MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Good morning, and welcome to the MeiraGTx Investor Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the MeiraGTx website following the conclusion of the event. I'd now like to turn the call over to Dr. Zandy Forbes, President and Chief Executive Officer of MeiraGTx. Please go ahead, Zandy.

Thank you, Tara, and good morning, and thank you all for joining us today as we present the very exciting data from the treatment of 11 young children with genetically inherited blindness caused by mutations in the AIPL1 gene. AIPL1 or LCA4 is a rare and very severe form of inherited blindness with babies born completely blind and by the time they're 3 or 4 years old, the entire retina has degenerated. We provided the AAV-AIPL1 gene therapy to physicians in the U.K. under our MHRA manufacturing Specials License. 11 children were treated between the ages of 1 and 4 years old, and every one of them who were all blind from birth can now see. We'll start by showing a video that includes 2 of the 11 children treated with AAV-AIPL1 presented by Professor Mike Michaelides. Professor Michaelides is consultant ophthalmologist at Moorfields Eye Hospital in the Departments of Medical Retina, Inherited Eye Disease and Pediatric Ophthalmology and is a Professor of Ophthalmology at the UCL Institute of Ophthalmology. Mike has also led all of the IRD clinical studies at Meira. Mike will then go on to present clinical data from all 11 children treated. The data from the first 4 patients have been published today in the Lancet. So over to you, Mike.

I'm Dr. Michel Michaelides, a Professor of Ophthalmology and Consultant Ophthalmic Surgeon at UCL Institute of Ophthalmology and Moorfields Eye Hospital in London. I've spent 20 years seeing both adults and children with inherited retinal diseases, approximately 50 adults and 30 children per week. Over the last few years, I've had the privilege and extraordinary professional experience of working with patients, all small children born with a congenital retinal disease, one of the most severe, rapidly progressive, irreversibly blinding retinal diseases known as AIPL1-associated LCA or Leber Congenital Amaurosis. And here's what makes it uniquely challenging. Children are identified from birth, often only being able to detect light, thereby being legally blind from birth. The profound visual impairment also often results in delayed and disrupted global development. The window of opportunity for treatment is tiny. Treatment must be administered before 4 years of age before the residual island of central retina degenerates. These aspects of LCA make it uniquely challenging compared to other retinal disorders in children, such as early onset severe retinal dystrophy, for example, that caused by RPE65. RPE65 by comparison is markedly less severe. In contrast to LCA's small and urgent window for treatment, RPE65 treatment can extend into the third and fourth decades of life. A treatment called Luxturna is an approved gene therapy for RPE65 that has improved patients' night vision, but this treatment is simply not applicable for AIPL1 LCA, for which there has been no known treatment until now. I've been working with MeiraGTx to help develop a treatment for this condition. Thanks to what is known as a Specials License here in the U.K., these 11 children received an innovative genetic medicine that resulted in an unequivocal improvement in retinal function and visual behavior. In short, these blind children can now see something unrivaled in treatment benefit in my experience and in the field. This is Arden, a patient with AIPL1, she had her left eye treated with the gene therapy, shown here 3.5 years after that treatment. In this video, you will see first how her untreated right eye performs and then the comparison against the treated left eye. So this is her untreated right eye. She's attempting to identify small objects of different sizes. Note, she's unable to use her right eye when the left eye is covered and that she needs to look around her glasses or to try to remove the occluder covering her left eye in order to identify the object. Compare that to this footage taken at the same time when the untreated right eye is now covered, and she can now use her treated left eye. She quickly and easily spots the 5-millimeter, 3-millimeter and eventually here, the 1-millimeter object. Even when the clinician introduces some random variability in the placement of the object, the severity of this disorder can have impact beyond vision into other areas, resulting in navigational, behavioral, developmental, emotional and social difficulties or delays. So it is common amongst these treated patients also to see marked improvements along these lines as well. Here, we see Arden playfully finding her way around the treatment area of the hospital. So Arden is an example of a patient who had one eye treated. Following the safety and outstanding benefits in the first group of 4 children in the second group of 7 treated children, both eyes were sequentially treated. The next chart is an example of a patient who had both eyes treated over the span of a few months. His name is Harvey, and this first video shows him before any treatment of either eye when he was just under 3 years old. [Presentation]

