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

Greeting, and welcome to today's conference call titled KOL Call on LUMEVOQ for the Treatment of Leber Hereditary Optic Neuropathy. [Operator Instructions] As a reminder, this conference is being recorded. At this time, I'd like to turn the call over to Mr. Bernard Gilly, CEO and Cofounder of GenSight Biologics. You may begin.

Good morning, everyone, and good afternoon, if you're in Europe. I'm Bernard Gilly, the CEO and Cofounder of GenSight. I'm more than happy to welcome you on this KOL event. I would like to start with extending my thanks to our guests today who have accepted to take on their time to participate to this event and tell you more about Leber Hereditary Optic Neuropathy disease and patients and also tell you a little bit more about LUMEVOQ, our product. Today, with us, we have Dr. Nancy Newman. Dr. Newman is Professor of Ophthalmology and Neurology at the Emory University School of Medicine in Atlanta. She's one of the most prominent scientists and clinician in disorder of the optic nerve and mitochondrial disease. And as such, she has been involved for many years in LHON treatment and patients, and she has been kind enough to accept to work with us as an international principal investigator in several of our trials. Dr. Sean Donahue is also an ophthalmologist and the neuro-ophthalmologist. Sean is the Vice Chairman of the Department of Ophthalmology and Visual Sciences at Vanderbilt University Medical Center in Nashville, and he also has been involved with LHON patients for many years. And he's also a principal investigator in one of our trials. Also, together with me today are Magali Taiel, our Chief Medical Officer; and Thomas Gidoin, our Chief Financial Officer. Now before handing it over to Nancy Newman, I'd like to give you a few reminders about LUMEVOQ, our product for LHON. First, LHON is indeed a very important medical need. The disease affects about 15,000 to 22,000 patients in U.S. and Europe, and that represents about 1,000 new cases each year. What we did recently is demonstrate the long-term safety of LUMEVOQ. LUMEVOQ had been proven to be safe and well tolerated through 5 years following one treatment. We show the efficacy through unparalleled clinical benefit that we have demonstrated in 2 Phase III studies. We demonstrate that we can improve visual acuity from the nadir, which is the lowest visual acuity achieved by a patient, by almost 6 lines, which is around 28 to 30 letters. We also demonstrated that this is a very strong clinical benefit if we compare it to natural history of the disease. And finally, we were also able to show that this improvement of visual acuity is paralleled with a meaningful improvement of the quality of lifetime in these patients. Third, we also show recently sustainability of the effect. Indeed, we have now entered into the long-term follow-up of the clinical trials, and we demonstrated that the clinical improvement we've seen at 2 years is maintained at 3 years. And we'll communicate at 4 years, then 5 years. With all this data, we are now heading for filing for market approval in Europe in September of this year. We indeed received temporary authorizations of use in France, and we expect to file BLA in September of '21 in the U.S. With this, I'll hand it over to Nancy Newman to take you through the disease and some of the results. Dr. Newman, please?

