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

I want to welcome Dr. Ian MacDonald, who is one of the leading experts in the inherited retinal disease space to be present here with us today. Just as a background, sepofarsen, which is formerly known as QR-110, is being developed for Leber's congenital amaurosis type 10. This is an antisense oligonucleotide and really targets a disease which has no other treatments available for it, and which is a blinding disease for patients. We think that there's probably about 2,000 patients in the Western world currently suffering from this disease, but probably even more because of lack of formal genetic testing. This drug, sepofarsen, is locally administered into the back of the eye, into the vitreous cavity through an intravitreal procedure, and it's anticipated that it will be twice-a-year dosing, ultimately. We have strong preclinical proof of concept through the retinal organoid models that has helped us in really shaping up some of the preclinical modeling around this. And indeed, you may be aware that, and I'll summarize this in the next couple of slides, some of the top line Phase I/II clinical trial results from an earlier study. In addition to having orphan growth designation and rare pediatric disease designation, we also have FDA fast track designation and only the second ophthalmic product to have the EMA PRIME designation also. As many of you may be aware, we have an ongoing Phase II/III Illuminate study also, which is involving sepofarsen for LCA10 patients. So I may just turn over to Dr. MacDonald, our expert at this stage and just ask him, maybe Dr. MacDonald, can you comment on the natural history of this disease? And how you manage these patients in your clinic?

Thanks for asking. It's a pleasure to be here. Yes, I have seen many patients with this group of disorders over the years, and they develop poor vision very early in life. And then unfortunately, there's a gradual decline in their visual function with time. And their function may be very limited such that they need supportive care from low vision appliances and maybe even need to be retrained in terms of their -- either their education or their employment. And so having the possibility of a therapy such as this is very important for these individuals and their families in providing hope to prevent degeneration, but also restore sight.

Thank you, Dr. MacDonald, and we'll certainly come back to you with regards to some more detailed questions. The Phase I/II study is summarized and outlined on the left-hand side here. We explored 2 different doses ranging in both pediatric and adult population. And we followed patients out for 12 months of treatment in typically the worse eye. And as part of the extension study, these patients, a total of 11 who suffered from LCA10, were also offered the possibility of being followed up as part of the extension trial. And all of these patients were switched over to the target registration dose of 160 micrograms loading and 80 micrograms maintenance. What you're going to see today -- in today's presentation is a snapshot view, a 3-month analysis of the current data that's available. And this study, the extension study is called the InSight study. And if we move to the next slide, just a summary of the Phase I/II study results in 11 patients across 2 different dosing cohorts showed a rapid but sustained benefit. And just to orientate you, we are looking at the best corrected visual acuity graph on the left-hand side, the full-field stimulus threshold test in the middle and the mobility course on the right-hand side. If we start from the left, the best corrected visual acuity is the gold standard for endpoints in ophthalmic trials and is a registrable endpoint. A downward movement is improved acuity and Y-axis is change in BCVA in LogMAR. And so you can see that the yellow bar is showing the second eye treatment. But the first eye treatment is what I want to focus on, which is in green. And this showed that the treatment with sepofarsen improved visual acuity by approximately 5.5 lines, or a LogMAR improvement of 0.55. A small blip that you can see at the month 9 is due to a cataract formation, which typically causes a worsening of visual acuity and therefore, an upturn in the graph which quickly returned back to its original trajectory when the cataracts were extracted. The yellow line, and just to make sure that we understand, at that stage, the fellow eye get any treatment at all. So this was the second eye, which was just left as a control, and that was a sham control arm. The FST in the middle really measures the retinal sensitivity, and this measures the most sensitive spot in the back of the eye. And typically, we use red and blue light to be able to look at different type of photoreceptors in the back of the eye. And in the solid red and blue lines, you can see the treatment arm, and in the lighter red and blue lines, you can see what happens to the fellow eye, the second eye. And again, you can see a downward movement being improvement or more sensitivity. And as you would expect, that in the sepofarsen arm, both the red and blue FST showed an improvement. And that was quite significant, showing an improvement of more than 1 Log in candela per meter square. There was also improvements seen in the mobility course, where there's an upward movement showing an increase in sensitivity and light levels in terms of the scores. And again, in the green line, you can see the treatment arm superseding the fellow eye, which is in the yellow. You can see some of the numbers there at the bottom. And this was across both cohorts, a total of 11 patients. And the next slide really focuses in on the target dose that we're taking forward into Phase III. So the target registration dose is 160 micrograms loading and 80 micrograms maintenance dose. And this is showing even more impressive results, as you can see here in the 3 charts. The BCVA, the best corrected visual acuity, reveals almost a 9.5 line improvement on the ETDRS chart. And I would just mention here that a movement of approximately 3 lines, 2 to 3 lines is clinical -- is considered to be clinically significant change. There was also a significant improvement in the full-field stimulus thresh testing as well and also in the mobility course. And it's interesting to note that the month 3 treatment effect is sustained out to month 12. And you can see the actual numbers there at the bottom as well. And maybe I'll just turn to Dr. MacDonald here, just to give me your take as an expert, what your view was when you first saw these results?

