MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

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, a 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. And for the 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. Specificity of these risks are described in our press release and most recent filings with the SEC. I'm joined this morning by Professor Mike 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 3 domains of vision in patients treated with botaretigene when compared to untreated randomized controlled patients at 6 months after treatment. Meira 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 3 phases. In the dose escalation phase, adult subjects were treated at 3 escalating doses, a low dose, an intermediate dose and a high dose. And in the dose confirmation phase, 3 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 6 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 are the modified prophylactic steroid regimen, a reduction in all inflammation-related AEs 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 3 domains of vision: retinal function, visual function and functional vision at prespecified 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 6 months; and, 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 6 months with this analysis conducted applying the Phase III Lumeos eligibility criteria. Importantly, all data presented here compares subjects treated with botaretigene 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 analysis 1 and 2, improvements were demonstrated in multiple endpoints across each of the 3 domains of vision. In analysis 1, comparing just the immediate expansion subjects to the randomized concurrent control at 6 months using prespecified exploratory analysis, mean retinal sensitivity and 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 provision 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 3 domains of vision and the sensitivity analysis, 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 6 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 illumination 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 6 months. And 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 point-wise responder analysis of the static perimetry data. Using the responder criteria of at least a 7-decibel improvement from baseline in 5 or more individual loci and with the additional restrictions that the same 5 loci show improvement at 2 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. And 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 Meira are leveraging our wholly-owned end-to-end GMP manufacturing and quality infrastructure to prepare for potential commercial supply of botaretigene, with the 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. And 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. And with that, I will pass you over to Professor Mike Michaelides who will provide a view from the physician and patient perspective of this severe degenerative disease and the potential impact that botaretigene treatment may have in this population with no currently available therapies. Mike?

Thank you very much, Zandy. So this is a condition that most commonly is identified in childhood, with poor mobility and dim lighting, and children often being referred to as being clumsy in that they bump into or trip over things. And 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 decade 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. And 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. And 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. And so 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 end points have been analyzed across multiple different metrics and in multiple different assessments of visual function, retinal function and functional vision. And it's particularly very promising indeed that the data was previously reported in the dose escalation phase has now been reproduced and broadened in a large randomized controlled expansion phase. And that particularly makes me very optimistic indeed about Phase III. And finally, as a clinician, evidence from another very important source is important, and that's the patients themselves. And I found that the vast majority of patients that have been treated with the 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. So 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. And with that, Sara, can we open it up for questions, please?

Absolutely. Thank you, Zandy. At this time, we'll be conducting our Q&A session. [Operator Instructions] So let's kick it off with our first question from Chris Raymond at Piper Sandler.

Great. Congrats on the data, guys. Just a couple for me, I guess. First, Zandy, the patient in the expansion [Audio Gap] the increased intraocular pressure. Can you just explain, was this patient -- was this before or after you instituted the prophylactic steroid regimen? It wasn't clear to me if that was the case. And then maybe secondly, when we talked to you guys last month, I believe, you talked about accelerating enrollment of the Lumeos study with more sites. And I think that the number I heard was 15 or 16 sites. I know clinic trial is not always up to date, but just kind of looking at the most recent update, there's still just, I think, 6 or so sites. Can you maybe give an update on the enrollment dynamics there?

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 specifically did. I'm sorry. We'll be presenting the full data at a medical meeting later in the year. So 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. Maybe just a follow-up on that patient. You mentioned resolved that treatment. What specific treatment was that?

We're not giving specific data on specific patients at this moment. That's not being released. But -- so I can't comment on that at this time.

Livshits at Chardan Capital Markets.

Congrats on the update. Also so now that you've described there's an improvements in the different domains of vision, are you able to provide any color on the endpoints for the Lumeos trial and then what has been important in the discussions with regulators? And maybe additionally, can you remind us how the Phase III inclusion criteria compare to those for this study that drove these differences in the inclusion criteria and some of the analysis?

Okay. So 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. So 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. So 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 endpoint -- 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?

Yes. Yes. So on the earlier question is about the Lumeos study and the relevant endpoints there. Anything you can share on that front?

Okay. So all of the assessments that were done in the Phase I/II and presented here are also being conducted in the Lumeos study. So 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. And in the Lumeos study, we are using the visual mobility maze as a primary endpoint. And all of the other end points mentioned here will be secondary -- prespecified secondary end points.

Got it. Great. And just last question on that as a follow-up. In terms of the endpoints, is there anything you can share on the, let's say, 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.

The next question comes from Josh Schimmer at Evercore.

Very interesting results. Can you review all of the vision endpoints that were measured? And 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 or where they're treated less?

So 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. And I'm not aware of any endpoints that went in the opposite direction.

So 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. So these endpoints are the endpoints that we're most interested in, in our Phase III. So it's reflecting for you what's most likely to come out of our Phase III study.

Got it. And how did the contralateral 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.

And then 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. But I'm asking, was there actual improvement from baseline? Or was it primarily just stabilization?

Yes. Improvement from baseline was seen.

Great. The next question comes from David Hoang at SMBC.

