Thank you for joining Q4 2021 REGENXBIO Inc. Earnings Conference Call. At this time, your lines have been placed on mute. Later in the call, there will be a question-and-answer session and instructions will be given at that time. [Operator Instructions] As a reminder, today's call is being recorded. [Operator Instructions] I'll now turn the call over to your host today, Patrick Christmas, Chief Legal Officer with REGENXBIO Bio. Sir, please go ahead.

Good afternoon and thank you for joining us today. With us today are Ken Mills, REGENXBIO's President and Chief Executive Officer; Dr. Steve Pakola, our Chief Medical Officer; and Vit Vasista, our Chief Financial Officer. Earlier this afternoon, REGENXBIO released financial and operating results for the fourth quarter and full year ended December 31, 2021. The press release reporting our financial results is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the Risk Factors and the management's discussion and analysis sections of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2021, and Comparable Risk Factors sections of REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, March 1, 2022, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I would now like to turn the call over to Ken Mills. Ken?

Thank you, Patrick. Good afternoon, everyone, and thanks again for joining us. I'm pleased to begin today's call with a quick recap of business highlights as well as an update on our corporate goals. Steve will then provide an update on our clinical programs, and Vit will provide an overview of financial results for the fourth quarter and year ended 2021. At the end of the call, we will open up the line for questions. I want to start off by saying how pleased I am with our performance as an organization over this past quarter and this past year. Against a challenging backdrop in 2021, REGENXBIO has continued to perform at a very high level, and I'd really like to take this time to thank our REGENXBIO team, our investigators and the patient communities for their commitment to the development of our innovative AAV therapeutics. One of the more important events for our company this past year was the signing and recent closing of our Eye Care Collaboration agreement with AbbVie for the development and commercialization of RGX-314. We're really pleased to be working with AbbVie, an industry leader in eye care as we advance RGX-314, a potential onetime treatment in clinical trials for the treatment of wet AMD and diabetic retinopathy and consider development in other chronic eye disorders. Aside from AbbVie's significant financial investment that we believe validates our innovative gene therapies and provide significant cash runway, the collaboration allows us to leverage AbbVie's leading development and commercial expertise. We plan to take full advantage of this collaboration as we work together to advance RGX-314 in multiple billion-dollar eye care markets. Yesterday, REGENXBIO, we recognized Rare Disease Day as we brought focus to this event, and thought to generate change for the more than 300 million people…

Thanks, Ken. I'll begin with an update on RGX-314, which is being developed in collaboration with AbbVie to treat multiple ocular indications, including wet AMD and diabetic retinopathy. RGX-314 uses the NAV AAV8 vector to deliver a gene encoding a therapeutic antibody fragment to inhibit vascular endothelial growth factor or VEGF. Wet AMD is the leading cause of vision loss in people over 60, affecting more than two million patients in the U.S., Europe and Japan. The current standard-of-care for wet AMD is anti-VEGF treatments, which require patients to receive injections into the eye every four to 12 weeks for the duration of the disease. Real-world evidence shows that patients with wet AMD are severely undertreated due to the unsustainable treatment burden of these frequent injections required with currently approved anti-VEGF therapies. As a result, the majority of wet AMD patients experience significant vision loss over time. RGX-314 is being developed as a onetime treatment for wet AMD that has the potential to reduce the frequency of anti-VEGF treatments and preserve vision for wet AMD patients. In our Phase 1/2 clinical trial of RGX-314 for the treatment of wet AMD, using the subretinal delivery approach and its long-term follow-up study, we have observed a durable treatment effect over three years, including mean improvement in vision and stable retinal thickness and reduction in anti-VEGF treatment burden. We believe RGX-314 represents a significant potential advancement for the treatment of wet AMD. We continue to enroll patients in the ATMOSPHERE trial, the first of two pivotal trials to evaluate the efficacy and safety of RGX-314 in patients with wet AMD using the subretinal delivery approach. We also recently announced in January the initiation of the ASCENT trial, our second of two pivotal trials evaluating the efficacy and safety of subretinal delivery of RGX-314…

