Regenxbio - Earnings Call - Q2 2025

Executive Summary

• Q2 2025 missed Street: revenue $21.36M vs $40.87M consensus and EPS $(1.38) vs $(0.90) consensus; larger operating loss and higher interest expense drove the EPS delta, while royalties (Zolgensma) declined YoY to $18.4M. S&P Global estimates marked with asterisks; see disclaimer below.*
• Cash runway extended to “into early 2027” following $150M non‑dilutive royalty financing; quarter-end cash, cash equivalents and marketable securities were $363.6M.
• Pipeline catalysts tightened: RGX‑202 pivotal enrollment now expected complete in October 2025 (earlier than prior), topline 1H26, BLA mid‑2026; RGX‑121 BLA accepted with Priority Review (PDUFA Nov 9, 2025); sura‑vec DR advancing to pivotal Phase IIb/III with $100M milestone upon first patient dosed from AbbVie.
• Management emphasized differentiated safety strategies (immune modulation, high full capsid purity), AbbVie’s increased investment (ACHIEVE Phase IIIb), and non‑dilutive funding optionality (potential PRV sale, milestones) as supports into multiple launches.

What Went Well and What Went Wrong

What Went Well

• RGX‑202 DMD program timelines pulled forward; enrollment completion now targeted for October 2025; commercial manufacturing to start in Q3 2025 to enable launch scale capacity (“up to 2,500 doses per year”).
  • CEO: “We now expect to complete enrollment in the ongoing pivotal study this October… initiating commercial manufacturing this fall… can produce up to 2,500 doses of RGX‑202 per year.”
• RGX‑121 BLA accepted with Priority Review; FDA mid‑cycle, PLI and BIMO inspections completed with no observations; PDUFA Nov 9, 2025.
• Sura‑vec (ABBV‑RGX‑314) DR program advanced to pivotal Phase IIb/III on positive two‑year ALTITUDE data; AbbVie milestone structure updated ($100M upon first patient in Phase IIb/III; $100M upon first patient in second Phase III); AbbVie to fund ACHIEVE Phase IIIb wet AMD study.
  • CMO: “A single in‑office injection… was well tolerated… dose level 3 achieving at least a 70% reduction in vision‑threatening events vs historical control.”

What Went Wrong

• Financial miss vs consensus: revenue $21.36M vs $40.87M consensus and EPS $(1.38) vs $(0.90); YoY royalty decline (Zolgensma royalties $18.4M from $21.8M) and higher R&D burden pressured results.*
• Operating spend rose: R&D $59.5M (vs $48.9M YoY) driven by manufacturing/clinical supply and pivotal trial costs for sura‑vec and RGX‑202; G&A also higher YoY to $19.9M.
• Interest expense jumped to $11.0M (vs $0.45M YoY), contributing to net loss $(70.9)M; company completed a $150M royalty monetization during the quarter, increasing financing costs.

Transcript

Speaker 1

Welcome, everyone, to the second quarter 2025 REGENXBIO Inc. Earnings Conference call. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press the star one. Please note, slides referenced during this call are available in the webcast and at the events page of REGENXBIO Inc.'s website. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of REGENXBIO Inc. Please go ahead.

Speaker 2

Good morning and thank you for joining us today. Earlier this morning, REGENXBIO Inc. released financial and operating results for the second quarter ended June 30, 2025. The press release 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 section of REGENXBIO Inc.'s annual report on Form 10-K for the full year ended December 31, 2024, and comparable risk factors sections of REGENXBIO Inc.'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, August 7, 2025, 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'll now turn the call to Curran Simpson, President and CEO of REGENXBIO Inc. Curran?

Speaker 5

Thank you, Patrick, and thank you everyone for joining us. I hope you're having a great summer. Today, I'm pleased to be joined by Dr. Steve Pakola, our Chief Medical Officer, and Mitchell Chan, our Chief Financial Officer, to review the exceptional progress being made by the REGENXBIO Inc. team as we prepare for our first commercial approval this year and multiple potential near-term product launches. Before we begin, I'd like to acknowledge the Duchenne community and the recent events they have faced. We understand these have been incredibly challenging and uncertain times and express our deepest sympathies to the families experiencing loss. These recent events have only reinforced our strong commitment to deliver RGX202 as a potential best-in-class gene therapy for Duchenne. We believe that RGX202 has the potential to safely provide strong functional benefit and durability, offering hope for better lives.

With positive and growing interest from the patient community and physicians, I am very pleased to share that we are accelerating our guidance for RGX202. We now expect to complete enrollment in the ongoing pivotal study this October. Our ability to move this timeline up from end of year further solidifies RGX202's position as the potential next gene therapy to market for Duchenne. The community is clearly in need of additional options. We continue to actively enroll and open new sites in the AFFINITY DUCHENNE pivotal trial, with plans to roll directly into a confirmatory study to support our accelerated approval. Additionally, we are in the unique position of having drug supply in hand for our pivotal and confirmatory trials.

We remain on track to report top-line data in early 2026, permit a BLA in mid-2026, and potentially be on the market by 2027 when the vast majority of the DMD population is expected to remain untreated. From the beginning of this program, we implemented a differentiated therapeutic approach. We pioneered a proactive immune suppression regimen to drive improved safety outcomes and reduce the potential risk of known liver issues found in other programs. Our Phase 1/2 data to date supports that our approach is effective. RGX202 also has consistent industry-leading purity levels in Duchenne, with over 80% full capsid content in our product. This is important because higher purity leads to less total vector load delivered to patients and may contribute to the positive safety profile we've seen to date.