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 of Luxturna in RPE65 retinal dystrophy?

Thank you, David. So the maze is an end point 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. And 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. So 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. And I just had a few on the point-wise responder analysis. I noticed you did do the -- you have selected 2 endpoints -- or sorry, 2 time points that you have to have consistency at. And so how did you select those specific points low side, if you're able to share anything there? And was there a statistical analysis performed on that -- on the drug-treated arm versus placebo one?

So with respect to the responder, again, with this endpoint, we've had a long series of discussions with regulatory agencies. And from our perspective, the endpoint that gets closest to what they would consider clinically meaningful is a 7-decibel change in 5 points, but that 7-decibel change in 5 points has to be in the same 5 points over time that those points are not prespecified. But 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. So 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. And if I could just sneak in one last one. I know that the -- at 6 months, the -- there was a deferred treatment, right? So the patients that initially received placebo were switched over to drug. In terms of some of these, for example, point-wise responder analysis, did you see, again, similar trends that would be supportive of what you saw in the initial treated patients?

Yes. So we haven't yet -- we are not yet presenting the sensitivity analysis, which includes the patients treated after 6 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.

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

Congrats on the data. A 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? And one question from us on the point-wise responder analysis, the 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. And then last question is just on the timing of a potential full data release, would ASRS, next month, makes sense? Or are you perhaps shooting for later in the year?

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?

So 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 offer 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 side. So we would not necessarily expect to see an improvement. You could through just random improvement, but it's not what we would expect. So we would expect, again, 0, as we've seen in the contralateral eyes with the dose escalation. But it's a control and, potentially, you might see a responder, but we -- I can't speculate on what that would have been at 12 months. And the full data will be submitted for presentation in medical meetings later in the year. ASRS is too soon.

The next question comes from Luca Issi from RBC Capital Markets.

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 would be helpful. And then maybe, Zandy, bigger picture, can you remind us some of the key differences between your approach and Nightstar. Obviously, their approach failed in Phase -- in pivotal trial, I should say. So I wonder if you can remind us sort of some of the key differences here between them that keeps you confidence that the Phase III will work out.

Yes. So your first question about dose response, these are small numbers of patients. And so we are -- 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. And 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. So your question about the differences between Nightstar and our program. There are quite a few differences and some of those may or may not have led to the failure of their study compared to ours. Number one is that the, their vector is somewhat different they used a full-length code-on 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. So 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. So 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. And in general, this tends to be 400 to 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. So they seem to be delivering a lot less drug to in volume and therefore covering a smaller area. In addition to that, there are 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 seem to focus on the very small region of the retina right in the center. And 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. And 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.

The last question will come from Gena Wang of Barclays.

I have 2 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 the second question is regarding the efficacy analysis. I just want to make sure I understand correctly. So the statistic analysis is on 33 patients in the expansion cohort and at between 19 patients that proved the low dose and then intermediate dose compared to the controlled 13 patients? Is that correct? And then Maybe I have 2 follow-up questions.

Okay. Sorry, which -- okay. So first of all, I don't have the details at this time of that 1 SAE other than it was intraocular pressure, and it was -- it resolved completely on treatment. So that will be discussed when this data is presented in a medical meeting. Number two, can you go through exactly, which cohort you're asking the patient numbers in, I lost...

Okay, sure. Yes. So my understanding of safety, you analyze on all 45 patients, right? Dose exploration phase, dose confirmation phase and expansion cohort. So the efficacy or you show all the nominal key value. First, I wanted to confirm, was that based on only the expansion cohort and then your [ through a ] low-dose and intermediate dose, that low dose, you have 8 patient, intermediate 11 patients, you put this together, and 19 patients, compared to the controlled 13 patients? Is that the stat you analyzing on all the efficacy you share today?

So I shared today, and we shared in the press release, 2 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 6 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 adult in both the dose escalation and the expansion at low and intermediate dose. And for that larger population of all patients, again, compared to the control arm, the same control arm reapplied the, Lumeos entry criteria. And 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 the 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. So those are the 2 different analyses and the patient numbers reflect what I've just said.

Okay. So the efficacy summary that slide basically is all the patients, not just the extension cohort phase, right? All the key -- nominal key value share here, that's the all patient. I just wanted to confirm that.

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 criteria in that -- in both arms of the study. All patients.

Okay. Okay. That's good. And then just wondering why you use nominal key value 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, have you adjusted for multiple -- multiplicity for the stats purpose?

So Gena, this is a Phase I study with the -- with safety being the primary endpoint. All secondaries were exploratory, right? So that's why we're saying -- that's why it's a nominal p-value.

Okay. That's fair. And did you adjust for multiplicity? Or did you do the P test for each individual endpoint?

The analysis was for each individual end point. That nominal -- so that's why it's nominal P.

Okay. So basically P-test is for each individual endpoint compared to the placebo.

Each individual endpoint was, yes, compared itself to the untreated control arm.

Okay. Great. Well, congrats on the data.

Thank you, 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 treatment for this potential -- working on this potential treatment for this severe unmet need. So thank you very much, everyone.