REGENXBIO Inc.

Welcome everyone to the fourth quarter and year-end 2024 Regenexx BioEarnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 1 again. Please be advised that today's conference is being recorded. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of Regenexx Bio. Please go ahead.

Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenexx Bio released financial and operating results for the fourth quarter and year ended December 31, 2024. The press release is available on our website at www.regenexxbio.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 discussion and analysis section of Regenexx BIOS annual report on Form 10-K for the full year ended December 31st, 2024, and comparable risk factor sections of Regenexx BIOS 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 13th, 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 to any unaudited or pro forma financial information, that may be provided as preliminary and does not report 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 Regenexx

Thank you, Patrick, and thank you, everyone, for joining us today. 2025 is a transformational year for Regenexx Bio, and we're off to an exciting start. We've submitted our first BLA and expect our first FDA approval in the fourth quarter for RGX-121, which is our treatment for Boy's with Hunter's Syndrome. We will build on this momentum by advancing our diabetic retinopathy program into pivotal stage this year, then head into 2026 and 2027 with potential BLA filings for large opportunities, including RGX202 for Duchenne muscular dystrophy and ABBD RGX314 for wet AMD. We are in a strong position as we prepare to launch multiple first or best in class gene therapies and have robust commercial capabilities and global partners. This is all with a view to sustainable profitability and is the result of 15 plus years of gene therapy leadership. On today's call, I will review our recent business highlights and outline a vision for what we believe will be catalyst-rich years ahead. Then, our Chief Medical Officer, Dr. Steve Kola, will summarize our clinical progress before handing it over to Mitch Chan, Chief Financial Officer. Mitch will provide an overview of our financial results and share the many potential non-dilutive capital sources ahead. I'll then make some closing remarks before we open for Q&A. Starting with our recent exciting news in MPS, we are thrilled to have completed the submission of the BLA for RGX-121 or Chlamyd-Sagin-Lamparbovac under the Accelerated Approval Pathway and partnered with Nippon Shin'yaku for both of our MPS programs. This partnership marries our collective strengths, Regenexx Bio's development and manufacturing expertise with Nippon's experience in successfully commercializing rare disease products. Our teams are planning for potential approval of RGX121 for MPS2 in Q4 2025, and are working diligently to prepare for the commercial launch. Along with enabling access to these important medicines for patients in the U.S. and Asia, this partnership is strategically significant to Regenexx Bio. As Mitch will share, this agreement provides meaningful potential milestones and revenue for us. The potential approval of RGX 121 also provides strategic value for the rest of our pipeline, as we'd receive commercial licensure of our manufacturing facility prior to launching in our larger opportunities, including RGX 202 for Duchenne. Moving to RGX 202, I am pleased to report that our pivotal study is advancing rapidly and that our unique second to market or fast follower opportunity is on track for a mid-2026 BLA filing. Recent updates have indicated tremendous interest in the patient community for new treatments with RGX202 as a valued option. Input from our growing investigator community supports our belief that RGX202 has the potential to be a preferred and differentiated treatment option. I'll remind you that RGX202 is the only investigational next-generation DMD gene therapy in pivotal study and with both robust microdystrophin and functional data available. The pivotal trial of RGX202 is rapidly enrolling approximately 30 ambulatory patients aged one and over. I'm pleased to share that this pivotal trial is nearly half enrolled, and we expect to complete enrollment this year. We are also on track to submit a BLA under the accelerated approval pathway by mid-2026. We expect more than half of the prevalent population to remain untreated through the next few years, And this large population will need more than one treatment to serve all Duchenne patients. That's why we're confident in the rapid progress we've made thus far and our path to delivering a potentially preferred gene therapy option. Also, let me remind you that we are commercial ready when it comes to manufacturing 202. Our in-house state-of-the-art suspension-based bioreactor process is currently producing 202 for our pivotal study, with industry-leading purity levels of more than 80% full capsules. Our Manufacturing Innovation Center can produce 2,500 doses of RGF202 per year. As we continue to aggressively accelerate BLA-enabling activities and commercial planning, we will share more meaningful updates. Specifically, we plan to share additional positive Phase I-II biomarker data later this month at MDA, as well as updated Phase I-II functional data in the first half of this year. With positive biomarker and functional data in hand, encouraging interactions with FDA and commercial-ready manufacturing, we believe our second-to-market position in Duchenne remains strong. Lastly, I will highlight a few updates on ABBV-RGX314, or SUROP gene lamparvovac. This is our global AbbVie-partnered retinal franchise that is advancing in late-stage studies. As announced with AbbVie in January, data from the pivotal studies evaluating subretinal 314 in patients with wet AMD are expected in 2026. We expect to complete enrollment of both of these pivotal studies this year. In our diabetic retinopathy program, evaluating in-office superchoroidal delivery of 314, we held a successful end-of-phase two meeting with the FDA in the fourth quarter of 2024. We are now planning a pivotal program with AbbVie to support future global regulatory filings. As we have said before, wet AMD and DR are very large commercial opportunities, and 314 represents a potential alternative for the patients losing vision with today's standard of care. Importantly, we will be entitled to additional milestone payments that are part of this $1.8 billion collaboration with AbbVie. In summary, we are excited for and well-positioned to deliver on the opportunities ahead of us to drive values, for patients and shareholders. With that, I would now like to turn the call over to Steve for an update on our clinical programs. Steve?

