GenSight Biologics S.A. (SIGHT) Earnings Call Transcript & Summary

Good afternoon, ladies and gentlemen, and good morning for those of you in North America, and thank you for attending our webcast today that we focus on the initial results of the Compassionate Use of LUMEVOQ in patients suffering from LHON and bearing the ND4 mutation. First of all, it is my honor and pleasure to introduce our speaker, Professor Sean Donahue. Professor Donahue is Professor and Vice Chair for Clinical Affairs at the Department of Ophthalmology and Visual Sciences of Vanderbilt University Medical Center in Nashville. I know your agenda is quite busy, so really, thank you very much for your time, Sean. What you are going to present is extremely important for the company and for our attendees. That's for many reasons, but I just want to focus on 3 important things. First, these 6 patients have been treated with LUMEVOQ and expanded access IND, and under the approval of the U.S. FDA. Second, it is in fact the first result of LUMEVOQ treatment in real life conditions with bilateral injection, nothing to do with the clinical trial. This is real life. And third, these results clearly support and corroborate the findings obtained during all the clinical trials that have been conducted so far. Again, thank you very much, Sean, and I'll leave you the floor to go through the presentation.

Thank you. I appreciate the invitation and the opportunity to speak and the kind introduction. I'm excited to be part of the study and be able to -- be the person coordinating these efforts. And we got involved with the Compassionate Use Protocol because there were patients who couldn't get into the REFLECT clinical trial for a number of different reasons. And then as a result, we felt we should share those data, and we wanted to share those data with you. So I want to talk about my collaborators, Dr. Gangaputra and Dr. Patel are both retina specialists here at Vanderbilt. They are specialists also in ocular inflammation, and so they were involved in making sure there's no inflammation in the eyes post-operatively. And then Crystal Nicholson is Director of our Clinical Trials even at Vanderbilt. He coordinated all of the patient care for this and followup visits. And then Terri Edwards, Rebecca Jerome and Dr. Meghan Jolly are from our -- our support group at Vanderbilt University, and they are the ones who arrange the Compassionate Use exemption with the FDA, communicated with the FDA and made sure that all the things that we were doing were appropriate with respect to the FDA and the Compassionate Use protocols, and we would not have been able to do that without them. Let's have the first slide. Yes, as a means for disclosure. I presented these data at the American Academy of Ophthalmology meetings. I was in fact at one of the American Academy of Ophthalmology meetings in New Orleans, and they require a full disclosure. And so as a disclosure, none of our co-authors has any financial interest in this, and my only potential financial interest is a fee for service consultant that I had to be able to prepare these slides today, and nothing with respect to my presentation at the American Academy of Ophthalmology. I have no equity interest in this -- this study, this company or any competing products. I think all of the people in this audience know that Leber's hereditary optic neuropathy is, although rare, a very significant problem, especially in the population 10 to 25 or 30 years old in males. It produces sudden bilateral vision loss, not something that's treatable with glasses, not something that's treatable with any known medication or surgery or treatment that we have in the world at this point in time. It was discovered to be caused by a mutation in mitochondrial DNA that happened about 40 years ago when I was in medical school, and we really never thought that -- at least, I didn't think that during my lifetime some type of therapy would be available for this. These patients are totally devastated with their vision loss. They are bilaterally blind. They cannot see to read. They cannot see to drive or to function. And there has been no hope for treatment up until gene therapy. There have been 2 previous studies of gene therapy with this particular -- this particular drug in this particular injection. They were REVERSE and RESCUE. I'm not going to go over the data with them because that's available in the literature. And then the REFLECT study is a 2-year follow-up -- 2-year study that, at least a year has been published. The 2-year follow-up data are still out there. But these patients that we had were not able to be enrolled in the REFLECT study, and so we offered them Compassionate Use because there was no other option. And we're fortunate at Vanderbilt that we were able to work with the FDA and be able to go through those hoops to provide us for these patients. So these patients came from essentially all over the country because they heard that we were able to do Compassionate Use in children. They had bilateral injections with the drug, so there was no placebo. All of them