REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Hello, everyone. Thank you for joining our Second Virtual Health Care Conference. My name is Gena Wang. I'm Senior Analyst at the Barclays. First, I wish everyone, stay healthy, and I would like to thank all the participants, investors, companies and especially the event team and corporate access team who made this virtual health care conference possible. With that, I would like to introduce our next presenting companies REGENXBIO. Today with us, we have Steve Pakola, Chief Medical Officer; Olivier Danos, Chief Scientific Officer. So with that, maybe I hand over to you, Steve, to give a few minute high-level description over the company and then we can go to the Q&A.

Sure. Sounds great. First, Gena, thanks for having Olivier and I here. We're very excited about our progress across our platform programs. So it's a great opportunity to always to sit down with you and have some Q&A across those programs. So the lead program, RGX-314 for treatment of wet AMD and diabetic retinopathy, recent update from angiogenesis, where our subretinal program, first-in-human study, we continue to have maturing data there where we have consistent efficacy with each additional time point that we get out to. And that includes to -- 3-year data now from cohort 3. And we're also excited to -- based on those results as well as the successful end of Phase II meeting, advance into pivotal development. So we actually started our first pivotal subretinal RGX-314 study atmosphere, and we announced that earlier this year. So a lot going on with RGX-314 subretinal but we're also, in parallel, developing the in-office suprachoroidal delivery route, where we have ongoing 2-studies with that route of administration. One, the AV8 study for wet AMD and the other for treatment of diabetic retinopathy, the Altitude study. So that's all within our retina franchise, but also recently at World Symposium, we had additional positive data on further follow-up of our 8 patients who've been treated in our MPS-II program. And the third prong or see the -- that we have a high priority on is our DMD program. And so we're glad to have Olivier Danos, our CSO, here, who has been an expert in this field for decade. So really a lot of different programs advancing. So I think a lot of great stuff we can talk about, Gena.

Sounds good. So maybe I will start with our AMD program. So you mentioned that at the androgenesis, you have longer follow-up data. So we did see some erosion of retreatment with 2 patients single once from cohort 1 and cohort 5 were -- had to take a rescue injection. So could you give a little bit more color on these 2 patients and particularly with the OCT like why they were retreated? Was that the OCT increase from the retreatment?

Yes. So you're referring to retreatments within our first-in-human study in our subretinal program, one of the nice things with that trial is we've got 42 patients where we continue to get longer-term follow-up, where we can look at issues like retreatment and whether that's changing over time. And you're referring to our traditional swim lane plots where we can actually look at each individual patient and see when they have actually needed retreatment. We haven't gone into each individual patient exactly why they may have needed an injection. But you'll recall from the angiogenesis presentation and update of where we showed across the board if you look at all the retreatments, on average, the amount of increase in fluid from the prior visit that led to retreatment for less than 20 microns. So we see that issue in this first-in-human study that we had a very low bar for patients to get retreated. And in fact, that's how clinicians have been proceeding where they have been giving injections even for relatively small amounts of fluid increase. The other interesting thing is if you look at those swim lane plots, each patient has its own variability in a certain way over time. So for every one of those patients who didn't have an injection early on and has gotten one later, there's other swim lanes that you see where a patient has gotten an early injection and then has a needed one since. So what we see is pretty remarkable consistency in the reduction in retreatments compared to the prior year at each of these time points that we look at. And we see that from the 1-year time point now out to the 1.5 year time point for cohorts 4 and 5. And we also see it out to 3-years for cohort 3. So basically, a continuation of what we've seen before, very few retreatments and those retreatments are for very minimal fluid.

Okay. That's very helpful because we do understand every trial has a complete different criteria for rest injection or retreatment. And that certainly, yours is a very stringent. It's 20 Microns and then other study, they will have 75 microns. So thank you for additonal color. So for the Phase-III dose, you choose slightly lower than the cohort-4 dose, and this all regarding the subretinal trial. So any decision that decision was due to, say, the feedback such as a low-risk effective dose? Is there any -- when you pick that dose, is that partly also reflective of the FDA feedback? Or was that purely based on the data or your own decision?