Thank you, Kern.

I'll start with RGX202, a potential one-time gene therapy for the treatment of Duchenne. RGX202 is the only microdystrophin construct to include the C-terminal domain, making it closest to naturally occurring dystrophins. In preclinical studies, microdystrophin with the CT domain was shown to better protect the muscle from contraction-induced damage associated with muscle breakdown in Duchenne. In November, we announced the initiation of the pivotal phase of the Affinity Duchenne trial, evaluating 202 at a dose of 2E14 genome copies per kilogram in approximately 30 ambulatory patients aged one and older. We also reported positive safety and efficacy data from the Phase 1-2 portion of the study. The data disclosed in November included positive functional outcomes from the first five participants in the Phase 1-2 portion at 9 and 12 months. We also shared microdystrophin and other compelling biomarker data from 11 patients. In summary, the results showed 202 recipients exceeded external natural history controls, and established benchmarks for clinical outcomes. Specifically, we observed functional improvements in all patients treated with dose level 1 and dose level 2 at 12 and 9 months, respectively. Consistent, robust expression, transduction, and localization of our differentiated 202 microdystrophin in the muscle and also a favorable safety profile observed at both dose levels. There were no serious adverse events or AEs of special interest, which is truly outstanding in the landscape of Duchenne gene therapy. As we've discussed, we've taken a thorough, proactive approach to safety based on input and partnership with treating physicians and the patient community, as well as learnings from the field at large. Our immune suppression regimen, including a short course of ecolizumab, combined with our novel microdystrophin and leading product purity levels, may be contributing to this positive safety profile. These positive clinical results further strengthen our belief that 202 has the potential to serve as a best-in-class gene therapy for Duchenne muscular dystrophy. We look forward to sharing additional biomarker data at the MDA meeting in the coming days, including the first microdystrophin data from our cohort of patients under four years old. As Curran mentioned, the pivotal study is ongoing and advancing rapidly. The one to three age group represents a significant portion of the prevalent population of Duchenne patients, yet this group has no access to approved gene therapy. With pivotal enrollment nearly halfway completed, we look forward to continuing to work with physicians and the Duchenne community to complete enrollment this year and report top-line data in the first half of 2026. Now onto our retina franchise, ABVB-RGX314, which is being developed in collaboration with AbbVie to treat wet AMD and diabetic retinopathy, or DR. I'll start with 314 for DR being evaluated in the phase two altitude trial using in-office supracoroidal delivery. Like wet AMD, DR is a progressive disease that causes vision loss and ultimately blindness if not treated appropriately. It is a leading cause of blindness in working age adults. As we've shared, we have completed our end of phase two meeting with the FDA and are now working actively with AbbVie on plans for our phase three clinical program. The program is expected to support global regulatory filings with the goal of preserving vision for millions. We previously expanded the broad multi-indication global potential of 314 by initiating a new cohort in the Altitude Trial. This cohort is enrolling patients with diabetic macular edema, or DME, a vision-threatening complication of diabetic eye disease. In wet AMD, we are evaluating 314 via two different delivery forms, subretinal and supracoroidal. Within subretinal, we have two ongoing pivotal trials, atmosphere and ascent, in the U.S., Europe, and Japan. These trials continue to progress well. As we announced in January, enrollment of both pivotal trials is expected to complete this year, and we expect to share top-line data in 2026. Overall, we continue to be encouraged by 314's progress. I'd like to particularly highlight the safety profile observed in our suprachoroidal program. In more than 180 patients treated in office, we're seeing a differentiated safety profile, particularly in the setting of short-course, seven-week prophylactic steroid eye drops. a significantly shorter regimen than those used in other gene therapy trials. This continues to support the potential of 314 as a meaningful treatment option for patients and physicians. Finally, on to our MPS programs. It's an incredibly exciting time for Regenexx Bio and the Hunter Syndrome community. With the submission of our BLA for RGX121, This filing is based on data from the CampSide trial, which met its primary pivotal endpoint with high statistical significance. Patients treated with 121 achieved decreased CSF levels of heparin sulfate D2S6, a key biomarker of brain disease activity, to below maximum attenuated disease levels, approaching normalization. Our BLA, using the accelerated approval pathway, is based on D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. We also previously reported that 80% of patients who received the pivotal dose discontinued enzyme replacement therapy or remained treatment naive, as well as neurodevelopmental skill acquisition up to four years post-dosing. This is a meaningful update for patients and families whose only option today is weekly enzyme replacement therapy that does not address the neurocognitive decline of this disease. 121 is well positioned to be the first gene therapy and one-time treatment for Hunter syndrome that can address neurocognitive decline. We anticipate a potential FDA approval decision in the second half of 2025. To conclude, we continue to make significant progress with data updates and trial progression across all programs in our pipeline. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who have been involved in and supported all of these trials.

With that, I'll turn the call over to Mitch to review our financial guidance. Mitch? Thank you, Steve.

