MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Ladies and gentlemen, the program is about to begin. [Operator Instructions] At this time, it is my pleasure to turn the program over to your host, Alec Stranahan.

Hey, everyone. Good afternoon, and welcome to the end of day one of the 2022 Bank of America's SMID Biotech Conference. Thanks for joining this session with MeiraGTx. My name is Alec Stranahan, I am Vice President and Senior Biotech Analyst covering Meira here at BofA. Pleased to be joined today by Zandy Forbes, President and Chief Executive Officer. Zandy, thanks for joining.

Thank you for inviting us.

Great. So this will be the fireside format, so Q&A, but for those on the line, if you have a question, feel free just to log them through the Veracast platform and I'll read them out anonymously as we go along, but Zandy maybe just to start on XLRP. You provided top line data from the Phase 1/2 at AO recently, could you maybe walk us through the data that we saw and how that sort of feeds into your confidence heading into the Phase 3?

So the data that we saw was interesting for a number of reasons, but one of the most interesting reasons is that this was controlled data in an inherited retinal disease and RPGR. So it was a Phase 2 extension or expansion of dose escalation Phase 1 study in which we compared an untreated arm, randomized against a low dose arm and an intermediate dose arm. In all patients as this was the first dose escalation study, one eye was treated and the eye to be treated was randomized. So when you then or when we then looked at the data, we compared the randomized low dose and randomized intermediate doses, the randomized treated eye to the eye randomized to future treatment in the untreated arm. So we had randomization of both eye and patient dose and then the analysis was of just the eye that would be treated versus the same eye in the low and intermediate dose arms. So it was done in that way to give the regulatory agency comfort that we had done everything we can to reduce and avoid bias in this study where you can't do a sham when you're dealing with patients with inherited retinal disease. And that was important because it allows us having got controlled data from this Phase 2 study to use this Phase 2 to support a single pivotal study for approval of the product. So that was why we designed the study in this way, the overall study had 45 patients with 35 in the expansion part of the study. And the analysis we did or the endpoints we looked at were across every different area efficient. So we looked at multiple perimetry endpoints which measure in many different ways how sensitive the retina is to light. And we showed significant improvements in retinal sensitivity using a number of different metrics and different measures. We also looked at functional vision, so that is how does it change in vision allow the patient or that person to function in-life and in that end-point we used maze and then we also looked at things like contrast sensitivity and visual acuity and those sorts of things which are visual function and aren't quite so important for RPGR because they are already pretty good in RPGR patients, so there is a ceiling impact you don't expect to see large changes in just that central vision. So we were able to show across a matrix of endpoints looking every aspect of vision, significant improvements in treated versus untreated patients as a whole cohort.

Right. Makes sense and that's positive a result, encouraged heading into the Phase 3 and I believe you also did a sensitivity analysis sort of framing the patient that would fit the Phase 3 criteria if you could just touch on that?

Yes, so isn't quite what it may seem. It was the way we presented that data. So this was related to the perimetry data. And we measure retinal sensitivity in a number of different ways, one uses machine called the Octopus and that measure static perimetry broadly across the retina. The other is micro perimetry which just measures the sensitivity in the middle of the retina. Now started perimetry using the Octopus, the Octopus machines have an internal mechanism for calculating the reliability of the patients conduct of that assessment. So it measures at every point, how the patient response in the same or different way to the same light level at that point and thereby calculate whether that patient is actually reliably doing the test. Now in the study we did, the Phase 2 study and in the Phase 3 whenever we use Octopus, we set the reliability criteria quite narrowly, so the patient has to reliably complete the assessment and that is a reliability factor of less than 20. 100 is completely unreliable, zero is totally reliable and our patients have to reliably complete the test with a margin of 19. So what happened in Phase 2 study was that at one site, this was being completed during COVID, the person that conducted the static perimetry test was not trained. And so what actually happened is we got into our data completely unreliable static perimetry data with reliability that is of 80 or 90 i.e., it was random. So when you have that would not happen in a normal study it would normally happen outside COVID, we train everyone. So rather than just move that data in the intent to treat population, we included those assessments which were essentially random. What we call the Phase 3 criteria removes the assessments and patients where those assessments will random, so they would never got into an actual Phase 3 analysis. So that was the difference and it was a way of us like showing what something should look like, but nevertheless not hiding the actual data because of the mistakes that were made. If you then look at the micro perimetry data, you'll see that the Phase 3 and intent-to-treat populations are identical. That's because Meira machines are not available in every site and the site that had the mistakes with Octopus didn't have a Meira machine. So none of the Meira patients were excluded and the Meira machine doesn't have this reliability factor. So that's why the 2 perimetry patient numbers are different and how we describe the intent to treat versus Phase 3. With respect to the actual entry criteria, so the retinal sensitivity required to get into the study and the ability to navigate mazes so to be able to do the endpoints of the study, they're very similar in the Phase 2 and the Phase 3. This reliability thing should have been similar, but that was a problem with one of the sites.

