Good morning. I'm Zandy Forbes, the President and CEO of MeiraGTx. Thank you for joining us today as we announce positive top-line data from MGT009 Phase I/II clinical study of botaretigene sparoparvovec for the treatment of patients suffering from X-linked retinitis pigmentosa with disease-causing variants in the eye specific form of the RPGR gene. Botaretigene sparoparvovec is an investigational gene therapy in development for the treatment of patients with X-linked retinitis pigmentosa, which was previously called AAV-RPGR. For ease of presentation today, I'm just going to call it botaretigene. Before we begin, please note that we will be making forward-looking statements as part of this presentation, which statements are subject to certain risks and uncertainties that may cause actual results, performance or achievements to materially differ from those forecasted.
Certain of these risks are described in our press release and most recent filings with the SEC. I'm joined this morning by Professor Michel Michaelides, MGT009 trial investigator, consultant ophthalmologist at the Moorfields Eye Hospital, and Professor of Ophthalmology at the Moorfields Eye Hospital and University College London. Dr. Michaelides is also head of our inherited retinal disease group at MeiraGTx. I'm very happy to announce positive top-line data from the MGT009 Phase I/II clinical study, demonstrating safety as well as significant improvements in multiple endpoints across each of the three domains of vision in patients treated with botaretigene sparoparvovec when compared to untreated randomized control patients at six months after treatment.
MeiraGTx and Janssen Pharmaceuticals are collaborating jointly to develop botaretigene for the treatment of XLRP, a severe inherited retinal disease that causes loss of vision starting in childhood and teenage years and inexorably progresses to blindness in the third and fourth decades of life. MGT009 consists of three phases. In the dose escalation phase, adult subjects were treated at three escalating doses, a low dose, an intermediate dose, and a high dose. In the dose confirmation phase, three pediatric subjects were treated with the intermediate dose. In the expansion phase, adult subjects were randomized to immediate treatment with either the low or intermediate dose or to an untreated concurrent control arm with deferred treatment following six months. The primary endpoint of MGT009 is safety in all patients treated. A total of 45 subjects treated in one eye throughout the study.
Safety findings from MGT009 demonstrate that botaretigene is generally safe and well-tolerated. Most adverse events were related to surgical delivery procedures, were transient and resolved without intervention. Importantly, there were no dose-limiting events. A total of 3 SAEs was observed in the overall study. Two of these SAEs, which have been previously reported, were observed in the dose escalation phase with an N of 10 patients. One was a retinal tear and the other was panuveitis, both in the low-dose cohort. A single additional SAE was observed in the dose expansion phase with 32 additional patients treated. This SAE was increased intraocular pressure and resolved on treatment. No SAEs were observed in the pediatric dose confirmation cohort. In addition to reduction in SAEs in the expansion cohort following the implementation of a modified prophylactic steroid regimen, a reduction in all inflammation-related SAEs was also observed.
With the primary endpoint of MGT009 being safety, all efficacy endpoints were exploratory and significance is based on a nominal P value of less than 0.05. Exploratory efficacy endpoints in each of the three domains of vision, retinal function, visual function, and functional vision at pre-specified time points post-treatment were analyzed. Sensitivity analysis were carried out on one, just the subjects treated in the immediate treatment arm of the randomized expansion phase of the study compared to the randomized concurrent control arm at six months. Two, from pooling the immediate subjects treated at the low and intermediate doses in both the dose escalation and expansion phases of the study, again compared to the randomized untreated control arm at six months. With this analysis conducted applying the phase III LUMEOS eligibility criteria.
Importantly, all data presented here compares subjects treated with botaretigene sparoparvovec to the cohort of randomized untreated controlled subjects who remain untreated for 6 months in the expansion phase of the study. This is in contrast to the data presented previously from the dose escalation phase, where subjects were not randomized and where treated eyes were compared to untreated contralateral fellow eyes in the treated subjects. This is important as this current data closely reflects the design of the ongoing LUMEOS phase III study. For both analyses 1 and 2, improvements were demonstrated in multiple endpoints across each of the 3 domains of vision.