We believe our in-house manufacturing capabilities are a highly strategic asset and give us a unique ability to serve the large Duchenne market available at launch. We are pleased to announce we are initiating commercial manufacturing this fall at our Manufacturing Innovation Center here in Rockville, Maryland. This GMP facility can produce up to 2,500 doses of RGX202 per year. With our strong momentum and as the only investigational gene therapy enrolling in a Phase 3 study in North America, RGX202 is well positioned to be next to market and a potential best-in-class gene therapy for Duchenne. Let's turn our focus to our retinal disease franchise. In partnership with AbbVie, we continue to advance ABBV-RGX-314, also known as Serabgine Lumparvovec or SURAVEC, as the potential one-time gene therapy for chronic retinal conditions.

I'm very pleased that earlier this morning we announced an update to our agreement with AbbVie to advance SURAVEC into pivotal Phase 3 for diabetic retinopathy. Based on positive two-year data from the Phase 2 ALTITUDE trial, we will initiate a Phase 2b/3 trial. The cost of the study will be covered by the accompanying milestones, including the $100 million we receive upon the first patient dosed in the Phase 2b portion of the trial. Steve and Mitch will share more about the data and financials shortly, but let me reiterate our excitement about this program, which gives us another pivotal program in chronic eye care with our partner AbbVie. Both wet AMD and DR represent large multibillion dollar commercial opportunities, and we believe SURAVEC has the potential to preserve vision, prevent disease progression, and serve as a meaningful alternative to today's standard of care.

Last but not least, the FDA accepted our BLA for RGX-121, now known as cabalistogene autogemtemcel, also known as camlidzogine lumparvovec, for the treatment of MPS II or Hunter syndrome. This BLA was accepted under the accelerated approval pathway with a target PDUFA date of November 9. Pre-BLA activities are progressing well. We have completed the mid-cycle review meeting and our first PLI and BMO inspections with the FDA successfully with no observations. These are exciting achievements and a testament to the exceptional quality of our people, process, and science. If approved, RGX-121 will be REGENXBIO Inc.'s first approved gene therapy. Commercial preparations with our partner Nippon Shinyaku are progressing well. Products intended for launch have already been produced, and we are committed with our partner to bringing this potentially transformative treatment to patients in early 2026.

These accomplishments demonstrate our seamless and focused execution against our strategy to bring potentially transformative gene therapies to patients. We remain excited for and well positioned to deliver on opportunities ahead of us. With that, I would like to now turn the call over to Steve for an update on our clinical programs. Steve?

Speaker 2

Thank you, Curran. Today, we're excited to share updates across our multiple pivotal programs. I'll start with our retina franchise, SURAVEC, which is being developed in collaboration with AbbVie to treat wet AMD and diabetic retinopathy, or DR. First, I'll address SURAVEC for DR, being evaluated in the Phase 2 ALTITUDE trial using in-office suprachoroidal delivery. I'm pleased to highlight the data supporting our advancement to pivotal stage. The data slides are available in the webcast and on the events page of our website, and you can follow along as I discuss. As outlined on slide 3, DR impacts more than 20 million people globally, and these patients are at increased risk of developing vision-threatening complications. Moving to slide 4, a one-time in-office injection of SURAVEC has the potential to provide long-lasting improvement to disease severity and reduce the risk of vision-threatening events or DTEs.

Using one-time in-office suprachoroidal delivery is convenient for the working-age population impacted by DR. Also, this route of administration allows targeted delivery into a compartmentalized space to limit exposure to the vitreous in the anterior segment. Slides 5 and 6 show the ALTITUDE trial design and baseline characteristics of participants with nonproliferative diabetic retinopathy or NPDR. Moving to safety data on slide 7, SURAVEC was well tolerated at all dose levels. Further illustrated on slide 8, we are very pleased to share that at two years in dose level 3 with short course prophylactic topical steroids, there were zero cases of intraocular inflammation. Moving to efficacy on slide 9, starting with the one-year results. As expected, in the untreated control group, patients generally get worse, with 41% experiencing at least two-step worsening in their diabetic retinopathy severity score, or DRSS.

In stark contrast, NPDR patients treated with dose levels 2 and 3 are generally improving. Now on slide 10, for the first time, we share two-year results. SURAVEC demonstrated a dose-dependent increased rate of meaningful DRSS improvement, with 50% of dose level 3 patients achieving at least a two-step improvement without need for any supplemental treatment, a rate six times that of historical control. Slide 11 further illustrates the durable efficacy seen over time at dose level 3 out to two years. Importantly, these imaging results are translating into benefit in terms of decreased risk of vision-threatening events. On slide 12, SURAVEC-treated NPDR patients had a dose-dependent reduction in DTEs, with dose level three achieving at least a 70% reduction in DTEs compared to historical control.

In summary, on slide 13, a single in-office injection of SURAVEC was well tolerated and demonstrated durable long-term efficacy, including meaningful DRSS improvement and significant reduction in the risk of vision-threatening events. Based on these compelling results and in agreement with AbbVie, we are initiating a global pivotal program. The initial pivotal trial will be a two-part Phase 2b/3 double-masked placebo-controlled superiority trial, including two dose arms of SURAVEC. The primary endpoint will be a proportion of patients with at least a two-step improvement on DRSS at one year. This pivotal trial will have two sequential parts. The first part will be the dose selection phase that includes dose level three and dose level four arms from ALTITUDE to allow interim evaluation of safety and efficacy to then select the dose or doses to carry forward into enrollment of part two of the pivotal protocol.