had to be treated within 1 year of onset of their initial vision loss in the first time. The next slide, please. There were 6 patients, 2 were not eligible for REFLECT because REFLECT took patients who were 14 and older. And these patients, when they have suffered their vision loss were younger than 14. And so, even though REFLECT was enrolling at that point in time, we could not enroll them in REFLECT because of the age group. Four additional patients came to us after REFLECT closed. Two of them were also children, they were 13 and 14, and 2 are adults, 26 and 34. So after REFLECT closed, we couldn't enroll them into that study. So we were the only place that could offer them Compassionate Use. I believe Philadelphia did some Compassionate Use at the same time, but for this part of the country, we were the only opportunity they have. All patients got bilateral injections, and as opposed to all the previous studies, which had 1 eye getting an injection, this had both eyes getting an injection and no placebo and no sham injection. We were very contentious about what we were trying to measure. The primary outcome measure was best corrected visual acuity. In other words, that's how you do when you're reading the eye chart. Contrast sensitivity is the ability to distinguish contract. So high contrast is black and white, and mild contrast is in dim light, black on white, or a light brown against the dark brown, much harder to see. And so the Pelli-Robson is a test that measures contrasts. That's contrast sensitivity, PRCS. And then we can measure the thickness of the retina and the macula, which is where [skew] well, and thickness of the nerve fiber layer, which is part of the optic nerve that carries the visual impulses. So we measured that at baseline, at follow-up, and then at 7 visits over 1 year, with the last outcome measure being at a year. We also look to see inflammation inside of the eye. There was some mild inflammation that you get with any injection and it was measured within the first week and they all resolved during at that time. Can I have the next slide, please? Can I get the next slide, please ? We had various time points from those 7 visits ending at a year. I'll put them all on the next slide, you'll see them. And then we list -- First, I'm going to present the data with the average mean values from all 6 of the patients combined at each of those time intervals, and then I'll present data for each of these 6 individual patients. And we're going to be discussing best corrective visual acuity, contrast sensitivity and then the OCT thickness in the macula in the optic nerve. Can I have the next slide, please? So this first slide here is, really, the primary data. And on the left side, you have the worst eye and the right eye, it's on the right side, you have the better seeing eye. So when they came in, the vision wasn't typically exactly the same. Some of them had better vision in 1 eye than the other. So all of them got bilateral injections. But we separated the worse eye from the better eye. And this is the mean of all the patients. On the left slide, for example, along the left axis, you can see from the worst vision being light perception that's way out of the top, going down to hand motion, count fingers and then letters that you're used to seeing, 20/200, 20/60 and 20/20. Many patients who have really severe levels of vision can't read the standard eye chart that has the big E at the top, and so you need to have a new way to test vision in those patients. And so we usually give that big E. So this is an E, and it turns out that's about the same size as the 2400 E is my 3 fingers here. And so what you ask patients to do if they can't read the big E is they count fingers at a certain distance, whether they can count about 1 feet, whether they can count about 2 feet, or 4 feet. And then further back they can count them is [indiscernible] vision. The vision is better, the further back they go. So someone who can count fingers at 20 feet is essentially reading that big E, which is a 2200 line. And then the closer you get before they can be able to count fingers, that gives you an indication of how good their vision is. Sometimes the vision is so poor that they can't even see how many fingers you're holding up even when it's right in front of the face, so then what you have to do is see whether they can tell your hand is moving. To go in front of their face, is the hand moving back and forth? Or is it moving up and down? And then the same thing. And if they can get that right, then that's visual acuity of hand motion. And some of these patients can't even see your hand moving. They can just tell whether the lights are on or lights are off, and that's light perception. And then the worst vision, which we fortunately don't see very often in Leber's, is no light perception or NLP. So if you start here at baseline, as we walk you through the slides, then the worst eye at the top of that black bar is where most of these patients have that was the mean counting fingers. And so we assigned a numeric value in what's called LogMAR acuity