All right. Wonderful. Well, hello, everyone. I've been asked to just speak about the disease of Leber Hereditary Optic Neuropathy. I know most of you probably have some understanding. Basically, what we're talking about is a piece of tissue that connects the eyeball to the brain, which is called the optic nerve. And the optic nerve is a piece of white matter of the brain, and it can be affected by any of the pathophysiologic processes that can affect any tissue anywhere. In particular, what we're talking about here are the inherited forms of optic neuropathy, something wrong with the optic nerve, which classically leave people with central defects in their vision and paleness of their optic nerves, as you can see in the picture here. Just to give you an idea of Leber, let me give you a case. This is a very classic case of a 21-year-old previously healthy man, has painless loss of vision in both eyes that's progressive over 1 month. By the time I see him, he is counting fingers only in both eyes, and he has these large dense central scotomas in his eyes -- both his eyes. Here is the back of his eyes. What you're seeing is the optic nerves in cross-section, and initially, they're fairly pink. The left eye, the one on your right, has already begun to show pallor, which is optic atrophy, which is death of the optic nerve. And 6 months later, you can see that he has had complete death of his optic nerves, and they are both very pale. This young man was a member of a large pedigree. And if you look and follow the line back, you'll see that all these people here are related via women, women are circled here, and that there are a large number of affected individuals with the closed-in squares and circles, most of them men. This pedigree was one of the original pedigrees which allowed Doug Wallace in 1988 and then '89 to show that a human disease, Leber Hereditary Optic Neuropathy, could be due to a mutation in the DNA that is included in all our mitochondria, not the DNA in our nucleus. So just to remind you all of your biology, the mitochondria, as you can see the little arrow down at the bottom, are the squiggly things that look like bacteria. And indeed, they have their own DNA outside of the chromosomes, which we naturally remember are in the nucleus. And there's an incredibly fascinating symbiosis that has been set up in the human body, the human machine in every cell, which is that proteins are the -- what make ourselves work, what make our body work. Proteins are made by DNA and RNA. In the mitochondria, which you see on the bottom, its own DNA is the red squiggle, and it makes its own protein, which is the red curlicue that you see. The nucleus codes for all our other proteins and as a matter of fact, 90% of the proteins necessary for the mitochondria to work are actually coded for nuclear genes and transported into the mitochondria where they complement the proteins that were coded for by mitochondrial DNA. Why do I bother with this explanation? The reason is because all the gene therapy that we can do these days to date is by getting the normal gene into nuclear DNA. But then we have to get that protein product into the mitochondria, and that's called allotopic rescue. And that's the basis of all gene therapy for mitochondrial diseases to date, which is we can't get the good gene into every mitochondrion and into every mitochondrial piece of DNA, but we can get it into nuclear DNA and tag it to get into the mitochondria. Now the gene that Doug Wallace discovered, the mitochondrial DNA mutation, the gene is in mitochondrial DNA, and it is at position 11778, which accounts for somewhere between 60% to 90% of all cases of Leber Hereditary Optic Neuropathy worldwide, about 90% in Asian countries, more like 60% of in North America. And it is the mutation that has a very poor prognosis for vision. So let's talk about, in general, what Leber Hereditary Optic Neuropathy looks like. It looks like the case that I showed you. It is a subacute sequential bilateral central vision loss. The age of onset is typically in healthy 18- to 30-year-olds. However, we now know from genetic classification, now that we have a test for it, that people can lose vision from this disorder as young as age 1 and as old as age 87. But about 82% of the people who lose vision due to the 11778 mutations are 15 years or older of age. There is a male predominance in all populations of 80% to 90% who suffer vision loss from this disease. That is not explained by mitochondrial DNA inheritance and it still remains a mystery, suggesting that there perhaps is something about the female that protects a carrier from expressing vision loss more than men, perhaps something on the X chromosome or something to do with hormonal things. Each eye progressively worsens over weeks to months, and there is a recognized interval between eyes in more than half of patients, which is days to months, which we've always thought allows you to have this window of opportunity to stop the second shoe from dropping, to stop that second eye from being involved. However, 97% of patients, so nearly 100% of patients will have bilateral involvement within 1 year, usually within 6 months. Visual acuity is usually worse than legal blindness, which in our country is 20/200 or worse in the best eye and ultimately, the nerves become pale with these dense central blobs or scotomas in vision. Vision loss is usually the only finding. Some people do have cardiac conduction defects but it's rare. And so this is purely a vision problem. Not everyone who has this mitochondrial DNA mutation will express vision loss in their lifetime. As you can see from the pedigree, there are more circles and squares that are not filled in than there are those filled in. About 20% to 50% of men and 4% to 32% of women will lose vision who carry this mutation. So there must be other reasons that are protective or that cause people to lose vision. That could involve the mitochondrial DNA itself, the nuclear DNA, as I mentioned, the X chromosome being protective factor or there are environmental factors. And we know for a fact that smoking, for example, does increase the rate of clinical expression. So what really is the most important question regarding a review of Leber Hereditary Optic Neuropathy