Site selection is already in progress, and we look forward to sharing more on this program as we progress. In wet AMD, we are evaluating SURAVEC via two different delivery forms: subretinal and suprachoroidal. Within subretinal, we have two ongoing pivotal trials, ATMOSPHERE and ASCENT, in the U.S., Europe, and Japan. These trials continue to progress well with enrollment nearing completion. Overall, we remain encouraged by the ongoing progress with SURAVEC, especially the safety profile observed in our suprachoroidal programs. This is particularly notable in the setting of short course prophylactic steroid eye drops, a significantly shorter regimen than those used in other gene therapy trials. Moving to RGX202, a potential best-in-class one-time gene therapy for the treatment of Duchenne. RGX202 is the only microdystrophin construct to include the C-terminal domain, making it the closest to naturally occurring dystrophin.

The C-terminal domain has been shown to prolong microdystrophin activity and preserve muscle health by protecting it against contraction-induced damage. This preclinical research was recently published in ASGCT's peer-reviewed journal. This construct, combined with the highest purity levels in the field and a proactive immune suppression regimen, are translating into the clinic with better functional outcomes and favorable safety profile, including in older boys. In June, we presented new positive Phase 1/2 interim data for RGX202 at the pivotal dose, showing meaningful functional improvements compared to expected disease trajectory. Notably, at 12 months, all patients demonstrated improvement on time function tests compared to baseline, with time to stand, 10-meter walk run, and time to climb results exceeding the minimally important difference. The majority of patients were eight years and older at dosing, an age when functional decline would typically be expected.

RGX202 also continued to be well tolerated with no SAEs or adverse events of special interest. Even at our higher dose level, we have seen no thrombocytopenia and no evidence or signs of liver injury in any patient, including as assessed by liver function testing. To build on what Curran shared earlier, the differentiated therapeutic approach for RGX202 includes a proactive short course immune suppression regimen that was developed from the outset of this program in collaboration with the patient community and leading Duchenne physicians. We pioneered this approach for improved safety outcomes. We're very pleased with how this patient-focused approach, along with our differentiated product, is translating into a favorable safety profile observed to date.

We expect to complete enrollment of the 30 patients in the AFFINITY DUCHENNE pivotal trial to support accelerated approval by October of this year, and we will continue to enroll after that for a confirmatory trial. Now on to RGX121. It's such an incredibly exciting time for REGENXBIO Inc. and the Hunter syndrome community with the ongoing progress for our RGX121 BLA. RGX121 represents a potentially transformative one-time treatment for patients with Hunter syndrome. We look forward to an anticipated FDA decision in November. Overall, we're making significant progress across all our late-stage programs. I'd like to express my sincere gratitude to all the patients, families, clinicians, site staff, and patient advocacy representatives who have supported these trials. With that, I'll turn the call over to Mitch to review our financial guidance. Mitch?

Speaker 1

Thank you, Steve, and good morning, everyone. REGENXBIO Inc. ended the quarter on June 30, 2025, with cash, cash equivalents, and marketable securities of $364 million compared to $245 million as of December 31, 2024. The increase is primarily driven by the $110 million upfront payment from Nippon Shinyaku in the first quarter of 2025 and the $145 million in net proceeds received from the royalty monetization with Healthcare Royalty Partners in the second quarter of 2025 and was partially offset by cash used to fund operating activities in the first half of 2025. R&D expenses were $60 million for the quarter ended June 30, 2025, compared to $49 million for the quarter ended June 30, 2024. The increase was primarily attributed to manufacturing-related expenses and other clinical supply costs and clinical trial expenses for SURAVEC and RGX202 pivotal trials.

Turning to the specifics around the SURAVEC announcement today, Steve went through the very encouraging data we continue to generate in diabetic retinopathy and a new Phase 2b/3 study that both AbbVie and REGENXBIO Inc. believe will be designed to strengthen the body of evidence for SURAVEC in diabetic retinopathy and maximize the probability of success in a planned global Phase 3 program. Under the terms of the amended agreement, we are effectively being paid in advance half of the $200 million milestone that would have been earned upon dosing of the pivotal trial. We will now be paid $100 million upon first patient dose in the Phase 2b/3 trial and receive the next $100 million upon dosing of the first patient in the second Phase 3 trial. This brings in $100 million upon first subject dose and more than covers the cost of the Phase 2b trial.

Additionally, the amendment reflects AbbVie's continued investment in the SURAVEC program and their independent pursuit of the Phase 3 ACHIEVE trial to further support the global commercial opportunity. We expect the June 30 cash balance reported today to fund our operation into early 2027 and enables us to accelerate towards multiple product launches. Please note this cash runway guidance does not include multiple non-dilutive financing opportunities that could further extend our cash runway significantly beyond 2027. These include development or sales milestones for RGX121, the sale of our anticipated priority review voucher for RGX121, development milestones associated with AbbVie's collaboration, including those in the diabetic retinopathy program, as well as the potential additional funds from the May 2025 Healthcare Royalty agreement. With that, I will turn the call back to Curran to provide final thoughts.

Speaker 5

Thank you, Mitch. Today's exciting updates make clear that we are executing at a high level across all aspects of our business, bringing us one step closer to becoming a commercial company. Our strategy is clear and focused. With our leading in-house end-to-end capabilities, we are rapidly advancing multiple late-stage programs. These potential first or best-in-class gene therapies represent the opportunity to address significant unmet needs for patients with rare and retinal diseases. We have our first potential FDA approval on the horizon this year. Most importantly, we maintain a strong financial position and have multiple avenues for non-dilutive financing to support the continued development and potential commercialization of our products. I want to thank our REGENXBIO Inc. team for their dedication, our physician partners for their collaboration, and the patients and families who participate in our trials.

Your contributions are essential to our mission of improving lives through the curative potential of gene therapy. With that, thanks for your time today. I'll turn the call over for questions. Operator?

Speaker 3

Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star one on your telephone keypad to raise your hand and join in the queue. If you would like to withdraw your question, simply press star one again. If you are called upon to ask a question and are listening via speaker phone on your device, please pick up your headset to ensure that your phone is not on mute when asking your question. Again, press star one to join the queue. Our first question comes from Judah Frommer from Morgan Stanley. Please go ahead.

