MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Thank you very much for inviting me to speak at the conference today. I'm going to give a slightly different talk than I often do to give an overview of the company and really talk about how we're focusing Meira on our late-stage clinical pipeline, which is 2 late-stage programs, as well as probably the most exciting use of our in vivo delivery system, which we've developed from our riboswitch technology. And we've been doing this over the last 6 to 9 months, and I'm really excited to have the opportunity to talk to you about the way we've streamlined the company today. So Meira was formed as a genetic medicines company, but really to focus to use DNA as a new pharmaceutical modality to be able to deliver any therapeutic peptide or hormone or biologic drug to diseases that can't necessarily be addressed by other pharmaceutical modalities. But in having that idea and in building that technology, we needed to set up an entire company that allowed us to support the delivery of the DNA and the delivery of those peptide hormones and antibodies. So we initiated with a pipeline. Initially, we focus not on inherited diseases, which a lot of gene therapy does, but we focused on small doses locally delivered in areas that were immune suppressed. And that took us into the eye, where we had a portfolio of inherited retinal diseases, which we partnered with Johnson & Johnson. In addition, the salivary gland, where we target xerostomia that occurs after radiation treatment, the head and neck cancer; and also local delivery in the brain, where we actually have a disease-modifying effect on Parkinson's patients who no longer respond adequately to dopamine. In addition, we built manufacturing initially one site now, end-to-end manufacturing, which is some of the leading manufacturing capabilities for viral vectors in the world. Every one of our vectors is optimized from capsid, promoter, translation. We do that using AI as well as human testing. And I'll move on to our riboswitch technology which we've now implemented for in vivo delivery of fast acting agonist peptides and hormones. So first of all, our pipeline. As I mentioned, we were indication agnostic. We chose small doses locally delivered, and that allowed us to manufacture at low cost the viral vector required. And in fact, as a consequence of this, we currently have 3 of our programs are in late stage and with the potential filings in 2025, '26, '27, large patient populations, unmet need, each has strong data and small doses means low cost of goods. Our first program is one of the partnered programs with Johnson & Johnson, which we sold back to them at the end of last year. It's currently in Phase III reading out later this year. We sold them the program, and we entered into a commercial manufacturing agreement with them, so that we will make money on the launch, we received $115 million so far, and there's about $285 million milestones, one-off milestones on approval in Europe and U.S. for that program. But we are no longer the owner of this program. And in fact, we have separated out our entire ophthalmology pipeline, infrastructure and capabilities into a separate entity, which we are discussing with potential partners. Our second program, radiation induced xerostomia, I'll talk about it in a moment; and Parkinson's, another large indication. So in the area of clinical, we're really focusing on these 2 areas. But the first is aquaporin. I will just bring you to the data. We presented extremely strong data 6 weeks ago or so at the AAOM that was incredibly well received. We showed completely unprecedented improvements in PROs, so the measure of xerostomia as well as saliva, and that's really supported the enrollment in an ongoing Phase II, which we've designed with all the criteria that the FDA discussed with us that they wanted to see for a Phase III approvable study. In addition, because we manufacture this material ourselves, and we have very strong regulatory interactions globally, the FDA approached us 9 months after we filed the IND and told us that if we use one particular assay, which we are doing and can doing, our manufactured material would allow us to consider this a pivotal study, which is the reason that there is a potential filing for this indication in 2026. This is a really interesting disease in that it is a large population for a genetic medicine. There are of target patients, 170,000 in this country with 15,000 new patients a year. These are patients who have been cured of head and neck cancer. They have all suffered, every one treated with radiation for head and neck cancer actually get xerostomia. They can't produce saliva. However, about 30% or 40% of those patients never recover the ability to produce saliva and have long-term xerostomia, which is a disaster for their way of life in a way that I haven't really understood until we started talking to the physicians and patients. They cannot exercise because they can't breathe faster to walk fast. They can't eat. They have to sit every few hours. These are the patients for whom no drugs work, and we were able to not only fully cure some of those patients, but we had the biggest impact ever seen on saliva production as well as xerostomia symptoms. We had -- this is a very low cost of goods. The patients are all sitting with health