In analysis one, comparing just the immediate expansion subjects to the randomized concurrent control at six months using pre-specified exploratory analyses, mean retinal sensitivity in the central 10 degrees using static perimetry, performance in the visual mobility assessment or maze at the lowest light level of 1 lux, and the PRO for vision in extreme lighting conditions, each demonstrated significant improvement based on a nominal P value of less than 0.05, and best-corrected visual acuity approached significance. Similarly, significant improvements were demonstrated in multiple endpoints across each of the three domains of vision in the sensitivity analyses, which included low and intermediate treated subjects in both the dose escalation and expansion phases of the study and applying the phase III eligibility criteria.
Based on nominal P values of less than 0.05, the following endpoints were significant at six months compared to the randomized control subjects. In the functional vision domain, performance in the visual mobility assessment or maze demonstrated significant improvements at low lumination levels. Consistent with this, a significant improvement was observed in the extreme lighting domain of the disease-related patient-reported outcome measure, with trends of improvement in other patient-reported outcome domains of this PRO. In the visual function domain, ETDRS visual acuity significantly improved compared to the randomized control at six months. In the retinal function domain, using static perimetry, mean retinal sensitivity in the central 10-degree area of the retina showed significant improvement with a nominal P value of less than 0.001. We also conducted a pointwise responder analysis of the static perimetry data.
Using the responder criteria of at least a 7 decibel improvement from baseline in five or more individual loci, and with the additional restriction that the same five loci show improvement at two time points following treatment is required for a responder. Based on this analysis, 5 out of 22 or 22.7% of the treated patients met the responder criteria at 6 months, compared to no patients in the randomized control arm. While the control subjects did not extend out past 6 months, the responder rate in the treated arm further improved at 12 months to 10 out of 21 subjects or 47.6%.
Overall, these improvements seen in each of the 3 visual domains is entirely in keeping with the real-life challenges patients with XLRP experience who have marked functional difficulties, especially in low light levels early in their disease, before progressing to complete blindness. This is reflected in some of the comments recorded by patients treated in the MGT009 study. An example is shown here, reflecting what the patient considers a life-changing impact of treatment with botaretigene in one of his eyes. We and our partners at Janssen are extremely encouraged by the consistency of the data from MGT009. Of particular note is that the data presented compares treatment with botaretigene to a randomized, untreated control, which, while it is only at 6 months post-treatment rather than at 12 months, as in the phase III study, quite closely reflects the design and analysis in the ongoing LUMEOS study.
As we continue to enroll the LUMEOS phase III study, we at MeiraGTx are leveraging our wholly owned end-to-end GMP manufacturing and quality infrastructure to prepare for potential commercial supply of botaretigene, with a BLA filing targeted for 2024, providing a successful LUMEOS outcome. I'd like to thank the investigators, patients, and families who have given their time to our clinical trials and who continue to support us in our efforts to develop this potential therapy. Importantly, our partner, Janssen, who work arm in arm with us across every aspect of this program, dedicating a huge amount of time, resources, infrastructure, and expertise, supporting our joint effort to bring important therapies to patients with RPGR and other IRDs, with the aim of making a meaningful difference in the lives of people with these serious diseases.
With that, I will pass you over to Professor Michel Michaelides, who will provide a view from the physician and patient perspective of this severe degenerative disease and the potential impact that botaretigene sparoparvovec may have in this population with no currently available therapies. Mike?
Thank you very much, Zandy. This is a condition that most commonly is identified in childhood, with poor mobility in dim lighting and children often being referred to as being clumsy in that they bump into or trip over things. These symptoms are due to the night blindness and peripheral visual field loss that are present early in life. Both of these challenges always progressively worsen over time, causing increasing limitations in everyday life at school, in the workplace, and also importantly, socially. Subsequently, in adulthood, central vision begins to be compromised in terms of visual acuity, contrast sensitivity, color vision, and the central field of vision, with patients being legally blind in the third or fourth decades of life. The emotional, psychological, social, and financial impact of blindness is vast and must not be underestimated.
I've been fortunate enough to be seeing both children and adults with RP associated with RPGR for the last 20 years. At almost every clinical visit, either the families or the patients themselves have been asking me if there would be any treatments to slow or halt progression, and if even there might be treatments in the future that could improve vision. I've always been saying to patients that I've been cautiously optimistic that in the future there would be treatments to slow worsening, possibly long enough for treatments to be developed to maybe improve or restore a degree of vision. Now, I tell my patients that we have a treatment in advanced development that is improving vision in ways that are changing patients' lives. I found the data presented today encouraging for several reasons, including, first and foremost, of course, the safety data.