Okay. Okay. Got it. I mean, either way, it's definitely encouraging that you're seeing similar effects by 2 analytical measures which I think differentiates your data from what some of your competitors have shown?

That's true and with respect to retinal sensitivity, so the static perimetry, we saw significant benefits in both our mean sets to the end point by point, even with the random data in there. So we know that we're having what appears to be a really good change and it can withstand even some random data in there and the intent to treat. It obviously got better when we actually have reliable measures. But it was very -- the perimetry data was definitely very encouraging and all our measures and all our statistical analyses went in the same direction and were completely aligned with one another, even with different machines.

Okay. And just thinking through the -- you mentioned all of the different -- the mean retinal sensitivity, but also the functional assessments as well, just thinking through as we near a Phase 3 readout, what from a regulatory perspective do you think the FDA is going to focus on the most? Is it the statistical benefit on the primary endpoint? Or do you think they'll take into consideration the functional assessments to which are arguably more important for patients?

So the primary endpoint is functional, so the primary endpoint is maze and that is the result of many, many discussions with the regulatory agency. So in our pivotal study, this -- the design of the study and the endpoints that are primary and secondary have all been discussed in I would say excruciating detail with regulatory agencies in the U.S., as well as Europe. And remember this is in partnership, this whole program in partnership with Janssen, so we do actually have a very large global regulatory group at Janssen working on all of these filings and all of these interactions. So the functional vision endpoint of maze is aligned with global regulatory agencies. The design of the maze has been tweaked and made fit for purpose based on discussions with the FDA and the statistical plan for analyzing the maze data has also been discussed quite extensively with global regulatory agencies. That maze has been validated with normally cited individuals, RPGR patients that are severe, RPGR patients that are less severe, pediatric adults, so this validation study is completed, has also been shared with regulatory agencies. So this endpoint was chosen as primary, not out of the blue, but after a lot of discussions with regulatory agencies, which included discussions around perimetry and retinal sensitivity. Now retinal sensitivity is sort of the gold standard for measuring a proxy of vision, how good your retina is at sensing light. That is considered by ophthalmologists and academics as a really, really good measure of vision, but to the regulatory agencies for primary endpoint, it's critical that you have a direct measure of clinically meaningful change. And the issue with retinal sensitivity is there's no well-established connection between a change of sensitivity and a clinical outcome. It's therefore very difficult to be able to go into a Phase 3 and know you're going to have approval by an agency, if you can't tell them what's clinically meaningful. So in a secondary or supportive group of end points that clinically meaningful aspect is not as important to regulatory agencies. As long as you have a primary that they can understand has an actual clinically meaningful effect on the patients that you're seeing and walking through a maze, avoiding errors, increasing speed, those sorts of things are easily understood to be of benefit to a patient and that's really important to regulatory agencies globally. So that makes that the primary as opposed to the statistics around the endpoint. It's this need for a clinical benefit that drove the final endpoint to be a functional vision endpoint. It doesn't mean the perimetry is not useful, it's just a different metric of vision.

Right, right. That makes sense. And I guess in terms of filing data, what's the latest guidance from you and Janssen in terms of that? I mean, where would that sort of put you versus the competition in XLRP?

So we are filing in 2024, the pivotal study is ongoing. It's a global study with around 30 sites, it's quite a large study. Janssen is fully supportive of this study infrastructure. They pay 100% for this study and it's very important product for Janssen with revenues hopefully from 2025 onward. And we're currently preparing as a commercial manufacturer for a commercial launch. So we're doing all the things you need to do to have a commercial gene therapy product, manufactured in-house, including PPQ, developing QC. And we have the Janssen projections and this is a big pharma company, this is an important product for them and we need to be prepared to supply a very strong launch into this market. This isn't something that if we were doing this alone would be more gradual, this is a large pharma company launching an important product into a really good market and we need to be prepared for a very strong launch. So that's what we're doing now in parallel to the completion of the Phase 3.

