Afternoon. Welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I'm a SMID Cap Biotech analyst at Barclays. It is my great pleasure to introduce our next presenting company, REGENXBIO. With us today we have Ken Mills, founder, president, and the Chief Executive Officer. We also have Steve Pakola, Chief Medical Officer. So maybe, Ken, before I start, do you wanna give a very high-level overview of the company?
Yeah, thanks.
Mm-hmm.
Gena, again, for hosting us this year in Miami. Pleased to be back. REGENXBIO, AAV gene therapy company focused in three therapeutic areas: retina, neuromuscular, and neurodegenerative disorders. We are a company that has, I think, led the field in development and discovery of AAV therapeutics, starting with our founding, using our NAV technology, which are our proprietary, naturally derived AAVs.
We've really been working on this for over 15 years, and it's resulted in not only, I think, a series of clinical successes for ourselves and partners, but also one approved product, Zolgensma, marketed, of course, by Novartis for treatment of spinal muscular atrophy. So a lot of successes, a lot of chapters in the history of the company. But the current chapter is, perhaps the one that I've become most excited about.
And it, you know, this year has already been something that has generated a great deal of enthusiasm for us internally with our lead product program, RGX-314, or ABBV-RGX-314. That's focused on retinal diseases including wet age-related macular degeneration and diabetic retinopathy.
We're in a global partnership with AbbVie, where we're in various phases of development with different modalities for delivery, but looking to accomplish the same thing: to achieve with a one-time treatment maintenance, stabilization, or improvement in vision on vision-threatening complications that are associated with wet AMD and diabetic retinopathy can be very severe if left untreated, or if not managed properly.
And I think a one-time solution like ABBV-RGX-314 is really an important new medicine alternative that's coming forward now. And we're in really advanced phases. I know we're gonna get into more details there.
We just recently had some data on our Duchenne muscular dystrophy program, RGX-202. That's our neuromuscular program, currently in its, you know, first phase of development, although we've already made it through dose escalation and have reported data on several patients. Highly enthusiastic about that.
And last, certainly not least, is actually our first BLA, or our first planned BLA filing this year, which is for a rare disease called Hunter syndrome, RGX-121. We reported our top-line data from a pivotal phase trial last month at the World Symposium, which is a clinical and scientific conference focused on lysosomal storage diseases.
This has shown us that the unmet need in Hunter syndrome for the neuronopathic phenotype of boys is something that we can find a way to control with a one-time gene therapy, change the course of disease progression, I think, in a way that is really important and compelling for what is a significant and high unmet need. So, that's just been the start of the year. Has been new data for our programs, new top-line data for a potential BLA.
And it's the middle of March. Fortunately, we have a lot of additional things that Steve and the team are working on to continue to expand value for shareholders. And we're really focused on important value for patients as well. So I know we're gonna get into the details, Gena, and we'll touch on some of the additional updates coming too. But thanks again for having us here.
Thank you. So maybe I will start with DMD since this is the latest update. So you did show, you know, very impressive protein level in the older patient. And you do show very clear dose response without, you know, giving still small number of patients. So maybe one question is why, you know, the expression level was so high? And we still leave to the, C-terminal domain what additional functional that could be that even leave that aside for now. Just look at the protein level.
And so what lead to this higher protein expression? And also, I think the other part I wanted to say is the consistency of each individual patient, right? When we look at the, data, say, competitors' data, you do see some variabilities of the protein level. It could be very high, very low.
Here, we do see very consistent protein expression in, you know, the first four patients. You do see dose response and a patient age response. So what led to that better translation of a protein in the muscle?
I think the answer to that question really lies in, I think, the underlying approach and the science behind RGX-202. It's really, I think, a modernization of microdystrophin constructs that was intentional. I think the first one of the first real rigorous candidate optimization programs that occurred with AAV and microdystrophin expression. \
So our Chief Scientific Officer, Olivier Danos, who, you know, comes to us from literally decades of research in gene therapy and muscular dystrophy, remarked early on in his, you know, tenure several years ago that, you know, there were encouraging signs early about both preclinical and clinical data coming from other microdystrophin product candidates. But his remark that landed profoundly was these are things that basically were reagents in laboratories, in academic laboratories.
