ProQR Therapeutics N.V. (PRQR) Earnings Call Transcript & Summary

Good morning, everyone. My name is Andrew Fein. I'm one of the biotechnology analysts with H.C. Wainwright. It's my pleasure to host a fireside chat this morning with ProQR Therapeutics. Joining from the company is Smital Shah, Chief Business Officer; as well as the Chief Financial Officer of the company. So thank you, Smital, very much for joining us.

Thank you, Andrew, and thank you, H.C. Wainwright for hosting us.

Our pleasure. So maybe the best place to begin in light of upcoming catalysts is with 421a. You guys recently held a KOL event that I thought was very, very useful. So maybe you can begin by overviewing the program and just kind of laying out what folks ought to expect as we get into the second quarter?

Yes, absolutely. As you know, we're working on a whole host of inherited retinal diseases and building our entire pipeline and portfolio on that basis. So 421a is a very key important program in our pipeline. It is a much larger market than what is for LCA10, so roughly about 16,000 patients in the western world. Usher syndrome is a syndrome, which, again, is a genetic inherited retinal disease, in which patients either have Usher syndrome, so they have the hearing and sight loss or they have what you call is non syndromic RP in which you don't have the hearing loss, but you have the sight loss. Now in both cases, it's actually a very slow progressing disease. So most patients who have site impairment or visually impaired don't experience any symptoms until they are mid-teens and then ultimately start losing all their peripheral vision and then are basically seen through pin hole in mid adulthood. And then it is lights out essentially. So it is very important in this disease to think about stabilizing this disease. So in reality, by the time you treat these patients, hopefully, you will get to these asymptomatic patients early on. And then they will have a completely normal life like you and I and not lose any vision. So that's really what we aim to do with QR-421a for ushers. So the data set that we have coming up is an interim analysis. Our second and final one for this program, in which we are studying QR-421a at 2 different -- 3 different doses now in different types of patients where we want to establish at the end of this interim analysis, what is the dose that we want to take forward, what is likely the duration of treatment as we're looking at a ascending dose? And then what type of patients set are we going to enrich for in that next trial that could potentially be a registrational track. So that's really what we are aiming to do. So now I guess, the big question is what are you looking for, as Dr. Yang was saying. And that's kind of why we hosted the call with Dr. Yang, which was really helpful for us as well as, I believe, the investor community in understanding what to look for. So I think broadly for most any inherited retinal disease, the endpoint that will be relevant will be absolutely based on their baseline. So I think baseline is critical. When you think about Usher patients, you can divide it into 2 buckets. One is the advanced-stage patients and one other moderate-stage patients. The very early stage patients are generally asymptomatic, right? So those are the 2 patient sets that we are studying in this trial, and we hope to then enrich for the next trial based on what we see. So for advanced patients, how we define that is patients whose visual acuity or central vision is already impacted. And therefore, they start seeing a decline in best corrected visual acuity or BCVA. So that is the most well understood endpoint in ophthalmology. So ideally, if in that set of patients, we are able to show a stabilization of disease, in their BCVA compared to their contralateral eye or their untreated eye, that would be a win. In general, Dr. Yang, as you know mentioned on the call, although there's not a natural history well established. Typically, these patients lose about 5 to 6 letters a year. And we have enough patients going out to a year, where if we can see a stabilization between those 2 groups. Beyond this, I think we would be very encouraged to then be able to discuss with the regulators and start potentially the next stage of the trial. But then in the moderate patients, what we'll also look for is changes in perimetry because they have very well intact central vision, right? So BCVA is intact. So you can't measure that. So for these patients, where the peripheral vision is impacted because they're not progressed enough yet, we will be looking for signals in static perimetry. And in general, on a mean level, 1 to 2 decibels. And Andrew, you've pointed this out in the past, is about the noise of the assay. So if we can see a difference of that. Then what is well accepted is also what you call a 5-point analysis where most companies have done that, but nothing has been approved on that basis. So that's also something that we will look for as well.

Okay. That's super helpful. And how should we think, at this point at least about sizing of a potential registrational study, length, that sort of thing.

