MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Good afternoon, everyone. My name is Gena Wang. I'm SMID cap biotech analyst at the Barclays. Welcome to our Fifth Gene Editing & Gene Therapy Summit. It is my great pleasure to introduce our next speaker, Zandy Forbes, President and Chief Executive Officer from MeiraGTx. Zandy, I'll hand over to you.

Thank you, Gena. Thanks for inviting us to speak at your conference. And I think the format is today, I'm going to do a quick overview of the company, 5, 10 minutes. And then we're going to have questions and answers. Is that correct?

Yes, that's correct.

Perfect. So for that quick summary of the company, I'm going to share a slide, just 1 slide, which sort of shows the whole company laid out as a whole. Can you see that everyone? Is that shared, Gena?

Yes, that's shared.

Fantastic. So Meira is a gene therapy company currently focusing on AAV. We're slightly different from many of the gene therapy companies you may have come across in that we're not specifically focused on a particular indication or a group of diseases or a particular application for gene therapy, but we are very much focused on building a company that broadly optimizes gene therapy and creates technology that allows us to use this new modality to cost effectively treat a broad range of serious disorders, not only rare inherited diseases. Having said that, our first pipeline products that are in the clinic are currently 6, are in 3 areas, one of which is in the eye, and we do have an entire pipeline of programs in inherited retinal disease, all of which are partnered with Janssen, and we have a very strong collaboration with them, particularly at the moment, a lead program in RPGR, which is a pivotal program as we speak. We focus our initial clinical programs on small doses in somewhat immune-protected areas, and that allowed us to avoid some of the pitfalls we're seeing today in gene therapies that are requiring very large systemic doses. So I mentioned the eye. We also have a program in the salivary gland, we're 2 Phase I programs, study is ongoing. One will have some clinical update in a few weeks. And Parkinson's study where we do Phase II [indiscernible] and we're opening a new IND with product made from our GMP facilities. We have broad vectorology technology for different promoter platforms, everything from bespoke promoters in our human organoids all the way through to AI-driven promoter enhancer shuffling as well as algorithms to further enhance and strengthen our promoter-enhanced combinations. We have capsid selection, capsid screening. We look at every aspect of the vector from the promoter to the sequence to introns, exons to make sure that we have the most potent and therefore, safest product where we take it into people. And importantly, we have the broadest manufacturing capabilities in the industry, I would say. We have our internal GMP facility that was approved now 4, 5 years ago, initially for GMP manufacturing. We are the manufacturer for clinical and commercial products, eventually [indiscernible] for eye programs. We have a flexible, scalable platform for manufacturing in the facility in the U.K. We have a -- we have our own process that's been developed over the last 5 years based on multiple capsids and multiple different vector genomes to quickly manufacture or take into GMP any viral vector. We have built a second scalable, flexible facility in Shannon Ireland, and that actually has built last year during COVID, we bought manufacturing for GMP plasmid in-house. So we now supply our own GMP plasmid. And by the end of next year, going to the other end of manufacturing, we will have brought in all our QC assays to a QC center in Shannon. So we really have end-to-end manufacturing, which allows us to initiate our INDs with a process, a material that with some modification potentially is ready for commercialization potentially. And finally, we set out to develop an entirely new technology, which is to regulate our gene therapies with small molecule -- with small molecules that are oral and switch our gene therapies on and off with oral drugs. We have taken a completely novel approach in that we have built riboswitches, which allow us to use all that promoter information that I talked about before. And we can now, in a really granular way specify the dose of a gene therapy from no expression to a very specific level of expression dependent on the oral dose of a small molecule. So we -- this isn't just an on/off switch, it is a very precise way of dosing biologics by gene therapy using orally delivered drugs. And we have multiple drugs that we're developing, the first of which is going into longer-term monkey studies right now. So that's broadly the company, very wide capabilities and deep from vectorology manufacturing to new oral switches for gene therapy. So should I stop sharing Gena, and then...

Sure.

There we go. Okay. So now, we just see us, I think.

Sounds good. Yes. Well, thank you very much for the overview. So maybe I will start with your upcoming data in xerostomia. So that would be the Phase I data. So maybe, Zandy, if you can just refresh our memory which those cohorts will be included? And then also is their target clinical profile, the measurement you will be looking for from this data set?