Next, once one feels confident in the safety, it's about whether the treatment works. I've been impressed by the efficacy being demonstrated in endpoints that are relevant and meaningful, both to the patients I see and my fellow clinicians. I've been impressed by the fact the endpoints have been analyzed across multiple different metrics and in multiple different assessments of visual function, retinal function, and functional vision. It's particularly very promising indeed that the data previously reported in the dose escalation phase has now been reproduced and broadened in a large, randomized, controlled expansion phase. That particularly makes me very optimistic indeed about phase III . Finally, as a clinician, evidence from another very important source is important, and that's the patients themselves.
I found that the vast majority of patients that have been treated with a low and the intermediate doses, which are the doses in phase III, have been and continue to request second eye treatments, with some of these patients now being several years after first eye treatment. I'm very enthusiastic about the data presented and excited to rapidly enroll for the phase III LUMEOS study. Thank you, Zandy
Thank you so much, Mike. With that, Sarah, can we open it up for questions, please?
Absolutely. Thank you, Zandy. At this time, we'll be conducting our Q&A session. As a reminder to the audience, you may submit your questions through the Q&A function at the bottom of the webcast. To our analysts, please raise your hand to indicate you have a question. Let's kick it off with our first question from Chris Raymond at Piper Sandler. Chris, you may hit star six and unmute your line.
Hi, can you guys hear me?
We can.
Oh, great. Thanks for taking the question. Congrats on the data, guys. Just a couple from me, I guess. First, Zandy, the patient, the increased ocular pressure. Can you just explain, was this patient before or after you instituted the prophylactic steroid regimen? It wasn't clear to me if that was the case. Maybe secondly, when we talked to you guys last month, I believe, you talked about accelerating enrollment of the LUMEOS study with, you know, more sites, and I think the number I heard was 15 or 16 sites. I know, ClinicalTrials.gov is not always up to date, but just kind of looking at the, at the most recent update, there's still just, I think, six or so sites. Can you maybe give an update on the enrollment dynamics there? Thank you.
Yes, thank you. The patient with the SAE in the expansion cohort was part of the expansion cohort, and I believe those patients all received the modified prophylactic. I don't know specifically if that patient did. I'm sorry. We'll be presenting the full data at a medical meeting later in the year. I'm not totally certain about that particular patient. With respect to the ongoing enrollment, the study is open. This study is a global study. There will be up to 30 sites opening and some are in the U.S. and some are throughout Europe.
Great. Thanks. Maybe just a follow-up on that patient. You mentioned, you know, resolved on treatment. What specific treatment was that?
We're not giving specific data on specific patients at this moment. That's not being released, but I can't comment on that at this time.
Got it. Okay. Thanks so much.
Geulah Livshits at Chardan Capital Markets.
Congrats on the update, and thanks for taking my question also. Now that you've described some improvements in the different domains of vision, were you able to provide any color on the endpoints for the LUMEOS trial and then what has been important in discussions with regulators? Maybe additionally, can you remind us how the phase III inclusion criteria compare to those for this study that drove the differences in the inclusion criteria and some of the analyses?
First of all, the inclusion criteria. The inclusion criteria for the phase I/II were essentially very similar to the pivotal LUMEOS study with respect to the level of vision that was required to come into the study. However, in the phase I/II study, some subjects did come in outside of those criteria. When we say we use the LUMEOS inclusion criteria, what we're actually doing is removing with only 5 subjects, 3 from the treated and 2 from the control, who, for example, were unable to conduct a static perimetry measure, for example. They could not do the endpoint reliably. It's those sorts of things that resulted in those patients not being included in that particular larger overall sensitivity analysis. It's not that the entry criteria are particularly different.
It's just that some of those patients didn't meet those when they came into the phase I/II. Can you remind me of your earlier questions, Geulah Livshits?
Yes. Great. The earlier question is about the LUMEOS study and the relevant endpoints there, and anything you can share on that front.
