold increase, that's where it happens. We've seen, as you may have seen in the poster at the ASGCT, that somewhere between 10 and 15% editing, we are crossing that twofold level in bile acid. So I would say that is, for now, the target. But again, once we present the data on our clinical candidates, we'll also refine what we expect from the clinical trial and what the target's gonna be for the biomarker.
I'm sorry, did you say the updated data with the clinical candidate, will that be in tandem with an announcement of the plan design or, or-
Yes. Yeah.
Okay.
So later in the year, we plan to announce additional data on AX-0810, and at the same time, announce our plans for the clinic, our exact timeline for starting clinical studies, and for when we will have data. The data will come relatively quick after the start of the study because this is a study in healthy volunteers, which is much quicker to execute. Recruitment is typically not as much of an issue, so we expect to have data fairly quick after we are able to start this trial.
Okay. Another interesting point has been, given the way that zero eight one zero works, an increase in serum bile acids is the positive marker, which might be a bit counterintuitive in this space. You've mentioned that you'll be exploring other endpoints, potentially. What is under consideration, or what are you thinking right now?
Yeah. So it is indeed counterintuitive for people. I think people are used to looking at a decrease in bile acid levels in serum when looking at the IBAT inhibitors. This is a very different therapeutic strategy. So instead of blocking the uptake from the intestine into the blood, we are reducing the uptake from the blood into the liver, and the liver is obviously the target organ here. That changes also how you look at the biomarker. So in our case, we want the biomarker to go up, where in the other therapeutic strategy, you want it to go down. So that's indeed counterintuitive for people and something that we will have to adapt to. Other biomarkers, I think, are mostly related to the bile acid profile. Bile acids come in different forms.
As soon as they cross from the intestine into the blood, they get conjugated, they get tagged for excretion, they get modified, and that profile is potentially an interesting biomarker. Again, when we come with our clinical plans, we are able to give a more complete picture around it.
Okay. And then thinking about that update as well, the NHP data, at the time of presentation, you said you were exploring LNPs and GalNAcs for delivery, in your studies. Are you getting close to a decision here? And what have been some of the design challenges or learnings when optimizing this technology?
Yeah. Look, I think we're on the steep part of the learning curve around this new platform. We are able to use all the different delivery modalities that have been used in other oligonucleotide approaches, which I think is great because a lot of the work is done there, and to a certain extent, it's de-risked. We are testing all these different modalities, LNPs, GalNAcs, other delivery modalities, to essentially help us understand the range of the applicability of our platform. So in our R&D enabling studies, we are testing both LNP and GalNAc, and ultimately, in a data-driven way, we will make the decision on which one looks best for the first in-human trial. And for that, we are currently doing the studies.
So once we announce the outcome of our and the selection of our clinical candidate, that will also come with what the exact delivery modality will be.
Is that decision around the delivery sort of a platform-based decision, or is it specific to a candidate?
Yeah, that's a really good question. I'm not sure we really made up our mind there. I think there could be differences from target to target, where in certain targets, you want a different exposure profile than in other targets, and obviously, with GalNAc, you have a more durable response, where with LNP, the peak exposure is higher, which is the same for every other nucleotide, so also here, so it may depend target to target.
... Okay, but the decision on delivery, will that also be in tandem with the other initiatives?
Yes.
Okay, so what work is left to do to support CTA, IND filing, and what kind of initial human data could we expect in twenty twenty-five? It doesn't take that long to get that initial data set, so.
Exactly, that's our expectation. Yeah, so what work is left to do? We're doing the IND-enabling studies now, you know, toxicology, manufacturing for the trial, regulatory preparations, et cetera. So all of that, yeah, we've done many times before, so we're going through that. I think in this case, we've taken more molecules forward into that stage to learn about the platform. I think, yeah, the more we can learn at this stage, the better. And then once we go into the clinic, yeah, we will have a typical single ascending dose, multiple ascending dose design, where we will study subjects for a number of weeks, the exact number of weeks to be decided. And then, yeah, the objective for this study is really to achieve a proof of mechanism.
So where we show a change in a disease-relevant biomarker, in addition to safety, understanding PK, understanding exposure, but really to validate the platform at a biomarker level.
Okay, and then, I guess another learning, you touched on sort of the decision factors between BA and PSC, where the hurdles may be different, the populations may be different. How are you weighing what you see in the data, I guess in the healthy volunteer data, to decide or prioritize between those opportunities?