As you can see in that clip, Harvey was relying on his sense of touch and guidance from his mother to try to identify and handle objects on the table. Contrast this with the following clip of Harvey just month after his left eye treatment. [Presentation]

You might wonder how after only 4 weeks, Harvey can read and identify objects if before he couldn't see it at all. The answer is that his parents who you'll hear more from in a moment, immediately after treatment took Harvey through visual identification drills on multiple times a day. The point being they were now actually able to do so for the first time. Here is another clip of Harvey 4 weeks after his first left eye treatment. [Presentation]

Here is Harvey 4 weeks after the treatment to his other eye his right eye. In contrast to the earlier footage of him feeling his way around a table top of toys, you can see him steering around obstacles and following the curb of the road. [Presentation]

As I mentioned before, often untreated patients with this severe retinal disorder face significant behavioral, developmental, psychological and social challenges as well. And in the same fashion, the 11 patients treated with this novel AIPL1 genetic medicine see great improvements to their overall quality of life, their social interactions, development and more. Here in the words of Harvey's own parents.

He really struggled to be left in an environment that he maybe wasn't confident in or if he felt like he was suddenly alone in a room and he couldn't sense that anybody was around, he would quite often just kind of call out and wait for a response to know that somebody was still around.

So I think presurgery he was very -- yes, his preference would be to hang out with adults or older children. But he wouldn't -- he'd come home from school and say, who did you play with today, and he would say his teachers' name. So that was something that was a bit of a concern for us because obviously, everybody wants their kids to have friends. And yes, that was something we noticed presurgery. After surgery, we were obviously in London for quite some time after, and we even noticed within our own kids, so Harvey has got an older sister that for the first time in forever, they started to really play together. And they were playing like role play, they were playing teachers and airplanes and all of these kind of things that at times did require vision, and we had never seen that before, and they were able to play together for like an hour. And anybody with small kids that know that your kids are playing for an hour is like. And I think one of the big things is that before -- you would see Harvey play, but he would never really know if the person had left or not, and he'd get frustrated. So as you know, kids are moving around 100 miles an hour, whereas now if a kid gets up and leaves, he knows. So he's not frustrated by that play. He'll often say like, where, whatever the person's name is gone. So that's really exciting to see and exciting to see him build some little friendships and yes, some more relationships now.