Thanks very much, Aniz, for asking. I'm just very impressed by these responses. They're very positive here. We see not only are you changing the dynamic of degeneration with loss of visual function, but you're actually restoring visual function. So from that standpoint, it's very hopeful. And we see 2 additional tests here, the FST and the mobility test that are supplementing the data from best corrected visual acuity, which, as you said, was the gold standard, so these are real changes. They're showing -- there's functional relevance to the best corrected visual acuity. And these are very much objective tests that you can depend on. The importance as well as you mentioned about the improvement in best corrected visual acuity at 3 months, and it predicts the improvement in visual acuity at 12 months, which is outstanding in its result, so I'm very enthusiastic about seeing these results as they are now. You mentioned as well a little bit about the improvement in visual acuity. Here, you have, again, outstanding results in a comparator study with Luxturna, another product of gene therapy, It only achieved half of the improvement in visual acuity that this product has. And so in summary, these are very positive results that we're seeing with. So I'll hand it back to you.

Yes. Thank you, Dr. MacDonald. And of course, it's early days. And what you will see next are the results of a follow-up study, an extension study to these patients being swapped over. And so if you then move to the next slide, please, Sarah. So the InSight study, which is the extension study. In total, we had 11 patients, of course, finishing the Phase I/II study. And out of those 11 patients, 11 subjects were rolled over into this InSight study. 2 of those subjects elected not to roll over due to personal reasons. 7 subjects have been dosed so far in the extension study, and out of which 4 have been dosed in the second eye. Now all subjects have been switched over to the Phase II/III target dose regimen of 160 micrograms loading and 80 micrograms maintenance. There are some redosing visits that have been, of course, delayed due to the current COVID-19 limitations at sites. And of course, the cross-border travel restrictions that have occurred. However, when we looked at the data, and of course, in most early phase trials, safety is paramount. We have realized that, of course, the changes of, from a safety point of view, very much mirror the Phase I study and that there is really no change to the overall safety profile. We have seen cataracts only in 1 patient, and there are certainly no retinal changes as expected because, of course, we're looking at the Phase II/III target dose regimen of 160, 80 micrograms where, of course, in the first trial, the Phase I/II trial, we had not seen any similar retinal changes either. And so it's not unsurprising that the safety profile remains the same. And if we then move to the next slide, we now begin to unearth some of the data that I want to share with you. What I'm presenting to you here are the 4 subjects that have been dosed in the second eye. However, I'm first presenting, in this green -- in the green bars, what their first eye response was in the Phase I/II trial. And we're looking at a change from baseline to 3 months post-dosing. And just to orientate you, the Y-axis is either a best corrected visual acuity in LogMAR change and an upward movement here is an improvement. And also, we are representing the FST responses in red and blue. And again, an upward movement is improvement here, which is -- and the units of that are log candela per meter squared. And you can see here that all 4 patients in the first trial had a response, both in BCVA and also in FST responses, both red and blue. So this was the first time. This was part of the Phase I, Phase II study. And now I'm going to show you the second eye response in the extension study. And really, you can see that the treatment response has been maintained in both of the eyes. So