Okay. So we have ongoing 2 Phase I studies in xerostomia. Very serious condition, no treatment. The patients that we're treating are all grade 2, 3, and they're all 2 or more years after they've been treated with head and neck -- with radiation for head and neck cancer. And they no longer have head and neck cancer, but the xerostomia that occurs when you have radiation has remained and has remained grade 2, 3, which means it can't be resolved with the current treatment. So it is really severe. Now the studies are -- we inject into the opening of the parotid gland, the gene therapy, aquaporin, and then what we're measuring the most meaningful [indiscernible] is the PROs or visual analog scores. They are measures of the patient's perception of their dry mouth. And that's the sort of data we've been looking at out of this dose escalation safety cohort of patients. So we have a study ongoing at the NIH, which is a single center study, and then we have our own multicenter study. The NIH are multicenter study started at the highest dose that the NIH had reached when we opened the study in December 2019. And we have escalated from that in the same way as we're doing in the NIH study, which is reaching its top cohort, and we have escalated to 4 cohorts in that study. Last year, we were able to treat 3 subjects. And at the end of the year, we had anecdotal data on the first 3 subjects in our own Phase I study. This year, we will complete the enrollment in our own Phase I study, and we will be by the end of the year and in early December, we'll give a further clinical update on the subjects that we have a cutoff point, but I think it's probably 6 months. I'm not quite sure what that cutoff point is. The clinical team will have to let us know on the actual date of the cutoff. And we will give the data on all of the cohorts up to that point. So last year's cohort as well as cohort 2 and whichever members of cohort 3 have reached that time point. Now with respect to the endpoint, what is interesting is that we looked at the measures that were used by the FDA to approve xerostomia drugs. And in the last xerostomia drug that was approved, I think in 2004, the FDA used a scale called the McMaster scale. And the McMaster scale involves asking the patients, do you have an improvement? Are you the same? Or is there a decrement in your dry mouth? And when they say one of those answers, if it's improvement, they then ask to score how big an improvement that is. So the FDA approved the last drug based on a difference in the McMaster Question 1. So do you have an improvement between treated and untreated for xerostomia? And this was actually for Sjogren's and not for radiation-induced xerostomia. So the data we're going to be looking at is data from readouts like McMaster. It's questionnaires that the patients can say whether they've improved or not, just like we asked last year. We had a complete responder, which we didn't expect and the type of levels of response we're getting. But just so the FDA considers clinically meaningful a change and improvement, not an improvement of 1 or an improvement in 2 or improvement in 7. 7 is a complete response. 1 is an improvement. So that's the sort of thing we'll be discussing for this preliminary data.

That's very helpful. Zandy, like regarding the FDA, since the last drugs seems pretty early, like 2004...

It was long time ago.

So any change -- yes, like a long time ago, like had you had a recent discussion with the FDA regarding updated...

We have not. We have not. And this is -- the study -- I mean the studies we're doing now are very much efficacy studies. It's a single gland -- sorry, very much safety studies. A single gland, dose escalation, looking for inflammation, looking for any problems. So far, it's been remarkably safe. It's a very safe almost topical treatment in that you don't cross into the blood, so to speak. But we are managing to get some efficacy data because patients are responding to these questionnaires. What we're trying to do now is treat both glands in the expansion of this study and start getting some more robust safety data -- sorry, efficacy data. But next year, we will actually be doing a sham-controlled Phase II study with randomization, different dosing arm against sham where we will be able to actually get a really robust measure of safety. And we'll be having discussions with the agency about what endpoints they consider most appropriate for approval. From our other discussions with the FDA [indiscernible] for payments, you have to show either by precedent or by correlation something that has a meaningful benefit for the patients you're treating. And that's why we think things like McMaster and those sorts of scales, which have been used for approval before, which really reflects the patient's perception of the benefit are most likely to be our endpoints that the FDA would favor, but we haven't discussed it anymore with them. But it fits in with what we hear. They want you to benefit the patients.

Okay. Okay. That's very helpful. And then beyond the master scales, will you also share the salivary flow in any other data you will choose?

So salivary flow is normally measured through us fitting into a tube over a certain extent of time whole saliva. And because we're measuring different glands and different aspects of saliva at different time points after you start the test, it's very, very confounding because if someone has saliva and you're doing 1 gland before you're doing the other and then you've done 10 minutes and then you try and make them do whole saliva, they can't make whole saliva. So the order in which you're doing the tests is very much changing what the data is. So we do some saliva collection, but this isn't really interpretable data because of how it's collected. So when we do, and we're trying to currently complete this study with some dual treated patients, we will be looking at whole saliva, but the whole saliva data here is quite confounded because of a number of different measurements we're doing. And we are actually collecting saliva so that we can see saliva components, the proteins and the salts to make sure the saliva we're producing has many of the functional elements of saliva. So we're doing quite a lot with this saliva. But we will be endeavoring to treat patients in this Phase I with both glands so that we can start getting that data ahead of the Phase II next year, just to use some of the patients that are coming in.

Okay. Okay. Very helpful. So maybe you mentioned next year Phase II. Any additional thoughts you can share regarding Phase II trial design? And then what kind of -- like say, the data point you'll be looking for from the Phase I data to help you determine the Phase II trial design?

We're definitely looking at the -- if we're getting good responses and durable responses, with -- and particularly if we get things that are complete response or near complete response as we saw in the 1 patient last year, if we see that sort of response on the McMaster, which is a validated well-known measure, that's definitely something that is a really useful Phase II endpoint. Whole saliva will be another endpoint that we'll be looking at, and there are many other PROs and certain questions within PROs. So as we get the full data, we will be -- from this current study, we'll be looking at what PRO questions are actually reflecting the greatest benefit if you see what I mean.

Okay. Okay. Very helpful.

And all our patients benefiting the sleep domain to all our patients benefiting in the sore throat domain, those sorts of things. So we'll be able to parse out which questions reflect the benefit that we're causing, hopefully, when we get all the data from the study.