All of the assessments that were done in the phase I/II and presented here are also being conducted in the LUMEOS study. Visual function, functional vision, retinal sensitivity with static perimetry. A lot of endpoints that we haven't presented here today that you may see later in the year at medical meetings are also being conducted. With respect to the primary versus secondary endpoints in the LUMEOS study, we have had extensive discussions with regulatory agencies globally, and regulatory agencies both here and in Europe are very interested in us being able to demonstrate what they consider is a clinically meaningful benefit. In the LUMEOS study, we are using the visual mobility maze as a primary endpoint, and all of the other endpoints mentioned here will be secondary, pre-specified secondary endpoints.
Got it. Great. Just last question on that as a follow-up. In terms of the endpoints, is there anything you can share on the degree of difference that the study would be powered to detect?
We are not able to present the full data on this study today. It will be presented in medical meetings later in the year, where you will see effect sizes as well as the degree of improvement from a significance point of view.
Thanks.
Thank you for the questions. The next question comes from Josh Schimmer at Evercore.
Hey, thanks for taking the question. Very interesting results. Can you review all of the vision endpoints that were measured? Can we assume that the ones that you didn't indicate showed an improvement, did not show an improvement, and did any of the endpoints go in the wrong direction and show a benefit for the untreated eyes over treated eyes?
We aren't releasing the full data today. There were other endpoints which showed improvement, and across the board, the endpoints either improved with the nominal P value of 0.05, or we tended to see a trend in other endpoints. We did multiple sensitivity analyses, and we have certain sensitivity analyses which are as positive or more positive than the specific data that we've presented today. I'm not aware of any endpoints that went in the opposite direction.
How did you decide on what to show today versus what to not show today?
We showed what is most appropriate for our phase III study. These endpoints are the endpoints that we're most interested in our phase III. It's reflecting for you what's most likely to come out of our phase III study.
Got it. How did the contralateral eye, untreated eye perform in the expanded cohorts?
We haven't presented that data today, but that's something that will be presented potentially at a medical meeting later in the year.
Last question. Were there improvements from baseline noted, or was this primarily less rapid deterioration in the treated versus the delayed treatment eyes?
All analyses here are baseline versus treatment versus a randomized control.
Right. I'm asking, was there actual improvement from baseline?
Yeah.
Was it primarily just stabilization?
Yes. Improvement from baseline was seen.
Got it. Thank you.
Great. Thank you for the questions, Josh. The next question comes from David Hoang at SMBC.
Hey, good morning, everybody. Thanks for taking the questions. I had a few, maybe just first on the visual mobility assessment. Can you just refresh us a little bit as to how that assessment is conducted? Is that comparable to the maze test that I believe was used to support the approval, Luxturna RPE65 retinal dystrophy?
Thank you, David. The maze is an endpoint that we have been in discussions with regulatory agencies about, and we have had a lot of feedback. We have developed and validated a maze specifically for this particular indication. That maze involves a maze with obstacles with the potential for errors, as well as a measure of how rapidly the patient is able to move through that maze. It is a bespoke maze that we've developed and validated with regulatory input, and it does include the types of things that you see in the Luxturna maze, although it's been specifically developed by us for this particular indication.
Got it. That's really helpful. I just had a few on the point-wise responder analysis. I noticed you did do the, you know, you selected two endpoints, or sorry, two time points that you had to have consistency at. How did you know, select those specific points loci, if you're able to share anything there? Was there, you know, a statistical analysis performed on that, on the, you know, drug-treated arm versus placebo arm?
With respect to the responder, again, with this endpoint, we've had a long, long series of discussions with regulatory agencies. From our perspective, the endpoint that gets closest to what they would consider clinically meaningful is a 7 decibel change in 5 points. That 7 decibel change in 5 points has to be in the same 5 points over time, that those points are not pre-specified. When you have a change in 7 decibels at 1 point at 3 months, you have to see it at 6 months for it to be considered clinically meaningful. That, that's why we did that analysis. It's because that's our understanding in our discussions with regulatory agencies of what was the closest to being able to be considered a clinically meaningful benefit.
I see. Okay. If I could just sneak in one last one.
Sure.
I know that, you know, at six months there was a deferred treatment, right? The patients that initially received placebo were switched over to drug. In terms of, you know, some of these, you know, for example, point-wise responder analysis, did you see, again, similar trends that, you know, would be supportive of what you saw in the initial treated patients?