They hadn't necessarily gone through, again, that modernization of technology and thinking on biology, on optimization of AAV and expression cassette. So we set out to do that. Certainly, one of the design intents was to add the C-terminal domain.
But I think as we reflect on the sort of scientific integrity of that approach and we start to see the clinical data now, I wanna highlight some other things that I think have been a focus of Olivier at that point in time and the team. One is stability, genomic stability, stability of expression. You know, AAV, of course, is, you know, we think of it generally as the capsid that's, you know, working towards delivering our gene expression cassettes into the nucleus.
It's not trivial to be able to just get it there, but then to get it there and be there in a stable way so that transcription and translation can start. And, you know, there's a lot of things that can interfere with that process. We often talk about the things that can interfere with that process upstream, like antibodies that may neutralize the capsid even before it, you know, can get to a cell or things that can happen to compete with capsids before they get to cell surfaces.
But, but some of the things that are happening inside the cells are, are incredibly important for getting reproducible and stable expression. So genomic stability is one of those things we focused on. And then there's the translational stability as well, Gena.
I think that we feel pretty strongly that designing a construct that has the addition of the C-terminal domain actually provides some additional post-translational stability to that protein intracellularly and even by the time it embeds itself in the cell membrane, in the sarcolemma. So, you know, these were things that we worked on to focus on.
We also focused a lot on making sure that the expression cassette as well as the capsid itself that we were using was non-immunogenic 'cause that can be something that can interfere with stability and reproducibility of expression. So, you know, here we are now. We focused those on those things in animal models.
We always felt pretty confident about our decision process and our candidate optimization and selection process in animals. Now, RGX-202 is kinda echoing that back to us in humans. And we're really proud of the investment in some of those things.
Mm-hmm. So, how about the manufacturing part? You know, in terms of the AAV, like, you know, did that also help with the higher expression? And I know how important is a, say, full empty capsid or the other whatever the doing the manufacturing process, the purity of the AAV?
Yeah, I think, you know, it's great. And all these things are interconnected, right? And as you know.
Mm-hmm.
I mean, I think, you know, Curran Simpson, our Chief Operating Officer, and, and the team behind building out not only our process platform for manufacturing, which supports, you know, the BLA filing for 121, the clinical commitments that we have both to development support and commercial support with AbbVie, we're, we're very, you know, invested in stable, high-quality, high-yield manufacturing processes that are ready to go commercially.
And, and it was perfect for RGX-202 to fit right into that investment thesis, because certainly, again, I think another thing that we reflected on is, you know, even if there hadn't been, well, we have experience with Zolgensma, which, of course, launched with, you know, kind of an earlier generation of a manufacturing platform still using adherent that in, in Duchenne, we wanted to be in a very stable, high-yield, high-quality, bioreactor suspension process when we started clinical development.
Because there had been so much focus on the fitness and the stability of RGX-202 preclinically, it plugged in really nicely into the manufacturing process. Because as much as you want an AAV to be fit and stable when you deliver it to a human, you want it to be that way in your manufacturing process as well so that it assembles and stays together and turns into the part of the yield that you're responsible for.
I think we have an incredibly strong focus on high quality, high purity AAV coming out of our NAV platform express process. And I'm absolutely convinced that it's contributing to some of the efficiency we're seeing in the reproducibility of expression.
Mm-hmm. Good. For the update in the second half this year, should we see two more patient data? And was also dose level two, the protein level, and, you know, CK level?
Yeah, what we've committed to is, you know, we're gonna show additional data on dose level 2. There's really one we have this now 3 + 2 design. So there's one more patient who hasn't, that's been enrolled so far that we've announced that hasn't achieved the 3-month endpoint.
This is something that we would expect to occur by mid-year, because we've announced that we've completed enrollment in this phase of the trial. We will bring that data forward. We also plan to bring forward basically our, our algorithm and thinking behind dose selection for our pivotal phase.
Mm-hmm.
At which point, you know, we'll, we'll be in a mode then of focusing on design of an accelerated approval trial to support the additional development of RGX-202, as well as strength and function data for dose level one and dose level two. So all of these things are literally happening across the remaining nine months of the year.