Yeah, hi guys, thanks for taking the questions and congrats on all the progress updates here. Maybe one on DMD and then another on DR. I guess with DMD, anything you can share, you know, regarding reaction from the DMD community, maybe more specifically about the conditioning or prophylaxis regimen that you have in 202. It seems like the community is probably a little more attuned to Sarepta specifically, you know, after that patient death in Brazil. Anything you can share about how the community is feeling about that regimen and then switching to DR, I guess.

Any thoughts on what's happening in dose level three between year one and year two to see that improvement in DRSS and more generally, can you share with us kind of how the discussions with AbbVie went in changing the plan for the pivotal design here to go through the 2b and then the 3? Any change in level of excitement from them, or is it more just kind of proving out the dose level? Thank you.

Speaker 5

Sure, thanks for the questions. I think on 202, I would characterize the interest at the patient community as kind of at an all-time high for our type of program. I think certainly the proactive immune suppression regimen that we've been talking about since the beginning has even greater appeal in this way that people think about safety and high dose AAV treatments. I think we are seeing that in our interest in the study itself. We're doing things like conducting webinars with Cure Duchenne to maybe more broadly get the word out about the program. Obviously, as related to enrollment, we're expanding sites pretty dramatically this year. I think, you know, at a base level, the interest in gene therapy is still very strong in the patient community. I think the interest in our program in particular has risen dramatically.

The one thing I would say is that I think the patients, initially, the immune suppression regimen was portrayed as onerous and potentially not commercially viable. We're finding that the patients actually love the level of monitoring and surveillance that we're doing as it related to the study because I think it brings them comfort that, you know, none of these, hopefully, none of these events that are controllable will occur. I think I'll ask Steve to characterize the DR data if that's okay.

Speaker 2

Sure. Thanks for the questions, Judah. As you pointed to the improved efficacy that we've seen over time, how do we look at that data? I think the overarching aspect is you certainly want durability to really confirm that you have the sustained anti-VEGF activity. I think if you're having disease modification, then you even have that opportunity to see continuing improvement even after a single administration. I think that's the part that is so compelling, particularly for this indication that you can have a single injection that has durable benefit both in terms of DRSS imaging improvement, but also very key preventing those vision-threatening complications.

I really think that we would have been excited with stability across the two dose levels, but to actually see this improvement at dose level three at two years has really given both us and AbbVie the excitement to pivot in a positive way to really make sure we don't leave any efficacy on the table. It's worth noting this data came in the first half of this year. We were rolling along, planning to move ahead given that we'd already met the target product profile. Now we've got this amazing opportunity. It's not only the efficacy side, but it's key that we're seeing excellent safety without intraocular inflammation with a relatively short topical steroid regimen. We have the flexibility to potentially not leave efficacy on the table because of our safety that we've seen with our compartmentalized delivery.

That's really how both we and AbbVie are looking at this as a tremendous opportunity.

Thanks.

Speaker 3

Our next question comes from Gina Wang from Barclays. Please go ahead.

Thank you. Maybe I just follow, Steve, your comments. Is that the reason you wanted to add in dose level four for the pivotal study Phase 2b to evaluate, you know, the potential further improvement with a higher dose and given the good safety? Also, for the pivotal study, are you thinking about one year or would that be two years study? Related question is, what is the reason to amend the agreement? If, Mitch, you can share with us how much cost will be for running the Phase 2b study? Quickly on DMD, just wondering if you have any recent interaction with the FDA since Nicole Verdun's departure, as well as Prasad's departure? Any concerns regarding the pivotal path that was agreed on by the prior administration?

Speaker 5

Thanks, Gina. I'll start and maybe work my way backwards to the questions. I think on FDA, we're certainly having a lot of interaction with FDA as it relates to the Hunter program now. I don't think there's a new facility inspection, the PLI that we mentioned that has come in with no observations. We're super proud of that. I think that not only plays well for our chances of approval on 121, but our future chances of approval on the Duchenne program and, of course, 314. We're really pleased with the FDA interactions that we're having, and we haven't seen any shift, more broadly on, say, clinical trial design, et cetera, to date, on any other programs. I would say right now it's still what we've been saying, which is consistent interactions with FDA as expected in the late-stage reviews that we're encountering.

Steve, I'll ask you to maybe comment on the question on, actually, before I do, I think Mitchell characterized the milestone amendment change, but there's actually a mechanical aspect to that that in the original contract, a Phase 2b wasn't really ever contemplated. We were actually pleased to see AbbVie basically update that amendment to recognize the 2b and initiate part of that full milestone as part of that. That was something that I felt helped us in terms of cash runway being able to be paid at the initiation of the 2b rather than how it was originally written as first patient in a pivotal, even though we see the 2b as being intimately combined as a pivotal. Steve, did you want to comment on the question regarding DR for DL4?

Speaker 2

Yeah, hi. Hi, Gina. The first part of your DR question, why DL4? Certainly, it's both efficacy and safety. The fact that we saw the improvement in DL3 and that data coming in at two years in the first half of this year. The other piece of the equation is safety. As you know, we have our ALTITUDE DME arm with DL4 as well as our AV8 wet AMD dose level four arm. In the first half of this year, we got to take advantage of interim follow-up on these patients, including those earlier months after dosing, which really gives you the read on the key time period as far as safety and tolerability. In short, we're seeing what we want to see in terms of efficacy in the DR study, as well as what we see across dose level three and four.

