MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Good morning, everyone. My name is Gena Wang. I'm SMID cap biotech analyst at Barclays. Welcome to our second virtual global health care conference. First, I wish everyone stay healthy, and I would like to thank all the participants, investors, companies and especially our event team and the corporate access team who made this virtual health care conference possible. With that, I would like to introduce our next presenter, Zandy Forbes, Chief Executive Officer, from MeiraGTx. Zandy, I hand over to you.

Thank you, Gena, and thank you for inviting us to present at your conference. I'm going to give a quick overview of the company, and then Gena and I are going to go into a Q&A. So I will just have one slide. Can you see that slide?

Yes.

Okay. Forward-looking statements, which you're familiar with, on this slide. And this is an overview of Meira in a one slide format as I introduce you to the company, for those who don't know about us. We're a gene therapy company started in 2015. And one of the things to note about the strategy that Meira was set up around is to develop a new pharmaceutical modality from gene therapy, to design cost-effective treatments for a broad range of serious disorders. So we didn't initially focus on a particular tissue interest or a particular disease area exclusively. Our initial pipeline was focused on areas where there was human proof of concept, there were small doses delivered, and there was some immune protection. And we brought these clinical programs together. We currently have 6 ongoing clinical programs, a group of programs in inherited retinal disease, a program in 2 studies in xerostomia caused by radiation treatment for head and neck cancer and a clinical program in Parkinson's disease. And in each one of those areas, we've got preclinical programs coming forward. So in order to support our clinical pipeline as well as our development of completely new ways of using gene therapy, in our case, a platform for gene regulation. We, from the very beginning of the company, focused a lot on manufacturing. So we built a manufacturing facility that was GMP-certified in just over 3 years ago. And that was built in collaboration with the regulatory agencies to really address their view of what they wanted to see in a viral vector manufacturing facility. We have that facility. It is up and running, has been for 3 years. It was reinspected and recertified last year, and we have quality systems and facility that can support Phase I all the way through commercialization. Importantly, we built the facility, this particular facility to be both flexible so we could supply multiple clinical programs and very scalable, so this can also support all of the programs that we have and more actually for commercial scale. And very importantly, at the same time, we focused our -- we have a large research team. in fact, the largest research team in the company that has developed a proprietary platform process that is used to manufacture multiple different viral vectors. It has been tested and developed with multiple capsids and multiple genomes, and that process development group for every new vector optimizes our platform process and tech transfers it into our facility. We've recently, last year, built a plasmid facility to bring plasmid production, GMP plasma production in-house, the upstream materials, and we're completing a second flexible, scalable viral vector facility by the end of this year, which will have larger-scale fill and finish as well as bringing in-house the QC that is required for the release of these materials, not just for the clinic, but also for commercial and material, so the QC to support BLA. So we've really got a broad infrastructure in manufacturing and process for producing AAV from Phase I all the way through to potential commercial. And we also have built a vectorology platform where we have 3 different platforms for promoter, making synthetic promoters, short, strong promoters, tissue-specific promoters because promoters really help you get tissue specificity as well as the correct levels in cells to drive the potency of your drug. We have a broad tool kit of vectorology that looks at everything from a poly A to the introns, to the ITRs and plasmid backbones to most effectively go into production for our clinical material. So from an infrastructure perspective, the company has clinical programs. It has really broad and detailed vectorology that goes into all of our new programs and manufacturing that can support all of that. And this was all built alongside the development of a forward-looking technology, which allows us to regulate gene therapies, transgenes using small molecules and riboswitches. This is very important because using RNA shape and a riboswitch to regulate genes, allows you to take advantage of all the things that are important about promoters and not lose that by regulating with a small molecule directed towards a promoter. We have designed this riboswitch platform entirely in-house. We have been able to regulate many genes in the context of many cell types and tissues. Now we can regulate in vivo with multiple small molecules that we create optimers to. We are able to regulate at a high dynamic range, unprecedented dynamic range, up to 5,000-fold or more in cells and very strong correlation between what we've seen in vitro in cells and the PK that we're seeing when we regulate in vivo. So that's an overview of the company from clinical programs to our really transformative platform. And I think with that, maybe Gena will go into some -- a bit more detail about some of the programs we had positive data in over the last 12 months. But...

Sounds good, sounds good.

Okay. Very good. I'll stop sharing my screen so you can see me. There we go.

Thank you. So maybe I will start with the clinical program that we already hear some data. I understand some of these partner programs, so you have some limitation how much you can save. But regardless, I wanted to ask. So just...

Of course.

Yes. First program is the X-linked RP. You did show a pretty good data. So wondering the impact, we did see some level of the improvement. So wanted to ask you in terms of the mean retinal sensitivity that you show, the improvement, how should we interpret the effect size? And then what threshold will be considered as a clinical meaningful?