Right. And there's a very good chance you guys could be the first gene therapy approved for these patients, right? So...

At the moment, the competition, we feel that we're definitely ahead of the competition with respect to clinical time lines and launch time lines and manufacturing time lines and in-house QC. All of those things we're preparing for and this is what Janssen, obviously, one of the largest pharma companies in the world does really well is that they prepare for BLA and launch rather than prepare for a Phase 3. So from the inception of our collaboration, one of the great learnings of this collaboration was as a small company rather than thinking of yourself as preparing for pivotal study from day one everything we did was focus on BLA and then commercialization. So yes, I think that we are well ahead of any competition in this area, in every aspect, clinical, regulatory, manufacturing and ultimately commercialization through our partner.

Very good. And switching gears, I guess, the most imminent data could actually come from your xerostomia?

Yes.

Could you sort of walk us through the extent of data we should expect? I think some patients have been in the study for over a year now at this point, right?

Yes. So yes, as we have done last year and the year before, we will be having an update on our Xerostomia program, just to outline the design of the study. It was a Phase 1 study, which was dose escalation with one salivary gland treated in grade 2/3 Xerostomia patients. So 4 cohorts, one gland. We then decided because we really wanted to get some efficacy data to do another 4 cohorts with bilateral. Now the unilateral study took 3 years to enroll because it was during COVID and it was just really difficult to treat people's mouth during COVID. And we completed the enrollment and treatment of that study at the end of December 2021. So we will have full 12-month data from the entire unilateral for cohorts next week. In addition to that, some of those patients, a few of them went out to 2 or 3 years. So there'll be long-term data on a few of those patients who are the first to be treated unilaterally and we'll see that data. In addition to that, the bilateral cohorts, another 4 cohorts dose escalating enrolled super-fast; a, because we've seen promising effects in the unilateral; and b, because we were coming to the end of COVID. And so the bilateral actually enrolled in 6 months and that enrollment in treatment finished in March of 2022. So we will have 6-month data from all of the patients in the bilateral cohort. So those will be the data sets and the data we will see will be various of the PROs on which Xerostomia drugs have been approved before and similar data to the PRO data that we presented last year and the year before, so ex-Q [indiscernible] right? So you see improvement in dry males and these scores. And what we'll also do is we will present for both unilateral and bilateral what we've seen in improvement in waterflow. So we'll also show that saliva improvements. And in addition to that, we have now had discussions with the regulatory agency with the FDA and received feedback and had iterative feedback with them, so we're quite clear on what they require for a Phase 3 primary endpoint, what we need to do in Phase 2 and how we're designing the next study, which will be starting early next year. So all of that will be discussed in our update next week.

Okay. Definitely -- definitely looking forward to that and good to see that study entering or proceeding towards next stages.

Exactly.

Talking about assets moving forward in the clinic, you've recently have started dosing patients in your in-house Phase 1 Parkinson's study. Could you sort of walk us through how you're approaching development, here I know you've brought this asset in externally and it had data from where you acquired it already?

Yes, so this gene therapy has completed a Phase 1 dose escalation. It has completed a sham controlled Phase 2. And in that sham controlled Phase 2, we showed a statistically significant benefit in UPDRS motor symptoms are on treatment versus sham. Now this is the only gene therapy or cell therapy or growth factor therapy that has ever shown a significant benefit versus sham. There's a very high placebo response that you often see in Parkinson's single-arm studies. So we've had extremely promising data on this mechanism using this particular vector. The study we have now started uses material that we manufactured in-house using our manufacturing platform. And this IND is an IND opening study, which is a small sham controlled treatment study that is required by regulatory agencies to open the IND with the material manufactured by Meira. This material has been manufactured in a facility with a platform that can be used for commercialization. So this will be the material that goes all the way through development, no more bridging, no more comparability required. With respect to BLA supporting studies, we will be going to the FDA, as well as global agencies next year to discuss what studies are required and it may be different in different jurisdictions to support BLA or approval or early approval in some jurisdictions and what studies are required to then get longer-term approval depending on where we get feedback. So we will be having those interactions with regulatory agencies in the first half of the year. We will complete treating in that study next year and then we'll be in a position to move forward with one or more larger studies to support BLA stroke approval in other jurisdictions.