We're going up because we can, and I think it makes sense that you really don't want to leave efficacy on the table, and it's worth evaluating in a dose selection phase. When you think of how massive this DR opportunity is, particularly for a one-time in-office treatment, we in AbbVie felt this was a great opportunity where we can look at two separate doses to really risk mitigate leaving anything on the table. As you know as well, it's not uncommon in retina pivotal trials where, relatively speaking, they're not too large that you can often take two doses into a pivotal. We're really trying to keep open our options given the results that we've seen.

Speaker 5

I think.

Speaker 2

On your.

Speaker 5

Mitch, you have any comment?

Speaker 2

I'm sorry. I missed that, Steve, on the one or two-year endpoint. Sorry. Yeah. We also have the benefit of a lot of regulatory history with the FDA, including our prior end of phase two meeting where we know that this DRSS endpoint is accepted for adequate and well-controlled trials, and we know it's accepted at the one-year time point. It makes sense for us to take advantage of that opportunity. The primary endpoint is at one year.

Speaker 5

Sorry for interrupting, Steve. Mitch, did you want to comment again on the milestone structure?

Speaker 1

Absolutely. It's a great question. I would say the $200 million remains intact. I think as Curran kind of mentioned, the amendment was made because the Phase 2b was not contemplated earlier. In total, the $200 million is basically split into two, $100 million and $100 million. The first $100 million will more than cover this clinical trial for the Phase 2b. We don't want to go into specifics in terms of the cost, but I will reiterate that the $100 million will more than cover the study cost. Thanks for your question.

Thank you.

Speaker 3

Our next question comes from Manny Parubar from Leerink Partners. Please go ahead.

Hey guys, you have Ryan on for Manny. Thanks for taking our questioning and congrats on the update. I know it's early days still enrolling the pivotal, but as you guys look to a DMD launch playing out, I'm kind of just curious how you see the dynamics of the broader prevalent patient population versus those ineligible for existing therapies right now. Do you see the first part of launch really being tailored to one more than the other, or is this just going to be a pretty broad launch across the board? Maybe just one on wet AMD. Can you just talk about whether the subretinal launch is a means to the suprachoroidal or whether you see a durable, albeit smaller market for this type of approach? Thanks.

Speaker 5

I can start with the second question. I think we see it subretinal as an entity on its own. Now, obviously, if down the road a suprachoroidal wet AMD approach for SURAVEC has the same product profile in the clinic as what we're seeing in subretinal, you could argue that the in-office procedure would be preferable. I think there will always be, as well, certain geographies that are very amenable to the subretinal administration. We're seeing really robust recruitment, for example, in Europe on our subretinal study. I think that both are very viable, and I think the subretinal product profile and clinical data we're seeing can sustain itself. Time will tell. I think on the approach to the commercial market for Duchenne, if you look at our study design, we're recruiting one and older.

We see the opportunity here for a broad label, and we see the opportunity with a differentiated product that we're seeing strong functional benefit and also a very favorable safety profile. We see opportunity to take a dominant position in the market based on our initial data. Right now, we're not exploring the non-ambulatory aspect of Duchenne, and that's something we're still contemplating, although you could make the thesis that our immune suppression regimen would be incredibly favorable for that patient population. Our focus is 100% on the ambulatory study that we're running now and a broad label as the outcome.

Awesome. Thanks, guys.

Speaker 3

Our next question comes from L. Mary from UBS. Please go ahead.

Hey guys, thanks for taking the question. Just a follow-up on the last question. Just curious how you're thinking about a potential strategy in non-ambulatory patients given your preconditioning regimen. Curious if you've had any discussions with the FDA on that in the past and any color you can share in terms of how they might be thinking about non-ambulatory safety. Second, as we think about the subretinal Phase 3, which will be a major catalyst when that comes up, can you elaborate a little bit on what you think would be sort of competitive or clinically meaningful, particularly as we look towards some of those secondary endpoints? Thanks.

Speaker 5

Sure. I think on the question around non-ambulatory, we have not, one aspect I would point out for our ambulatory ongoing pivotal study, which we pointed to completion in October. We do have a broader set of mutations allowed in the inclusion criteria than other studies. We are taking, as I said, a broad approach to the label, not just age, but also mutation status. I think in non-ambulatory, there's still a lot to learn from some of the recent events that we've all heard about. I think we're taking a cautious approach to that right now. We have not had detailed discussions with the FDA around a non-ambulatory study design, that is something we plan to. I think that's going to be related with the expansion of our safety database in our existing program.

We want that to be a prerequisite to exploring non-ambulatories, that we establish early on a good safety profile in the ambulatory population. I'll ask Dr. Steve Pakola to comment on the subretinal question for secondaries.

Speaker 2

Sure. Hi, Ellie. Yeah, I think as you mentioned, it's a very significant milestone coming up, the completion of our two pivotal trials for subretinal treatment of wet AMD. As far as what we're looking for and what we think will fill a significant unmet need in the space, the two aspects are, of course, the primary endpoint where safety has to be maintained, and we need to show non-inferiority on VA, both from a regulatory standpoint, but also from a commercial standpoint. You raise an important point on the secondary endpoints, particularly the injection burden, because with a one-time injection, that's certainly one of the key value propositions here where we know that patients are not getting the injections in the real world and are continuing to lose vision. How do you quantify that?

It roughly hasn't changed over time where what we hear from clinicians and a lot of discussions that we've had over the years, it's been pretty stable that we'd like to see at least a 50% reduction in injection burden. To be able to achieve that with a one-time injection while maintaining vision in a controlled study where the control arm is getting very prescribed on-label treatment, we believe that not only will lead to lower injection burden and treatment burden for patients in the real world, but because they have that sustained anti-VEGF activity, it also will be a benefit for vision maintenance, which really makes the total package of the value proposition quite compelling.

Great. Thanks.