That's a very interesting question, Gena, and I could spend many hours talking about that. There is -- and we do have a collaboration, a very close collaboration with Janssen on all of our IRD programs. And it provides us both the financial support but also a lot of regulatory, clinical support to expedite the development of this program. This particular program and the IRD programs are very important to Janssen, and you'll see that, in fact, in their public releases and their comments. So as a group, we've had a lot of regulatory interactions around what end points can be used in these sorts of diseases and specifically RPGR. And in contrast to maybe 4 years ago, 5 years ago, where there was a thought that structural changes in the eye, the maintenance of retina structure, could be an end point. We and other companies and regulatory agencies around the world are looking at perimetry. So retinal sensitivity as a measure that can show a statistical benefit, but also indicate that there's a real clinical and meaningful benefit to these patients. So what is the threshold for that? There are many ways of looking at perimetry, that is the mean sensitivity. So when you look at all the perimetry dots across the field, what's the average improvement? You can look at individual dots. What is the maximum threshold improvement in individual dot? Or you can do a very detailed analysis and integrate all the data and have a volumetric measure. There is no consensus view on what threshold for each of those different things, what actual decibel number correlates with clinical meaningfulness in this population. So we -- at the moment, we -- I can't tell you a particular number is clinically meaningful. However, from the perspective of the physician, we've had a lot of interactions with physicians globally, and a positive change in a degenerative disease that is durable over time, whether it's the 7 decibels, 5 points or an increment in the decibels in a mean or the improvement of decibel-steradian, that sort of improvement because over time, you see degeneration. If you see a stabilization or an improvement in retinal sensitivity, that is considered something that is highly likely to have a clinically meaningful impact on those patients' lives.

Okay, okay. I think that makes sense and certainly this evolving field. So maybe also, when should we expect the data, from the data from this program? And what is your plan for registrational trial?

So the Phase I/II study, we've released the data from the dose escalation portion of that study. And within that data, we were able to show within cohorts and within populations treated with low and intermediate dose, significant benefit between treated eyes and untreated eyes. When the study was expanded, we had a discussion with the FDA, and we entered into an expansion phase where we randomized between 2 doses, low and intermediate, and an untreated arm. We did that because the FDA said that to have a BLA with 1 registration study, which both eyes would be treated. The Phase I, only 1 eye was treated. They wanted to see a randomized data and data against the control. So that part of the Phase I/II was enrolled at the first quarter of last year, and the patients were treated at 2 different doses, and there is deferred patients for 6 months. So the full data from that study will not be released until we're well into the Phase III study that is currently being prepared, I will call it. So that data will support our BLA, but it won't be -- the database won't be locked and released until after the pivotal has at least started enrolling. So it's not a gating factor. And I can't tell you that exact date right now.

Okay. That's fair. So maybe switching gear to the Parkinson's disease. So what is the now expected IND submission time? Is it first half this year? So what are the last steps of the preparation? And regarding the Phase III trial design, if you can give a little bit more color there. And obviously that also from FDA as well.

Yes. So this study, we are opening a new IND. We have a new manufacturing process. The limiting factor on the time of that filing of that IND is the QC tail for the release of the GMP material, which is manufactured. So we are working diligently with CROs to bring forward that time frame as much as possible. There is a big capacity constraint in CROs right now with this sort of QC because of the COVID vaccines that they're releasing. But we are nevertheless -- that is the limiting -- the critical path is CRO/QC to release the material. This has highlighted to us something we were doing already from a cost perspective, which is we are bringing in-house into our new facility and currently, our current facility, we are bringing as much QC as possible so that we will not rely on CROs for release of material. That has a huge time impact but also a huge cost impact. So in our facility, that's going to be completed this year. There will be QC labs that will support the QC to release material. So that's the answer to that question.

Okay. So for the QC part, do you also need FDA inspection to sign off?

On QC, no. CROs, -- oh. So the QC is out [indiscernible] GMP .

The only thing -- yes.

Okay. So for every assay, it needs to be appropriately validated, and the FDA looks at the assay and the validation, and it has to be a proper GMP assay, yes. And that is done by a CRO, and then they test your material or we're bringing a lot of that in-house. So it's not done in the GMP facility per se for manufacturing, but we have labs outside, and the assays are qualified, validated for use for GMP release. Is that an answer to your question? So you have to develop each of those assays and show the agency that each of those assays is fully qualified and robustly shows reproducibly what you're saying it's going to show. And one of the most important assays actually, which we do already in-house, and we have a group that works on this is the potency assay. So taking specific vectors that may have a specific promoter and moving potency assays in vitro, and this is something the FDA is very focused on. In order to release the commercial material, you need a reliable potency assay that gives reproducible data on every one of your batches. So we -- that was one of the things we've always been doing in-house, but it's a very, very important part of development of the QC for any gene therapy to be released for clinic or eventually to support a BLA and commercial.

Okay. So Zandy, can you give a little bit more color, the potency assay exactly, how you can do that or the part of Parkinson's?