when one is trying to assess the efficacy of an intervention is what's the natural history of vision in 11778 LHON patients, which is the population that is being used for all gene therapy trials to date. And so the problem is when you look at the literature, you have to take into account several important issues. First of all, it's what mutation are you looking at. But in this case, we're just going to talk about the 11778, which has the worst prognosis for vision. First of all, what is the age of the patient? As I mentioned earlier, patients under the age of 15 have a better prognosis for visual recovery than those over the age of 15, and this is particularly the case in patients who are 10 years old and younger and probably those who are 12 years old and younger. What is the visual function measured? And how is it measured in these studies? Where along the curve of visual loss, baseline versus when you're on the downside versus at the very bottom or what we call the nadir, is the vision measured? What's the definition of recovery or improvement in these studies? And is the improvement in one or both eyes of the patient in order to say that a patient has improved? And finally, is the patient taking or has ever taken idebenone which is -- at least we believe, has some effect on the natural history of this disorder. And so recently, a group of us independently reviewed all the literature on the natural history of vision recovery or improvement or outcome in Leber Hereditary Optic Neuropathy since the discovery of the point mutation in mitochondrial DNA so that we could look only at the 11778 cases. This article -- we reviewed. We then wrote an article, and it is in press, in the Journal of Neuro-Ophthalmology. Let me show you what we did and then I'll summarize. So for example, we looked at all the studies that had some information on outcome, and we looked at retrospective studies such as these and these and these. And then we looked at these, which are prospective studies. And then we looked at all the studies that allowed us to pull out those patients by age. And that left us with fewer studies because most of the studies did not specify the age of the patient at the time of recovery. And so we were left with this group of retrospective and prospective studies. And to summarize these results, there were 12 retrospective and 3 prospective studies. The definition of recovery or improvement vary greatly among them. If you take everyone, all ages for which we had some vision information, we had 695 patients, of which 100 or 14.4% had some recovery. If you only look at those patients who were 15 years or older, which is the cutoff for inclusion in our gene therapy trials, there were only 204 Leber's patients with vision information, of which only 23 or 11.3% had some recovery. Vision better than legal blindness remained rare. Now to remind you about the studies for which we have results on gene therapy from GenSight. There are the RESCUE and REVERSE Phase III trial, which had the exact same design and the same endpoint but different patient inclusion criteria with the REVERSE study including patients who had lost vision in each of their eyes 6 months to 1 year from when they are enrolled; and the RESCUE study, which is exactly the same except only enrolled patients who had vision loss in each of their eyes within 6 months of enrollment. Each patient was randomized to receive an intravitreal injection of the gene therapy in one eye; and sham therapy, meaning the eye was anesthetized and something was pressed on the eye but no -- nothing was inserted into the eye, in the other eye. And the outcomes were recorded for vision and other measures at 48 weeks and then all the way up to 96 weeks. And if patients agreed, they were enrolled in another long-term follow-up study. So here are the results. I'm sure you've seen these. Much to everyone's surprise, patients' eyes improved, but not only did the treated eye improve but the sham eye improved. This happened pretty much from baseline with the REVERSE patients who were already 6 months out. And it did not rescue the RESCUE patients from the typical deterioration, but then there was subsequent improvement. If you put the 2 next to each other, you'll see that once the nadir was hit, there was improvement in both treated and sham eyes. So how does this compare to our natural history review of the literature? So to remind you, if you take all ages for the 11778 patients, we -- and you give any kind of definition for improvement or recovery, there are -- 14.4% of patients will improve. If you only look at patients 15 years or older at the time of vision loss, then only 11.3% of patients showed any kind of improvement. If you then look at the REVERSE and RESCUE results, which you see on the bottom, even if you look from baseline, more patients improved. And you can see that the definition of improvement was actually more stringent than required in most studies. This was an improvement as required by the FDA of 3 lines improvement, in this case, from baseline or from nadir. And you can see that the percentages are indeed greater than what was calculated for the natural history. If you look at a slightly less severe definition of improvement, which is 2 lines or 10 letters, which is the -- what we call the clinically relevant recovery that was claimed by the Santhera people for idebenone, they have an arm of natural history which included 61 11778 patients, which were followed without treatment with idebenone. And you can see that the numbers from baseline and from nadir for the Santhera natural history study was 15%, whereas from baseline -- 15% from baseline, 28% from nadir for the natural history. And for REVERSE and RESCUE, it was 70% and 32% from baseline and 81% and 71% from nadir in comparison. So there does appear to be some improvement that is beyond the natural history. And if you look at the REALITY registry study, which plotted where you would expect patients to be at certain time frames from their onset based on these patients who were enrolled and had visions taken over this period of time and you put the REVERSE and RESCUE data on it, you can see that it is not the typical decline or stability that has been expected for this disease. Thank you.