Speaker 3

Our next question comes from Luca Isayev from RBC. Please go ahead.

Oh, great. Good morning. Thanks for taking our questions. This is Lisa on for Luca. Maybe just on diabetic retinopathy. Just wondering if you can walk us through the potential path to approval here. Can the Phase 2b/3 be used as a registrational study alone, or will an additional two Phase 3 studies be required for approval? Maybe just on the efficacy here for DR, it looks like 50% of patients did not require further treatment, but just wondering if you can comment on the 50% that did. Did they go back to a regular cadence of anti-VEGF injections, or did they need only periodic supplemental injections? Just last one on subretinal for wet AMD on the pivotal study. Can you comment on the state of enrollment? Has this trial been fully enrolled? If so, when did enrollment close? That's all for me. Thanks so much.

Speaker 5

Thanks for the questions. I can start with the last one around subretinal enrollment. We're seeing really robust enrollment, and I think we're in a situation where completion of enrollment is essentially imminent. We will certainly update when those studies are both fully enrolled. Looking forward to that. We feel really good about enrollment. As I mentioned earlier, maybe unexpectedly, a really strong trend in enrollment in Europe, which AbbVie is conducting those sites. Stay tuned. That is why we continue to guide to top-line data in 2026 based on optimism around completing enrollment for those studies. I'll ask Steve to comment on the DR data.

Speaker 2

Yeah. The first part of your question, Lisa, on the potential path to regulatory approval. We believe there is the requirement traditionally needed, of course, of two adequate and well-controlled studies. That's our plan. Notably, the Phase 2b/3 study that will be starting would be intended to be one of those two studies. I think that's encouraging. That's why we say we're starting our pivotal program. In terms of the data from the two-year results that we showed on DL3, 50% of the patients had at least two-step improvement without needing supplemental injections. That doesn't mean that the other 50% of patients needed supplemental injections. It actually was a minority of patients who wound up getting any intravitreal injections. We felt it was important to really lay out how each of these DL3 patients did over one year and two years, so you can see that evolution.

I refer you to slide 11, so you can see those details. Again, it was only a minority of patients that wound up getting any injections. Those 50% where we saw at least two-step improvement without any injection is really the key take-home message.

Speaker 3

Our next question comes from Alec Stratten from Bank of America. Please go ahead.

Hey guys, thanks for taking our questions. Just a couple from us. First on 202, I guess given everything that's happened the past few months with Sarepta, what is your current view on the market dynamic at launch? Any updated sort of % breakdown of the prevalent pool at that point would be helpful. I appreciate the differences between 202 and Levitus, as well as the emerging safety profile for 202. Do you expect a class effect for liver injury could be applied to the label given they are both AAV gene therapies? Lastly, on 314, how should we view the two pivotal studies versus the Phase 3 ACHIEVE study that AbbVie is planning to launch? Do you think data from the first two subretinal studies will be sufficient to file, with ACHIEVE more for being leveraged for commercialization with physicians? Any color there would be helpful. Thank you.

Speaker 5

Sure. Thanks for the question, Alice. The last one is fairly straightforward. The subretinal pivotal studies, ATMOSPHERE and ASCENT, will be sufficient for filing an approval. The study that we mentioned today is really a post-marketing approach to judge the efficacy of the product against real-world outcomes. They are very separate. The two pivotals that we're running, which are highly powered as a result of some sample size increases we made, we feel will be very adequate for filing. I think in terms of the market dynamic at launch, for back to your question on 202, we certainly see a really significant level of the prevalent population still being available to us based on some of the interruptions in launch, maybe greater than 90% of what we initially estimated of the prevalent population.

That will lead us to potentially at launch itself, ensuring that we have adequate quantities of drug available for launch, which is readily possible given that we have in-house manufacturing. We have a really highly productive process, and we can stockpile at launch a significant number of doses. Our intention is to be able to be in a position to take on a significant portion of the market at launch. I think where we're positioned in terms of timeline and our differentiated product profile really makes this a potential blockbuster opportunity. On the question around enabling.

On the liver injury.

Yeah, Steve, I was going to defer that to you.

Question.

Speaker 2

Yeah. Okay. Great. Alec, you refer to the existing therapy and the liver injury components and liver failure components in the label and how that could potentially lead to any kind of class effect considerations. I think each program has to be looked at in its own right, and I think that's why the points Curran has made about the clear differentiation that we have in terms of product purity with a much higher full-to-empty capsid ratio that's industry-leading. Of course, our proactive immune modulation approach and the existing therapy has per label up to a 40% rate of liver injury. I think we're seeing our differentiated approach translate in the clinic to a clear differentiation in terms of risk of liver injury where we in our Phase 1/2 study see zero of 13 patients with any signs or symptoms of liver injury, including on LFT assessment.

This gives us a lot of confidence in terms of how we can show differentiation on safety overall, but also in terms of potential risks to the liver.

Speaker 3

Our next question comes from Jack Adovano from Stifel. Please go ahead.

Hi, team. This is Jack on for Annabelle. Thanks for taking our questions. On the rationale for the Phase 2b with 314, I know you mentioned that you don't want to leave efficacy on the table, which makes sense. The two-step improvement for dose level two seemed equivalent to dose level one at year one. Sorry, I think I may have gotten that mixed up for dose level three equivalent to dose level two at year one, and the real differentiation only emerges at year two. Was the decision to include dose level four here partially driven because you feel like you need to improve efficacy even further to sufficiently convince FDA with just the year one data? Essentially asking if that 21% to 22% efficacy is sufficient for approval already, and you just think you can do even better.

Speaker 5

I think it's the latter. I think we feel dose level four has the opportunity to do better, but on its own, the dose level three results we feel are sort of the anchor dose that met our product profile and would be, I think, received well in a review. Steve, do you want to comment a little bit on just the power of the signal that we're seeing?

