Good afternoon, everyone. Thank you so much for joining our day two of our Piper Sandler Healthcare Conference. Really excited to have the team from REGENXBIO here with us, who have been a pioneer in the space of gene therapy with really a broad portfolio. We have lots to cover in the 25 minutes. I don't even know how we can get through all of them. But what I would like to start off is maybe a very simple question. A lot of clients at this junction are looking forward to 2024, and I don't think that anybody has any doubt as REGENXBIO as the leader in the space. But the question for them might be: Why own REGENXBIO going into 2024? If you could just maybe highlight some of the key events that you believe will be significant share value inflection points, that could be really important. We'll start there. Yeah, I love that question. We're almost into December here. Yeah. We should be sort of as forward-looking as we've ever been. Thanks again for having us. I think the conference has been going really well and excited about the tree lighting. Yes. Feeling the effect. In the last couple of months, we've had some amazing milestones and events occur- with respect to our three lead programs. So we had our first ever data for our Duchenne muscular dystrophy program, which finally put us on the map in terms of not just safety, but showing those early signals of, biomarker expression. And the beginnings of sort of unfolding a story about how we're gonna move into later stages- of development with something that we think is a best-in-class- product profile. We also, just a few weeks ago, had an update to our RGX-314- program, which has been our lead program for years now. It's partnered- Yeah with AbbVie on a worldwide basis. This is a new indication where we show data in diabetic retinopathy that really, I think, communicated the fact that at some of- the first dose levels that we've been exploring- that we're seeing the types- of signals now from a longer-term efficacy and safety perspective, that are also lining up to give us consideration about how we're moving into pivotal phase. We're already in pivotal phase, of course, with- Yeah one aspect of that program, in wet age-related macular degeneration. And then the last event that occurred was a regulatory interaction. Now, this is a special one because this is something that we did with FDA. That was our first meeting under RMAT or the Regenerative Medicine Advanced Therapy label. This basically was an interaction that told us we're heading in the right direction with respect to a planned BLA in 2024. I think what's important about all three of those is we also just went through a strategic update- Yeah planning process. We identified RGX-314- for wet AMD and DR, Duchenne muscular dystrophy- Yeah and RGX-202 for Hunter syndrome, the one with this RMAT label, as our priority programs. Yeah. Because things are happening- Yeah in late stages, and they're gonna be unlocking value, I think across the entirety of 2024. You know, we made the restructuring a priority because there's been constraints on capital- Yeah lately with respect to our and others' ability to sort of weather this economic climate. But at the same time, we were incredibly excited about sort of the enriching science that's Yeah being told by the story of these programs. So you can be in our stock for a variety of reasons. But I think, you know, the really strong reasons are late-stage pipeline- Yeah sort of pivotal phase, near pivotal phase transitions that are occurring. More data coming to unlock more value in, number one, one of the largest indications in all of- Yeah cell and gene therapy, probably the largest, wet AMD- Yeah and diabetic retinopathy, and Duchenne muscular dystrophy, that we know is an important market- Yeah still with continued high unmet need, one that's gonna support multiple gene therapy products and the potential for a best-in-class profile there. With that RMAT program that's likely to be our first BLA- Yeah which will be filed, according to our plans, next year. So a lot to be excited about- Yeah a lot to sort of, you know, get into in further discussion right now. Yeah. No, that's great. Maybe one question on the recent reprioritization. Maybe walk us through as you look through the pipeline, like how much of the capital allocations are going to each of the programs, the way that you're foreseeing over 2024 and 2025? Yeah. Capital allocation and sort of prioritization of the pipeline on that basis was so important. You know, we'll start with 314. Steve will talk a lot about the data- Yeah and sort of where the program's going, but let me address it from a capital perspective. So we're partnered with AbbVie and they spend about $2 for every $1 that we spend. Yeah. Right? In terms of how we set up at steady state now the R&D partnership. That's because we have a 50/50 profit share- Yeah in the U.S., and we have a royalty-based deal outside the U.S. We also have some significant