I'm Sean Donahue from Vanderbilt University Medical Center in Nashville. And appreciate that great summary, Nancy. I'm going to just talk about 2 clinical cases which we encountered here through either the REFLECT trial, which is the third trial, or in some compassionate use patients that we've had. So compassionate use happens when a patient doesn't qualify for a study but we were able to have the FDA be petitioned and allow use of the gene therapy for these patients. And so we're able to share those results with you. The first is a 41-year-old man who had a family history of Leber Hereditary Optic Neuropathy. This man had a brother who had lost vision in the past, and he had never been tested for LHON but he knew that he was at risk. And he started noticing vision loss in his left eye in June of 2018. So he came in relatively early, first to his ophthalmologist in another state and then was referred to us. And when he got here, he had already had the 11778 test and had come back positive but only had about 3 to 4 months since the first vision loss. He presented, and he had visual acuity of 20/40 in each eye at that screening visit. And he received an injection on October 11 of 2018, so about 4 months after the initial loss of vision in the left eye. His vision did start to improve, and within 2 months, he had come back to 20/32, which is 1 line of vision. He'd come back 2 lines of vision in the right eye and 1 line of vision on the left eye at 6 months. And we saw him last at the 1-year follow-up visit with 20/16 or better than 20/20 vision in each eye in September of 2019. And you saw that Dr. Newman's natural history data show that the vast majority of patients never even got to 20/200. This patient got better than 20/20. These are his visual fields, and Dr. Newman had used what we call Goldmann visual fields. These are an automated visual field. And the left eye is on your left, and the right eye's on your right. And you can see in the lower parts the dark black points. Those black points are ones that are distinctly abnormal. And you can see he has that central defect in vision in the right eye more than the -- sorry, in the left eye more than the right eye. And that was at presentation right before he had the injection. And then at his follow-up visit, here's our visual fields. And you can see that there's been a marked improvement not just in his visual acuity but also in the visual fields. And his recovery of vision is now nearly complete, back to normal, based upon his visual acuity and visual fields. And why he had such a great response, I think nobody really knows, but we did get him only 4 months into -- after the onset of symptoms in the first eye. The second is a younger patient who was a compassionate use patient. He was at 13 upon presentation. And the GenSight trial had excluded patients under the age of 15 so he could not be part of the study. But he lost vision in his right eye in April of 2018 just as the REFLECT study was getting set up. And at that time, we saw him. He had light perception vision, so all he could see was light in the right eye. He still had 20/30 vision on the left eye, and his left eye looked good at that point in time. But he started to lose vision in the left eye during the summer, and we were able to get compassionate use exemption from the FDA. And August 30, 2018, we injected him, and he had injection in both eyes of active gene therapy treatment. We didn't just choose one eye because of the FDA exemption. We were able to apply for it and obtain approval to treat him with both eyes. Just before we started to inject him, about 2 to 3 weeks before, he started to notice vision loss in his left eye. And shortly after the injection, as he came back, his vision loss continued to progress. And to the point, he was light perception and hand motion vision. He had to be led around by his father. He could not see to ambulate in a room, could not get into the exam chair, could not get into the exam lane. And his vision had gotten so bad that his eyes no longer stayed straight. He developed what we call strabismus, which is misalignment of the eyes because there's just no incentive for the brain to keep the eyes straight because the vision is so poor. He also then applied for and got low-vision technology through his school system, closed circuit television and a number of other things to be able to use to get ready to go back to school. His vision started to improve in the fall, however, and we saw him back in October, now 2 months after the injection. Still off-chart vision 20/800 in the right eye, but was between 20/400 and 20/200 in the left eye. 6 months later, the visual acuity continued to improve, 20/80 in the right eye 20/30 in the left eye. And in his last visit, which was 1-year follow-up back in September, he had 20/40 visual acuity in each of his eyes. His eyes are now straight. He's able to ambulate in the rooms. He does -- he plays basketball without any low-vision aids. He's back reading and back performing in school and with really a remarkable recovery. And yes, he's a younger child, a younger individual, and they do have a better natural history of recovery. But again, in Dr. Newman's series, even in the younger patients, they did not have this type of recovery from this level of poor vision loss. This is our picture of his optic nerves before the injection, the right eye on your left, the left eye on your right. And then you can see that post injection, not a lot different. There's a little bit different magnification. So he did -- still has marked pallor and still has a significant visual field deficit. We don't have formal visual fields on him, but he still has some significant visual field defects. But he has come back to essentially functional vision and being able to read and go back and learn in school. So he has just been absolutely thrilled with his response. And again, he had gene therapy in both of his eyes at the age of 13. So that's the end of my presentation. I think I'll turn it back over to the rest of the team. I certainly appreciate your patience and your listening today. Thank you.