the yellow bars are now the second eye treatment as part of the extension study. I'm going to start going through each subject at a time and really describe the subject and really what happens to the BCVA as well as the FST responses. So this subject, P2, was a 41-year-old male heterozygous patient started off with both eyes having light perception. And you can see in the top graph, the BCVA response change from baseline. The green line is the first eye and the yellow orange line is the second eye. And remember, this is changed from baseline. And also, you can see at the top, the time at which the dosages have been administered. And so you can see the time line at the bottom there going from baseline out to month 24, which is the latest visit for this patient. And this is change from baseline. So of course, an improvement is a downward movement in each one of these graphs. The full round circle is the onset of any lens capacities that could be there. And if they're green, they will be in the first eye; if they're yellow, they'll be in the second eye. And if there's been a lens placement like in this patient's case at month 12, there's an open circle that's there. And so you can see that the treatment response for this patient was enormous, a minus 2.66 log improvement, and this wasn't even the maximum treatment response, which was minus 2.74 LogMAR improvement. This patient really has improved quite significantly with that first dosing. As the doses went on, this patient was actually traveling internationally to the site. And you can see that the month 12 after the cataract extraction, this patient carried on with the improvement in the vision in the first time, but did not want to come back to the site again and travel internationally until the eyesight went down and the treatment effect went down. And that happened at month 21, when he was -- he visited the site again. And of course, subsequent dosing has been planned at that stage. And then when that patient arrived at the month 21 visit, this patient's evaluation took place in both eyes. And it was decided by the investigator that they should treat the fellow eye, the second eye, at this stage. And so now you can see in yellow the treatment response with the second eye. And it's actually very interesting scientifically that the second eye has responded almost the same way as the first eye did. And note, of course, that this patient has had light perception in both eyes. So this patient has had a period of time where the treatment effect has waned off because this patient was not getting frequent 6-monthly dosing of the sepofarsen drug in the first eye. And the second eye has now responded in the same way as the first eye did with a huge improvement, both in visual acuity as well as the FST, as you can see in the graphs in the red and also the blue as well. The second eye is being denoted by the lighter colored lines. And so this is a very interesting phenomenon. And of course, as the patient will return back to the site, the first eye will also be scheduled for dosing, COVID-19 allowing. And Dr. MacDonald, for a patient like this, who's starting off with light perception, what is a 2.66 LogMAR improvement mean to them? What kind of practical advantages that gave for their vision?

Well, this would mean that this individual going from light perception would then be able to see things probably navigate without difficulty, be able to read signs in a public place that they wouldn't have been able to before. So it would be a great advantage to them. And we'll come back to this later with some personal anecdotes .

And it is interesting that this patient rank their treating physician when they're at an airport reading signs and telling the physicians that actually they can actually read signs now, whereas before they could hardly even perceive light or dark.

And that is, again, outstanding. It is not heard of really for somebody going from light perception to exactly what you've described.