to each of those levels of vision. And so that is described here from 0, which is 20 -- 20/20, all the way up to -- all the way up to 5 or 6, which is light perception and then we average those means. And you can see the error bar and the standard deviation there. But when we've started the baseline, they averaged 2 points on this LogMAR scale, increasing in the downward direction. In other words, as the bar gets smaller, that means better visual acuity. And you can see that there is a slow and steady improvement throughout all of those visits down to the 1-year follow-up visit, and that difference between the 1-year follow-up and the baseline follow-up is statistically significant. You see the R square and P value there. So they did improve, so that most of them ended up in the 2200 range in that worse eye. The better eye is over -- on the right side, and it's, again, the same -- the same coordinates for time along the right, on the lower axis, the X axis, and visual acuity along the Y axis. Going from the worst vision, light perception of 4, all the way down to 20-20, which gets 0. Two things, first to note is that the overall visual acuity in the better eye at baseline and in all these visits is better than it is in the worst eye, and that makes sense. These are the better seeing eyes. But even the better seeing eyes had an improvement as well. Again, it is slow and gradual and steady and does improve significantly over that 1 year, and you can see the R squared value there on the slide and on the graph. So both the worse eye and the better eye, both got injected and both have improvements in the mean throughout that. We'll go over individual patient data at the end of the talk. The next slide will show the Pelli-Robson contrast sensitivity data. And so this is contrast sensitivity data, and it's measured in the total number of letters that you can see. The Pelli-Robson contrast starts with very, very dark letters on a white background. And then as you get further down the chart, makes it harder and harder to see by decreasing that contrast. And so you read the number of letters, and that's how you determine how good the vision is. And so a higher amount of letters seen is better visual acuity. And again, we have the worst eye on the left and the better eye on the right. And for each of the time frames from baseline up until a 6-month follow-up, we don't have 1 year follow-up on patients to make this worthwhile, so I did not include that. But a higher number of letters is better visual acuity from a contrast standpoint. And you can see that in the worse eye, they averaged about 4 at baseline, and then we got a slight increase to about 6 or 6.5 in those patients by 6 months. The better eye did a little bit better. It went from about 7 letters to somewhere in the neighborhood of 15. And again, a significant improvement. Slow, gradual and steady that really parallels what we saw on the visual acuity in the same group. Let's go to the next slide. This slide here looks at the thickness of the macula measured by OCT. So OCT is a special test that measures the thickness of cells, whether it be in the retina or in the optic nerve. The retina is where you have the rods and cones and photoreceptors where you get the images. And then they get transferred to the optic nerve, and the optic nerve takes that image back to the brain. And so rather than measuring function, which is what those first 2 graphs did, this measures the structure of the eye to see if there's been any change. And we have measurements in microns, that's 1/1,000 of a millimeter. So 240 microns, there is about 0.25 millimeter. So that's the normal thickness of the macula. At baseline, for 1 month and 6 months, both in the worst eye on the left and the better seeing eye on the right. And what you see, again, and very similar to what we've seen in the previous studies, there's been essentially no change in the thickness of the cells in the macula and the thickness of the cells in the retinal nerve fiber layer. And that's not unexpected. You wouldn't anticipate that new cells are being formed, but I think what's important to hear is that no new -- no cells are dying. What is expected to happen in Leber's is there is a continual decrease in the thickness of the macula and OCT. And so the lack of that continued decrease tells us that the therapy is maintaining the cells within the macula. So you wouldn't expect an increase here, but the fact that we're not seeing a decrease is what's important. Let's go -- and that's true both for the worse eye and the better seeing eye. Let's go to the next slide. So when I was at the Academy of Ophthalmology meetings, they asked me -- they said, well, Sean, this is -- these are good data with respect to the overall function. But can you tell if it was all driven by 1 or 2 patients? You need to see the individual data. So I'm presenting here now the individual data for all 6 patients. I apologize, it is a busy slide, and this will be available, I believe, from the company afterwards. But you can see now for each of the 6 patients, individual worse eye on the left, individual better eye on the right for best corrected visual acuity. The same graph, but instead of showing the means, we show the overall level of -- in vision. So again, the worst vision is towards the top, and each patient there is -- is marked as a single bar. So at baseline, you'll see that there are 6 different bars. Each 1 of those bars is an individual patient. And that same patient then is reflected along each 1 of those bars at each 1 of those time periods. 