insurance, seeing their physicians every year. And this is a market that we can readily address internally. It's not just radiation induced xerostomia, but this exact same vector addresses. This is a pipeline in a product. Sjogren syndrome, we are ready to open an IND in Sjogren's, which in preclinical models has been shown to have very similar effects on dry mouth to what we've seen in radiation induced xerostomia models. In addition, many of you will be aware that the new prostate cancer drugs have a very severe side effect, which is, in fact, xerostomia. So while we look at radiation induced xerostomia from head and neck cancer, there's another label-expanding Phase III we could do in these newly xerostomic prostate cancer patients, a huge and expanding market. And finally, we are currently doing IND-enabling studies to use treatment before radiation and prevent xerostomia in all patients that are treated. So you can appreciate this one viral vector currently in a pivotal study, has a very large market, even larger than the large market for radiation induced xerostomia. Our second late-stage program is in Parkinson's. And here, we actually circumvent the issues caused by dopamine lack and dopamine treatment. So all patients with Parkinson's actually stop responding to dopamine. They can no longer control their movement with sufficiently high levels of dopamine that don't give them side effects. There is a very well-validated mechanism for circumventing this hyperactivation of the subthalamic nucleus, which occurs in these patients. And that is by delivering the Rhopressa of activity GABA to the subthalamic nucleus, very similar to what's done in deep brain stimulation, which targets the same spot in the brain. We have the only positive sham-controlled Phase II study ever achieved in Parkinson's disease with gene or cell therapy or growth factor therapy, which shows by delivering the GABA enzyme, the enzyme that makes a repressive neurotransmitter GABA specifically to this tiny locus in the brain, we're able to return motor function to these patients. In addition, we're able to show that through FTG PET, we have actually called a recircuitry of the brain, so disease modifying. So we've curemented that need for dopamine in these patients with very strong motor symptom data. And this is -- we've manufactured this material to commercial grade in our own facilities, and we are preparing for Phase III and again, in discussions with partners to move this forward in a global Phase III program next year. So I have mentioned our pipeline and the focus on those 2 programs, xerostomia, by ourselves; Parkinson's, hopefully, in collaboration with a larger company to globally market that to neurologists. And the next silo that we have, I'll quickly mention is our manufacturing. And this is something I'm very proud of Meira. We initially -- when we first started the company 8 years ago, 9 years ago now, we built our own manufacturing facility because there was not capacity in the industry. And we worked with regulatory agencies to build the first of our 2 GMP facilities. We importantly made this state-of-the-art single-use facility, single-use capabilities and highly flexible and scalable. What that means is every room has its own air handling that you can move in a 100-liter bioreactor, move it out the next day into the same suite, scale up 20-fold with a 2,000-liter bioreactor. That's what we mean by scalable and flexible, so that we start our INDs with commercial-ready process in commercial-ready facilities, which has a huge regulatory and time implication. Over the last 8 years, it's been important for us to bring in plasmid production, not only for cost of goods, but also for speed of manufacturing. As I mentioned earlier, we're the commercial manufacturer for J&J's first gene therapy for retinitis pigmentosa. We had to build our own QC facility because the current CDMOs are unable to release material in a timely fashion for an effective launch. We have our own fill and finish. We have a specials license, which I won't talk about now. And really importantly, we spent 8 years developing a proprietary manufacturing process which is best-in-class for full ratio and yield. And we've done this not for one vector, but for more than 20 different viral vectors from pre-GMP, and we have made over 50 batches of GMP material successfully. This has resulted in really strong regulatory relationships throughout the world. I mentioned that with respect to our xerostomia program, also feeding into our Parkinson's program. But why do we care about this, right? Why do we care that we have end-to-end manufacturing? Number one, speed. So we can probably speed the clinical development from IND to BLA for any program that we manufacture by 2 to 3 years with a significant reduction in development time lines to beat competition and increase the ROI on any product that we manufacture and develop. Cost of goods with the same process, if you were to do the same process, manufacturing in-house, 50% less than if we were to manufacture outside based on plasmid and QC, which is the highest cost of outside manufacturing, that doesn't include probably one log improvement in cost of goods from our very high-yield process. And in addition to that, there's a valuation floor to the company. We've recently been audited by a company called Dark