Okay. Let's take the next patient, patient #3. So this patient, it was a 44-year-old male heterozygous patient. Started off with their first eye at hand motion, an equivalent of 2.4 LogMAR on the visual acuity scale. And the second eye was slightly better. And of course, it's important to point out that out of the Phase I/II study, traditionally, the worse eye was treated and the fellow eye can be, of course, much more improved. Here is an example of that where the second eye was 1.66 LogMAR, equivalent to counting fingers, so slightly better vision than the first eye. And if we look at the charts, you can see that the first eye, the green line, improved within 3 months by 1.28 LogMAR, and the maximum response was minus 1.82 LogMAR improvement. So again, quite significant clinically. This was mirrored by the FST, both red and blue with clinically relevant changes of more than 1 log candela per meter squared. And you can see the frequent dosing that was occurring at the top as well. This patient subsequently developed a cataract, and that has now been -- now this patient had a lens replacement. And follow-up is also planned post lens replacement surgery. This patient also received a stat dose of 160 micrograms loading in the second eye, followed by an 80 micrograms dose 6 months later. And you can see the change from baseline that occurs in the second eye also. And that also is showing an improvement. At the 3-month time point, we have a minus 0.8 LogMAR change. So an 8-line improvement equivalent on a LogMAR change in the second eye as well. So again, Dr. MacDonald comment on what you see here and what are your thoughts overall?

Well, again, these are very positive results. The fact that the second eye didn't demonstrate the same degree of improvement is not unusual, since he's starting out with a better visual function to -- and -- but you see how at 3 months, that improvement is sustained all the way out to month 9. So again, very positive effect. And this individual happens to be somebody who I know as a patient. And before this treatment, he -- his visual acuity wasn't on the chart. And afterwards, after treatment, it's definitely on the chart. This is a man who could not work. He's a carpenter. He has since returned to work. And he joyfully said, "Gee whiz, I could see how beautiful my wife is. I hadn't seen her face for 20 years." And so just a remarkable story of the functional improvement in this man.

Let's move on to the next subject, our patient #11. This is the homozygous patient, 14-year-old female. Started off with the first eye at a relatively good vision. This patient had 20/80 in the first eye and had even better vision, 20/50, in the second eye. And this patient was unusual in 2 ways: one was that this patient was a homozygous patient; and secondly, the management -- the treatment of this patient was that the physician gave 1 dose of 160 micrograms in the treated eye and did not give any further doses because this patient improved significantly by a visual important level and did not need any further treatments at all, and hasn't needed any further treatments in that first eye. And so this patient has gone out to month 21 now already without any further maintenance doses of 80 micrograms. This patient came back at that time point and has had the second eye now treated, and you can see that in the yellow line, and you can see the change from baseline such that this patient has got an improvement heading downwards, but perhaps not the same trajectory as the first eye. But let me draw you in again, Dr. MacDonald. So help us understand these results in the context of also the FST changes that are going on. What's going on here?

Well, thanks very much for asking. Yes, the second eye treatment hasn't had that same dramatic effect, but you only have 1 time point here at 6 months that you're looking at. One might consider that there'd be continued improvement, perhaps even down to the level that the first eye was treated, so that's one thing. The other thing, if you compare what's happening with the final scotopic threshold with the red stimulus and the blue stimulus, and the next 2 graphs, you can see that the responses mirror the responses from the first side. So it's probably telling you that best corrected visual acuity perhaps is underestimating. And especially, in this case, the effect of treatment because the scotopic threshold has changed just the same as in the first eye. So again, the best corrected visual acuity is a measure, but in and of itself isn't the only measure of functional improvement in this patient.

Right. And I guess we've also got to remember that, that second eye did start at a much better visual acuity at baseline.

I forgot to mention that as well. Good point.

And I guess that the improvement of 0.25 LogMAR, that's about 2.5 lines of improvement. Help us give us a sense of what does that mean for the patient?

So for the patient, the patient can -- well, taking it back to one of the patients, he'd be able to measure with a measuring tape where he couldn't do that before as a carpenter. So these are truly meaningful changes in visual function.

Okay. Great. And of course, this patient, I think we heard that this patient would be legally able to drive as well now that the patient fits the driving license eligibility. A bit young for driving, but at least being able to -- eligible to be able to drive once she gets to the right age.

Right. So...