These were just glimpses of 2 patients of the 11 patients to date. This gene therapy for AIPL1 LCA, one of the most severe congenital, rapidly progressive blinding retinal diseases has resulted in an unequivocal improvement in retinal function and visual behavior, which is to date unrivaled in treatment benefit. You've just seen 2 examples of remarkable benefit of the genetic medicine for AIPL1 LCA. I'd now like to share some more details on some of the other children that have benefited from this treatment. This genetic medicine delivers the wild-type human AIPL1 gene under control of a photoreceptor-specific rhodopsin kinase promoter. It's delivered subretinally using standard surgical technique. 11 children have been treated to date successfully aged from 1 to 4 years of age, and this has been provided under an MHRA Specials License. These 11 treated children have been divided into 2 different groups. The first group, the initial group of 4 children received unilateral treatment in order to ascertain the safety and allow comparison with the untreated eye. This group has been recently published in the Lancet. Subsequently, a second group, group 2 of 7 children received bilateral sequential therapy. There have been no safety concerns in either of these patient groups. We have observed efficacy in all 11 patients treated. The unilateral treatment group, which was the first to be treated, has had durable efficacy out to the longest time point, which is 4 years to date. I'd now like to talk about Group 1, the unilateral treatment group in greater detail. We've seen improvements in visual acuity and cortical responses in this group. At baseline, their binocular visual acuities were limited to perception of light. There's been a mean follow-up of 3.5 years after surgery. We've observed benefit in all 4 of these children with dramatic improvements in functional visual behavior, the ability to record reliable visual acuities, reduced nystagmus and objective recording of vision-driven brain activity using EEGs as well as relative preservation of retinal architecture in the treated eye compared to the untreated eye. The visual acuities of patients treated improved to 0.9 LogMAR on average with the untreated eyes not improving. We used a second method to determine visual acuity called the PopCSF, which is a touchscreen-based test. This also showed improved performance in the treated eyes when compared to the untreated eyes. The visual acuity of the untreated eyes was either unmeasurable or lacking perception of light. In addition, cortical responses to visual stimuli using steady-state visual evoked potentials obtained from EEGs have revealed retinocortical signal transmission selective to the treated eyes, demonstrating objective evidence of treatment benefit in visual perception. Here, we look at retinal structure in Group 1, the unilateral treated group. These are cross-sectional images taken with handheld optical coherence tomography of all 4 children starting at baseline before intervention and then 2 time points following surgery. There's been relative preservation of retinal structure in the treated eye post treatment compared to the untreated eye. For child 1, the difference is primarily observed with regard to central retinal thickness being better preserved in the treated compared to the untreated eye. In child 2, 3 and 4, we see better preserved outer retinal lamination in the treated eye compared to the fellow untreated eye. We now move to Group 2, which was the group of 7 children who were treated bilaterally sequentially. We saw meaningful improvements in all 7 of these children with respect to functional vision, visual acuity and retinocortical signal transmission. At baseline prior to intervention, in 2 of the children, their vision was limited to perception of light. In 3, they were able to perceive motion. And in the remaining 2, they could only see high contrast large shapes, LogMAR 1.3 and LogMAR 1.7, respectively. The binocular visual acuities have improved to a mean of 1.0 LogMAR with the best LogMAR visual acuity being 0.6. There's been a mean follow-up of these children out to 5 months to date. So in summary, children with AIPL1 LCA4 are legally blind from birth. By age 4, retinal degeneration is complete. We show that treatment with our genetic medicine results in unequivocal improvements in visual function in all 11 children with more than or equal to 3 lines of visual acuity gain, often from light perception or hand motion detection to being able to record visual acuity up to LogMAR 0.6 as well as improvements in retinal function and visual behavior. These improvements are unrivaled in treatment benefit compared to any ocular therapies to date. These dramatic visual improvements in all 11 children have also resulted in life-changing benefits in all areas of their development, including better communication, behavior, schooling, mood, psychological benefits as well as social integration. This is supported by videos from patients in both treatment groups as well as family testimonials. I'd like to now pass over to Dr. Zandy Forbes.

Thank you, Mike. We are incredibly excited to see such a huge impact of AAV-AIPL1 treatment, completely transforming the vision, behavior and lives of these young children. We are currently engaged with global regulators to expedite approval of this product and make it available to any baby born with AIPL1. In the U.K., we received an innovation passport mid last year. And following that, the MHRA advised us to file for approval under exceptional circumstances based only on the data from the 11 children treated and no further clinical studies. In addition, we aligned on an expedited CMC package for approval. This is made possible by our broad internal manufacturing capabilities and platform process, which we have developed to meet the stringent requirements of the FDA and global regulators for pivotal and therefore, commercial supply. In addition to the MHRA, we are engaging with the FDA on a path to expedited approval in the U.S. We have orphan status in Europe and U.S. and have been awarded a rare pediatric disease designation, and we are, therefore, eligible for priority review voucher on approval. We're in discussions around the addition of AIPL1 to the newborn testing panels to allow babies born with this severe inherited retinal disease to be identified and potentially treated as infants. We will now open the call to questions.

[Operator Instructions] So our first question comes from Sam Leach at Piper Sandler.

So I guess you've talked about starting to engage with the FDA on a path here. Do you have any more color on what the specific pathway is with the FDA and whether you can meet all the hurdles before the priority review program sunsets in 2026? And is there anything different between what the FDA seems to want versus what you've heard from the U.K. and the EMA in terms of clinical data, et cetera?

Thank you, Sam. And with respect to the FDA, we have had informal discussions where there was excitement about the data. And we are entering into more formal discussions with the FDA about the package we have in hand. With respect to manufacturing, which is really the critical path here for approval, we have a lot of interaction with the FDA, and that would be the timeframe around which we would file in both the U.K. and with the FDA when we have completed the, I'm going to say, BLA supporting or MAA supporting manufacturing package. So we haven't had feedback yet from the FDA, but that's our expectations. The timeframe for our filings would be around the same time.

Our next question comes from Elemer Piros at Rodman and Renshaw.

Sorry about that. And both of the eyes are treated in the 7 children. Is there a synergistic benefit that is measurable, whether it's related to functional vision or neurological benefit?