milestones that are, have the potential to be earned in the sort of coming period- Okay because of transition into later stage with our suprachoroidal. It was really important to us to make sure that RGX- 314 which is among, I think, the most valuable assets- Yeah in all of cell and gene therapy, was supersaturated- Yeah from a sort of capital investment perspective. Yeah. Because we have, I think, nine ongoing clinical trials- Right. Right two pivotal phase trials. Yeah. A bridging study excuse me, for our, subretinal route of administration, two late-stage phase II trials- Yeah going on with suprachoroidal, and more expansion work going on to support that value. So we locked that in. Yeah. I think the next most valuable program, and this was definitely informed by the recent data, is our Duchenne program. Yeah. I mean, again, we just presented the first efficacy data that we've ever had on this in the beginning of October. Actually, this morning- Yeah we just announced that we've dose escalated and dosed the first patient at dose level two. That's great. That means more data- Yeah is gonna be coming very quickly when it comes to biomarker measures longer term first ever measures of functional outcomes- Yeah and more safety. We're setting that program up to move into pivotal phase- Yeah and accelerate it as quickly as possible in 2024. So again, sort of the second tranche of capital- Yeah for us was fully saturate Duchenne- Yeah but importantly, make it move as quickly as possible. And then with respect to the Hunter program, that RMAT designation was great because it was validation. We had announced at the beginning of last year that we were going to be filing a BLA, but we really wanted wind in our sails with FDA here. Now we feel like we have it. The fact of the matter is, we've already fully enrolled- Yeah that trial. We've completed most of what's necessary to support the manufacturing for the BLA, and continue to Tie those things out. Yeah. Now we're in that data collection mode- Yeah and sort of transition to the paper filing mode. If you will. People don't do anything with paper anymore. Yeah. But electronic, maybe. Yeah. You know, that has to be saturated- Yeah As well from an investment perspective, but it really is leveraging the partnership with AbbVie. the great value that exists in wet AMD- Yeah and DR, being focused on Making Duchenne happen as quickly as possible. with this potential best-in-class profile and getting our first BLA Yeah filed next year. And that allowed us to extend runway after we saturated those things by, about another six months. Okay. We feel like the capital structure of the company is strong, the people we have in place science is working, and we have now guidance to continue to support those things into the second half of 2025. It was It was important work to do. Good. That's, that's great. Given that, you know, we have a limited time on the fireside chat, I want to spend, as you noted, to RGX-314, that's partnered, is a very big value-driving asset. So would love to just spend quite a bit of time on that program. Out of the, you know, nine studies that are ongoing, you know, and, and especially, you know, ATMOSPHERE and ASCENT are very key. Could you maybe start off giving us an update how is enrollment progressing into the studies? When do you expect to be in a position where you could give some color around timing of the top-line data? Sure. I can take that one. So as Ken mentioned, you know, just to lay a little groundwork, this is in collaboration, of course with AbbVie. At the beginning of the year, we were glad to announce that we'd expanded the pivotal program which I think it's great validation with AbbVie. of the global potential and the opportunity to expand outreach. So, that expansion included more patients and also going global. So to speak. Which of course makes sense for our goal of having further outreach. So in short, enrollment's going great. That's what's allowed us to continue to guide toward our overarching goal of BLA and also European regulatory submissions in late 2025 through the first half of 2026. So, we haven't given any guidance in terms of results or top line. But you can sort of work backwards. Knowing that it's a one-year endpoint. Yeah for example. How do the two studies differ from one another, and how much site overlap exists between the two studies then? Sure. So the designs are virtually identical. One of the key differences is a different comparator. So they're both non-inferiority designs on a primary endpoint of change in BCVA at one year, which fortunately is a Yeah well-trod path. Yeah. There's no regulatory risk on, on that endpoint. Against a comparator of repeated anti-VEGF. Yeah. One of the differences is different anti-VEGF- Yeah comparator arms. So ATMOSPHERE is with monthly Lucentis as the comparator, and ASCENT is with Eylea. Okay. So loading doses and then every other month. And for us, that's a great opportunity to show the most