MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Hey, everyone. Good afternoon, and welcome to Day 3 of the BofA Healthcare Conference. Thanks for joining this session with MeiraGTx. My name is Alec Stranahan, I'm the analyst covering Meira here at BofA. And I'm pleased to be joined by Zandy Forbes, President and Chief Executive Officer of Meira. And I believe Zandy is going to run through a few prepared remarks to start off, and then we'll jump into Q&A. So with that, Zandy, over to you.

Thank you, Alex (sic) [ Alec ]. Zandy Forbes, CEO of Meira, and I'm going to give a very brief overview of the strategy as well as the capabilities and pipeline at Meira, just a couple of minutes. We are a company that was formed not just to address rare inherited diseases with gene therapy, although we do have a pipeline of rare inherited diseases, clinical and preclinical in collaboration with Janssen. We also focus on other diseases which are not inherited, currently in the clinic, Parkinson's and xerostomia. And we focus on noninherited larger eye diseases like AMD, wet and dry; glaucoma and uveitis. One of the platform technologies that we've developed over the last 5 years is to be able to regulate genes using RNA shape to an unprecedented dynamic range. We can regulate genes to a 5,000-fold dynamic range using different small molecules that we have selected and created aptamers to. So we are currently regulating a number of different therapeutic -- potential therapeutic genes in vivo, which we will talk about in more detail later in the year. We have a broad set of capabilities from vectorology all the way through to commercialization, a CMC for commercialization. So we have 4 promoter development platforms. So all of our products have bespoke promoters, which provide potency as well as cell specificity for our products. We have capsid selection and capsid engineering platforms. We optimize all of our viral vectors. Really importantly, we have our own internal manufacturing facility in the U.K., which was certified 3 years -- 3.5 years ago, recertified as GMP last year, quality systems that cover all manufacturing from [ Phase I ] material through to potential commercialization of that material. We recently, last year, completed a plasmid production facility that will be supplying GMP plasmid or plasmid for our GMP process this year. And in addition, we're expanding our manufacturing to have increased flexibility and scalability with another facility, which will be completed this year. So we have really broad manufacturing infrastructure, which has been built in collaboration with the European agencies to really fulfill what they viewed as the gene therapy viral manufacturing facility and process that they would like to see in the future. And very importantly, to support all of that, if I could go into those GMP facilities, we've spent probably more on R&D of a platform process to manufacture AAV than any other area of R&D. So we have a proprietary platform process, which allows us to manufacture AAV that can go into our facilities for IND all the way through potential commercialization of our product. So we've got very broad infrastructure, which allows us, as we move forward, to internally support a large pipeline of different viral vectors in many different indications as well as looking into the future of regulated gene therapy.

Okay. Great. Thanks, Zandy, for that intro. So now we'll move into the Q&A. I have a few here. [Operator Instructions] So I do want to talk about your manufacturing capabilities later as I do think that's a big differentiator. But maybe we can just start on the inherited ocular programs that are partnered with Janssen. So could you talk a little bit about this partnership, sort of the economics and how it's helping to support your R&D efforts for these indications?

Yes. So we've got a very close collaboration with Janssen. And at every level of the collaboration, from clinical, regulatory, CMC, we work as one team with Janssen. For the clinical programs, the lead of which is RPGR, that is a big focus for Janssen as well as us, and they talk about it on their Analyst Days. They have a target for approval in 2023. So for the clinical programs, Janssen pays 100% of all the costs and we receive a 20% flat royalty globally, no tiering. And we are the commercial manufacturers, so we obviously get paid for that. So it's -- from an economic perspective, it's a very positive collaboration for us. And from a collaboration perspective, when we entered into this collaboration, Meira was a company who could manufacture for first-in-man, and we'd initiated a number of Phase I/II clinical programs. But our collaboration with Janssen and working so intimately as a team with them across the board has really turned us into a company that focuses on preparing for BLAs rather than preparing for first-in-man. So we have really changed how we approach not only gene therapy manufacturing, but everything we do through this collaboration to really be thinking about how do we provide to agencies the material to get something approved rather than just get something into man. So that's been a really important transformation for Meira over the last 2 years of our collaboration. And you'll see we have this year an RPGR pivotal trial with Janssen and by the end of the year, an RPE65 pivotal trial as well.

Okay. Great. Well, maybe we can talk about the RPGR program first then. I guess, what are the sort of the remaining steps before the Phase III study takes off? Maybe we can start there.