Speaker 2

Sure. Jack, you point to the equivalence in terms of two-step improvement at one year. The key consideration is the effect size we're seeing there meets our target product profile. The reason it meets that is we know that that's an acceptable endpoint and an acceptable effect size from a benefit-risk standpoint when you take into account this being a single injection and the ability to decrease treatment burden when you look at that overall benefit-risk consideration. The other key aspect is what the clinicians care most about is the effect on imaging translating into actual benefits for patients in terms of not only decreased injection burden, but actually preventing patients from developing the blinding complications. That is why we feel comfortable with the one-year results where we've seen that translate into a meaningful reduction in those important events.

We see that held up to a very significant, clinically meaningful level at the two-year time point. That is why we in AbbVie feel very comfortable with the one-year endpoint. We know we're going to continue to get two-year data and long-term data to give even more confidence to the clinical community.

Speaker 5

Great. Thanks.

Speaker 3

Our next question comes from Brian Skorney from Baird. Please go ahead.

Hey, good morning, everyone. Thank you for taking my question. I also want to just push to get a little more granularity on the diabetic retinopathy 2b versus 2b/3 versus 3 study design. On the 2b/3, is this a 2b portion where you get some interim data from a small sample size and then roll into a phase 3 portion, or is sort of the whole thing run and blinded before full readout? I'm trying to get a feel for the cadence where this is going to be one readout, and then you would start the second pivotal phase 3, or there's an earlier 2b portion readout that leads to a start of the phase 3 portion of the 2b/3, and then at some time later at the start of the second phase 3 portion. In terms of the control arm, is it going to be sham or open label?

Have you potentially thought about an active control in any of these studies? Just looking at the event rates you have in diabetic retinopathy 3, it wouldn't be out of the question to even potentially show benefit over EYLEA, particularly if events are compliance-driven there.

Speaker 5

Thanks for the question, Brian. I think at a high level, I can comment. The way the Phase 2b is designed is to as efficiently as possible move through different phases. It is structured that the Phase 2b has an interim readout in which it rolls into a Phase 3. The concept and the plan with AbbVie is that would also trigger immediately starting the second pivotal so that we could go as quickly as possible. I'll let Dr. Steve Pakola comment on the other details you asked about.

Speaker 2

Yes, I think that the key is really that the Phase 2b/3 study, we are going to roll over into the part two of that study, and it's all under one protocol. Yes, the part one informs that. We do plan to take advantage of interim looks at that data to really help inform by assessing the ongoing safety and efficacy of the ability to then advance into part two. On your second question, both pivotals, including part one of the first study, will be double masked. We really want to get the highest quality from these studies. We are going to use a sham injection to get the greatest validity in terms of looking at actual treatment effect.

The interesting question about active control for diabetic retinopathy before vision-threatening events has occurred is that while other drugs like EYLEA have treatment of DR on label, the reality is this is clearly not standard of care precisely because of the unsustainable treatment burden of repeated injections indefinitely, because when you stop those repeated injections, patients reburn, and you wind up going back to the risk of vision-threatening events. Even if we wanted to run an active comparator, it would frankly make enrollment almost impossible because patients don't want to go through that repeated injection. It basically validates why we feel a one-time injection has so much potential for this massive unmet need.

Speaker 5

The inclusion, Steve, of the SAM control was something we covered in all of the regulatory sessions we had last year. Is that correct?

Speaker 2

Yeah, that's right. That's always been our plan, and we've always had alignment with the FDA on that.

Thank you.

Speaker 3

Our next question comes from Bill Mogan from Clear Street. Please go ahead.

Hi, good morning, and thanks. You've mentioned a few different aspects of RGX202 that make it differentiated from Levitus, those being, for example, the full capsid ratio, your manufacturing process, and your immune suppression regimen. I just wanted to ask around the immune suppression and whether or not you think that is the majority of the differentiation. If so, if you simply added immune suppression to Levitus, is there a chance that this could become more similar than different in terms of safety? Thank you.

Speaker 5

Thanks for the question. I think in general, it's hard to pull those apart from each other. You know, we wouldn't have preclinical data where we look at each effect in isolation. Maybe I'll let Steve comment. I do believe from what we're seeing that they all play into effect because our goal is to deliver the maximum dose that's in line with our preclinical data to deliver a functional benefit. That's what drove us really to initially go to the highest purity we could, which is above 80%. The immune suppression was a separate thought from our clinical development group, as Steve mentioned. Put together, I think that both of them have power in establishing the safety profile that we've seen so far. I can't comment on whether or not that immune suppression regimen would perform the same with a Levitus. Steve, do you have thoughts on that?

Speaker 2

Yeah, I agree that we think all of these components play a part. It's really not possible to give any percentage breakdown on that, and they probably all interact as well. I think one of the key considerations is because we built this in upfront because we cared about safety in the overall sense of benefit-risk for our product and realized that that was a key differentiator. We're the only program that actually has safety and efficacy data where we can begin to answer that question in terms of with this constellation of differentiation, are we seeing a favorable safety profile? As Curran mentioned, we don't know what would happen with other programs if they added any of our proactive immune modulation. That would remain to be seen.

Thank you.

Speaker 3

Our next question comes from Sean McCutchen from Raymond James. Please go ahead.

Hey guys, thanks for excusing me. One on 202. Moving the full enrollment of that pivotal cohort up to October, can you speak to the flexibility this may or value?

Speaker 1

to potentially over-enroll or to get a head start on the enrollment of the confirmatory study to position yourselves well amid some of the shifting, let's call them, perspectives and uncertainty at the FDA? Thanks.