standard comparators that you can choose. Yeah. So the clinicians can have a- Yeah you know, confirmation of how one-time treatment stacks up Yeah against repeated injection. With, of course, the main difference Yeah beginning with RGX-314 Yeah It's a one-time treatment. Have you guys publicly disclosed what your non-inferiority margins are, or to show in both of the studies, or how you're thinking about it? Yeah, it's fine to discuss those because it's- Yeah generally recognized- Yeah via the FDA's comment. The FDA bases that on the variability that's been seen with comparator arm. For that reason, the non-inferiority margin is slightly different between- Okay the two studies. And that explains one of the other differences. Yeah which is a little different sample size between the two studies, because we, of course, wanted to make sure. We had both studies well powered. Okay, great. I guess, did you. Given that study is powered for primary, any key secondary endpoints that you powered for, that you want to show another aspect of differentiation for your product, versus what the current standard of care is? Yeah to high value? You know, certainly aside from the primary endpoint, one of the key benefits is reducing treatment burden. Yeah. That's a key goal that we know from other agents that still require repeat injections. Yeah. But still a value add of decreasing the treatment burden with greater treatment interval. In our case, our goal is to have dramatic reduction in treatment burden and even 50% or more patients that need no injections. Wow! So, that's one of the key drivers of some of the key secondary endpoints that we care about, and that's actually one of the reasons we expanded the studies to have even more power on some of these key secondary endpoints. You could almost think about it as not just one- Yeah but almost anywhere along the scale Yeah we can look at proportion, not just proportion of patients not needing any injection. We can look at proportion with 50% reduction Yeah et cetera, et cetera. That totality went into the consideration of- Yeah, I mean, certainly the regulatory primary- Yeah Endpoint is visual acuity. Yeah. Right. The commercial primary endpoint- Yeah is reduction in treatment burden. Yeah. Right. This is a one-time therapy- Yeah -that we're bringing forward as, and we've seen in phase I, II-A development that we've had a high proportion of patients often well over 50% Wow! that are going injection-free. Longest time points now are out to four years. Wow! That's an endpoint that we really sharpened up and especially AbbVie's input on the global negotiations that were going to occur ex-U.S. Yeah with the health technology assessment agencies put an even finer point on how to look at the stratification of Different types. We often talk about this in the context of sometimes how people talk about CAR T therapy. Yeah. Where you have, you have a proportion of complete responders. Yeah. Those are the patients that go four years- Yeah and never need another injection again. Yeah. And then you have partial responders looking at that from a stratification perspective, I mean, partial responder that for four years gets one or two injections a year Yeah is very different than Yeah someone that gets three to four. Right. We often see it in that stratified view. Again, reducing injection burden overall in these populations. Yeah being reduced by over 80%, and that is... That and the continuity of the treatment, the durability of it- Yeah that eliminates what's truly happening. Yeah -in the real world setting, where they just stop going on treatment- Yeah if they have to go on a regular basis. Visual acuity falls off at least by year two, if not sooner. Yeah. That, that's the commercial story. That's the power of gene therapy and a power of a one-time treatment Yeah that I think so far, we've only seen gene therapy- Yeah through RGX-314 be able to deliver on. Yeah. No, that's great. Definitely no doubt about it, the commercial advantage of having that data right on the label and drive strong adoption. Sticking with sort of the steps for filing and approvability, given that both of the studies are well conducted, well powered, with all the builds and levels you just discussed, do you need to. And they have two different comparator arms, but is there a need that you need to be positive in both of the studies to move forward to a filing perspective, or do you have to hit the, or could one study be sufficient to move forward, or is it just from a safety database requirement to see positive signals for both? Certainly, the default view is you would need both- Okay because of the standard of two adequate and well- Yeah controlled studies. One of the nice things is, because of our powering to hit a lot of key value driver endpoints. We certainly, safety exposure. Yeah is not an issue. Yeah. For this division, it's as low as- Yeah anywhere from 300- 500 patients Yeah for safety. So we'll have easily that