Yes. So this is a very important study for Janssen as well as us, and we have a lot of input from their teams. This is a study with many centers globally, not just in the U.S., and the logistics of setting up those sites is critical. Remember some of the assessments are unusual or unique assessments, including the maze. And when you have a multicenter global study, those sorts of assessments have to be set up all over the world. Logistically, the team has done an incredible job in preparing sites, in making sure that the assessment measures such as maze are set up and are ready to go and people are trained to do those assessments in multiple global sites. And we do have sites opening currently in the U.S. and starting to screen patients who may be potential patients for enrolling in the study. So we're really focused, both companies, on getting sites up and running, communicating closely with the sites to identify patients and screen patients and make sure we have the patients ready to come into the study. So that's what's happening as we speak.

Okay. That's helpful. And I guess when you look at the clinical endpoints, both for the Phase III study and for what we've seen from the Phase I/II, what is sort of your sense of maybe what matters most in terms of is it the anatomical changes, is it the changes in mean retinal sensitivity or is it more of these functional sort of tests, not only for the regulators, but also for patients and prescribers longer term?

Yes. So for -- 5 years ago -- or 3 years ago, when one spoke to the FDA about RPGR, there was no understanding yet because no one had treated RPGR that you could improve retinal sensitivity. It's a degenerative disease. So when we first started talking 5 years ago about these sorts of diseases, the agency for the structural changes might be an endpoint, the ellipsoid zone. And to see those changes or changes in the progression of the disease by structure, you need to look over a multiyear period of time. So as we and other companies have done clinical studies in RPGR, it's become evident, and our data shows this quite clearly, that you can with gene therapy improve retinal sensitivity as measured by perimetry. And perimetry is clearly an endpoint that is accepted by regulatory agencies, I think, quite broadly as one that is indicative of the benefit of this sort of gene therapy, indicative that that's retinal function. There is another set of endpoints called functional vision. How is retinal function manifest in the patient's ability to do things as a consequence of seeing? The maze provides information about functional vision. Is this important to patients? Yes. So the maze is important to patients and shows that's importance to patients because these young men, the first thing that impacts their life and impacts their independence and makes them worried they won't be able to work is in dim light, they've become blind. So this ability to navigate maze in dimmer and dimmer conditions and improve that actually reflects an important function for these patients at this stage in their disease, and it's one that they talk about all the time. That is augmented by patient-reported outcomes and patient testimonies where you hear from the patient's point of view what's important. With respect to clinical meaningfulness and meaningfulness to the agency, that perimetry data which tells you there's improvement in retinal sensitivity, that data coming out of the machine can be looked at in many different ways. You can look at single points on the grid. You can integrate all the information coming out of the machine from all the points and all the areas in between, and you can get more or less granular ways of analyzing the data. They each have their pluses and minuses, but that's all perimetry data, so it's all retinal sensitivity data. And we can discuss the pros and cons of point-by-point or V30. But I think, in general, retinal sensitivity is considered by global agencies as something that can be the basis of the primary endpoint. And when we step back from the disease and we look at what's actually happening, these patients are degenerating. There's never patients that suddenly get better with RPGR, their disease is progressive and just goes down. So if you're able to show stabilization and even improvement, from the patient's perspective and the physician's perspective, you have had a meaningful, clinically meaningful, a meaningful impact on their lives. So that was a kind of -- it's the truth, right? I mean.

Yes. That's helpful. That's helpful. And I do want to talk about the rest of your wholly owned programs as well. You obviously -- [indiscernible], achromatopsia. I mean we could talk about the XLRP program probably for more than 30 minutes. But maybe for the sake of time, we can move on to the wholly owned programs, maybe starting with xerostomia. And we saw early data at the end of last year that I think looks very encouraging. And obviously, this is an interesting application of gene therapy outside of the eye, given that it is an accessible injection site in the mouth, so it is quite a large patient population. So maybe you could just talk about how you're approaching this market and when we might be seeing additional updates over the course of this year.