By the time we finish the year, we will have initiated our pivotal trial for accelerated approval. We will have shared our strength and function data at a minimum on the patients that have enrolled to date on dose level one and dose level two. We do have the potential upside for some additional patients who may be enrolled as part of an expansion phase of the ongoing trial.
So there may be more data that we can sort of contribute to people's general understanding of the direction of where the program's going and also be a bridge and even contribute to the totality of evidence that we think would support accelerated approval. And, taking a breath, we'll, we'll also be thinking very much about confirmatory study design by the end of the year as well.
So, a lot on our plate but standing on top of the data that we started to report late last year and and recently updated on, I think, incredibly well-positioned to be able to move efficiently here. And, you know, really, the team is highly motivated. We've got everything we feel like we need in place. Just working on continued execution the way that we have for the last several months has been the key.
Okay. Maybe why 3 + 2 now, not 3 + 3?
Yeah, we were able to. So it was all about us wanting to move quickly.
Mm-hmm.
After we saw the initial safety data from dose level 1, and we were able to share it with FDA. We basically went to them and with the ask of amending the protocol so that we could start the potential for expansion phase. What the expansion phase means is parallel enrollment, right? So in the 3 + 2 design, we have serialization of enrollment where we have intervals between each patient dosing that can be weeks, maybe even over a month.
So, we were getting really encouraged by what we were seeing, what we were hearing from investigators. The safety profile in human was starting to expose itself. And so, you know, this was all in the name of acceleration.
Okay. I think that that makes perfect sense. So, like, the fifth patient, you've already enrolled it?
That's right.
Yeah. Can you remind me the age?
I think it's about an 8-year-old. Yeah.
Okay. Okay. So then we should be looking for similar level of the protein expression, right? But could be potentially higher.
Yeah, again, you know, this is our fifth patient.
Mm-hmm.
But it's our dose level two. So we're expecting to, you know, see higher expression than we saw from dose level one.
Mm-hmm.
You know, we acknowledge that there can be heterogeneity, but I think we've talked about the fact that we think that we've, you know, set ourselves up for, you know, really strong reproducibility in terms of stability of expression. And, you know, in animals, we saw clear separation between expression levels, between dose level one and dose level two.
And we also saw separation in terms of functional performance, strength, and function in the animals that, you know, gave us the confidence to wanna do this dose finding. And, you know, to the extent that we continue to see a really strong safety background with a higher dose, we're gonna feel strongly that that should be the dose to bring forward. We'll keep.
Mm-hmm.
Keep our eye on it.
So later this year when you provide an update, will you also share some functional data like a North Star time to rise and, you know, some of these?
Yeah, we've committed for both dose level 1 and dose level 2 to be able to, in the second half of the year, share strength and function data.
Okay.
As part of the assessments in the trial.
Okay. So how soon do you think that, you know, say, like, if it's three months follow-up, is that enough to see some benefit there?
I think that's not been the convention that I think, you know, we've come to expect from North Star. Maybe on certain types of domains of North Star, there are things that you can see where you can get early separation, in some of the boys. Again, can be very age-dependent. I think we're guiding to the second half of the year, Gena, to give us.
Mm-hmm.
More time in general for those assessments to have occurred. Certainly, that would mean that, you know, at least one or two of the patients should be out to 12 months by the second half of the year given when our dosing started last year.
Mm-hmm.
And so, you know, with again, we announced completion of cohort two, just last month. So, you know, we might be at six months, or a little bit more with one of the last patients enrolled. And, look, the reason we're gonna be bringing data forward at that time is because we're gonna be transitioning into a pivotal phase of development in the second half of the year. And we wanna, you know, sort of be responsible for continuing to be really transparent with our dataset.
Mm-hmm.
with the entire community. You know, this is something that, you know, we, we feel really strongly about. I, I think, you know, you-you've, you've seen, you know, first-order data from us even when we presented it last year.
You know, we had a 10.5-year-old patient that, you know, if I, if I may be open with everyone, we got criticized about it a little bit as being a relatively low microdystrophin expression level, you know, something on the order of 11%, which I think, you know, landed, for some people in a way that was, that seems a little bit, you know, lower than we might have expected or different than things that had come into focus, especially with, some of the recent regulatory actions that FDA had made with, microdystrophin product.