That was our own decision, and there was no resistance to those doses from the FDA from our end of Phase-II meeting. So -- and this gets to the reality of when you look at the results, you have to think about the retreatment criteria. And you also have to look at the type of patients that you're treating and the variability that you can see from cohort to cohort and the reality is when we look at our data set from the 42 patients, we're seeing what we want to see from cohort 3, 4 and 5 and really any differences on individual endpoints that you might look at. We're seeing -- that's really driven more by underlying patient characteristics than by dose. That's why we felt confident going with the 2 doses that we've gone with for the Phase III.

Okay. And then -- and you did mention the underlying disease. There are a few patients, especially maybe cohort 3, that was not well controlled by the current standard care. So for your Phase III trial, can you also give a little bit more color, the enrollment criteria that how you can exclude those patients? And also you did change your rent rest injection criteria you do little bit comparison versus Phase-III trial versus the Phase I/II trial?

Yes. So those are really, Gena, the 2 main updates, I'd say, for the pivotal program compared to the Phase I/II study. And they're both directionally in a favorable direction, I'd say, in terms of derisking. So as we learned, and I think all expected a first-in-human study, you tend to get more chronic more recalcitrant type patients, we still were able to see an effect across cohorts 3, 3 to 5, in spite of including these pretty recalcitrant up to treat patients. Still for a pivotal study and for both the atmosphere and the second pivotal study, we -- now that we've gone through the first-in-human study phase and have our selected doses will exclude those tougher-to-treat patients as well as patients who have very chronic disease. So for example, patients, we have more than 4-years of anti-VEGF treatment or patients who even with existing anti-VEGF treatment can't have their fluid well controlled. So we'll basically -- we basically have inclusion criteria to get rid of exactly those patients that you don't want to have in a pivotal study.

Okay. And then for your second study that compared versus EYLEA, as a comparator. What are the some key gating activities before you can start the trial?

Yes. So our second pivotal study, the main difference is really going to be the different comparator Arm flopec set. So we're excited at the opportunity to have comparative data against the 2 most used approved agents for any of the VEGF driven retinopathies. So it's a great opportunity for us. We're just putting on the finishing touches on the protocol, but it's really going to be very similar to atmosphere with just some slight tweaks based on exactly when visits occur because of the every other month dosing that exists with aflibercept. The other aspect is really making sure we get atmosphere off the ground and that's going well. And it just makes sense to do the studies in this kind of staggered way so that we can get the first study up. And we also have the opportunity to use some of the same excellent centers in both studies where they can complete their allotment of patients, for example, an atmosphere before switching over to the second pivotal study.

Okay. Okay. That makes sense. And then last question regarding this subretinal program. For the breeding study, could you share a little bit more detail on the trial design in terms of number patient follow-up dose?

Yes. So we have our current clinical material that we've used for the Phase I/II setting that we're using in the pivotal subretinal program is the adherent cell-based culture approach, which actually would be viable commercially given how small the amounts of drug that you need for subretinal delivery. But nevertheless, it would be much better to for scalability reasons to transition to the suspension-based cell culture approach, which we've advanced here at REGENXBIO. So our plan is to bridge and actually for our BLA submission in 2024, have that be with the commercial suspension-based cell culture approach. And we have that discussion with the FDA and ask specifically about that and our approach at our end of Phase-II meeting. And there was no objection to our approach of using a small bridging study, looking at the 2 doses that we're including in our pivotal program and looking at that with both the existing clinical process as well as the suspension-based process. It will be in wet AMD patients. So we will do it in patients, of course, given the procedure. And a really relatively short-term duration, we're talking dozens of patients not anything more than that. So really a pretty straightforward bridging type program.

Okay. And then regarding your suprachoroidal area Phase-II study in wet AMD. I think on the last call, you mentioned that 15 patients treated with cohort. And then there is no any a sign of any grade of inflammation. So I'm sure now you pose more patient. Any is the safety profile remains similar, consistent with what you've seen so far with additional enrollment?