Regenexx file ended the quarter on December 31st, 2024, with cash, cash equivalents, and marketable securities of $245 million, compared to $314 million as of December 31st, 2023. The decrease was primarily driven by cash used to fund operating activities during the 12 months ended December 31st, 2024, partially offset by $131 million in net proceeds received from an upsized public offering of common stock and pre-funded warrants completed in March 2024. R&D expenses were $209 million for the year ended December 31, 2024, compared to $242 million in 2023. The decrease was primarily attributable to decreases in headcount and preclinical activities. We expect the balance in cash, cash equivalents, and marketable securities of $245 million as of December 31, 2024 to fund our operations into the second half of 2026. This cash runway guidance is based on the company's current operational plans and excludes the impact of any future potential commercial revenue associated with RGX 121. If we include additional non-diluted financing, we expect the cash runway to potentially extend meaningfully beyond 2026. For instance, some examples of our non-diluted financing options include our expected DR milestone payment from AbbVie, development milestone payments from Nippon Shinjuku, reversion of our Sojansma royalty income, and the potential monetization of our priority review voucher on RGX 121, if approved. Collectively, we have many non-diluted financing optionality that could extend our cash runway well beyond the second half of 2026. In summary, we feel we are in a strong financial position as we near potential commercialization of three late stage programs. With that, I will turn the call back to Curran to provide final thoughts.

Thanks, Mitch. As you heard today, there's strong momentum across our pipeline as we advance towards key milestones. To recap, we have officially submitted our first BLA and closed an important partnership with Nippon Shin'yaku for our MPS programs. We look forward to a potential FDA approval of RGX121 this year. The pivotal study of RGX202 is moving rapidly and we believe remains well positioned to potentially serve as the next and preferred gene therapy in Duchenne muscular dystrophy. We plan to share additional positive biomarker data later this month, followed by updated functional data in the first half of this year. And with enrollment nearly halfway through, we expect to complete enrollment of the pivotal study this year and share top-line data in the first half of 2026. Our partnership with AbbVie is advancing towards multiple large global commercial opportunities. We expect to complete enrollment of two global pivotal trials for subretinal wet AMD and are working with Abby on a pivotal study in diabetic retinopathy in 2025. As we look towards the next nine months and beyond, we are well positioned to deliver on multiple late stage opportunities. Our programs are demonstrating beneficial differentiation against standard of care and available treatments. Each of our assets represent one-time treatments with the potential to transform the trajectory and management of disease for patients in need of new and better options. We look forward to sharing additional updates on our plans and achieving our critical milestones this year. With that, thanks for everyone for your time today. I'll turn the call over for questions. Operator?

As a reminder, if you'd like to ask a question at this time, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

Our first question comes from the line of Judah Frommer with Morgan Stanley.

Judah, your line may be on mute. Hi.

Can you hear me now? Yep. Thanks for taking the question. Hi. Congrats on the progress here. Just one on cash runway and one clinical question. So I was hoping maybe you could delve a little deeper into the components of non-dilutive financing that are still available, and maybe you could give us kind of some internal insights into probabilities around realizing those. We do get questions around the PRV and then anything that could get in the way of the ABV milestone coming through for DR. And then just on the clinical side, another question we've been getting, just expectations around potentially going to an EDCOM for 202 once you have the full data set. Thanks.

Yes, thank you, Judith, for the question. So regarding non-dilutive options, as I kind of mentioned, it really comes in three different flavors. The first one is the DR milestone that we expect to receive in the second half of this year. That really is gated upon the first patient dose, and Stephen Curran could definitely speak to the clinical program timings and so forth, but that's really the potential risk to it. It's more of a timing issue than anything else because our expectation is that it will move forward. Regarding the PRV, I think the question here is when do we receive a potential regulatory approval? Because upon regulatory approval, that's when we're eligible to receive our prior review voucher, and we could then choose to monetize it at our discretion. So I think that's, you know, I'll say it's more of a regulatory approval risk than anything else, which you do not expect to have anyways at this moment in time. And the other non-dilutive financing option really is on the potential Sojansma royalty stream that may revert back to us. Once we hit the HCR cap of $300 million, that royalty stream does revert back to us. So again, it's hard to predict future revenues from Sojansma, given that it's promoted by a third party, Novartis here. But once we reach the cap, that revenue stream will revert back to us, royalty revenue stream.

Hi, Judah. It's Curran. I can talk a little bit about just the PRV and probability of success. I think the fact that we've had a pre-BLA meeting with FDA and reviewed the pivotal data really helps in terms of de-risking. They've seen the data. They've seen our approach. And while, of course, it's a regulatory review and, you know, that has risk associated with it like any, We feel like we're in a really good place, particularly because I think over time, MPS II and therapies like ours have been referred to as perfect fits for an accelerated approval pathway. So I do expect this to be a high probability event in terms of receiving both an approval and the PRV. And, you know, that's in line with all the discussions we've had with FDA. I'll let Steve comment a bit on DR, but I think, you know, the events that are occurring for DR now are really just regulatory discussions with in the lead in terms of conducting those meetings. We talked last fall about the end of phase two meeting with FDA and related that that meeting was very positive. in terms of our approach, and we've also discussed that they're also seeking regulatory advice ex-US, and that's an ongoing process. But we feel like two key things, the data's strong and so far the feedback's strong, again, pointing towards a positive movement towards the DR Pivotal this year. Steve, I don't know if you have anything to add to that.