1, 2 weeks, 1 month, 3 months, 6 months, 9 months. So individual worse eye. So for example, the first patient at baseline had a score of 4 and then improved to 2.5, stayed at 2.5 for a while, and then at 3 months was at -- about a 1.4. And then slowly continued to increase and ended up being quite good in that eye at a 1-year follow-up. So you can get a general idea for each individual patient how they do. Or you can kind of look at that and average them in your head and then you get the same set of mean data that I presented in that first slide, both for the worse and the better eye. And I think you can see that it isn't that there's any particular 1 patient that's driving this here, but all of them seem to have a slow and steady gradual improvement in vision. We don't see any of that really lost vision, and you see that happening both in the worst eye and in the better eye. Let's go to the next slide. Same thing with contrast sensitivity. Now, we don't have contrast sensitivity in all of the patients, especially in the worst eye. And the reason for that is that some of these patients' worst eye saw so poorly that they weren't able to read the contrast sensitivity line at all of the data points, and that's why they had 0s there. But in the better eye, you see a slow and gradual improvement. Now, the way this graph is, is that better vision is going up on the chart rather than down on the chart. And so we see, especially in the better eye a slow improvement in contract sensitivity in most of these patients as it goes from baseline to 6 months. And then the next slide is going to be the OCT data. Remember, the OCT data, we would expect to see a slow, gradual, continued decrease in macular thickness. And you can see for the most part every patient stayed about the same. Not only were the means the same, but each 1 of those patients is a single bar and you can see the ones, for example, of the 1 that's most to your right on the worst eye. That's the highest one, 280, stayed about the same. The 1 that's in the middle, they stayed about the same. Each of those is 1 individual patient. It's the same patient 1, 2, 3, 4, 5 and 6, along each set of bars. And you can see that each of those patients stayed about the same. So I think we've got good data from the individuals that says it isn't biased by any 1 particular patient or a couple patients that are driving this year. Let's go to the next slide. So these are the summary data I've provided the -- the individual data [indiscernible] and these are the numerical data. So the ETDRS is the way we measure best corrected visual acuity at both baseline and 1 year, so I have the baseline and then the final follow-up. Baseline and 1 year for visual acuity, baseline and 6 months for macular thickness and contrast sensitivity, and then you see the worse eye and better eye. The worse eye goes from about 2 LogMar to 0.9 LogMar. So almost a doubling of the visual angle. The better eyes also has almost a doubling of visual angle, 0.7 LogMar going from 20/640 to 20/100. Pelli-Robson contrast sensitivity from 4 to 6 letters and from 7 to 14 letters. And the macular thickness, again, stayed almost identically the same in the worse eye and the better eye, so that's another way to numerically actually summarize the data that I showed in the first set of slides. Next slide, please. So in conclusion, all of these patients had bilateral injections. And this is the first presentation of patients with bilateral injections of gene therapy into each eye at the same visit. And all of those patients did well and tolerated it, tolerated the injection with minimal to no significant inflammation in the eye and no long-term consequences from the injection protocol. The best corrected visual acuity as measured using ETDRS criteria improved slowly and gradually throughout that entire 1-year period of time. We used to think that Leber's had constant decrease in vision and stayed the same. We now know that there's likely a slowly progressive, continued decrease in vision in patients who have Leber's. So the fact that we're seeing an improvement not only means they're improving over baseline, but they're certainly improving over the natural history would be continued loss. We also saw improvement in the contrast sensitivity, with no change in the thickness as measured of the OCT. So these data are not consistent with the published natural history data of the 11778 mutation which is visual acuity staying the same or slightly decreasing and thickness in the macula and retinal nerve fiber layer is slowly decreased over time. Next slide. That may be my last one.