But we actually were incredibly prideful of the fact, not just about sharing it transparently but about the fact that we thought that this was a strong signal, that in a 10.5-year-old, there was not a lot of evidence of stable microdystrophin expression, period. And so to see anything, and especially anything at dose level 1, was really important for us. You know, that's how we're gonna, you know, we're gonna, we're gonna keep sharing data.
Mm-hmm.
We're gonna keep communicating about what we think it means. And I think that's really important transparently. And that's certainly gonna be true for, as the domains mature around strength and function. That's what you can expect from us.
Mm-hmm. So, when you went back to the FDA ask for the amendment of the, say, 3 + 3 to 3 + 2, did you also?
Mm-hmm.
Ask about, say, pivotal study, alignment of that?
I mean, not literally in that filing. I mean, we had to.
Mm-hmm.
File a protocol amendment, you know, to.
Mm-hmm.
Change the trial design.
Mm-hmm.
You know, yeah, I think that we found, you know, a really healthy dialogue with the FDA when we're trying to think about ideas and we generate new data that may impact ideas we're thinking about for acceleration that they are incredibly constructive and open to having conversations about our specific program, having conversations about our specific data as we update our file, and having conversations in general about, you know, kinda workshop style about sort of.
Mm-hmm.
You know, what is happening with microdystrophin. And, and even, you know, we're in a unique place, I think, in the microdystrophin spectrum 'cause we've got this new element of science. I know we're gonna get there. But our, our C-terminal domain is, I think, incredibly important.
And, and people are really intellectually curious about what the data is now that's gonna be coming out reflective of this new biology that is designed into our construct that, that isn't necessarily or certainly isn't biology that's been seen in other data that they've been able to see. So, highly interactive, highly constructive, and, and frankly, very much resembles the, the constructive nature of our discussions in our MPS II program. We're, we're quite a bit further along as well, but it's been similar.
Mm-hmm. So that's all the same division, right?
Yeah. Yeah.
The, the.
Absolutely. Same center, same office.
Yeah. Yeah. And then regarding, say, the pivotal study or accelerated approval, you know, the pivotal study design, the, well, depends on the, say, Elevidys label expansion. Will you will you plan to change? Depends on the label, how broad label could be. Like, will you adjust your patient age range and also how much, like, Pfizer data will impact your decision regarding the pivotal study design?
Yeah, I think the biggest impacts on how we're thinking about, you know, pivotal study design and sort of acceleration of 202 is our own data to start with, right? I mean, that I think I wanna overemphasize that point. You because our construct is different, because I think we have a, you know, even a very mature manufacturing process that I think can help things move quickly, we're really emphasizing, you know, what it is that we're seeing in our own data first with the agency as we're thinking about how to bring something forward in a high unmet need area.
One of the things we're really challenging ourselves about, and I think, you know, are curious about sort of the thinking of the agency on, like, where are gaps in knowledge and understanding about microdystrophin products in general, and the treatment of Duchenne? And are there things that we can learn from that to use to be able to bring forward RGX-202 on an accelerated basis?
Mm-hmm.
And so, you know, it's I mean, it's I think it's an interesting and important exercise and set of conversations because, you know, on one hand, you know, you could sit back. You could not engage in that. And you can go, "Well, we've seen the FDA accelerate something already.
We've seen how they've done it. We've seen how they've made the decision. It's been made public, you know, pretty substantially to all of us. And we've seen what that labeling is." And we could, you know, take a very narrow focus and say, "Maybe we just follow that pathway. That would probably be the fastest way," right? Because it's the precedential evidence on one hand.
I think we're, you know, we feel the difference in our product candidate is something that's really important, the biology of it, I think, the investment we've made in the science, the manufacturing capability, and the quality. And we want it to address high unmet need.
And I think so we're asking questions around the edge. Well, you know, where are areas where you have no data? Where are areas where you would like to have more data so that we may be able to optimize a design and a development plan approach that not only is happening quickly but is expanding knowledge? And I think that's our focus.
Mm-hmm.
Some of that certainly is a reflection of data from others, data from other sponsors, other sponsors who have, you know, shared data or have shared data, you know, with the FDA on a confidential basis. And then, you know, FDA may make some decision on that. And, you know, I think we feel like we're in right you know, it's a rich time.
Yeah.