I'm going to pass that over to Mike Michaelides, the physician in charge. Mike?

Yes. Thank you, Elemer. Yes, it's a great question. At the moment, I'm not sure we can answer that question as yet. We haven't had a long follow-up -- as a long follow-up for the second group as we have for the first group. However, that being said, we have had one child in the second group whose vision has improved to a greater extent compared to the improvements we saw in Group 1. So I think it's conceivable we might see a greater benefit with both eyes treated compared to one. But at the moment, it's not entirely clear with the data that we have.

And just a quick follow-up, Zandy. Could you talk about the incidence of this disease in the U.S. and in the U.K.

Okay. I will give the numbers that we have in hand. So this is something that is rare. It's 1 in 1 million live births. And having said that, Mike, with this data in hand, Mike has 2 kids in the U.K., and I believe around 100 children have appeared in China. So Mike, do you want to talk about the supposed numbers and the numbers that you're thinking of here?

Sure. No, that's absolutely right. I'd agree with the 1 in 1 million. That's what's often stated in the literature. But of course, these numbers are not entirely accurate. You are correct that I already have 3 children in the U.K. that would be eligible for this treatment. And I've got in the order of 15 to 20 physicians and families that have contacted me globally who are waiting to hear when they might be able to access this. So look, I think it is rare, but it may be slightly less rare than we previously thought. And you're right, Zandy, there's been a recent report out of China suggesting that this might be more common in China. They have in the order of 100 patients they're reporting who have disease caused by AIPL1. It's not entirely clear how many of those would be eligible for therapy in the sense of how much retinal architecture they retain. But yes, there certainly could be parts of the world where it's more common.

Our next question comes from Gavin Clark-Gartner at Evercore.

I just first wanted to ask on your commercial plans. Are you planning to actively commercialize this program yourself? Or are there some other strategic considerations or options that you may pursue?

We're looking at all options, and there is obviously strategic interest in this product. It works so incredibly well. So we're looking at the best way that we can most rapidly get this to kids globally.

Great. That makes sense. And I just separately wanted to ask, what's the status of discussions with the European Commission? And when may we expect an update there?

So the European Commission has similar pathway to the U.K. and there is a new linked pathway with the FDA. So we are engaged with the U.K. and the FDA, and we will bring the Europeans in when we're fully aligned on filing with those 2.

Our next question comes from Alec Stranahan at Bank of America.

Congrats on the really amazing improvement in these children. Median 3.5 years of follow-up from the initial cohort feels like a long time for a clinical trial. Was this based on feedback from the regulators or really needed in this patient group to separate treatment benefit? Just thinking in terms of length of follow-up you might think is needed from the additional 7 patients for filing.

So Alec, just to be clear, this wasn't a sponsored clinical trial. This was initially -- it was physicians treating kids with material supplied under a Specials License. So we produced and paid for -- we paid for the production of the material. We released it to physicians in the U.K. under a Specials License, which allows physicians to treat kids when there's no other opportunity to benefit with no clinical data. So this wasn't initiated as a clinical study. It was only the results of the initial 4 kids that was so striking that the remaining cohort of kids were treated, and we'll have Mike talk about that. And with that data in hand, the first half of last year, that's when we engage with regulatory agencies who in the U.K. told us that the data on those 11 children that had been treated was sufficient for filing for expedited approval and the manufacturing package would be needed to support it. So Mike, do you want to -- if you want to go and explain a little bit more how the patients in the 2 cohorts came about?

Sure, sure. So we're seeing improvements in vision as early as 4 weeks. So absolutely, we don't need to have a long follow-up to discern difference between the eyes. That's often apparent as early as 4 weeks. The apparent delay going from Group 1 to 2 was primarily because it -- COVID occurred during Group 1, which delayed our ability to see these children from abroad in London to directly assess how they were doing and ensure there were no safety concerns. Those first 4 were 2 from Turkey, from Tunisia, 1 from the U.S. The second group, by the time we're able to start the second group, I had already identified patients in the U.K. So there were 2 families from the U.K. and then the remaining 5 from sort of coming around the globe, 1 from New Zealand, 1 from Australia, 1 from Thailand, and there were 2 siblings that came from the U.S. So in essence, we see benefit super early. The long follow-up in Group 1 is just reassuring in terms of there being durability and would expect to see similar durability in the second group. And certainly, our interaction with the MHRA, as Zandy has said, have not requested any further clinical data or follow-up. They were very compelled by what they've seen.