Got it. And obviously those conversations would revolve around your small internal study that's ongoing now, plus the studies already completed by Vector?

Yes, that's right. So really, the discussions are -- we've got the same product, we've got a Phase 2 that's positive published, peer-reviewed everything we got, Phase 1 dose escalation. We've now done a study with material made in a different facility. What do you need us to show you to leverage all of that data most efficiently to get approval in different jurisdictions. So we'll be talking to European agencies, FDA and the Japanese.

Very good. And maybe in the last 4 minutes or so, we can touch on your riboswitch platform, which is one of the more exciting things in my opinion, that you've got in the early pipeline. So we saw the preclinical update last year, I guess what is sort of the path forward here? Is it testing the small molecules first and then the combo of those 2? How are you sort of approaching that clinical development of riboswitch?

So we are approaching both in parallel, so as not to work sequentially and lose time. What we've done this year is in 3 areas, we've developed 3 completely new areas for regulation. One of those is in cell therapy and this is really exciting because it can be applied not just to CAR-T, where we demonstrated really granular control of CAR in CAR-T, but also NK cells and other immune cells. We have a number of small molecules ready to go for those sorts of indications, okay? But that's one of the exciting areas that we've really got working extremely well this year that can be broadly applied to any cell therapy and we can regulate more than one gene within a particular cell. The second area that we focused on is regulating nucleases. And here what we've done is really, really tightened our switches. So we can now switch on nuclease from zero, so there's no baseline expression, really, really minimal. That's number two. And number three is, we've used our switches to create cell lines for manufacturing. And this is almost a holy grail of manufacturing. We can now with completely inert small molecules control how and when a particular cell line produces virus, for example. So those are the 3 areas that we've really developed are -- well, we've developed our other areas as well, but these new areas that we've developed this year. In things like regulated antibodies, for example, last year, you saw that we can basically take any antibody. We can optimize vector, express it at high levels and regulate it. We've now done things such as take Herceptin. We can create vectors which increase expression 4, 5 fold over an unregulated. We can reduce tumor burden using Herceptin with oral pills, not pills because they're mice, but -- so in that sense, we've really advanced the in vivo efficacy of our switch to actual oncology models for example, as well as entering these new areas of regulation. And with respect to small molecules, we've gained increased confidence that we can make many molecules. So far, we make little libraries of molecules to be blood-brain barrier penetrant, to be eye penetrant to have high serum exposure. We're actually getting about 20% of our libraries turn out to be more potent, safer small molecules. We've got 2 molecules of blood-brain barrier penetrant, 5 that appear to be ophthalmology penetrant and 30 molecules that can be systemically delivered to regulate things in the muscle, in the liver or cell therapy. So we do have large libraries of small molecules that are going through full tox to enter the clinic and are ready to be paired with cell therapy, editing antibodies and our peptide work, which we described last year. So we've made huge advances this year in expediting the whole platform towards being used in the clinic.

Good, exciting. And maybe last quick question, just looking to next year in terms of the catalyst path, do you think we could be seeing some updates on the riboswitch platform? And I guess, what would be sort of the top 3 update there, data or clinical, preclinical that you would sort of point people to that you're most excited about?

I think we -- you will probably see at medical meetings further data. I would say that in this environment, we have cash to the end of 2024. I don't know if we would use that cash to start our own regulation study without a partner right now, even if we have small molecules ready. So we are in discussions and continue to have discussions with many companies and there might be potential partners that will allow us to really speed forward the clinical development of things like cell therapy and editing and antibodies, right, which could be a lot earlier than when we would take these into the clinic in the year or so ourselves. So that we're working on and we obviously have a lot of interest in the areas I've just mentioned. So those could be areas that would go into the clinic before we do that alone.

Okay. All right. Very good. Well, I think with that, we're up for time. But Zandy, really want to thank you for the thoughtful discussion and for taking the time for participating in the conference.

Well, very nice to speak with you. Thank you, Alec.

Thank you. Take care.

You too. Bye.