For us as a company to be, you know, working from behind but working with a new set of tools and a new set of biology.
Mm-hmm.
And now our own dataset to influence something that I think, you know, we're hopeful will be really important for Duchenne community.
Okay. So maybe related question, like, say, accelerated approval path, you know, I think a previous list that could be 20 patients based on the protein level. So regarding the safety data package, so you're using AAV8, right?
Yeah.
Yeah. And then maybe, like, you know, and you have, you know, the many partners, partnerships. And then maybe how much safety data we have in hand so far on the AAV8? And then how would that help you to build your, like, say, total BLA package?
Yeah. I mean, that's a great and important point is sort of what's the knowledge and familiarity of AAV8 delivered intravenously.
Mm-hmm.
Specifically, right? I mean, we use AAV8 in close to 1,000 patients. I don't think the relevance of that necessarily is a read-through for the intravenous administration, but it's a familiarity. Now.
Mm-hmm.
Some programs that are in development. I know Emil was here, you know, from Ultragenyx talking about their OTC deficiency program, their GSD1a programs. There have been hemophilia programs that have been run in that FDA's seen intravenous delivery of AAV8 is something that, you know, it's familiar to the agency.
I think it's helpful when you're talking about things like safety in particular in terms of, you know, I mean, the equivalent of master data file type things that sometimes sponsors themselves or in cooperation with others generate. I think that's a real advantage. And at the same time, you know, then you've gotta get down to the sort of bespoke discussions of, you know, how many patient exposures do you wanna see with RGX-202.
I think, and both from an efficacy and a safety perspective, what I mean, I think you can use our MPS II program as kind of an interesting surrogate, right? I mean, I think.
Mm-hmm.
By the time we submit our BLA for RGX-121, we may be at the upper bounds. We'll have just under 30 patients that have at different dose levels been exposed and, you know, maybe 10 or 15 with respect to the what we call the pivotal dose, what we expect to be, you know, the potential commercial dose.
Again, a familiarity already for us with the agency on talking about opportunities for acceleration and biomarker-based acceleration. So, yeah, we've got that example. We've got the example of the agency's familiarity with AAV8. We've got the agency's familiarity with microdystrophin products in general as a class and the difference in our biology. I think it all sets up very well for, you know and I think you're hearing it from them.
You know, publicly, these are the types of tools that they wanna have to be able to support acceleration.
Mm-hmm. Okay. Good. I know we are running out of time, but quickly, one question.
Yeah.
Maybe for Steve.
Yeah. Sure.
You know, we do see, you know, some other data on the also gene therapy, intravitreal in the past that we saw similar approach has tons of inflammation, but now we start to see some improvement. So maybe from competitive landscape, you know, perspective, how do you see, you know, the 314 positioning now? And then what are the pros and cons there?
Sure. First, thanks for having us, Gena. Always great to be here with you and the rest of the team. So yeah, that's always been an area of a lot of focus. Safety, of course, always, always comes first, though from an efficacy side, a massive unmet need for the treatment burden reduction and ultimately better vision. But we've all seen the issues that have occurred from intraocular inflammation from different programs.
And that's predominantly been with intravitreal administration because of the non-localized delivery area. And that's precisely why for our two programs going way back, we always targeted localized, compartmentalized administration. So our lead program in pivotal development, subretinal, has always been the gold standard for both safety and efficacy. And then we have our follow-on program, suprachoroidal delivery, again, not only in office but still maintains the compartmentalized delivery.
The recent data that we have from suprachoroidal delivery in both wet AMD and also diabetic retinopathy, we see with very short course, topical steroids, no intraocular inflammation. That's really a safety package that we don't see elsewhere.
And I think that's particularly notable when you think of the number of exposures that we have with 314 in subretinal where we're gonna wind up, you know, basically enrolling in AbbVie, the largest in vivo gene therapy program ever done, plus all of the exposures that we're now getting with suprachoroidal delivery.
And this is across multiple dose arms where we're seeing the efficacy that we wanna see and also now the very good safety, including no intraocular inflammation. So we feel very good about the path that we selected years ago based on the data that's come out.
Mm-hmm. Good. Well, we are running out of time. Well, thank you very much. And thank you, everyone.
Thanks, Gina.
Thank you.