So potency assays, and you'll see this, the discussion with AveXis and others, potency assays for many inherited retinal diseases in the past have been a rescue of a null animal model. So for RPE65, for example, the current potency assay is an RPE-specific promoter, is inject your product, your GMP product into the eyes of mice, wait a month and then test the response on an ERG. So that's where one starts off in potency assays. So as you develop potency assays, taking them from in animals to in vitro, it's a way of how do you transfer something that works in vitro in specific cells to a cell line or a cell type that will express that gene, will show the function of that protein and will do it reproducibly in a way that you can get a really clear statistical response. So it's very specific for every different gene therapy and every different gene and different promoter. So you need -- so it's quite -- it's almost like a platform for developing them, and we have an organoid platform, iPSC cells as well as many cell lines, all of which are used in developing all these different potency assays for every single product.

Okay, okay. And then for Parkinson's, you need to -- now it need to clear the potency assay? That's the one [indiscernible].

No. We're doing -- the potency assay is in-house. For Parkinson's, we have, at the moment, CROs completing multiple of our release assays.

I see. Okay.

Okay, that we are bringing in-house. So potency assays for all our products, we do ourselves.

Okay, okay. That makes sense. Okay. And then for the Phase III trial design for Parkinson's program in...

We haven't discussed that. When we file the IND, we will go immediately to the regulatory agencies, request a Type C meeting, and then we'll discuss the size and design of studies. We obviously have our view and expectation of what we would like to present, but we're going to discuss that with the agencies to have support from our old studies with this new material as we move forward into larger BLA supporting studies. But I'm not going to tell you what that design is yet because we need to have that discussion with the agencies.

Okay. That makes sense. In the last few minutes, I wanted to say for your new riboswitch gene regulation platform. So I'm wondering like if you can walk us through how do you achieve tissue-specific property?

Right. So our riboswitch platform is a platform because what a riboswitches is a cassette of RNA-DNA sequence that is read on transcription that we put into any gene therapy, right? So it's in the transgene and it doesn't affect the promoter, and it doesn't affect the capsid. So we use all of that vectorology tool kit that we've developed for unregulated genes to develop vectors that are expressed at the right level in the right tissues. That's how we achieve the tissue specificity. We then put into that specifically promoter-regulated gene, the cassette, which then allows you to switch that gene on or off with a small molecule. So we maintain the promoter control and specificity, and then we can very specifically only switch the gene on when the small molecule is present in the right place at the right time.

Okay. So basically, it's a rely on the promoter to...

For the specificity, yes. For the switching, it relies on the RNA shape. So they're separate.

Okay. So for RNA shape, how do you also make a specific thing, the RNA shape you put, the secondary or tertiary structure, less?

So we have, for the first time, we have a platform switches that switch on to a very high level compared to the off state. So riboswitches in life have a low dynamic range. You can switch them on to double the off level, okay? We can switch something on to 5,000 times the off level. And as a consequence of that, we have been able to make and screen thousands of RNA-binding sequences in our switch, in cells and find small molecules that specifically bind to our switches. We can then mutate the switch sequence of binds a small molecule and make it more and more specific to that molecule and more and more potent. So we design our cassette, and then the small molecule binding part of that cassette, we have made bespoke optimers, RNA-binding sequences to small molecules, for specific small molecules. So we can use a small molecule, for example, that crosses the blood-brain barrier to activate things in the blood-brain barrier. We can use small molecules that accumulate in muscle to activate things in muscle or systemic small molecules. So we design our switch to match the small molecule, and the PK of that small molecule is something that we can choose that's appropriate for the indication that we're going to treat with that particular gene.

Okay. And then, Zandy, can you share some color on the preclinical? What are the top targets that you see very promising data? And then what is your plan for this technology going forward?

So there are broad buckets of what this allows you to do. By being able to switch genes on with a pill, you can now dose antibodies or biologics just with an oral small molecule. So antibodies like a PCSK9 antibody, VEGFR2 antibody, even an anti-cytokine antibody, all of those antibodies could be dosed with a small molecule and just switch on exactly when you want them and exactly the right time. They could be dosed in the brain, if you were a large company like Lilly had an anti-amyloid antibody. So you can -- we have regulated, made different antibodies, and we can regulate antibodies to therapeutic levels, right, that don't require weekly, biweekly, monthly injections and give you a really good dosing and efficacy profile. The other area that is very interesting is really quick-acting molecules that you can't make into drugs easily because they disappear too quickly. Things, particularly that might be involved in metabolic disease, look at the gut peptides, not only GLP-1 but PYY and those peptides that really need to be infused in order to have their benefit. And we have an entire portfolio of hormones, peptides and metabolic disease drugs that you can very readily uses gene therapy or combinations of them that are active with a small molecule, and that allows you to dose appropriately with these short-acting molecules. So there's a wide range of potential here. It completely opens up gene therapy to be a delivery device for many biologic drugs. But things like peptides and hormones as well as antibodies are likely to be the first things that you'll see regulated by us in having a therapeutic level of expression and impact in disease models.

Great. Well, thank you very much, Zandy. We're running out of time, but a very productive discussion, and we look forward to a great 2021.

Thank you so much for inviting us too. Great to speak to you.

Okay. Bye-bye.

Goodbye.