Yes, that's a great question. So sizing of the study, as you know, in most of these inherited retinal diseases, Luxturna is a great example. What we're doing for -- with sepofarsen in LCA10 is another good example. You typically tend to have a dozen plus patients in your Phase I/II, which then informs what you do for your next trial which is ideally our registrational trial. And that tends to be, call it, a couple dozen odd patients for LCA10 in sepofarsen. We are studying 36 patients. We overenrolled the trial, which was originally designed at 30, but we have about 3 dozen patients in that. Ushers may be slightly larger, but not that much. But again, we'll have to look at what the data is, what are we powering to what those results show -- discussed with the regulators. But these are not trials of hundreds of patients. It is in a few dozens. Is how I think about it. But then to your other question in terms of the length of the trial, that's also key because as you're going towards disease stabilization, you want to be able to show that difference in a slow progressing disease, right? So it's not a 3-month trial, right? So likely, it's probably between 12 to 18 months is probably what you could expect. But again, this data set predicted kind of based on what we see as to if that's about the length of what we would want to design for the next trial.

Okay. That's helpful. And since you -- you also wear a title of Chief Business Officer in addition to Chief Financial Officer. Maybe you can speak a little bit to both the commercial opportunity and with a number of different programs in development. How you're kind of contemplating strategic licensing versus driving things yourself, just high-level thoughts there?

Yes, absolutely. Indeed, as I mentioned upfront, for us, this is a platform. We have demonstrated with sepofarsen by rationally designing these Antisense oligonucleotides, you can actually make a difference in the inherited retinal diseases through intervening at the RNA level. With long durations of treatment in between doses and as well, it has a lot of stability and generally a pretty benign safety profile. So we think there's a big opportunity for these molecules in the eye, and which is why our whole portfolio is based on that. So with Ushers, if we are able to do something similar and advance this program as well and eventually get it to patients. That will be a huge win for us from a platform perspective as well. So as we think about fast forward a few years, and we have a multiple of these, maybe it's LCA, ushers, others, it's a very concentrated call point. So it's a few different centers of excellence across the U.S. and Europe that you can target. So it has a lot of operational synergies, both from a development perspective as well as from a commercial perspective on who you're targeting. So we hope to build our business by commercializing these programs in the U.S. and Europe ourselves. Of course, we're learning that there are a lot of patients outside of that as well. South America has a number of patients in LCA, which are not in our calculus, right, and other parts of the world. Ushers has a pretty big population in Asia too from our initial work. So would there be such geographies that we would partner to make sure we get these to patients. Most efficiently? Yes, but currently, our strategy is to be able to commercialize in the U.S. and Europe.

That's very helpful. I guess then turning to 1123. You also have data coming from that program later this year. So along the same lines as 421a, how should we just set expectations appropriately for 1123 data?

Yes. No. And that's also a very important program for us. Again, what we are aiming to do is basically stabilize the disease for these patients that also have what you call autosomal dominant RP or retinitis pigmentosa, which generally means a slow progressing disease due to a specific mutation. This disease is a little bit different in that, that it targets an autosomal dominant form of the disease. So it's a different mechanism and a different target, so to speak. But phenotypically, the disease is very similar to most RPs is that you start losing your symptomatic a little bit later in your life than the very aggressive IRDs like LCA10. And then you progressively lose your peripheral vision, then your central vision. So all that we learn from our ushers data will be very helpful in how we think about the data from 1123. So indeed, it's very similar in that sense, phenotypically, genotypically a bit different. But we finished 4 out of the 5 cohorts already and are underway with the fifth one. So we will have data from that this year.

And in terms of interpretating what you share, we should, once again, look for visual stability as the key?

Yes, absolutely. Because again, it's a slow progressing disease. And in that, also the patient baseline will likely be very important in where you pick up this patient in their disease progression. But it manifests very, very similar to ushers. So indeed, the goal, ultimately, from a patient perspective will be the same.

Okay. Very helpful. And I guess then turning to the LCA10 program. I guess it's going to be a little while still until we get the final results. But how about from the extension study, the Phase I/II insight extension study, which should come back half of this year, right? What can we hope to see from that data set? And how does that inform your thinking about the program more broadly?