course, who came with a very positive report on all of our infrastructure and all of our people. They went to every site over a couple of weeks, interviewed 120 people, and they came back and thanked us for allowing them to see our infrastructure and processes and said that they hadn't seen anywhere in the world, such comprehensive or high-quality manufacturing. So this included CDMOs, pharma companies and biotech companies, and you can appreciate that some CDMOs, for example, have been acquired for many hundreds of millions over the last 6 to 9 months, and we know that our infrastructure, our process and the number of batches we've done exceeds what some of those have actually achieved before they were sold. Next-generation vector optimization. One has to do this. Every aspect of your genetic medicine has to be optimized to really maximize the outcome for patients. However, there is another really important aspect to this optimization. We focus on everything, capsids, promoters, vectorization technology, which increased expression using the same promoters by up to tenfold. We have data over the last 9 years that can -- we can give to our AI models and generate new promoters for specific cells. We test everything in human organoids. So we don't just make technology that works in man. And when we look at the improvements in potency we get, it's not trivial. We can get 3 or more logs improvement in the potency on a vector-per-vector basis. Now that's important for patients that these drugs work, but it's got really big implications for cost of goods. A 3-log improvement in potency means a 3-log lower dose, which means 0.1% cost of goods. Very important, when I move to the next topic, which is treating some of the largest diseases that are out there, in fact, one of the most talked about, thought about and focused on diseases, indications at the moment, which is metabolic disease, which turns out to be the problem that our gene control system exquisitely solves. So we've developed a way of controlling the production of RNA from any DNA templet, whether it's delivered as naked DNA, whether it's crisped into a cell, whether it's delivered by AAV or lenti, we can precisely control the RNA and then protein that's produced by that template. We've done this for antibodies, peptides, hormones across the board and in multiple cell types, we've shown in vivo efficacy. But the place where this is having the most obvious, but nevertheless, surprising impact is when we deliver short-acting agonist in a physiological time frame. And that is in metabolic disease where we provide a solution to efficacy using gut peptides, for muscle loss, delivering myokines for fat regain, delivering -- like leptin. And because we in vivo deliver, i.e., the body makes the short-acting peptides in the physiological form, we don't have the manufacturing barrier to entry that currently exists for both oral as well as injectable peptides. In addition, cell therapy is another area where agonist receptors when delivered in CAR T, the CAR, if you control that CAR and deliver it in a pulsatile fashion, it massively, not trivially, but massively improves the efficacy of those CAR cells -- CAR T cells. So what is our switch? Essentially put a DNA template into the body, it can be in cells, it can be any delivery mechanism. And into that DNA template, we put a cassette, which allows us precise control of RNA production from that DNA template when you deliver a small molecule. I'm not going into the mechanism now, but essentially, one small molecule delivered allows the splicing out of this controlled cassette, a perfect messenger RNA. Because of splicing event occurred, this is irreversible. So one small molecule makes one message. With no small molecule, that entire message is degraded in all cells by non-cell mediated -- a ubiquitous process that gets rid of, in some cases, 30% of the transcripts in any cell. So we do not squelch it, universal process. This slide, I'm just going to spend a minute on to show you how incredibly precise this is. We set out to make a switch, turn RNA production on or off using a small molecule that's oral. And we can screen -- we've got many small molecules that we screen for. And this was one of our first in vivo experiments. What I'm showing you here is the expression of a marker gene luciferase. This top blue line is a luciferase construct delivered to the liver that is unregulated. A normal luciferase gene that [indiscernible] is exactly the same gene, but it's got our control cassette in it. And you can see you add small molecule at 10 -- a dose of 10 mg per kg, you get that much produced. 