Well, I think it's going to be a fairly complex decision, which indication to go in first. I think both have pros and cons. Ultimately, we aspire to get to both indications. In BA, we likely are able to pick up a signal somewhat earlier because of the rapid progression of the disease. But in PSC, we are able to do our studies in adults, which may come with certain advantages. So yeah, I think the data is gonna be helpful in understanding and guiding us where to go first. I think we're also engaging with a lot of key opinion leaders to understand the endpoints and the developability in the different indications to make an informed decision there.
Okay. I wanna be mindful of time. Can we run through your other program, AX-1412? You've guided to reporting the preclinical and translational data this year. Can you set the stage in terms of what we should expect and what the minimum thresholds there are?
Yeah. So AX-1412 targets the B4GALT1 gene. This is also known as the Old Amish Order variant, which is a variant that has been found in population research that comes with a reduction of 30% in the risk of development of cardiovascular disease. This happens through two independent risk factors, cholesterol and triglycerides. And, by making a single point mutation in the B4GALT1 messenger RNA, we are modifying the protein, which has its effect on both of these independent risk factors.
So what we're doing right now is we are testing editing oligonucleotides in non-human primates to validate that we can achieve a similar effect as what is observed in humans that carry the variant such that we can validate this target and the approach of editing oligonucleotides for introducing this variant in cardiovascular disease. We are looking then at biomarkers that are yeah standard for cardiovascular disease. So yeah LDL triglycerides all of them. And that would then also be indicative of what we're gonna look at in the clinic. So once we complete these non-human primate studies those will be presented later this year indeed together with some translational data. And then our plans are to on the basis of that data move forward into clinical studies.
Will the proof of concept data and translational data also come in tandem, or are those sort of staggered?
We're not really sure yet. Depends a bit on what the data is gonna tell us, but yeah, depending on what the data will be, that will either come in tandem or separate, but it is on track to be delivered this year.
Okay. And then just thinking about the broader space, Wave Therapeutics gave us a first look at clinical administration of RNA editing in humans for their AATD program this year. I'm just curious to hear how you're thinking about that data and what read-throughs or limitations on read-throughs could be to you guys.
No, look, I think it's a really exciting time for RNA editing. The field is really rising. There's a lot of activity ongoing, both in the biotech as well in the pharma space. Large pharmas are getting engaged into RNA editing, doing deals in the space. So we're really excited to see that. Yeah, ten years ago, we invented this technology, and to now see this at this scale, moving into development, into multiple diseases, into humans, is great to see. I think there is a lot of learnings in the field, and I think we are obviously following others' people's data with significant interest. I think it's a bit too early to tell what the read-through will be. The platforms and the underlying design of the molecules slightly differ from each other, although they all recruit ADAR.
I think there's some time needed to see how this all will shake out, but it's all really exciting to see.
Since you talked about the pharma partnerships.
Mm-hmm.
You have a partnership with Lilly. How is that progressing, and any thoughts on when we could get more visibility?
Absolutely. So Eli Lilly and ProQR have a partnership on the development of editing oligonucleotides for a variety of different indications, with a specific focus on central and peripheral nervous system. This is a $3.9 billion partnership, where they paid us $125 million in upfronts, and they pay us, yeah, milestones along the way for each target. Then targets, as I mentioned, and we're making really good progress in the partnership. Obviously, the partnership is relatively early. It's preclinical, so at this stage, there's not much that's public about the programs in the partnership.
But, I think in the not too far away future, there will be more that will become known about the programs that are part of the partnership, and potentially some data and some indication of what diseases will be will be pursued there. The partnership with Lilly is going really, really well. Lots of excitement on both sides. Great partnership in terms of complementarity of the science that comes together, and to us, it's it's a partnership that's really enabling for the business and, and, and supporting our our overall growth.
And then thinking about other targets where you could leverage Axiomer, are there learnings from the first two programs that could help you move faster or de-risk any new targets? And understanding that cash is finite, how do you think about expanding into new targets?
Yeah, it's a really good question. So I think we have a bit of an embarrassment of riches with Axiomer. It can be so broadly applied. So, you know, a kind of disciplined prioritization of targets and continuous incorporation of lessons learned, I think is key to make that work. So we have a really active target hunting and validation group that is continuing to expand the pool of targets that we work on. As we progress, we've seen really exciting data across a number of new targets, across other organs. We are, yeah, primarily focused on liver delivery, but are increasingly interested in CNS as well. We learn a lot from the partnership with Lilly, where we spent a lot of time in CNS.
So yeah, I think there on that front, there's also more to be expected, and as we progress, we will carefully select next targets to advance into potentially the pipeline.
Okay, great. I think we're close. We're at the end of our time. So Daniel, thank you again for a great discussion, and I'm looking forward to what's ahead for ProQR. Thanks, everyone, and enjoy the conference.
Thanks for having us.