We are not yet presenting the sensitivity analysis, which includes the patients treated after six months of control in the treated patient group. However, none of our sensitivity analyses that we've done have been inconsistent with the data that we're reporting today.
Okay. Thank you very much.
Thank you for the questions, David. The next question comes from Alec Stranahan at Bank of America.
Hey guys. Thanks for taking our questions and congrats on the data. Couple of questions from us. First, with the phase I/II now completed, are there any additional milestones to be triggered from Janssen, or is it really now based on the phase III and commercial rollout if approved? One question from us on the pointwise responder analysis. Improvement in the responses from 6 to 12 months, obviously encouraging. Do you have a sense of what the randomized control arm would have done between 6 to 12 months? Obviously, it's a pretty impressive benefit. Last question, just on the timing of a potential full data release, would ASRS next month make sense, or are you perhaps shooting for later in the year? Thanks.
What was your first question again?
Just on the milestones from Janssen. Is it really just based on the phase III and commercial at this point?
We haven't disclosed our milestones. However, the phase III initiation milestone has already been paid, and for these programs, most of the milestones after that are for later development. In the control arm, you're asking what we would guess the responder would be at a later time point. As the responders get longer, it actually becomes less likely that you get repeated improvements at the same loci. We would not necessarily expect to see an improvement. You could through just random improvement, but it's not what we would expect. We would expect, again, zero, as we've seen in the contralateral eyes with the dose escalation. You know, it's a control, and potentially you might see a responder, but I can't speculate on what that would have been at 12 months.
The full data will be submitted for presentation in medical meetings later in the year. ASRS is too soon.
Thank you.
Thanks, Alec. The next question comes from Luca Issi from RBC Capital Markets.
Oh, great. Can you guys hear me okay?
We can.
Great. Congrats on the data. Two quick ones here. The first maybe on dose response. I think you're obviously combining the data between the low dose and the high dose together. Wondering if you can comment on whether you actually saw a dose response between the two. That'd be helpful. Then maybe, painting bigger picture, could you remind us of some of the key differences between your approach and Nightstar? Obviously, their approach failed in phase in pivotal trial, I should say. Wondering if you can remind us of some of the key differences here between them that keeps you confident that the phase III will work out. Thanks so much.
Yeah. Your first question about dose response. These are small numbers of patients, and so it simply isn't powered to show differences between particular doses, so we can't say anything about a dose response based on this particular data. Given that we're moving forward in a pivotal study with both of these doses, I think that indicates to you that we don't have knowledge that one of these doses is obviously better than the other at this particular point. Your question about the differences between Nightstar and our program, there are quite a few differences, and some of those may not have led to the failure of their study compared to ours. Number one is that the vector is somewhat different.
They used a full-length codon-optimized vector, and this is a different approach from the one we took. We used a stabilized version of a shorter natural messenger RNA, so it's a different vector. We have very strong preclinical data, including data in human organoids. We're very confident that our vector is a good one, and I think that's borne out in the clinical data that we now have in hand. With respect to the Biogen study, we obviously only know what is publicly available, but there are a number of things that were very different. Number one is the area treated and the volume of drug given.
In our patients, the surgeons are given the leeway to treat the largest possible area of viable retina that can safely be treated in the whole central region of the retina using one or potentially more blebs. In our particular case, the volume that we deliver can be up to 600 microliters or 700 microliters actually, and that volume can be distributed broadly around all viable retina. In general, this tends to be 400-500 microliters for these particular patients. In contrast, in the Biogen study, if you look at the volumes that they report delivering, you see under 50 microliters in some cases. They seem to be delivering a lot less drug to, in volume and therefore covering a smaller area. In addition to that, there were differences in the design of the endpoints that they used.
The way they designed the responder analysis, for example, was quite different from us. They seemed to focus on the very small region of the retina right in the center. In this particular disease, that region may be an area where in healthier patients, there is not so much room for improvement because that area of the retina is the healthiest as these patients go through retinal degeneration. Those are some of the differences. I can't tell you exactly what the issues were that resulted in the failure of their study, but there could be some relation to some of the things I've just said.
Super helpful. Thanks so much.