Let's move to the next patient. I'm mindful of the time. We've got subject P1, which is the first patient that came into the study. This patient was a 19-year-old male, a heterozygous patient with light perception in both eyes. And you can see in the top chart with the BCVA that the patient had in the first eye, multiple doses, both a loading and maintenance doses without any seeming visual acuity benefit. And also has had a dose in the fellow eye, in the second eye, again, without an improvement in the perception of light in both of the eyes. What's interesting here is that we see, despite the fact there was no BCVA response, we see an improvement in the FST, both red and blue. So how do we interpret this Dr. MacDonald?

Well, starting out with the best corrected visual acuity, you're really at the endpoint, unfortunately, for this patient. So this patient has light perception. The next level would be no light perception or no perception of light. So you have a very limited amount of visual function. And yes, despite that, there's an improvement in the final scotopic threshold or the full-field scotopic threshold for this patient. So there is an improvement, and it's really demonstrating that here's a treatment that's being tested. And it's not just for a specific defined level of visual function, it's much broader. You can enroll patients with light perception vision and expect that there would be some benefit for them. And so the fact that this individual had only light perception, it would be remarkable to take a look at what the mobility was of this patient later on to see if there had been, in fact, improved, reflecting the scotopic threshold responses as well.

Actually, the investigator did report to us that the subject mentioned and swears by it that they have an improvement in their overall vision. So it indeed maybe tested by what you've just said that even though the visual acuity may not be improving, perhaps there's other measures of visual response that can't be picked up maybe by tests like these FST that are more subtle and that actually patients can perceive it, but maybe our tools or assays that are available may not be that sensitive to pick it up apart from some of these newer tools like the FST.

Yes, exactly. So one of the patients who, for example, just use his phone to answer a call but can actually use his phone to tell what time it is and can see the date. Couldn't do that before. And so we've picked some measures that we think are scientifically valid, but we also need to concentrate on what the patient is telling us.

Sure. So really, in summary, all 4 of the second eye-treated patients have responded consistently with the first eye with clinically measurable and clinically significant changes, both on visual acuity as well as FST responses, really confirming what we've seen in the Phase I/II study. The safety profile is consistent with what's observed in the Phase I/II results. We know that the data now supports the selection of the target registration dose of 160 micrograms loading and 80 micrograms maintenance dose. Additionally, the longitudinal data support the 6-month dosing intervals, and we saw a very nice example of a retraction study being occurred with one of those patients where they didn't have 6-monthly dosing intervals and their visual acuity declined. And so it's very interesting that, that actually supports this as well for a regular dosing interval. And of course, all of this really builds additional confidence for our ongoing Illuminate study, the Phase II/III pivotal study, moving forward. And so this is that subject B3 that had, should we say, the relatively modest response, even though they had such a huge improvement of over 1 log, which is over 10 lines improvement in visual acuity. And what we see on the left-hand side panel in the panel of 3 photographs is the baseline for that patient's eye, the first eye. And we see then the month 3 evaluations in the middle. And of course, you can now see the difference in visual acuity in what the patient will actually try and see. And of course, this is a simulation. It's an illustration. We think this is how the patients feel and this is how the patients will have the benefit of the improvement in vision. And you can see that the most significant improvement for this patient was further out even at month 9 and counting. And you can see the improvements that the patient may even be able to make out different letters on the ETDRS chart up on the wall there as well as make out the chair. And so this is quite a stock improvement in the visual acuity for the patient. May I just also ask you, Dr. MacDonald, just as a final comment, this kind of improvement, what does it mean to patients? And what does it mean for you as a treating physician? .

Well, it's so hopeful. For this individual, as I mentioned before, his visual acuity wasn't on the chart. And now you can see with this simulation, he can see the chart and he can view things. As a carpenter, he can actually work. He can use his ruler to see what cuts to make. And so he has been rehabilitated by this procedure. And when we're talking about some of these rare disorders, for some patients, they would be just satisfied to have their vision remain stable, so it doesn't get any worse. But to restore vision, my goodness, this is so wonderful, and it has been transformative for this individual.