Thank you very much, Sean. Very interesting and congratulations for conducting this trial, which is really well done. I have a first question on the chat. And the question is, in these 6 patients, where all the worst eye is particularly the first affected eye? And what was the average time from diagnosis? I suspect the question is about the average time from vision -- the onset of vision loss.

Yes. So I think that -- I agree that's probably the nature of the question. So the worse eyes were not always the first affected eyes. Sometimes the vision in the second affected eye was actually worse. So it wasn't always the first and second eye being involved. With respect to how long all of the patients were under 12 months from the initial onset. The vast majority of more than 6 months because it took 6 months or more to get seen, get diagnosed and then be able to have individual FDA approval. We did not have a global approval for FDA or an exemption for that. We had to request individual approval for each 1 of those 6 patients, and that generally took a few weeks. So the majority of the patients were 6 to 8 months. I don't have those data, but we can probably provide those.

And the next question is a little bit more difficult. It's raised by one of the analysts that is -- who is following GenSight. Question is, could you perhaps share your view on the emerging gap between what we see in terms of bilateral efficacy and the difficult probability of LUMEVOQ in the U.S., given the strict 10 to 15 ETDRS letters inter-eye difference?

I'm sorry. I don't see it on the chat, so I'm having a hard time understanding. Let me look and see how here we could go. Share your view on the emerging gap. Yes. Let's do -- I'll do the first half, and then he has a second half, that's a very interesting question, too. The -- I think the analyst gets at a really, really important point, and the FDA has required certain levels of visual improvement to be called before you can say something is clinically significant. And they've had it at 10 to 15 letters on the eye chart. And the reason they had it at 10 to 15 letters on the eye chart is if you take people who have a reasonably normal visuals, that's the 20/40 or 20/50 vision, and you test them multiple times, the 95% confidence interval above that is about 2 lines of vision. So 20/40, plus or minus 2 lines of vision is normal. While 2 lines of vision, it's about 10 letters on the ETDRS chart. The problem is, we don't have ETDRS charts for people who are off the scale. And can't -- when you go from light perception to hand motion or from hand motion to count fingers, that's very, very different to quantify. In patients who have severe inherited retinal diseases and the LCA mutation with the RPE65 mutations, so the other Leber's disease that has gene therapy. Leber's congenital amaurosis, very different disease, also has gene therapy for it. But those patients go from almost completely blind to be able to navigate around. You can't put a number and quantitate that amount of improvement. And so the ability to say, we've had 10 letters just doesn't apply to most patients who have very severe and inherited retinal or optic nerve pathology. And at the time the FDA put this -- this requirement together for 10 to 15 letters, we didn't have the thought of having gene therapy out there. And most of our patients were in the 20/80 to 20/100 range. And so that was very reasonable to have -- to have that as your measured outcome. The problem is that the FDA and their ability to determine what's the clinically relevant difference hasn't been able to keep up with the times that way. And I hate to say that, but we need to, as a group of scientists, get with the FDA and say, how are we going to measure visual acuity and visual function and detect the difference for people who have severe inherited retinal ocular disease. Because the standard method of using an eye chart just isn't going to apply. And that's going to happen. It just hasn't happened yet, and it's going to take some time. And unfortunately, during the COVID pandemic, we couldn't get together to have those meetings. Well, that's the first question, Bernard. The second is also, I think, really important you asked the second question. That has to do with a placebo group. And frankly, the issue that all of us scientists have with the data from the gene therapy study is the first through the sham injection. And then the real injection is that the acuity improved in both eyes. Now, improved more in the eye that had the active product than the one that had the placebo, but there are a lot of reasons why that could happen. I don't like to consider it a placebo effect, but I think it may well be a learning effect to some of it. They learn how to take this test better. And the only way to get at how much that learning effect is, is a true natural history study. Now, the true natural history -- And you can't just not treat somebody and say it's a natural history because there is some impact of actually having an injection in an eye, even if it doesn't have product. Because you're going to stimulate inflammation, you're going to stimulate optic nerve swelling and retinal swelling, and that could cause some improvement. So I think the only way that we're going to get an answer to this is with the placebo, placebo group. I don't know what the company thinks about this. I don't know what the FDA thinks about this. I'm talking as a scientist. I think you get a number of patients and you randomize them and some of them get placebo, placebo. And say, well, is that ethical? And I think it's definitely ethical, because we don't know how effective this is over the natural history. I believe it's effective, but we don't know how well it's effective. And I think that's very reasonable to do it. And I have colleagues who disagree vehemently with me, but I think that has to be the next step.

Thank you, Sean. The next question is from a contrast sensitivity perspective, how many letters can normal healthy eyes detect? And based on the BCVA Pelli-Robson curve, do you expect these patients to reach normal?