Thanks, Steve, for the really good updates, and especially to the team for the progress over the past quarter and this past year. Let's see. Before turning the call over to Vit, I wanted to circle back to discuss our manufacturing a bit more and its importance to our overall strategy. We have over 21,000 square feet of our corporate headquarters, that's dedicated to our in-house GLP pilot plans, advanced analytic labs, multiple 2,000-liter bioreactor suites for cGMP manufacturing of bulk drug substance and a new flexible and state-of-the-art fill/finish suite to support all of our multiple programs focus. And we've been talking about our investment in an in-house GMP facility is an important next-step to have better control over our manufacturing process and supply. But specifically, I want to highlight that there's a real close alignment that exists between our research team and our manufacturing team. We believe that this is a key differentiator for REGENXBIO in two ways. First, it allows for us to move quickly from candidate selection to production of clinical-grade material, which supports accelerating the early development of our AAV therapeutics. And second, we believe that our approach focuses early on product quality and process control, which lessens the need for changes during clinical development to enable efficient transition from clinical trials into that commercial readiness. And another piece to add is that our manufacturing team has also formulated AAV therapeutics to be used in a number of different innovative delivery device solutions and techniques, including the pioneering work and clinical use of suprachoroidal and intracisternal intervention. So we believe being a leader in innovative device delivery of AAV therapeutics is a distinguishing competency of REGENXBIO as we progress our new 5x25 strategy. With that, I will turn the call over to Vit to review our financial guidance.

Thank you, Mr. President. REGENXBIO ended the quarter and year on December 31, 2021, with cash, cash equivalents and marketable securities, totaling $849.3 million compared to $522.5 million as of December 31, 2020. The increase was primarily the result of the $370 million upfront payment recognized upon the closing of the AbbVie Eye Care Collaboration and $216.1 million of aggregate net proceeds received from our follow-on public offering of common stock completed in January 2021. The increase was partially offset by cash used to fund operating activities and capital expenditures during the year ended December 31, 2021. Based on our current operating plan, we expect the balance in cash, cash equivalents and marketable securities of $849.3 million as of December 31, 2021, to fund our operations, including the completion of our internal manufacturing capabilities and clinical advancement of our product candidates into 2025. With that, I will turn to the state of REGENXBIO address back to President Mills to provide final thoughts.

Much appreciated, as always, Vit, and thanks for the highlights of the financial position of the company. So as you've heard from Steve and Vit in our update today, we've had important progress across our pipeline of AAV therapeutics. Furthermore, we look forward to steering in the direction of supporting more late-stage development and commercialization of AAV therapeutics through our 5x25 strategy, and utilizing our internal GMP facility to support the acceleration in the development of our AAV therapeutics. We're confident that we have the right team in place across all key business levels, including science, manufacturing and commercial. We believe that our science has been validated, both by our own growing body of clinical data as well as key collaborations like our Eye Care Collaboration with AbbVie and the numerous other license agreements with leading biotechnology companies who use our NAV technology. We believe truly that we have the end-to-end capabilities in place to support our plans to efficiently and successfully advance our exciting pipeline. And as Vit noted, we have capital in a balance sheet to support our strategy. I'm more confident than ever in our science and our people to support our ability to develop AAV therapeutics for diseases that have the potential to significantly impact patients' lives. We look forward to continued progress in the coming year. I'm particularly excited about advancing our new 5x25 strategy within the company and progressing our Eye Care Collaboration with AbbVie in dosing the first participants in our RGX-202 clinical trial for the treatment of Duchenne. For now, I'll turn the call over to the operator for questions.

Thank you. [Operator Instructions] Your first question is from the line of Gena Wang from Barclays. Your line is now open.