30 that much produce. You get a really clear dose response of luciferase expression in the liver. Peak comes on and off. When you look at the individual mice, making up this blue line here, you see a spread of expression, just like you normally see in hemophilia, right, about half a log. However, if you look at the controlled expression, every mouse expressive virtually the same amount of the luciferase based on the dose of the small molecule. So we're super pleased about this, really precise control, real accuracy in dose response. Then we put the exact same construct into muscle. And here, you can see constitutively active. It's going along very similar to what you see in the liver. And then -- we gave the mice exactly the same small molecules, same protocol, 10, 30, and you see the dose response, but the shape of the curve was different. So we asked the CRO, did you give them an extra dose? Why is the curve different? They went no, it's exactly the same. So we went back and we looked at the bio distribution -- tissue by distribution of this particular small molecule in a mouse following a single oral dose. The liver here in blue, the molecule goes in and out, a little peak exactly like we see in our luciferase expression. However, the muscle, we hadn't previously realized, it goes in, it accumulates, and then it goes out, which is precisely reflected in the pattern of expression of the gene in the muscle. Why I show you this slide is to really illustrate that we haven't produced a switch. We've produced an incredibly sensitive sensor for small molecules that's so sensitive, it can actually distinguish the tissue by distribution differences between liver and muscle following one oral dose in a mouse. And this precision and sensitivity allows us to deliver very clear and precise doses of any biologic therapeutic encoded by DNA. We've screened for small molecules. We have multiple molecules with different PK. I'm not going to go into that. And here are some of the functions that we have been able to show use in these control systems, vectorized antibody, CNH expression using blood-brain barrick, penetrant small molecules, same for the eye. We can put genes for AMD in the eye, all of these different activities. But the 2 places where we really are completely differentiated from anything the pharma industry is able to do to date, is the delivery of agonist receptors and agonist peptides. These are some of the library of drugs that we have regulated and shown efficacy in vivo. Every pharma company, say for antibody, cell therapy, basically CAR-T work 4x better, than they do with an unregulated the approved CAR T, hormones and peptides and nucleases. First sign that things work better when you show them in a physiological way, came when we looked at CAR-T, and I'll go through this super fast. So [indiscernible] approved with anti-CD19, constitutive. This is what's approved. We knock in our control system. And what you can see here is you give increasing small molecule, you activate an increasing amount of CAR on the surface to slightly higher than constitutive, that's shown in this graph as well. Constitutive dose response of the CAR on the surface. You remove the small molecule, you activate, you remove some molecule, but the CAR cycles of the surface. It's no longer expressed. When we then go and look at CAR expression, low levels of CAR expression actually when we look at cytotoxicity, that's shown here, you get stronger cytotoxicity than when you had the constituently active CAR. And we're like, "Oh, really?" Low receptor density is supposed to be more active, but that's interesting, likewise here, same. Lower level of CAR than in constitutive and it works better. So we went to primary T cells. And when these are controlled T cells, totally naive T cells that will make T memory cells. These -- this is a profile of the approved anti-CD19 where it's unusual and they're more mature and not as functional. And these are ribo CAR T cells, where all we're doing is rather than having constitutive receptor, we are actually turning it on and off with a small molecule, okay? They are identical to naive T cells. Likewise, they're not exhausted. They don't have increased exhaustion markers. This is the approved CD19 -- anti-CD19 CAR-T. When you look at function, that's the approved CAR-T. This is a dose response in function, 4x more cytotoxic on a cell per cell basis, when you look at proliferation, approved anti-CD19 proliferation. So what we've actually done is by physiologically controlling CAR, we get highly functional, physiological CAR-T. When you put them into a tumor model, this is the approved model. Notice 2E6 cells don't cure the tumor, 66 cells do when you have the ribo CAR. So this is just switched on once-a-day pill, no small molecule, you don't cure the tumor. Small molecule, daily, you cure the tumor with only 2E6 cells. We've made super potent, totally normal CAR T cells where you don't need CAR to manufacture where you put them into the body. And once a small molecule is not there, those are no longer CAR-T. They just sit there as memory cells, really powerful. Where this we think is having the greatest impact is in peptides and hormones. So we have regulated this is dose for the many peptides -- EPO, growth hormone, PTH, insulin, the incretins. So we thought to ourselves, everyone knows GLP-1 is works. It's one of the biggest drugs out there. How do you make it better? The whole industry is looking at adding new gut peptides. So we thought it's super easy for us to just put in a construct where we add GLP-1-GIP glucagon, and we did that. And we made a whole library of triple double combination peptides and we started looking at them. And then what we did is the following experiment. We compared the activity, the efficacy of constantly active peptides to gut peptides that were physiologically activated with all small molecules. So it's like comparing long-acting synthetic peptides that may be injected once a week, so that driving receptor activity all the time to physiological short-acting peptides delivered as the