Got it. That's very helpful. And maybe one more, Dr. Michaelides, for you. Looking at the ages in the study, it ranged pretty meaningfully -- do you see an optimal age in which the gene therapy should be administered? Is earlier or better here from your experience, maybe looking at the 11 patients dosed to date?

Yes. No, it's a great question. Look, I've got no doubt they benefit up to 4 years of age on the basis if they have architecture, they will benefit. But I would absolutely agree the earlier, the better, the earlier the better. How young we'll be able to get approval for? I'd certainly want to be starting at 1. Whether it's going to be possible to go earlier than 1, I think, will be something that we're exploring. My understanding, for example, Luxturna is from 1 year of age and older. But yes, younger will be better.

And just one thing to add here is that these children are actually born blind. And this is a product that we are trying to get on a gene that we are in discussions for getting on the newborn testing panel because if you have a child born blind and as an infant, you can diagnose them with AIPL1, when there's a treatment available, you would be able to treat them as early as possible and potentially have the biggest benefit. So we're very much looking at the newborn testing panels globally.

Our next question comes from Daniil Gataulin at Chardan.

Congrats on this data. For patients who are treated bilaterally, what is the time between the treatments? And are there any safety signals in those bilateral patients?

Mike, that's yours.

Sure. Yes. So there was a bit of a range in the interval between surgery for the second group for lots of different reasons, including children getting ill in between and not being fit for GA. But it ranged from 2 weeks in between the 2 eyes to about 2 months. And there's no clear difference in the children that had a 2-week gap compared to those who had a 2-month gap in terms of any safety considerations or any efficacy signals. So I think my preference would be the shorter the gap, the better just in terms of not potentially resulting in a difference in visual maturation between the eyes, almost inducing an embryogenic type effect. But certainly, we didn't see that with the 2-week to 2-month interval between surgeries.

Our final question comes from Lisa Walter at RBC.

I'm just curious, did you have to exclude any patients who had neutralizing antibodies against AAV8?

No, we didn't. Mike, do you want to go ahead with that?

Yes. We did not. We did not. There was actually only one child that we did exclude for the first group because they did have other developmental delay that would have been challenging for the child and the family. But no, no other reasons.

And in general, for all our IRD programs, we don't exclude based on neutralizing antibodies, and local delivery to the eye or brain or indeed salivary gland. So it's -- when you deliver to somewhat immune-protected areas, we found that, that isn't necessary.

And Zandy, were the presence of neutralizing antibodies an issue when considering treating the second eye?

Mike, no, those aren't in. We don't look at that in our IRD studies. Mike, do you want to take that?

No, I would agree with you, Zandy. It's not a limiting factor. As you say, we have relative immune privilege in the eye, and we've not found that these titers make any difference to the safety or the effectiveness.

Got it. And maybe just one last one. I know it's still a bit early days, but wondering if you are -- how you are thinking about pricing here? Does Luxturna maybe serve as a good comp for LCA4 patients?

So right now, we're not discussing pricing. And what we are looking at is if you would like to look at a comparison with Luxturna, if you look at the ISA report that was done on Luxturna and you look at the age at which kids were treated, you'll see that when kids started to be treated below the age of 15, 14, 13, the quality of life benefit started to support a price over $1 million. That was what I'm remembering from that ISA report. Clearly, here, we have an unprecedented benefit and change in the lives of these young kids at a treatment that is between 1 and 3 years old. So we feel that the benefit provided results in a huge benefit to their life and should be able to justify a reasonable price, but we haven't started talking about pricing yet.

Thanks for the questions, Lisa. So this concludes our webinar for today. I will now turn it back over to Zandy for closing remarks.

Thank you, Tara, and thank you all for joining us today. We're really excited to show you some of the data underlying this incredible benefit in these kids and want to thank Mike Michaelides, who's led this program, knows these kids and who spent his life developing drugs to help them, and this one really, really does. So thanks for joining us, and thank you, Mike and the team at Meira who manufactured.