Okay. Great question. So, let's do ETDRS first. Do we have the opportunity to go back to the slides that have overall mean data there? That's probably Slide 4. So the -- while we're waiting to try to find that, the ETDRS slide has 15 lines, and each of those lines has 5 letters. So at the top, they're very big letters, and then they get smaller and smaller, but there's only 5 on each part as compared to the Snellen letters, which have a different number. And then they are -- letters are set up, so they're all equally challenging to be able to read. An I, for example, or O, it's much easier to see than a Z or a Q, and so those letters aren't put in the ETDRS chart. So there's 15 lines, 5 letters. So there's 75 total letters. So the maximum you could get is 75. And so someone who's 20-15 and has a totally normal vision would have 75 letters. from 7 to 15 or something. That's still very impaired, and you're exactly right with your intuitive comment. These patients are still insignificantly impaired. This is not going to have them come back to normal. We do expect them to be cured by this and to be normal because those cells that were damaged have died, and that's why the nerve is thinner. And that's why the macula is thinner. We have not been able to completely rescue that. And this is not a panacea by any means, but there's nothing else out there. And these patients are not only legally blind, but completely impaired. One of the patients that I saw was the first one, kind of 13-year-old boy, he did not qualify for REFLECT because he was too young. He came in to see us. We actually made the diagnosis of him when we were setting up the REFLECT study. The results came back of his mutation testing, while we were doing the protocol, and so we were hopefully to get it enrolled, but because of the age criteria, he couldn't. He got injected in both eyes and continued to decrease for about 6 to 8 weeks as this has been seen and described before. When I saw him at 2 months, he could not even walk with a cane. His father was bringing him in with -- around his arm and was following his dad, and his vision was so poor that his eyes were no longer straight. His eyes had started to deviate, one in one direction and one in the other. So that's called strabismus, and it was a sensory strabismus because his vision was so poor, he couldn't keep his eye straight. He started to improve slowly and gradually, and you can see this patient #1 on that individual chart. And he went to the point where he ended up getting 20/30 vision back. He was back playing basketball. And his eyes straightened back up again. Now, he still has some significant visual impairment. His macula did not improve, his nerve fiber layer did not improve. But he's functional. He can drive a car now. He can work in class, he can read. And even playing basketball, and he's got no sensory strabismus anymore. So presumably, he has developed some binocularity again, and I think that's just a phenomenal -- phenomenal result by this. But if we look at them from any other measurement of visual field, he's still a significant visual impairment, and he knows he has significant visual impairment too. So I don't think we can set up as an endpoint 20/40 vision or 20/20 vision or even, really, 15 letters of improvement. We have to find some way who have -- patients who have severe visual impairment to come up with a legitimate measure of visual function. So sorry, I talked too long. And now, what other slides -- what other questions do we have?

We have a question about -- that compares Lucentis effect which is 9 letters improvement after 12 months with the result that you've shown. So the question is how clinically relevant do you think the benefit of LUMEVOQ is for LHON patients?

I'm trying to find the -- from contrast sensitivity, is that the one you asked me?

It's although -- the question is, although it cannot be compared, Lucentis [indiscernible . Yes.

Yes, it's 9-letter improvement at 12 months of treatment, and we had about -- So yes, the question is not completely accurate. This is not 11 lines. This is 11 letters, okay? So Lucentis improved to 9 letters after 12 months. And here, we saw an improvement of 11 letters after 12 months. So the question isn't -- isn't right. They're misinterpreting the data. We saw 11 letters, not 11 lines. And so the overall amount of improvement between Lucentis and the gene therapy here was similar. The problem is that the Lucentis eye, the fellow eyes didn't have any improvement. So it was 9 letters compared to baseline and 9 letters compared to a fellow eye. Whereas in the REFLECT study and the REVERSE study, you had 11 letters of improvement. The other eye had some improvement as well. So the difference was the visual acuity difference between the eyes. And as a result of that difference, the intraocular difference didn't reach 10 letters. And that's why the FDA didn't like it, and that's why we didn't meet the primary end point for the previous studies. It was because that was set up on the difference between the eyes figuring we wouldn't see any improvement in the sham-treated eyes. And in fact, we did.

And the second part of the question is how does it -- what does it mean clinically for the patients or for the patient itself?