Hi, guys. Thanks for taking the question. This is Tom for Gena. Thanks for the update as well. We have three questions. First question is about the bridging study following your comment on manufacturing. Just wanted to get a bit more color on the current status of the study and estimated time of completion. And also, do you plan to present data some time later this year? The second one is for 315 suprachoroidal wet AMD study Cohort 3. As we know, the total dose was the same as Cohort 2, but deliver only by one injection versus two injections in Cohort 2. Is there any reason to expect one could potentially lead to better visual acuity or better safety? And lastly, for the Duchenne trial design, how should we think about the patient baseline, age, NSAA score and what would be the initiatives? Thank you.

Thanks, Tom, for the questions. Steve, I'll start with the bridging study, and maybe you can follow up on the two additional questions. I think Tom, with respect to the bridging study, it's part of our overall pivotal program, which we announced last year with respect to providing guidance on a BLA date of 2024. We're right now operating all three studies in parallel and enrollment is ongoing in all of the studies ATMOSPHEREs and as well as the bridging study. We don't have any additional guidance beyond that. All of this is on track, and we continue to – including on the other side of the announced collaboration with AbbVie, AbbVie with respect to the Eye Care collaboration continue to support the 2024 plan for BLA for the subretinal approach. So that's our answer to that question. With respect to suprachoroidal 314, Steve, do you want to take that one?

Sure. So as you pointed out, Cohort 3 is a single injection of 100 microliters. The same total dose though, in terms of GC per eye as Cohort 2. Where in Cohort 2, had two separate injections of each 100 microliters. Our plan is that one injection is better than two from an overall feasibility and patient and doctor delivery standpoint. We have no reason to expect one approach would be better than another, though on a safety tolerability standpoint, certainly, a single injection is much preferred. And I’ll take that opportunity to say, all our other cohorts are going forward, are with the single injection with 100 microliters in both our AAV8 study and our ALTITUDE suprachoroidal delivery studies. Regarding – and then you also asked about when we could have the status or when we could have results. We’re excited about the agreement we have with the FDA from the end of Phase 2 from our overall bridging plan. As Ken mentioned, we’re very excited about our global partnership with AbbVie. So we’re very excited with collaborating closely with AbbVie on talking about our future plans for other disclosures, but we don’t have any other updates to give in terms of that program in terms of what we’ve already discussed. Your third question on our AFFINITY Duchenne study. So as we’ve disclosed, we’re starting with 1E14 GC per kg, and this is a dose that we’re excited about based on our overall preclinical package and the findings that we have there, where, of course, in onetime gene therapy for Duchenne, it’s important to start at a dose that you believe you will see some effect and potential for benefit. So we’re excited about starting that study in the first half of this year.

Yes, Steve, I think the question was to do with the inclusion criteria. Tom, we – as we’re starting up the study, we have disclosed that we’re going to be focused on males in the age range of, I think, it’s four to 11 with ambulatory function, including mutations in the DMD gene that are between certain exons and we will be excluding patients on the basis of anti-AAV antibodies. So that’s some flavor for the inclusion and demographic criteria for the study. Thanks for the question.

Thanks, very helpful.

Thank you. And your next question comes from the line of Alec Stranahan Bank of America. Your line is now open.

Hey guys. Thanks for taking our questions. Just a couple from us. First on the suprachoroidal DR patient that had a sustained four-step improvement. Are there any characteristics unique to that patient that you can point to, say, outside response? And given the anticipated pace of enrollment for a couple of the higher dose cohorts in the first half of this year, is it safe to assume we could see three-month data from both the wet AMD and DR suprachoroidal studies maybe later this year? Would you prefer to wait for a more mature six-month data update? And then just on your 5x25 plan and use of cash going forward, good to see runway into 2025. I guess, would you consider maybe bringing in any external technologies to supplement the NAV platform, or is the plan really to support the later-stage development and maybe add to it de novo? Thanks.

Thanks, Alec. Steve, do you want to jump on the 314 DR question?