Sure. Hi, Judah. Yeah, I think as Curran mentioned, we're very happy with the end of phase two meeting with the FDA. AbbVie has always been very interested in global advancement and really getting access to 314 globally. That's one of the reasons we struck the deal with AbbVie. So not surprisingly for a global diabetic retinopathy plan, they do want to get EMA and feedback from Japan. So those are some of the aspects that we want to tidy up those ends before we give any more details on the plan. But I think, fortunately, we have the benefit of precedent in treatment of diabetic retinopathy to know what to expect in terms of a regulatory path here. We feel this is pretty darn de-risked based on our regulatory discussions to date. You also, Judah, had a question on adcom probability, which I believe is probably related to 121 since we announced completion of the VLA submission. We don't know. You know, it's not the kind of thing we can say with 100% certainty either way. We, as of now, don't see a significant issue anywhere that would suggest one is needed. If one comes our way, we'll be ready for it. So I think with any development program at this stage, you plan in case you may need it. If we have one, we'd be very confident with the discussions because of the compelling data we have and the different stakeholders that could be a part of getting across that benefit and the benefit risk for the product. But as of now, we don't know. Thanks.

Our next question comes from the line of Gina Wang with Barclays. Thank you for taking my questions.

I apologize if this question is already being asked. My phone got dropped, so I missed the previous question. So I have two questions. One is regarding the NDA update, just wondering how many patient data from one to three-year-old should we expect to see? And also, you know, giving the younger patient age, should we expect to see higher coding expression? Related questions, any thoughts regarding lower age to zero? Giving, I think, a solid mention, they will start a cohort between zero and the 18th. And then my second question is regarding the altitude, DME cohort. Just wondering what would be the timing of data update and then in terms of also number of patients and type of data you would share with us?

Great. I'll take the first one and then I'll let Steve answer the second one. So, we're planning to update at MDA. likely one patient in the 1 to 4 cohort in terms of their microdystrophin value. And I would suggest, based on the emerging database that we're gaining on age versus microdystrophin, that it's a fair expectation to expect a high number in terms of microdystrophin level, but obviously we'll save that specific for the conference itself. But

We're seeing a general trend that the younger patients will have higher micro dystrophin numbers Both in our study and other studies that we're able to see in the public domain Yeah, hi Gina, thanks for for the question so altitude our diabetic retinopathy study where we've already shown very solid data in terms of diabetic retinopathy patients without a And that's why we're so excited with Abby to go into Pivotal. You referred to the DME cohort, which we currently have enrolling. Enrollment is progressing quite nicely. We haven't given any guidance on when we would read out, but it's safe to say that when we do, to your question of what you could look for, you could look for the typical things that we've looked for in a wet AMD population. but with different reference points of what you'd expect. So in DME, you care about visual acuity, and you also care about disease activity assessed by retinal thickness on OCT. And, of course, the third part of the triad is can you achieve good disease control and good visual acuity with a reduction in the need for injection, so basically treatment burden. So we would report on all three of those as well as safety.

Thank you.

Our next question comes from the line of Manny Ferruhar with Learing.

Hey, guys. You have Ryan on for Manny. Thanks for taking our question. So, maybe just to, can you talk about what you're seeing in terms of pace of enrollment for the DMD pivotal trial and whether you, you know, expect this to accelerate as the year goes on as you activate new sites and share more data in the first half of the year? And then maybe just on the younger patient enrollment within DMD, have you moved on to enrolling those patients in the pivotal trial yet, or are you still enrolling that separate cohort from the Phase 1-2 trial? Thanks.

Yeah, I think it's safe to say that we're seeing really encouraging enrollment in terms of the Duchenne study. And I think to the second part of, and we know that from the screening logs and what we're seeing at sites as sites are activated that, you know, there's a significant number of, there's a significant amount of interest in a significant number of patients that are going through screening. And the second part is, yes, we do expect it to accelerate primarily because we're increasingly adding sites to the study. you know, the overall productivity of the study will just continue. So it'll be a nonlinear enrollment curve, if you will. And we're super optimistic about how, certainly meeting our guidance, which will be concluding enrollment this year. But we're aiming to exceed that guidance by beating that timeline significantly.

The second question.

The other interesting aspect, Ryan, is it's not just increased sites, which certainly is going to help as we bring more sites on board, but we really saw a lot of interest after our November functional data update. We've heard from patient advocacy and investigators that there's a lot of families that have been waiting on the sidelines for a next gen gene therapy as long as they could see some functional data. So I think having the nine and 12 month data has really bolstered our case across our clinic. So I think we're in a good shape there. You also asked about the younger patients, the one to three year old age group. We look forward to providing the initial data in terms of micro dystrophin in that age range. And we do know, by the way, hearkening back to Gina's question, that younger we have seen with other programs that you have higher microdystrophin levels. And I think one of the massive unmet needs is in the older patients where you don't see with other programs high microdystrophin levels. So we're really excited about that. But we really want to treat broadly across the entire age range, and that's why we're enrolling not just the traditional four and up, but actually one-year-old and up. To your question, any patients that come in now that are one and above are going to count for pivotal treatment. So we are very excited to enroll across the age range, that one to three years, four to seven, and also eight and older.