Yes. So we completed cohort 1 at the end of the year and announced that at the beginning of January. And at that point, we had an interim cut because we completed and made a statement on the findings and are happy with the findings to date and announced that our next interim update would be Q3 of this year. Why Q3? Well, this phase are very consistent with what we've done in the past. And given the variability of the disease that we've already discussed, we think 6-months follow-up is key for assessing not only safety and tolerability, but all of the typical efficacy parameters that we look at. So we look forward to giving that update in Q3.

Okay. Did you -- since then, did you also dose cohort 2 patients?

Yes. So we have announced that after completion of dosing in the first cohort, we -- after having traditional IDMC review as per protocol, we're allowed to then proceed into dosing of cohort 2 and cohort 2 dosing is ongoing.

Okay. And then 3Q, when you share the data from cohort-1 efficacy data, will you also share cohort-2 safety data?

That's a good question. We'll have to see how far along we are, since we're still actively enrolling. If things go well, there could be the opportunity for us to give some update on C2 as well. We'll have to see.

Okay. And then for the 6-months follow up, what type of data you will be sharing with us.

So there's the traditional safety, tolerability and then also the traditional markers of efficacy very much along the lines of how we previously have updated on our subretinal Phase I/II study. So we'll be able to look at 6-months of functional outcome in terms of best corrected visual acuity as well as anatomic outcome by looking at central retinal thickness and also retreatment based on updated retreatment criteria, which, by the way, are the same as the updated retreatment criteria that we have for apheresis, the pivotal SR study.

. Okay. So these 2 are the same, the region and quite. Okay. And then for the -- so is it fair to say you will report visual acuity data, OTC data will you also show the protein data from the patients?

Yes, that will that will depend on the -- I don't know if we'd have the 6-month data in time for that, but earlier time points, we'd have the ability to look at protein -- batch sampling, et cetera, for assessment of that. But yes. Well, it will depend on the timing, but more important for us is really how the patients do. And that's one of the things that we've learned from the subretinal study.

Okay. Very helpful. And then switching gear already maybe on the DMD gene therapy. So your construct, when we look at -- there's actually slightly different from where we see solid Pfizer Sarepta, you incorporate C-terminal domain to allow the recruitment of additional proteins. And so think it functionally make microdystrophin more resilient in a pre-clinical model so any comparison we can give in terms of a preclinical your construct in addition to this other additional benefit you could have? And how that benefit can translate to the human study.

Okay. Thanks, Gena. Yes. So we've added this C terminal domain because we believe based on the data out there, that it's useful to bring back more out the dystrophin function, not only the part that's linked to for transmission when the muscle cell contract, but also how it recovers from all that. and a lot of things that are happening physiologically at the level of the cell membrane. So we think it's key, and we came up with a with a construct that works very well in our study in the mouse model of Duchenne Muscular Dystrophy. So the interest of this model is that it's been worked with for years and years, and it's pretty standardized in terms of assays and the way you can evaluate the potency of your microdystrophin. So we've looked internally, we've compared different constructs, we haven't really looked at comparing this consult precisely with the competition construct because that -- I mean, that was not to point for us at that. We -- but we definitely -- we're definitely sure that this construct has a great activity. So we are very happy with it. We have produced the vector at clinical scale. And that's also very important because we are ready for -- definitely for Phase I/II, but we're also ready for the pivotal. And so we have a process that is something that -- I mean, this is important in the context of the competition as well. So that's where we are -- we've introduced a number of optimization at each step of the vector design. Meaning that we worked on the promoter, we worked on optimizing the sequence itself, including remove all of the CpG sequences and colon optimization. So that's the world that's been done. And that's the concept that we've now -- we're now completing all our IND labeling studies our package is going to be already within weeks. And we hope to be able to -- and our goal is to find an IND by midyear. That's where we are.

So I think several questions. One is also regarding the vector, AV8, and I understand AV9 because the rights actually only Pfizer has, right? So -- but any thoughts regarding AV8, the benefit, pros and cons versus, say, AV9. I think Rh74 is pretty similar to AV8. Any thoughts on the AV8 choice? And also -- yes. So I will stop there.