Yes. So I think the importance of this therapy and the size of the market is somewhat overlooked. This is a large indication of patients who have been cured of head and neck cancer, who after 2 or more years still have xerostomia, 30% to 40% of patients. And this isn't just a sort of mild irritation. This is an extremely difficult change in their quality of life, in their ability to eat and sleep and speak and they have pain. It's very debilitating. And that's one of the reasons that Dave Pfister, who's the Head of Head and Neck Oncology at Sloan Kettering, was so enthusiastic about this study and this potential therapy is because when he effectively treats his head and cancer patients, they come back annually to make sure the tumor hasn't recurred. But #1 problem for over half of them is now they have xerostomia, and he hears this year after year after year and there's nothing we can do about it. So it's a large indication. It's completely unmet need. It's really debilitating. We have a Phase I study ongoing at Meira. We have -- we're now treating our second cohort. We are hoping and we intend to complete dosing in this study by the end of the year as well as treating additional patients in the study to try and get first signs of efficacy, and we will be going into a Phase II bilateral sham-controlled efficacy study next year. So we will release data from the ongoing study once we've completed dosing. We really don't like releasing data patient-by-patient. We'd like to know that what data we're releasing is meaningful and to be able to discuss that at the time. So by the end of this year, we're on track to complete enrollment of that current study, which will allow us to initiate a Phase II later next year with material manufactured at Meira.

Okay. Okay. Great. And maybe just talk a little bit more about the thought process going into the Phase II. I mean is the decision to push the asset forward, has that been sort of guided by the early responses that we saw at the end of last year? Or are there maybe some other factors?

So the current study is unilateral, and it's very much a safety study. We want to incorporate some potential efficacy bilateral patients in the current study to get a first feel for actual efficacy. Clearly, the response that we saw last year in those initial cohorts was really encouraging, so one of the reasons for trying to treat a few more patients in the current study. The plan to do the Phase II as bilateral sham a couple of doses was the plan. I mean I think that's how one has to move forward with this. And large enough study to be able to, hopefully, have a significant benefit on these patients that you can see to be able to move into a single pivotal.

Okay. That makes sense. And maybe switching gears to Parkinson's, actually. I'd be interested to hear sort of what you guys saw in the AAV-GAD program that was attractive to you when you brought it in-house. And then sort of the steps that are being taken now to move it into the clinic using your own manufactured product.

So as we all know, the focus in Parkinson's is often dopamine, and there are a couple of dopaminergic gene therapy studies that have gone on. There's many cell therapy, growth factor therapy biologic interventions in Parkinson's. This program was developed by 2 of the leaders in early gene therapy in the CNS, who have -- were really thoughtful about their view on how do you treat Parkinson's. And one of the important things when we looked at this program was it does have Phase II sham-controlled data, positive, significant data in a sham-controlled study and no other gene therapy, cell therapy or biologic, has ever shown a difference between sham in any study. All of the study that have been positive as single arms have completely failed to differentiate against sham. So the strength of the data was important, but the mechanism also is important. And we often think about dopamine. But with respect to Parkinson's, the suppression of GABA input to the subthalamic nucleus is really, really important in the control of the motor symptoms of Parkinson's. If you inject GABA into the subthalamic nucleus on the operating table, motor symptoms go away. It's very well known that GABA can suppress the motor symptoms in Parkinson's disease. The issue has been that the GABAergic drugs as small molecules to be developed, you can't get high enough GABAergic effects in the subthalamic nucleus without getting them all over the brain. And yet with gene therapy, you can localize where your GABAergic effect is. You can put that gene making GABA into just the subthalamic nucleus. So the target was very well identified, the mechanism extremely well validated. And as a gene therapy, the surgery is actually very simple because the exact same route of administration that's used to deliver deep brain stimulation wires is used to deliver our gene therapeutic to the subthalamic nucleus. So there's no worries about crossing the brain into the putamen or anything. This is something that surgeons all over the world do on a daily basis. And for all of those reasons, starting with the positive data in Phase II, this was a very -- a compelling program for us. And indeed, we've had big studies done for us on this market globally, on physicians, on the patients, on the payers, and we've got extremely good feedback on our product as the profile is today from all of those stakeholders. So we're really excited about this program.

Okay. Definitely looking forward to seeing those studies start up, I think, in the back half of this year.

Which will be with, again, this new IND opening with material using our process coming from our GMP facility.

That's great. And obviously, you guys have a lot going on in your clinical pipeline, but there's a whole another development area that I think has gone sort of under the radar for a lot of people, which is your riboswitch gene regulation platform. So maybe we could talk about that a little bit. We're obviously excited to see the preclinical data later this year. But I guess just at a high level, how do you see regulatable gene therapy playing into the future of the gene therapy space? And I guess, how are you guys preparing to spearhead this effort?