And we're particularly interested in that cohort because, as you know, there's no approved therapy for patients in the one to four age category. So that's a key element of our pivotal plan, and these patients will be included in that.

Thanks, guys.

Our next question comes from the line of Luca Easy with RBC Capital Markets.

Oh, great. Thanks so much for taking our questions. This is Lisa on for Luca. Just on the DMD program, can you remind us if you are measuring cardiac endpoints like left ventricular injection fraction or cardiac biomarkers like troponin I as part of the affinity studies? And if so, could these be a meaningful way to differentiate your program further from Alevitas? And I have one question on what AMD on the subretinal study. I'm just curious if you're considering maybe cutting the enrollment a bit short in order to accelerate the readout timeline. We know the wet AMD space is very competitive, and there are also two long-acting TKI studies that are also anticipated to read out in that same 2026 timeframe. And as we know from the BISMO's launch, being first to market does matter. So any color here on DMV or the subretinal pivotals, that would be appreciated. Thanks so much.

Great. Thanks. I think I'll let Steve comment certainly on the retina discussion, but in terms of cardiac, Steve can describe what we're measuring in the clinic, but certainly from our preclinical data, when we looked at biodistribution in our early preclinical studies, we certainly have reason to expect good biodistribution, not just to the peripheral muscle, but to the heart and to the lung section. that's represented well in studies that we did preclinically like the treadmill test for MDX mice. So I think in terms of do we expect our study to differentiate on that, of course, that'll come down to what we consider for cardiac little bit longer term outcomes. We don't expect to see dramatic cardiac improvement in a four or five year old, but over time, that something will certainly be monitored. Maybe I'll let Steve cover how we're doing that. Sure. Hi.

Hi, Lisa. Yeah, for the reasons Curran mentioned, we feel very positive about the potential to have a benefit for Duchenne children, not just based on skeletal muscle, but also the cardiac manifestations. I think one context to give is that these patients decreases or deterioration in cardiac function happen at an older age than the typical functional assessments that we look at in the younger age group. So it's really as the boys advance into the teen years that you see the unfortunate cardiac deterioration. So that's one of the reasons we're so excited that we're seeing very high and consistent micro dystrophin expression in these older boys so that also bolsters our confidence so how can we look at this certainly ejection fraction as you mentioned is one of the measures you can look with echo which isn't as accurate and sensitive as looking with mri so we do incorporate both of these so we're going to have the ability to look at that we do also look at troponin levels So again, I think the key aspect is it's not going to be really meaningful to look at these while patient's cardiac function is normal. So in the traditional age groups up to eight, for example, and really it's going to be more once the patients get above 10, where you start to see abnormal ejection fractions, for example, where you can then monitor stability and more or less preventing worsening in these boys. So the fact that we have patients already enrolled that are older, I think we're in a better position to monitor this over a long time. And we have patients already out nine and 12 months and further as we go out further. But it's really something that takes more time for sure than a year, even if you're looking in the older age group before you anticipate seeing a potential drug effect. Your other question about wet AMD in our pivotal trials for subretinal delivery, whether we'd consider cutting short the enrollment. We would not, and AbbVie would not as well. One of the key reasons we increased the size was to be able to go global. And you can imagine with a partner like AbbVie, we want to do things right. We don't want to skimp, especially when it comes to fully characterizing safety and efficacy. So this is a unique opportunity to compare to established approved treatment regimens to really inform the clinical community, not just the regulatory bodies. So our view would not be to cut these short. And as Curran has summarized, we look forward to completing enrollment this year and being able to have results next year. And there is a lot of trial competition out there in the wet AMD space with, as you mentioned, some of the longer acting TKIs. One of the things we're encouraged about is that this is really a paradigm shift. This is not a matter of incrementally increasing injection burden reduction from every two or every three months, every four, every six months. it's really being able to, in potentially a majority of patients, prevent the need for injections. So we're seeing that as a strong differentiator, and that's, again, why we are pleased that we're going to be able to complete enrollment this year.

One thing I would add, too, just we are certainly cognizant of timing and moving as quickly as we can to a BLA filing, and that's one thing. reason that AbbVie, for example, will be doing the preparation and filing of the BLA. They have upwards of 700 people in their regulatory group. And so, it's a very large study, and we're going to rely on AbbVie, who has, I think, a great track record of speed to BLA from top-line data. So, that's something to follow in the next year. We're with you in terms of going as fast as possible, but as Steve mentioned, we want to do it the right way.

All right. Thanks so much for taking the questions.

Thanks. Our next question comes from the line of Annabel Samini with Stifel.

Hi. Thanks for taking my questions. Just following on the regulatory discussions for DR, Are there any specific key areas of difference between the US and the OUS regulators that we should be thinking about? I know that the pathway is pretty clear for the US. I'm curious about OUS. And then on DMD, for the upcoming, not the Muscular Dystrophy Association, but the one where you're going to be disclosing functional data, will we be seeing just a follow-up from patients we've already you've already disclosed, or will we see new patients of the 11 that had already been treated? And then finally, for DMD, the 50% enrollment, can you just clarify whether this includes new patients that were enrolled into the pivotal, or does it also include the patients from the Phase 1-2 study? Thanks.