amount of Got it -safety data. I assume there's quite a bit of site overlap between both of the studies, right? In terms of execution like, or is it slightly different that some sites are running one study versus another? There's a bit of a Venn diagram- Yeah but not that extensive. Yeah in overlap intentionally. Yeah. Also, there's the ability to cap sites for- Yeah -uh, uh, ex- Yeah -enrollment, you know, per study, to make sure there's not too much overlap. And of course, ASCENT went global- Yeah So that further reduces the amount of overlap. Remember this point, too, I guess, about. I mean, I think an expectation about hitting- Yeah -the margins in both studies. So RGX-314 is a product that by design is largely based on the antibody fragment that is Lucentis. Yeah. Right. So in our first study, ATMOSPHERE is based on a comparator to Lucentis. Eylea of course, was approved. Yeah originally as non-inferior. Right to Lucentis. Yeah. Right. So in some ways, the bar is actually higher for- Yeah -Lucentis- Right than it is for Eylea, and our molecule is more similar to Lucentis and it's the basis for the. First study design. So we really think the waterfall effect. Yeah There is in our favor. Yeah in terms of what's happened from a regulatory Yeah precedent perspective and the science itself. Yeah. No, that's, that's very helpful. And, and obviously, as you guys are really executing with your partner across studies and getting the data, getting ready for BLA, there's also a need to start thinking about commercially, right? From payer strategies to market access strategies. Could you maybe talk about what your vision is, right, if you're filing a BLA in 2025, right? Yeah. 2024 is sort of a very big year for you guys to kind of transition the company from a development stage to commercial. So would love to hear, like, how you're visualizing sort of the commercial readiness and anticipation for the BLA. Yeah, I mean, a lot of things are happening, and I think your point about, you know, the ramp-up that's gonna occur in 2024 is gonna be really meaningful. I mean, first, obviously, Steve already alluded to the fact that kind of the influence of the global commercial thinking. Has already even had an impact on clinical development. Exactly, yeah and on the expansion needs of being in additional jurisdictions, enrolling different types of patients. Yeah and the stratification work that we talked about. In addition to that, one of the primary roles that REGENXBIO plays in commercialization is in manufacturing. We opened up our own manufacturing facility. We've been using it for clinical development, and now we're readying it to- Yeah support commercial supply. And we're the primary source of commercial supply. Wow! at launch Yeah and we'll continue to be the primary source Yeah in the U.S., so that's a big deal for us. Yeah. I mean, we're also, by the way, looking to get there with respect to our BLA- Yeah filing for RGX-121 Yeah for Hunter syndrome. So there's a lot of sort of parallel reuse Yeah that's happening on the CMC side. And I think we've talked a lot about the fact that even before we built out our facility to be able to make product in the U.S. in Rockville, at our headquarters, we've actually been investing in the process for years. And the process across. All of our programs is very similar if not, if not identical in certain ways. And also, it benefits from the fact that we've already run it Yeah in GMP environments and are now just really installing it into a facility where our people are running the operation. That's a huge advantage for us, I think, both to move quickly to support that work. And then it comes to, you know, the—this is where the next step in the process is starting up this year, the interaction between AbbVie and REGENXBIO on more commercial readiness- Yeah outside of finishing off the trials, preparing the work- Yeah. preparing the CMC. A lot about value, a lot of discussion about you know, how we're going to come in and think about value-based pricing. Yeah. Yeah. I think this is gonna be a fantastic event for AAV gene therapy in general. Yeah. I've been excited about this for years, Yaz- Yeah because, you know Yeah We've been forecasting that there were gonna be, you know, low-hanging fruit, rare disease- Yeah approvals very early on, and they were gonna. We saw this with LUXTURNA. Yeah. We saw Zolgensma. Yeah. Now we're seeing the launches of the hemophilia products which also have been predicted to be the next approvals overall. Yeah. We took inventory of all of that. We said, "They're gonna check a lot of boxes. Yeah. But, a few boxes they're not gonna check are getting to millions of patients- Yeah and really entrenching themselves in a very important and sort of stable chronic disease that's not genetically based. Yeah. And so that's what RGX-314- Yeah is gonna deliver on in wet AMD first- Yeah and I think as an extension into other indications. It's gonna be giving people, and, and