Speaker 2

Thanks. That's a great question. I think we've pointed out in the release and other venues that we do intend to continue to enroll once we fully enroll the pivotal program. Our protocol was originally written to enroll approximately 30 patients in the pivotal arm and then an additional 30 patients in the confirmatory study as well. We have plenty of room to continue to add patients throughout the year, and we can make amendments along the way. I think I would express our main goal is to continue enrollment and expand our safety database. We have all of the drug supply we need, and we're making more, as we pointed out, because we think that that will be important. It will address any risk in sample size discussions, for example.

That's one of the rationales as well as why we're expanding sites dramatically from where we were only a year ago.

Speaker 5

The next question comes from Daniel Gottlein from Charleston. Please go ahead.

Speaker 3

Yeah. Hey, good morning. Thank you for taking my question. I have a couple. First on 202, given the uncertainty in the DMD gene therapy space, are you considering requesting another meeting with the FDA before your pre-BLA meeting to ensure that you think it has not changed too dramatically? Maybe if you can mention if you're considering a special protocol assessment for 202. Second, for 314, with your suprachoroidal space microinjector partner going through significant restructuring, what is the strategy to ensure that you have access to microinjectors going forward? Are you considering switching to a different microinjector partner? Thank you.

Speaker 2

Sure. I can address the last question first. I think we feel confident with continued supply of microinjector regardless of business situation with Clearside. We have significant inventories in hand and also provisions for continuing supply that were part of the original contract that we've signed. We feel very confident in our ability to continue to access the devices and are in close contact with Clearside as well to just ensure no issues with continuity. In terms of the first question, an FDA meeting sooner than planned, that's something I think we're thinking about. I don't think there's any urgency to do that because right now our primary goal is enrollment and not just the pivotal but the confirmatory study. As we get further along, I would expect we'll look for a check-in with FDA.

I don't think right now we're getting any signals from FDA that make that urgent because we're in constant contact with the review teams both for 121 and for 202. We're not detecting any significant shifts in what they're looking for in the study or study design. I think in particular, McKerry's statements about rare disease development, I think the situation in Duchenne over the last couple of months has only underscored the need for additional therapies to be available and for that to be done urgently. I feel like our data package, if what we did in phase one two replicates in our pivotal program, will be very compelling for FDA.

Speaker 5

Our next question comes from Paul Choi from Goldman Sachs. Please go ahead.

Hi. Good morning and congratulations on all the progress. Thanks for taking our questions. I want to maybe continue the questions just on the FDA landscape here and I guess what your confidence for the DMD program is in the absence of a permanent head of CBER just given the sort of focus on that particular disease state and indication. My second question is, I guess, as you think about the Medicare changes to the recent IRA changes for reimbursement of injectable VEGFs, how are you potentially thinking about pricing for your product there over the longer term given what seems to be continual downward pressure from the Medicare reimbursement side? Thank you very much for taking our questions.

Speaker 2

Sure. I think on this last question, it's pretty early days. We haven't really had substantive discussions with AbbVie regarding pricing strategy. I think as we conclude enrollment of the subretinal studies and we look forward to top-line data next year, those discussions will increase, and we'll be able to talk a bit more about at least how we're thinking about that. I think early days right now and not something I would want to comment on in the absence of discussion with AbbVie. I think in terms of FDA and leadership change, if you think about it, we're enrolling our pivotal study. We've said that we will conclude that in October, and then we will continue enrollment for the confirmatory study. We will probably still be enrolling the confirmatory study at the time of our pre-BLA meeting.

If there's anything that surfaces along the way, we have the opportunity to adjust and either increase enrollment if that's the ask or stand on our data, which we think will be extremely strong. I don't think there's any near-term need to contact leadership at FDA. We have good contact at the review division level and avenues for information requests and going back and forth or meetings, type C meetings if we choose these out other elements of it. I do want to reiterate, our pivotal protocol was reviewed by the review team that was very similar to the team that reviewed Elevadys, and in detail. That review team, from what we can tell, is largely intact today, even though there have been many changes in leadership at FDA. I think that's comforting to us.

Again, the urgency for additional therapies in Duchenne couldn't be at a higher level in my view based on what we've seen happen over the last couple of months.

Speaker 5

Our next question comes from Mitchell Chan from REGENXBIO. Please go ahead.

Thank you for taking my question. Could you please comment on whether the dosing level of ABBV-RGX-314 for the subretinal delivery for wet AMD is much lower than the suprachoroidal delivery for wet AMD, BR, and DME, and whether the dosing difference is associated with the route of delivery to achieve similar efficacy? Thank you.

Thanks. Steve, I'll have you comment on that.

Sure. Thanks for the question, Yi. The doses that we're looking at in the subretinal pivotal studies are lower. These are two separate routes of administration. We've been leaders in the exploration in suprachoroidal, looking across two different indications. We knew from the start that a different route of administration, and also in the case of diabetic retinopathy, a different indication with different VEGF drive, meant that we had to really look for a dose response anew in that new route of administration. We thoroughly looked at that and also looked at safety with this new route of administration where going higher on dose, we knew we had that flexibility from our preclinical data.

Here as well, we were able to go higher and show importantly not only the clear meeting of target product profile with the suprachoroidal, but also we wanted to replicate the good parts of subretinal but not needing a surgical procedure to be able to do that in office. Early on, we chose suprachoroidal because it preserved the targeted local delivery into a compartmentalized space, the suprachoroidal space. That really increases the belief in safety both within the eye or any systemic effect. We also have bilateral dosing with good safety and efficacy results that we've seen in a bilateral study. All this constellation of aspects had us confident to be able to go higher on dose with this new route of administration.

There are no further questions at this time. This concludes today's conference call. Thank you for joining. You may now disconnect.