Sure. So Alec, you pointed out the four-step improver that we included in our presentation from Cohort 1. And the nice aspect of the diabetic retinopathy severity score is the ability to actually see the evidence of disease and what ultimately progresses and eventually leads to bad outcomes for these patients. So we don’t go into the granularity of the specific changes, but the consistency that we see across the data set in terms of being able to see a significant a meaningful proportion of to achieve at least two-step improvement and also have some cases where you get more than two-step. The more step changes you have, the more evidence, the stronger the improvements are in the underlying evidence of disease when you actually look at the retinal disease. So we’re excited that we have Cohort 1 that we have a six-month data and that we can continue to follow those patients longer. Similar to the answer to the prior question, we’re not in a position to give specifics on when we’d have data coming out from later cohorts, but we and our partner, AbbVie, are excited about advancing not only with longer-term follow-up for Cohort 1, but also being able to do the same at a higher doses in cohorts 2 and 3 where we also get to look at NAV-negative as well as NAV-positive patients.

And on the 5x25 questions, Alec, I think I hope that this strategy emphasizes several points. One is absolutely our focus on our medical and our operational, including our GMP capabilities to enable the development of current and emerging late-stage programs towards commercialization is absolutely a focus. I think it also places emphasis on our research and early development team to bring forward new innovations and connect with the types of things we’ve evidenced that we can do in the past, bring forward new biology, bring forward new focus for AAV therapeutics on targets and made that up potentially either organically or in partnership with new devices and new routes of administration. So I think the next few years are for us about getting into later stages of development, establishing the company having capabilities for late-stage development as well as commercialization. But bringing forward that continued innovation that’s been there all along in my view. And as you alluded to, and I think we feel that we’re in a strong financial position to be able to make those types of investments on an end-to-end basis through 2025. And with evidence of a BLA in 2024 and other things emerging, I feel really encouraged that we’re in a really good place for shareholders and stakeholders.

Thank you.

Thank you. Your next question comes from the line of Vikram Purohit from Morgan Stanley. Your line is now open.

Thanks for taking our call. This is Gospel on for Vikram. So we have one question. So for the suprachoroidal delivery of RGX-314, you have observed some intraocular inflammation in wet AMD, not in DR. Do you have a current hypothesis as to what could be driving this difference?

Thanks, Gospel. Steve, would you like to provide an answer here?

Yes, I can address that. Thanks for the question. Keeping in mind it’s relatively small numbers across the different groups. But as you pointed out, we haven’t seen any intraocular inflammation in Cohort 1 in the DR patient population and we see low rates and easily managed rates in the data that we’ve presented for the wet AMD population. So we don’t conjecture that there’s directionally a greater likelihood to have an inflammatory response. Some have wondered could ER patients be more prone to an inflammatory response. There’s no evidence of that from our historical epidemiology and all the interventions that exist with biologics that have been used to treat both wet AMD and DR, but certainly, from our data, there continues to be no suggestion of an increased risk. So we’re just very glad to see across the both platforms, the wet AMD patient population and the DR population that we don’t see any signs of concerning inflammation. And that’s particularly key since this is in the backdrop of no prophylactic steroids unlike other programs out there. So we’re very pleased with the overall safety and tolerability that we’re seeing to date in suprachoroidal in-office delivery for both wet AMD and DR.

Thanks, Gospel.

Thank you.

Thank you. Your next question comes from the line of Dane Leone from Raymond James. Your line is now open.

Thanks for taking the questions. Just two simple ones for me. Regarding the A8 study and next follow-up on the clinical data. Is it possible that we’re going to get the 12-month data from Cohort 1 during the back half of 2022? And would it be possible to get a six-month data from cohorts 2 or 3 before year-end? And then the second question I have is, could you just remind us of how the economics work now that you have the ASCENT study open with 314? And when some of the cost of the trial and program for ATMOSPHERE and ASCENT transfer to AbbVie from your P&L? Thanks.