I think a larger proportion of people in the public Yeah a sense that gene therapy is here. Yeah as a medicine for millions of people. Yeah. And I think that's really exciting. In doing so, I think the approach to the commercialization plan Yeah the discussion of value and the pricing has to be conscious of that, and how many more audiences, and stakeholders there are, rather than some of these small congenital diseases- Yeah or, you know, of course, diseases with very, very high Unmet need in pediatric mortality. Yeah. I mean, they land in a- Yeah completely different way on the payer and caregiver system. Yeah. You know, we've been working on our own, and I love the collaboration with AbbVie here, the caregivers in an important way for years. And honestly, these retina specialists have seen a lot. Yeah. They've dealt with a lot. Yeah. Especially since, you know, the mid-2000s when some of the first anti-VEGFs have come forward, but now there's other things coming forward- Yeah for them as well, that are creating, sort of exciting Yeah potential, but also burdens Yeah like some of the geographic atrophy products. Here's gene therapy coming in a way that I think is perfect timing. Yeah for, changing how they manage patients. How they manage practice. And I think in important ways, we'll be looking at, you know, sort of what are the economics- Yeah of how they practice? Yeah. Undoubtedly, like, getting this product approved changed the entire landscape for gene therapy, right? As like you would be going after, you know, the first largest indication and making it accessible. Yeah. The question that sometimes comes up from investors always is: Well, is the regulatory agency gonna be more stringent on you, given that you have a one-time gene therapy product? Do they have to go through additional hoops and hurdles and data safety packages and etc., to allow to grant that approval? So I don't think anybody has a doubt how big of a deal the approval is. Maybe the question that they may wanna know is like, how do you ensure that they can get to the approval, given that the risk reward is different? Yeah. As you guys have been, again, interacting with the agency, do you see their engagement being very, like, data-driven? Everything we've seen is like, like, as long as you can execute in these studies and the totality of the data package, like- Yeah, I- they're not gonna make you jump extra hoops, you know? I'll Steve talk to the details. Yeah. He's been in retina for so many years. Yeah. Let me just give, you know, two important facts. Yeah for people. Number one is, you know, we had an end of Phase II Yeah discussion after doing dose escalation Yeah at 5 dose levels Yeah and looking at all patients for over a year. Yeah. Many of them had gone out over two years before we had that discussion. So it was very careful a deliberate set of data and conversation. We came into a discussion with the FDA, and it felt very, like, typical for them Yeah for just how they address any sort of- Yeah agent for wet AMD right now. Right. Because they've been seeing device-based products. Yeah. They've been seeing other new injectables. Yeah. They've been seeing injectables with different mechanisms of action. Yeah. You know, our view was we got treated no differently- Yeah at the sort of clinical and regulatory. Review level. That, that was point one. Point two was, we had already done that when one of the largest pharmaceutical companies in the world- Yeah came in, did diligence on our package Yeah on our end of phase II work, and paid us $400 million Yeah close to upfront Yeah validating the work that we had done, and helping us expand on it from there. Yeah. But Steve's been in the trenches in you know retina and with literal people at FDA Yeah for years. So, you know, what have you seen? Yeah, exactly how you described it, Ken. So from those trenches, it really was evaluated and discussed exactly the way other programs have been. There was no unique aspect for gene therapy, other than the things that are in the guidance like needing to follow up. Yeah for five years, which doesn't relate to the initial approval process. So strikingly similar. Really, which makes sense and when you think about it, that statistically and clinically. What are we trying to do? Yeah. It's the same concepts from a regulatory standpoint with the big benefit of decreasing treatment burden. Yeah to ensure patients get sustained anti-VEGF activity. Well, team, I can't believe, like, we need to have, like, a four hour fireside chat... Well, we've been talking about it. with you guys because you guys are like, have so much great work, great programs, and, and a lot of work that has gone behind. Just as I said, I just wanna say thank you. We're I think 2024 is gonna be a very big year, and we're super excited to work with you. And just wanna say thank you on behalf of all of us here at Piper Sandler. Let's thank the team for being here. Thanks for having us. Thank you.