body deliver them, but using an oral pill. Now this is a bit of a complicated slide, but this line here, the dark blue line control is a DIO mouth. This light blue line is that mouse or that group of mice, treated with GLP-1-GIP. And as you can see, there's a big improvement in their weight. And this is essentially the GLP-1-GIP combination that exists in a number of drugs today. And we were pleased we made that. And then what we did is the same combination, GLP-1-GIP, we put the construct in and we controlled it. And we gave these mice an oral drug once a day and look what happens. Bam, they lose weight faster until lean. This is a lean [ mouse ], weight more than the constantly active GLP-1-GIP. Here is just weight loss. This is using the once a day. Why is this a zigzag line? It was actually a mistake, but it was really informative. It's a zigzag line because these mice were not dosed on the weekend. Our scientists left on Friday and didn't come back until later on Monday morning. So what you can see is the dose that we're giving is just sufficient to make them lose weight, but you don't give that dose and guess what, they start eating Saturday morning. This was a long weekend, so they didn't get it for 5 days. Interestingly, we always look at postprandial glucose. These are the 2 controls. This is persistently activating the GLP-1-GIP receptors through constitutive activation and you can see control but much better postprandial control, super important for microvasculature in diabetes. Sugar is toxic and you want it in the blood for as little time as possible. So we made a GLP-1-GIP glucagon. You add glucagon, you'll lose loads more weight. And indeed, that's what we saw. DIO mouth here in dark blue, this is the controlled construct with no small molecule, low dose of small molecule, you're starting to lose weight, mid-dose or small molecule, you're losing a good bit of weight. But look what happens when you use the right dose of small molecule. By the way, they were dosed on the weekend, bam, straight down. Here, you can see the weight loss graph. And this is a very potent GLP-GIP-1 (sic) [ GLP-1-GIP ] glucagon. But when you speak to physicians, they are concerned that glucagon because it causes gluconeogenesis is going to increase the risk of diabetes. So 16 weeks after daily treatment, we looked at what happens in postprandial glucose control. So these are the controls, very bad at controlling. This dotted line is what happens when you have persistent GLP-1-GIP glucagon for those 16 weeks. Disastrous glucose control, right? This is what happens when you give GLP-1-GIP glucagon with a daily oral dose in the short-acting physiological form. Low dose, you get some control. Look at the dose that causes weight loss. Bam, really, really good. Postprandial glucose control in the presence of glucagon 16 weeks after treatment. So by delivering the short-acting agonist in a physiological way, we do 2 things. Number one, it turns out that in systems that are homeostatic and responsive, like metabolic systems are. Things short-acting like GLP-1, for a good reason. They need to turn off to be responsive again. If they're persistently on, are the systems try and switch them off, you have to give higher and higher doses to keep getting efficacy. So it seems that in these systems, you need short-acting physiological time frames in order to get maximum efficacy. Number 2 is by physiologically delivering even things like glucagon, we're able to get the massive weight loss and circumvent the tolerability toxicity that you see with long-acting glucagon. In addition to efficacy, which is really remarkable, we've also drive -- efficacy and tolerability other than using myostatin and activin inhibitors to block the inhibition of muscle down regulation, what we have done is we have taken the actual mediators of muscle strength of fat metabolism of bone strength and of cognitive flexibility and appetite suppression that come from the muscle, that called myokines. This is what activin inhibitors and myostatin work on, and we can deliver physiological myokinds, which have impacts across the dynemic exercise. Exercise a muscle strength are absolutely essential in aging, as well as for frailty, muscle and exercise are the one thing that can help cognitive flexibility, Alzheimer's and Parkinson's as you get old. So the lot of muscle due to starvation is not only essentially important in frailty. It's also important in all the cognitive issues that occur in aging. Fat regain, we can deliver natural leptin. We can completely prevent the regaining of fat. And by the way, because we're driving the production of these peptides in vivo with an oral small molecule, we totally circumvent the need for massive production of peptides outside the body. So what I've shown you today is a company with late-stage clinical programs, the infrastructure from manufacturing to vector development to support a pipeline of programs, though addressing some of the biggest problems in one of the biggest indications out there, small molecules going into the clinic at the end of this year, and the vectors address muscle loss, efficacy and tolerability. And when I say efficacy, massive efficacy improvements in metabolic disease and other responsive systems. Those will be going into the clinic sometime next year. Thank you very much for your attention.