Great. Yeah, I'll take DMD first, and then I think we'll let Steve comment on, he's part of the joint development team with AbbVie that's conducting these regulatory meetings and can comment. For Duchenne, the data that we're speaking to around functional updates later this first half will be all of the above. So patients that we've already discussed at dose level two, that were at nine months moving out to 12. New patients that have not previously been reported in the dose level two phase one two study likely at nine months. And then also long term data on the dose level one patients that'll be out at least to 18 months depending on the timing specific timing of the update. So that's what we're planning for. We don't have a specific number for new patients yet, but as you know from the past, there's seven patients total in that cohort. So we're just incrementally adding hopefully meaningful updates, not patient by patient, enriching that data set as we go. I think to the question of does the pivotal enrollment include new patients, the answer is yes. We have new patients that have been enrolled since we announced that we were recruiting for the pivotal trial. And also some of the patients that were dosed, actually the majority of them that were dosed in the Phase 1-2 study would also be eligible as part of the pivotal data set. And just recall that's an N of 30 that we're driving for to complete that study.

Hi.

Annabelle, I'll take the first question now on diabetic retinopathy and the pivotal plan. As you mentioned, fortunately, there's a clear path from precedent of getting an indication for treatment of diabetic retinopathy from drugs like Lucentis and Ilea. where what's been accepted and what's still accepted is use of the diabetic retinopathy severity scale, which has been clinically validated to predict bad outcomes for patients with diabetic retinopathy. And we know the path is there, but these drugs are not being used because of the significant treatment burden that's needed to keep the disease at bay. So that's important because that means it's still open the ability to use a negative control. So for example, in our case, the potential to use a sham control arm where we know that those patients don't magically get better. And in fact, they... on average, get worse. So it allows us to power a study with the traditional one-year endpoint to look for a difference in active treatment compared to a negative control arm. There isn't that known precedent for Europe, so that's one of the reasons we want to work with the EMA and also in Japan. We think there's a very solid case for use of the diabetic retinopathy severity scale. And in fact, the more years that go by and the more studies that are done, we think that case gets stronger. And so we look forward to, in the future, giving an update on discussions that we've had with regulators around the world.

Thank you. Our next question comes from the line of Brian Scorney with Baird.

Brian, you may be on mute.

You're right. I'll see you now. Thanks for taking the question, everyone. You've now submitted a BLA for Hunter with CBER, had discussions going into a physical program for DMD and planning a program for diabetic retinopathy. You know, we get a lot of questions about continuity at CBER, given the change of guard at HHS and FDA, and I don't really know anyone who's probably had more interaction with CBER than you guys over the last couple of months. I'm just wondering, you know, with Celia Whetton's departure a couple of weeks ago, if you could give us a sense as to how up-to-date your discussions with CBER and OTP are, and if you're seeing significant change within the review division, the Austin Therapeutic Products, and how much that could potentially impact future gene therapy reviews?

Yeah, I think our general comment is, from our perspective, it's business usual in terms of the submissions that we're making. We're, on a pretty frequent basis, providing amendments to protocols, amendments to INDs, and those are, you know, we're getting questions back and forth on certain things. we're really not seeing a significant difference either in timing of responses or availability of the teams. And I think we were encouraged by some of the comments, especially on the rare disease side around accelerated approval from McCary and just the overall sentiment. So to date, I think we feel Number one, that we've got really good connections and really good previous dialogue with the review team. The review team seems stable from what we can tell from those interactions. And therefore, we don't see any change in sort of the risk profile of our pending BLA now and ongoing discussions for Duchenne.

And then maybe if I could ask a follow-up on DMD, now that you're about 50% enrolled into the 202 pivotal, can you give us any flavor as to how screening kind of goes? Are you seeing any particular favoritism by age or characteristics in terms of patients looking at the screen? I'm in particular wondering if like the availability of 11S and 11S's data, if it's sort of like, you know, are four to five-year-olds favoring coming in? to be screened for gene therapy, or because the data's strongest for Levitas, do you see sort of in that age group, do you see patients coming outside of that four to five-year-old on a demand basis?

Yeah, I'll generally comment, and then I'll let Steve maybe discuss, because he does see the screening logs in more detail than I do. I mean, one of the reasons that we wanted to point to nearly half enrollment of the pivotal study is that in addition to that, are screening logs and patients testing for neutralizing antibodies. It's a significant number of people, of patients being screened, and that just points to the strong interest we see from the patient community and from the Duchenne patient advocacy groups as well that are supporting us. Steve, I don't know if you want to comment. Are we seeing any difference in terms of the ages Or is it just a broad distribution?