Thank you very much, Sean and Nancy. Bernard Gilly speaking again. And this is very encouraging, and it's so good to hear about the life of these patients. So thank you very much again. So thank you, Nancy, for this presentation as well. So let me open up the Q&A session, and I'll turn to the operator to tell you how to ask questions.

[Operator Instructions] Our first question comes from Gbola Amusa with Chardan.

This is Sam Lee on behalf of Gbola. I have 3 questions. First, how definitive is the natural history of LHON ND4 to feel confident that the GenSight GS010 results are actually a breakthrough?

Nancy, will you take...

Sure. So that's really why we did the review we did. Let me go on record and say that the level of the evidence and the quality of the studies -- remember, 12 retrospective and only 3 prospective, all with varying definitions of what they say is improvement. The level of evidence and the quality of the studies have a lot to be desired. There is not great, well-designed prospective study. The only one came out of the University of Miami, and their numbers ended up being way too small because they took in people of all ages and people dropped out. But the numbers are pretty compelling that what we're seeing with these results are different from the natural history. It's not the slam dunk that I was hoping for with every case being like the cases that Professor Donahue showed you, but this is different from the natural history.

Got it. And next up, what aspects of the preclinical data for GS010 give confidence that the gene therapy given in one eye can have contralateral effects? And do you know of other preclinical data sets not from GenSight that support the possibility of contralateral effects?

Yes. I'll be happy to answer that as well because, again, we just recently did a review on this for one of the papers we're writing for the RESCUE results. In the other 2 groups that have moved to -- that have Phase III studies of this type of gene therapy with allotopic rescue, specifically for the ND4 mutation, one out of China and one out of Miami, both groups have shown bilateral improvement.

Got it. And one final question. Would GenSight discuss the long-term follow-up strategy of patients treated with GS010?

I'll leave that to someone else.

We released earlier this week, the result of the follow-up -- the long-term follow-up study, which is an interim result, but 1 year after the readout of RESCUE and REVERSE. So it's only a subset because, I mean, patients were asked to volunteer to participate to the long-term study. And yes, at 3 years, we demonstrated that the effect in visual acuity is maintained. Obviously, this study goes on for another 2 years, and we'll communicate each year about those results. But I think at 3 years, we see that the effect has been maintained.

Our next question comes from Martial Descoutures with ODDO.

Martial Descoutures from ODDO BHF. First of all, you -- and sincerely sorry, but my line did not work as well. So you have maybe already answered my question, but I would like to ask you. For Dr. Newman, what is your experience with LHON ND4 patients? So how do you follow them? And how do you treat them? And maybe if you have more visibility on the diagnostic. Is it difficult to diagnose them? So yes, I would like to have your opinion on the current treatment and the situation, et cetera.

Yes. That's a very good question. If the implication -- I'm trying to read into why you would be interested in that. And from what I understand, you're asking is -- how soon can we get these patients, how easy is it to diagnose them. Certainly, if patients come from a family with the disease, they're more likely to have an inclination, what's happening and their doctors are more likely to know. I think if you would ask me this question 10 years ago or 15 years ago, I would have told you that it is the rule that patients, especially what we call singleton patients, who either don't have a family history or they aren't aware of their family history, which is very common in the United States, which has a much more mobile population, that 10, 15 years ago, every -- I would say nearly every one of those patients would have gone down the incorrect diagnostic path of being called optic neuritis first and would have gone through multiple unnecessary studies and treatment. This has really changed. And the reason it has changed is because of lhon. org, the lay group, the patient advocacy group and website that Lissa Poincenot pretty much single handedly put together a little bit more than 10 years ago when her son Jeremy was the first person in her family to be involved, came down with Leber's and went through that kind of unnecessary diagnostic process. Now with lhon.org, the families are literally way more linked together for education, support. Plus Lissa has been in -- this group has been an amazing resource for recruiting patients. I did the first treatment trial for Leber's to protect second eye involvement, to protect against it, back in 2007 or 2008, and it took 9 sites almost 2 years -- a little bit more than 2 years to get 9 patients enrolled. With Lissa and her ability to reach out to families and get the word out and then get the word to us without her having HIPAA requirements of patient privacy, we were able to enroll more than -- if you look at all 3 studies, we're talking well more than hundreds of patients. And then you look at the Chinese studies and Miami's, it's getting them in within 1 year of vision loss -- of their onset of vision loss. So I think that it's still -- people still don't -- may not clue to it quite so quickly until the second eye is involved, but the recognition of the disease and the diagnosis of the disease is much easier. And finding these patients is much easier than it used to be.