So that is interesting. And we will be covering a lot in our Analyst Day towards the end of the year, including data in vivo from a number of different potential therapeutic genes. But I think what will be really important is an understanding of how transformative this particular technology is and why the approach we've taken to gene regulation is really differentiated from anything out there today. We hear a lot about regulation, gene regulation, and many of the gene regulation platforms involve small molecule responsive transcription factors. And the regulation of transcription is fine as a tool, but historically, give very low dynamic range. You can switch things on 2-, 3-, 4-, fivefold, maybe. The big problem of using it therapeutically in gene therapy is one of the #1 important optimization that you do to make your vector highly potent and specific and therefore work and therefore safe is using promoters and enhancer elements to drive cell-specific expression at exactly the right level and drive the potency and safety of your drug. So to regulate with a small molecule responsive promoter obliterates all of your highly designed and optimized promoter specificity and regulation. So we chose to regulate using RNA shape. We use that entire promoter platform to optimize. We've got libraries of synthetic promoters, the different tissues and different levels. We use really optimized promoters and other elements to express our gene therapies. Then we insert into our gene a cassette of RNA shape, which has a shape which results in a transcript, which is immediately degraded. So there's none left, no protein, no truncated proteins. It's literally you don't get protein production. We can then add a small molecule, which causes a change in the shape within that cassette, which results in the whole cassette being spliced out, and you get a totally normal message. And then you get protein produced exactly at the same level as it would have been produced if you haven't been regulating it. The consequence of all that -- and we designed these riboswitches in-house base by base. Others have tried to do riboswitches and taken riboswitches from bacteria, which have many, many different riboswitches, and tried to regulate eukaryotic genes with bacterial riboswitches. We didn't do that. We considered the theory of what a riboswitch was, and we built base by base in eukaryotic cells riboswitches for mammalian cells, that worked in mammalian cells. And as a consequence, we now have a whole platform of switches that regulate, not at 2-, 3-, 4-, fivefold dynamic range, but to 5,000-fold dynamic range. And they don't switch on to low levels. They switch on to whatever level your promoter drives. So we have this platform where we have switches that regulate to incredibly high levels, and we can now switch them on because we have those high levels we can select RNA shapes that bind to small molecules that we choose. We don't have to use the molecule that's available or the naturally occurring molecule. We are now able to screen randomized aptamers for small molecules whose only function is to bind our aptamer. And we are now able to put a gene, that therapeutic molecule, in vivo into the liver or into the muscle or other places in an animal. And with a small molecule, we can add a small molecule, and we can see the regulation of that -- the switching on of that gene to exactly the right level. We get tighter regulation of a gene therapy-delivered gene product using our riboswitch than by just delivering a gene therapy or just injecting a biologic once a week. So this is a very, very powerful way of regulating gene therapies, so you can pay for them every time you give a pill; of delivering biologics, so you don't have to make them outside the body; of dosing very accurately biologics; and also of delivering whole classes of drugs that you can't currently use those drugs. One of those is biologics in the CNS. You can put the gene for a biologic, an antibody to amyloid, should you wish to do such a thing, into the CNS, switch it on with a small molecule that crosses the blood-brain barrier. You don't have to worry about the 99.9% of antibody that doesn't cross the blood-brain barrier. So that's a powerful use of that gene regulation technology. And even more powerful potentially is that there are many, many drugs, which are peptides and hormones, that are too short-lived to actually become drugs. For 20, 30 years, as an example, we, as a field, have been working on combinations of [ dot ] peptides for metabolic disease, for diabetes. Can we deliver them in combination? No. We haven't been able to make them all long acting. We haven't been able to dose them but you can put the genes for those into the body and switch them on with a small molecule. Things like insulin. We look at, can we have oral insulin with our gene regulation? Yes, you can. And so there's -- it hugely expands what you can do with gene therapy as well as really allowing you to look at things that aren't particularly good drugs today and extracting the therapeutic benefit from them and allowing them to be drugs in metabolic syndrome and all of those diseases, which are huge indications and really hard to address today.

Very interesting. Very interesting science. And the sort of 2-part mechanism, it separates the PK/PD of the small molecule from the therapeutic effects, so that's an interesting application. And it seems like there's a lot of different areas that could be applied.

Yes.

But -- so definitely looking forward to seeing that data later this year. I've got a bunch more questions here, but I think we're out of time. So I think, unfortunately, we'll have to end it there. But I really want to thank you for your time and participating in the conference. This was a really great session. Thanks, Zandy.

Well, thank you for inviting us.

Okay. Great. Thanks a lot. Take care.

You too. Bye.

Bye.