I'd say it's a broad distribution, Brian. I think families across the age range have certainly different needs or different ways they look at evaluating different treatment options. I think that's where our differentiation comes into play. So I think certainly the microdiscipline levels that we're seeing, that's clear. differentiation in the eight and older. As you mentioned, the four to seven and particularly the four to five is really the subset of patients where there's the most evidence for a levitis. I think one aspect that is a differentiator across the spectrum is safety. So safety first, that's certainly how investigators think about it and that's how patient families of course think about it. So We believe with various aspects of our program, both our proactive immune suppression, transient approach, our high purity levels that are very differentiating. And overall, what we're seeing is very good safety. We have seen no SAEs, no AEs of special interest, so that includes no LFT elevations, no thrombocytopenia. And these are findings that have been seen in other programs. And with Alevitis, I think upwards of 40% have LFT elevation. So that's a clear differentiator that we think is important across the age range. Certainly in the three and under bucket, those are patients who do not have access to approved gene therapy in the U.S., One of the aspects we're excited about our program is some of the, not just microdiscipline expression, but also vector genome copies per cell that we're actually seeing, which are much higher than has been reported by any other program. So we think that gives added confidence when you think of that younger age group where there still be some muscle cell division. In short, in summary, we see good differentiation aspects that are compelling for doctors and patient families to consider. And that's why we're confident we're going to get a widespread, which is a goal, given the broad patient population we want to have safety and efficacy in.

I think particularly if you think about it, 95% of the prevalent market is still available for these studies. So I think that plus the the focus on next-generation therapies is really helping with enrollment. So we're excited where we are this early in the year, and I can guarantee we're pushing to go as quickly as we can on all fronts for the BLA submission.

Great. Thank you.

Our next question comes from the line of Paul Choi with Goldman Sachs.

Thank you. Good afternoon, and thanks for taking our questions. I want to ask on affinity and how you're thinking about your post-trial or post-approval commitments and just your thoughts on the, you know, sort of requirements, I guess, down the road for a confirmatory city or other regulatory requirements and just your thoughts there. And second, you know, based on the data you're seeing to date in the ambulatory population, I want to see if you, you know, what's the current appetite to potentially explore 202 in a non-ambulatory population at some point, even if it's an exploratory study? Just your thoughts there would be great. Thank you for taking our questions.

Great, thanks. I think in terms of confirmatory study, we're going to have that discussion in more detail with FDA in terms of what's required, but I think in general, We intend to continue to enroll post-enrollment of our pivotal N equals 30 data set towards the end of completing a confirmatory study as quickly as possible. And we'll have further discussions with FDA in our pre-BLA meeting about what exactly that will mean. I think, and the second question, just remind me,

So on non-ambulatory.

Yeah, so we are considering, yeah, we're certainly considering strongly conducting studies in non-ambulatory patients, but right now not at the expense of going as fast as possible for the ambulatory one and older patients that we're conducting as part of our clinical studies now. So it is definitely a consideration given the size of the prevalent market there, but we just don't want to use our sites for that purpose at this point given that we want to close out our pivotal study as quickly as we can this year.

Given the excellent micro dystrophin levels and also functional results that we're seeing in eight and above including a 12 year old it's uh it's an interesting uh dilemma really like current said we we gotta focus on the the population uh for our our pivotal but More and more, once we showed that data, investigators and also patient advocacy are asking about non-ambulatory because it's quite logical given the results we've seen. So it's something we'll be looking at but not acutely adding to the pivotal.

Right. One thing I would add just to finish the question on planning for confirmatory study. We do have drug supply already prepared to cover both the pivotal study and a future confirmatory study based on some planning assumptions that we've made. So I think that's really important that we can seamlessly move into a confirmatory study with existing drug supply.

Our next question comes from the line of Ellie Merle with UBS.

Hey, guys. Thanks for taking the question. Just a little bit more on the functional data. Specifically, what should we be looking for at this upcoming data update and both of this update, but then thinking longer term, both from the pivotal study and then potential confirmatory? What do you think would be differentiating in terms of functional data? And then in terms of the pivotal study, I guess, how do you plan to analyze some of this functional data? Do you have any stats protocol for, say, doing a natural history comparison? And if so, is this something that you've discussed at all with the FDA? Thanks.

Great. Yeah, I'll cover just the general specifics of the functional updates, and then maybe I'll let Steve talk about the analysis of the data versus baseline and the external match controls that we're doing. I think in terms of the near-term functional data, as I mentioned earlier, You should expect to see additional patients that were treated at dose level 2 in our Phase 1-2 study. We'll be specific about the number of patients, more around when their visits occur and when the data is updated. We'll also report 12-month data on patients that we previously reported. There were two at nine months in that release. we will update patients' dose at dose level one that were at 12 months who are now likely out to about 18 months, maybe two years on some longer-term data. But of course, that's not at the pivotal dose. So it'll be just informational at that point. So that's what you should expect to see near-term. And then Over the course of the year, I would expect to see most of the data for all seven patients that were dosed at dose level two out to 12 months, but that'll be much later in the year.

As far as what we see or what we'll look at will be the usual suspects, Ellie, as far as time function tests, so time to stand, 10-meter walk, run, time to climb. And NSAA, which traditionally has been viewed as less sensitive than the time function test, but actually in our November update, we saw encouraging results not just on the time function test, but also on the NSAA. So we're excited to see if we can confirm those findings on longer follow-up on the existing patients and then increase the sample of patients at dose level two, what we see on those We'll continue to look at this the way we've done in the past, which is not just in isolation, but compared to matched external natural history controls. So that's really important given disease trajectory is different depending on age and baseline severity. So we match on all those factors to give greater confidence in terms of whether individual patient's trajectory is positive or not. We have discussed this with the FDA, so this was certainly a part of the successful end of phase two meeting that we held before starting Pivotal, and we had no issues getting into the Pivotal design.