You asked us about why we're confident in our phase III study. I think that confidence is not so much due to the differences with the Biogen study, but rather when we look at the data from this phase I/II study and we look at data that is compared to a randomized untreated control, even though that's just for 6 months and the primary endpoint is at 12 months in the LUMEOS study, this gives us confidence that the similarities really suggest that we should be able to show the types of benefit we've shown here in the larger, similarly designed phase III study.
Great. Thanks so much, guys.
Thanks for the questions. The last question will come from Gena Wang at Barclays. Gina, you may unmute your line.
Thank you for taking my questions. I have two sets of questions. The first one is also going back to the third SAE, the intraocular pressure. Just wondering how soon was the onset after injection? And a second question is regarding the efficacy analysis. Just want to make sure I understand correctly. The statistical analysis is on 23 patients in the expansion cohort and between 19 patients that pool the low dose and the intermediate dose compared to the control 13 patient. Is that correct? Maybe I have two follow-up questions.
Okay. Sorry, Okay. First of all, I don't have the details at this time of that one SAE other than it was intraocular pressure, and it resolved completely on treatment.
Okay.
That will be discussed when this data is presented in a medical meeting. Number 2.
Okay.
Can you go through exactly which cohort you're asking the patient numbers in? I lost.
Okay, sure. Yeah. My understanding of safety, you analyze on all 45 patients, right?
Yes.
Those expansion phase, confirmation phase and expansion cohort.
Yes.
The efficacy, are you show all the nominal p-value. First wanted to confirm, was that based on only the expansion cohort? You pool low dose, intermediate dose. That low dose, you have 8 patients, intermediate 11 patients, you pool this together in 19 patients compared to the control 13 patients. Is that the stats you're analyzing on all the efficacy you share today?
I shared today, and we shared in the press release two different sensitivity analyses. One was an analysis of the patients in the expansion arm only. So that is the patients treated with low and intermediate doses in the expansion arm compared to the patients that were not treated at six months. So that's just the expansion arm
We also show a sensitivity analysis, which includes all patients treated, not just the randomized expansion. All patients treated who are adults in both the dose escalation and the expansion at low and intermediate dose. For that larger population of all patients, again compared to the control arm, the same control arm, we applied the LUMEOS, the LUMEOS entry criteria. That resulted in 3 patients in the treated arm and 2 patients in the control arm not being included in that particular sensitivity analysis because of things like their inability to reliably do a perimetry test. Now, unreliable patient and an unreliable assessor should not be included in a pivotal study and, actually shouldn't have been included in the phase I. Those are the two different analyses, and the patient numbers reflect what I've just said.
The efficacy summary, that slide basically, is all patients, not just the extension cohort phase, right? The all nominal p-value shown here, that's all patients.
That's correct.
I just want to confirm that. Okay.
The slide specifically as I was talking about the sensitivity analysis number two, that includes all patients treated at low and intermediate in the immediate treatment, so it doesn't include the patients that were later treated in the deferred arm compared to the deferred control with the LUMEOS exclusion trial criteria in both arms of the study. Right?
Okay.
All patients.
Okay. Okay, that's good. Then, just wondering why you use nominal p-value. You know, if you're only analyzing, say, the extension cohort, wouldn't that be the primary assessment? Why we're using nominal p-value? And also, have you adjusted, because you did do quite a few different tests, for multiplicity for statistical purposes?
Gena, this is a phase I study with safety being the primary endpoint. All secondaries were exploratory. Right That's why we're saying it's a nominal p-value.
Okay. That's fair. Did you adjust for multiplicity, or did you do the t-test for each individual endpoint?
The analysis was for each individual endpoint. That nominal-
Okay.
That's why it's nominal p.
Okay. Basically t-test for each individual endpoint compared to the placebo.
Each individual endpoint was, yes, compared.
Okay
itself to the untreated, control arm.
Okay, great. Well, thank you very much. Congrats on the data.
Thank you, Gena.
Thank you for the questions, Gena. This now concludes our Q&A session today. I'll now hand it back to Zandy for any concluding remarks.
Thank you very much, everyone. Just want to reiterate how excited we are about this data and moving forward with our partner, Janssen, to continue and complete enrollment in this LUMEOS study. We have additional confidence in that study, and we're very happy to be working on this potential treatment for this severe unmet need. Thank you very much, everyone.