Thanks, Dane. So I think as we’ve talked about with everyone since the announcement and closing of the AbbVie collaborations. We have a partner here in AbbVie, and we’ve been aligning with them and sort of setting in place a lot of important structures for us to continue to leverage one another’s experience and expertise to accelerate as quickly as possible, all the work that’s going on around RGX-314. In terms of plans for updates, while we don’t have any specific guidance right now, what we are saying is that we continue to use the intervals that we’ve been updating on with respect to the program. So in the case of wet AMD, we view that things at the six-month and 12-month time points for cohorts are meaningful and contributory in terms of making decisions about programs as well on the diabetic retinopathy side, we’ve seen evidence of intervals on the order of three months and six months. We plan to continue to use those as milepost to establish communication with all stakeholders, including investors, and we plan to continue to do that at major medical conferences with investigators who are involved in our studies making presentations. So I think that what we’re able to do right now is show everyone where we are with respect to enrollment and talk about the fact that we look forward to in the future being at medical conferences with similar intervals of updates as we have in the past. And as we get closer to those dates like we did with respect to angiogenesis just, I think, a few weeks ago, then we’re able to get more clarity when things are actually accepted by these submissions of these investigators for these presentations. And with respect to the economics, Dane, thanks for bringing that…

Thanks.

Thanks for the question.

Thank you. Your next question comes from the line of Mani Foroohar from SVB Leerink. Your line is now open.

Thanks for taking the question. Regarding 5x25, just that we think on modeling and timing. Obviously, there’s pretty straightforward to think about what the metrics are to consider in 2025. But can you give us a sense of how to think about ramp of investments and specific events that you think we should be focused on in the interim between here and 2025 in terms of timing of moving certain things in the clinic as the late stages and temporal lobe [ph] late-stage data sets, et cetera?

Yes, Mani, thanks for the question and the focus on that strategy. I think – look, we’ve outlined and identified that we view that RGX-314 is obviously a major contributor to the 5x25 strategy. We’re looking at, obviously, the continuation of the pivotal program for subretinal and we have given guidance for a BLA in 2024. I think that communicates that this is obviously a lead program that we’re looking to make that transition into in late stages of development and beyond from 2024 into 2025. Super choroidal, our Phase 2 studies that are being run both in wet AMD as well as diabetic retinopathy. And we view the kind of runway in front of those programs as having the types of experiences and decisions that we had when we were sort of in the Phase 2 stages of the subretinal program. So seeing those transition into later stages of development, would be considered to be options for sort of a base plan of achieving metrics. And RGX-121 is already obviously clinical phase. We’ve talked about that we’ve recently shown data that we believe is supportive of really good outcomes for some of the children that have enrolled in these studies. We’ve done significant dose ranging in the clinical trials. We’ve seen evidence of biomarker changes that are dose dependent. And we’ve seen correlations to outcomes when it comes to cognition and other things that are both measurable and important. So we’re feeling really good about clinical data there, putting us on track to make advancements with respect to 121. And frankly, RGX-202 as a program, we continue to be really encouraged by the science we’ve seen preclinically, the safe to proceed and capabilities that we have in place, especially on the quality of product manufacturing we are giving guidance…

No, that was really very useful. Thanks.

Thanks, Mani.

Thank you so much. And your next question comes from the line of Luca Issi from RBC. Your line is now open.

Okay. Thanks for taking our question. This is Lisa on for Luca. Two from us. Firstly, on the Phase 3 wet AMD, the pivotal trials. I believe this Phase 3 for wet AMD is really one of the largest ever to use subretinal injection as a route of administration. And given this is a surgical procedures, I’m just wondering if you can provide us any color on what efforts you have employed to maintain consistency from site to site in order to help limit any variability. And my second question has to do with the bridging studies. I know your bridging study is powered to show non-inferiority on protein concentration as a primary end point. But we also see a few secondary endpoints listed including BCVA. Just wondering if you could also provide more color on whether or not meeting non-inferiority on the secondary endpoints will also be required by the regulators here. Thank you.