We actually like AV8 a lot. I mean, we were using it in the eye. we know very well how to make it and how to make it at a very large scale. And it's been validated in the clinic by others a lot. I mean, historically, they did all the hemophilia trials, I mean, have really demonstrated a very good safety of IV administrated AV8, the Audentes trial, although there has been adverse events, but not probably related to the disease itself, show very good targeting to the muscle. And a good safety profile, which is something that is really consistent. So we -- based on the activity based on the manufacturability, based on all that, with AV8. We think it's a great careful muscle and heart.

Okay. And then thinking about future competitive landscape, which you do have a Pfizer and Sarepta and sole, and you could have Ultragenyx he actually also coming at some point. And to clinical study, we don't know which factor yet, but my guess, maybe also 88. So like how do you see your candidate differentials, like what do you need to see in order to be able to differentiate from the other competitors?

Well, I think we need to -- of course, we need to see efficacy, and we need to see something that's at least that's as good as the other -- we'll have shown at that time, right? But the jury is kind of still out on what this really will be, although it's pretty clear that -- but to me, that there will be some benefit, right? So it's difficult today. I mean we look -- today, there's not a standard of care to which we want to compare our candidate, right? So it's a bit of a moving target. We don't believe that at the time where we plan of finding a BLA, there'll be actually an established standard of care. So we're not going to be in a situation where we're going to have to demonstrate superiority or non-inferiority or whatever. We need to have -- we need to have something that's a credible option for patients, and we also know that there is a high demand from patients for differentiation, different options. One thing we bring is AV8 is also a capsid that may be a good one for certain patients with an immune profile that would not allow them to be treated with the other ones. So that's kind of an added benefit. Actually, that's not the whole thing. That's not -- we're not playing just that. But -- so it's kind of a constellation of things. If you see what I mean, right? But we believe that -- I mean, given the high unmet need, the high number of patients, we believe that we have a seat at the table here with a product that even though we start -- we're not going to be first, but again, it's still a moving target, still something that's going to evolve within the next 3 years.

Okay. Just curious if a few people, I think Arch 74 and AV8, the mutualizing antibody likely overlapping, AV9, maybe a little bit distant, but may have some level of overlapping. So in the end, might be competing against the same patient population. If we think about the neutralizing antibody, is that fair?

Yes, that's fair. That's fair enough. we don't think that we have a very clearly defined population that will be -- could be only treated with AV8 and nothing else because of the even problem. There'll be overlaps. There will be overlaps. What is clear is that there will be a proportion of patients that -- first one will not be included in clinical trials and could be including ours. But then with the commercial product, it would kind of be the same. The other products will not be recommended for some patients with a given profile, but maybe we commented for us.

Okay. Last question. Based on what we learned from Sarepta the fair trial, in, I think, a Pfizer study design. So what will be your target patient population for a Phase-I trial? And then what is your goal to reach the protein level and in terms of that come back to the dose you'll be using? And then patient population at age cohort?

Okay. So we're not disclosing these details yet, but this will definitely be young patients, ambulatory patients, right? That's where we'll be. The dose level will be within the same bracket as to those levels, which are being used today. I mean, there's not going to be like a very large difference, either less or more. And that's pretty much what I can say. In terms of...

Yes. Sorry. So the dose will be like in the 2 -- in the 14, that range, right? That's what we see from everywhere else. At least in 14 range?

Yes. In this kind of range, right? It's not going to be 10% to 12%, or it's not going to be turned to the 10% to the 15%. So -- yes, I mean, this is something that's not going to be like a big surprise from what we can tell today, right?

Okay. Okay.

But in ranges, which again had been already derisked in the clinic with AV8 IV. So that's something that we have some confidence around that.

That makes sense. Yes. Well, thank you very much. We already running all the time. Great talking to you guys in the we look forward to talking with you in the near future. And I keep my fingers crossed, and hopefully, all the data will be -- we will see great progress this year.

Yes.

Thank you Gena.