Yes. So first of all, we are very happy and excited that the trial is fully enrolled even through the pandemic and we over enrolled the patients, as we announced in the first week of January. So the data is not very far away in the future now. It is in the first half of next year. So we're very much looking forward to that data set as well. Now to your question on the Phase I/II extension trial, that is indeed ongoing. As you do have to give access to these patients who participated in your trials until you hopefully and potentially get approved for that indication commercially. So in these patients, given we would do this extension, they're also treating their second eye or their contralateral eye as well. Obviously, that follows a different cadence because it's very much patient and physician dependent on when they dose, how they doses because it's an extension trial. It's not an interventional trial that they're conducting, right? But in last year, in the summer, as you saw, we actually did have data from 4 of these untreated eyes. And we were very, very pleased that actually their responses on multiple endpoints were very similar to what they were in the treated eye. So it gives us a lot of confidence, again, in all of the assumptions that went into our Phase II/III registration trial for sepofarsen. So that's kind of how we look at that data set. So there will be more follow-up on these patients. So you'll have a better understanding of, again, safety as these will be chronic treatments. We will have additional data on the contralateral eye that hopefully should give more confidence again in the upcoming Phase II/III readout. So that does depend a little bit on the timing of when the patients get dosed and what have you. So we will have some of that in the back half of the year, but it will be updates to what we've already shared.

Okay. That's very helpful. And maybe just it's worth spending a few minutes on the platform and the pipeline beyond the programs we've discussed. There's always been a science backbone to the company and a platform capable of doing other things. How should we think about learning more and seeing perhaps that somehow monetized?

Yes, that's a great question. As I said, we are building a whole portfolio and platform of these. The eye is a very unique opportunity for these RNA-based molecules. One, you have decades worth of experience in their chemistries that you can actually have very stable molecules for a long period of time, and you need very little. You don't need viral vector to deliver those. And with intravitreal treatment, you can actually target the entire peripheral retina instead of some other approaches, which are more localized, if you will. And of course, these are reversible changes as well. And so you can have chronic but infrequent treatment for many of these diseases. And we're just belly scratching the surface, right? Luxturna is the only one who's made really an impact in these patients, sepofarsen is next ushers next. So there are a whole host of diseases with 300-plus genes in the eye with pathogenic mutations. And the thing with RNA-based molecules is, once you know the sequence, you can very rationally design them. So it's not like small molecules where you have thousands in a library that you're screening for. We design maybe 15 to 20 molecules at the outset and for optimization, it's just a handful of 3 or 4 that we take. So this process is also not very lengthy and then layer it on what we're also building is our translational capabilities through the optic cup model where we build patient retina essentially in a [indiscernible], you could test it. There's a lot of progress being made on that in-house because there's a lot of know-how to it for each disease and how you grow these cells, what you measure. So what we're hoping to do is through this translational process, shorten the time in development to be able to better inform dose and duration like we did for sepofarsen as well to build further on this platform. And then on the back end, on the commercial side, as I said, it's the same folks and they take you through clinical studies and ultimately are the ones who see patients. So there's a lot of synergy there. And with that in mind, we built this portfolio, which targets a whole host of diseases. We have multiple other targets in Usher syndrome in LCA, in Stargardt, as well. And then finally, one program that's a bit different, which we didn't touch on, and which we will talk more about this year is the one for a corneal indication, although it's also genetic in nature, different because it's corneal and it's not orphan, which is also going into the clinic this year for us. And that will be one that we may look to look for strategic alternatives after we've established proof of concept. So that's one that's going to go into the clinic this year as well. So yes, there is a huge platform opportunity for something that's very rationally designed and tested. So as we go through these, we look forward to bringing more of these into the clinic.

Great. Well, thank you very much, and I appreciate all the information you shared. It was very useful. I look forward to all the updates this year and into the beginning of next year.

Yes. Thank you very much, again, Andrew, for all your support through the years and as well as H.C. Wainwright for hosting us.

It's a pleasure. Thank you very much