Thanks, Lisa. Steve, do you want to answer both of those questions?

Sure. Hi Lisa. Thanks for those two questions. So the first one, yes, we’re really proud of the scale, so to speak, in terms of both the size of the trial and overall advancement for the field in terms of subretinal delivery of gene therapy for a big indication like wet AMD. To your point, one issue is scalability in terms of surgeons and actually training on this. And this is something that we have a lot of experience on over the years given that we advance first through our Phase 1/2 study and those 42 patients. And as with that study, we carry forward what you might expect a surgical trainer or liaison team that trains new surgeons in performing this procedure. And as we talked about during Phase 1/2, what we’re seeing in action now that we’re into two pivotal studies now, ATMOSPHERE and ASCENT is we actually get to see this real time in terms of training additional surgeons. And as we anticipated, we’re seeing that it’s fairly straightforward because of these are retina specialists and retina surgeons who have experience doing a lot more complicated procedures than this procedure of a standard small-gauge vitrectomy and injection of the gene therapy subretinally. So it’s something that we’re glad to be actually implementing on and actually executing. And we’re basically following the same process of training new surgeons and following these. But as anticipated, we’re not seeing any issues with new surgeons coming online for this. The second question on the bridging study – so we reached agreement with the FDA at our end of Phase 2 on our overall plan. We have a primary endpoint looking at protein to show general comparability. The reality is, as we already know, with that number of patients 15 in an active comparison type approach, there really is powered to differentiate or show non-inferiority on those other types of anatomic or functional endpoints, but we do obviously measure them and take advantage of having that to continue to learn more about and gather more data. But there – I think you can – the main answer to your question is they’re not – the study is empowered to really look at those in any kind of definitive way. So we don’t see that as a key aspect.

Thank you. Very helpful. Thanks for taking the questions.

Thanks, Lisa.

Thank you. And your next question comes from the line of Andreas Argyrides from Wedbush. Your line is now open.

Thanks for taking our question. Just a quick one from us, and apologies if it was asked previously, we had a little connection issue. But – so based on the subretinal 314 data showing that patients with baseline NAbs to AAV8 did not impact the transduction. Can we – or how do you expect – are there any reads since the Cohort 3, the data that we’re going to see from AAV8? Thanks.

So with...

Yes, Steve, you’re on it? Good.

Okay. All right. Thanks, Ken. So for subretinal, as you mentioned, we did not see any impact of preexisting neutralizing antibodies to aviate nor did we expect to because there’s so much known about subretinal delivery, and that’s why that’s been historically the gold standard, including the relative immune-privileged status of the subretinal space. But we still measured baseline map status and confirmed in our Phase 1/2 that patients who had preexisting NAbs did just as well from a safety and efficacy standpoint as patients who were NAV negative. For suprachoroidal delivery, we’re very encouraged that preclinically. We don’t see inflammation in any type of response, and that’s what allowed us to feel confident to go into dose ranging without prophylactic steroids. We did intentionally set up different cohorts so that we could answer the question you’re asking of whether like subretinal delivery, can we deliver RGX-314 to the suprachoroidal space and weather neutralizing antibodies matter or not when delivering to that space. So that’s why we’re excited to be able to look at that in both Cohort 2 compared to Cohort 3, but then also at the third dose level Cohort 4, which we completed dosing in and Cohort 5, the NAV positive corollary of Cohort 4. So we look forward to answering that question.

Great. Thanks for the color.

Thanks.

Thank you. There no further question at this time. I would now like to turn back the call over to Ken Mills to make any closing remarks.

Thanks, operator. I just wanted to say thanks, everyone, again for joining us today, and I hope that all of you have a great weekend. We look forward to seeing you all soon. Thanks.

Ladies and gentlemen, this concludes today’s conference call. Thank you for your participation. You may now disconnect.