Cool. Thanks.

Our next question comes from the line of Sean McCutcheon with Raymond James.

Hey, guys. Thanks for the question. One for me on NPDR. Steve, to your point, we've seen some reticence from patients to receive anti-VEGF therapies due to that high rate of frequent injections. And you've shown some meaningful decreases in vision-threatening events up to 12 months in altitude at the higher dose in line or better than the panorama study of Flibercept. What do you view as the treatment durability at which we could start to see more utilization in NPDR? And how do you view that as this thing for a gene therapy versus, say, a sustained release TKI?

Thanks. Sure. That's a great question, Sean. And I think that is the key observation that we've seen is that even though repeated anti-VEGF injections definitely work, It's just too much of a burden for patients and doctors to give injections indefinitely because once you stop giving the injections, the severity comes back. So you're basically signing patients up who are currently asymptomatic to get injections the rest of their life, basically. And that's really the barrier also to even longer durability TKIs. since it's certainly better to only need an injection every six months or even every year. But if it's repeated injections, we see that as a major barrier. And that's why we in Appy are so excited about the DR indication because of supracoroidal in-office one-time injection is really the way to address this massive unmet need. And that's why we're excited with the data that you referred to where we've shown an 89% reduction in vision-threatening complications at a year. So that really was the impetus for us and AbbVie accelerating the end-of-Phase II planning. Now that we have the positive outcome of that study, now we're both excited to advance into pivotal this year.

Thank you.

Our next question comes from the line of Alex Stranahan with Bank of America.

Hey, guys. Thanks for taking our questions. Maybe two from us, both on DMD. Appreciate the updates on the pace of enrollment in Affinity Duchenne. I guess, how long after completion of enrollment do you think we could see data? Would 12-week microdystrophin for the primary be enough maybe for the top line, or would you want to wait a bit longer for some of the other endpoints? And second, I'm sure you guys are tracking the evolving commercial market in DMD pretty closely. I guess maybe following up on a previous question, what's your expectation around the market dynamic in, say, a year or two when you're a bit closer to approval? Any updated thinking around current supply and the addressable market at launch would be great.

Thank you. Great. In terms of...

The second question I think I'll take first. I think one of the key aspects of our plan is that we think at least half of the prevalent market will still be available by 2027, which is what we're targeting for a potential approval. And if you look at the updated guidance now, we're pointing towards a mid-2026 BLA filing. So that could lead to an approval potential approval in early 2027, which I think is really important. And we're already planning how to address the market. We'll be making our first lots that are eligible for commercial sales starting this fall. And we have the capability with our in-house manufacturing to stockpile a significant number of doses ahead of the launch. Assuming we can establish a broad label, I would expect we're going to be very aggressive commercially in 2027 to take a significant amount of the prevalent population in terms of market.

And then, Alec, as far as your first question about when would we have actual results that we could disclose, The 12-week time point, that is our accelerated approval endpoint time point for micro dystrophins. So that's a very significant step. So we certainly would be coming out with that data since that's really what's going to drive actually going ahead with the BLA submission by mid next year already. So we'd also have safety at that time point as well. So I think that really puts us in a good position.

I think if you think about what functional data would we have in hand at the time of filing, certainly the full phase one, two dose level two cohort would be past 12 months at that point. And a good proportion of the patients treated in the pivotal study will have at least nine month, if not 12 month data. So we'll have a healthy level of functional data to accompany the primary endpoint of microdystrophin at the time of filing and probably be able to update that somewhat at the 120-day safety update as well.

Got it. Makes sense. Appreciate the color.

Our next question comes from Yi Chen with HC Wainwright.

Thank you for taking my question. Could you comment on Nippon Shinyaku's sales team presence in the U.S.? How many of them will be promoting RJX121? And do you expect that any sales related milestone could be triggered within 12 months of commercial launch? Thank you.

Didn't quite hear the first part. Could we repeat just the beginning of that question? I got the, it was a little bit muffled. Yeah, the audio was just a little rough.

The sales team presence of Nippon Shiaku in the U.S., how many of them will be promoting RGX 121?

Okay. Yes, Nippon Shiaku has a significant U.S. presence in rare disease. They have an existing sales force that services their Duchenne launch, and we expect that a majority of that same team would be applied towards commercialization of RGX-121. Given the timeline now that we've filed the BLA, we're pointing towards a PDUFA date somewhere in Q4 of this year, and that would point to a launch either late this year or early next year, of course, and feel positive that the partnership with NS Pharma allows us to do that as rapidly as possible. Good alignment initially with them on site selection for commercial sale. There are dosing centers that we've worked with clinically that we feel are obvious choices that have also previously handled commercial products. So more to follow as we go through the review process on the BLA. In terms of achievement of sales milestones, there are some that could be realized in the first year of sale. They're sort of staggered throughout the growth of the product. We haven't commented previously on what proportion that might be of the 700 million total potential milestones. But some of those could be realized in the first or second year of launch.

Thank you.

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