Okay. For the sham-controlled study, like how big a study you've seen...

We haven't decided on the stats and the measures here, and we will want to see the responses and the sizes of responses in our full phase 1 because the data you're seeing, we're completing enrollment this year is preliminary data that you'll be seeing live.

Right. Okay. And then -- like would that be Phase II then in the future, do you will have to run a Phase III or the Phase II could turn into pivotal study?

We need to discuss data with the agency and depending on how strong Phase II data is, and we need to make that study randomized, well-controlled, multidose. We will have discussions with the FDA about what additional studies they need to move forward. So we can't make assumptions until we've done the study, but we can design the study. So it has all the features that the FDA wants to see in [indiscernible]

Okay. Okay. That's fair. Now switch to your riboswitch platform. There seems like very exciting new technology. So Zandy, can you share a little bit more in terms of types of genes or indication that's in your top list that could move to the potential the discovery candidate?

Yes. So the riboswitch is really exciting. And it's most exciting because it's really the first time that anyone's been able to regulate gene therapies with such precise control with small molecules that we can choose. So we have libraries of small molecules that we can create bespoke regulating aptamers too, right? And there are a number of things that immediately come to mind, problems in medicine, pharmaceuticals today that we can address. One of the problems is biologics crossing the blood-brain barrier. That's a big problem in cancer, and is a big problem in neurodegenerative diseases, for example. So we have regulate -- we have vectorized and regulated many, many antibodies, many, many. At the moment, I think we've got about 10 -- 8 vectorized, optimized and precisely regulated, dose-responsive regulated antibodies and -- such as Herceptin and Lilly's anti-amyloid. So it could be any anti-amyloid or any neurodegenerative disease antibody. So you can see of putting the genes through intrathecal injection into the CNS and then activating those genes with a blood-brain barrier penetrant small molecule. And in the case of Herceptin, we all know how many women respond really well to Herceptin's systemically and then unfortunately, succumb to brain mets because Herceptin doesn't go through the brain. So this is a way of addressing that need, which has been really, really difficult to achieve through systemically delivered oncology drugs. So that's one good use. And obviously, there are many companies working on neurodegenerative disease, antibodies, and you would be able to avoid the need for large systemic doses of an antibody or biologic by simply putting the gene within the blood-brain barrier. So that's an area where there's quite clear unmet need. Biologics crossing the blood-brain barrier is a problem that many companies are extremely interested in and it's a really good use of regulation in gene therapy. One of the things that has really been most interesting to us in doing this is the smaller short-lived proteins and peptides and hormones. So we have regulated a wide range of peptides, hormones and proteins, such as, for example, EPO, such as insulin. We have done growth hormone, PTH, GLP-1. And we're able to really precisely regulate the levels of these, both in vitro and in vivo. And one of our first in vivo experiments with EPO is we can control in a dose-responsive fashion the hematocrit of the mice by different doses of small molecules. So this is really precise in how we're able to dose these biologics. Now we can do that for all of those peptides and hormones like I just mentioned, but one of the things that has been really interesting for us is that we have built into individual vectors combinations of peptides. So for example, as you know, companies like Lilly have worked for many years on a GLP-1 GIP co-agonist. And we have a high-expressing GLP-1 GIP single vector, which regulates both peptides, both natural peptides, very precisely in response to a small molecule. We also have triple combinations with PYY, holy grail of peptides. And so using this technology for the first time, we're really able to deliver these combinations of peptides, which we see in GLP-1 and incredibly effective in diabetes and obesity that have much greater efficacy when given at the right time in the right combination [indiscernible] not with injections, but with the [indiscernible] small molecule. So there are many, many uses of the gene regulation technology and those are just a couple that we currently have in-house in our [ fridge ] of ready-made vectors to regulate. And with respect to the small molecule, we have a library and a growing library of small molecules with different drug properties. And our most advanced is currently in repeat dosing in NHPs with IND-enabling studies next year.

Okay, Zandy. So regarding small molecule, how much you can share? I know you just say you can have a very precise control and how do you do that?

So we are -- so our riboswitch is -- has very, very high dynamic range, up to 5,000 volt. And what this really high dynamic range has allowed is it has allowed us to, for the first time, screen for small molecules that bind RNA sequences in cells, in mammalian cells. So we don't use [indiscernible] to find small molecule optimal binding. We actually use -- within the cells, we mutate our switch and then look for small molecule binding. So we've done screens using randomized mutated aptamers in living cells in our switch to identify new -- completely new structures that bind to and activate in a mammalian cell are switch. So it's not 1 compound that we got from nature or whatever, it's very much a platform. It gave us the technology to screen for the first time in living cells for small molecule aptamer binding, and we're looking for binding that's functional and that functionally activates the switch. So that's how we get our library, and it's this dynamic range and ability to screen for specificity and potency that allows us to have really granular control of our different switches.

Great. Thank you so much, Zandy. We're running out of time, but I will see you later today at the panel discussion.

Yes. Okay. Thanks, Gena.

Bye-Bye.

Bye.

Bye-bye.