REGENXBIO Inc. Price & Performance (RGNX)

Good afternoon, and thank you for joining us today. Earlier this afternoon, REGENXBIO 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.regenxbio.com. Today's conference call will include forward looking statements regarding our financial outlook, in addition to regulatory and product development plans. [indiscernible] 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 similar meaning. [indiscernible] such forward looking statements are not guarantees of future performance and involve certain risks and uncertainties These risks are described in the Risk Factors in the Management's Discussion and Analysis section of REGENXBIO's annual report on Form 10 ks for the full year ended 12/31/2024, and comparable risk factors sections of Regenxbio Bio's quarterly reports on Form 10 Q which are on file with the Securities and Exchange Commission and available on the SEC's website. [indiscernible] Any information we provide on this conference call is provided only as of the date of this call, March 13, 2025, and we undertake no obligation to update any forward looking statements we may make on this call on 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 form a 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 REGENXBIO. Curran? Thank you, Patrick, and thank you everyone for joining us today. 2025 is a transformational year for REGENXBIO. We we're off to an exciting start We've submitted our first BLA and expect our first FDA approval in the fourth quarter RGX-one hundred and twenty one which is our treatment for boys with Hunter syndrome. We will build on this momentum by advancing [indiscernible] into pivotal stage this year then head into 2026 and 2027 with potential BLA filings for large opportunities including RGX-two zero two for Duchenne muscular dystrophy, and ABVD RGX-three fourteen for wet AMD. [indiscernible] 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 a result of fifteen 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, Doctor. 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 and A. Starting with our recent exciting news in MPS, we are thrilled to have completed the submission of the BLA for RGX-one hundred and twenty one or chlamydia lamparbovec, under the accelerated approval pathway and partnered for with Nippon Shimmyaku for both of our MTS programs. This partnership marries our collective strengths, Regenxbio Bio's development and manufacturing expertise, with Nippon's experience in successfully commercializing rare disease products, Our teams are planning for potential approval of RGX-one hundred and twenty one for MPS II in Q4 twenty twenty five. And are working diligently to prepare for the commercial launch. Along with enabling access to these this partnership is strategically and significant to REGENXBIO. As Mitch will share, this agreement provides meaningful potential milestones and revenue for us. The potential approval of RGX-one 21 also provides strategic value for the rest of our pipeline as we receive commercial licensure of our manufacturing facility prior to launching in our larger including RGX-two zero two, for Duchenne.

Moving to RGX-two zero two, 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-twenty twenty six BLA filing. Recent updates have indicated tremendous interest in the patient community for new treatments. With RGX-two as a valued option. [indiscernible] Input from our growing investigator community supports our belief that RGX-two zero two has the potential to be a preferred and differentiated treatment option. I'll remind you that RGX-two zero two is the only investigational next generation DMD gene therapy and pivotal study and with both robust microdystrophin and functional data available. The pivotal trial of RGX-two zero two 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 twenty twenty six. [indiscernible] We expect more than half of the prevalent population to remain untreated through the next few years we 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 two zero two. Our in house state of the art suspension based bioreactor process is currently producing two zero two for our pivotal study. With industry leading purity levels of more than 80% forecasted. Our manufacturing innovation center can produce 2,500 doses of RGX-two zero two 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 onetwo biomarker data later this month at MDA. As well as updated Phase onetwo 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 RGX-three 14 or Surab gene [indiscernible] This is our global AbbVie partnered retinal franchise that is a advancing in late stage studies. As announced with AbbVie in January, data from the pivotal studies evaluating subretinal three fourteen in patients with wet AMD are expected in 2026. [indiscernible] We expect to complete enrollment of both of these pivotal studies this year.

In our diabetic retinopathy program, evaluating in office suprachoroidal delivery of three fourteen we held a successful end of Phase II meeting with the FDA the fourth quarter of twenty twenty four. We are now planning a pivotal program with AbbVie to support future global regulatory filings.

As we have said before, wet AMD and Doctor are very large commercial opportunities. And three fourteen 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 $1,800,000,000 collaboration with AbbVie. [indiscernible] In summary, we are excited for and well positioned to deliver on the opportunities ahead of us to drive values for patients, shareholders. With that, I would now like to turn the call over to Steve for an update on our clinical programs. Steve? Thank you, Karen.

I'll start with RGX-two zero two. A potential one time gene therapy for the treatment of Duchenne. RGX-two zero two is the only micro dystrophin construct to include the C terminal domain making it closest to naturally occurring dystrophin. In preclinical studies, microdystrophin with the CT domain was shown to better protect the muscle from contraction induced damage associated with muscle breakdown.

Duchenne. We In November, we announced the initiation of the pivotal phase of the AFFINITY Duchenne trial evaluating two zero two 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 onetwo portion of the study. The data disclosed in November included positive functional outcomes from the first five participants in the Phase onetwo portion at nine and 12. We also shared microdystrophin and other compelling biomarker data from 11 patients In summary, the results showed two zero two recipients exceeded external natural history controls and established benchmarks for clinical outcomes. Specifically, we observed functional improvements in all patients treated with dose level one and dose level two at twelve and nine months respectively. Consistent robust expression transduction and localization of our differentiated two zero two microdystrophin in the muscle and also a favorable safety profile observed at both dose levels. There were no serious average 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 eclizumab 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 two zero two 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 Karan 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 twenty twenty six. Now on to our retina franchise, ABBB RGX which which is being developed in collaboration with AbbVie to treat wet AMD and diabetic retinopathy or Doctor. I'll start with three fourteen for Doctor. Being evaluated in the Phase two Altitude trial using in office suprachoroidal delivery.

Like wet AMD, Doctor is a progressive disease that causes vision loss and ultimately blindness if not treated appropriately. 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 three fourteen 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 three fourteen via two different delivery forms subretinal and suprachoroidal. Within subretinal, we have two ongoing pivotal trials [indiscernible] 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 three fourteen progress. I'd like to particularly highlight the safety profile of observed in our suprachoroidal program. In more than one hundred and eighty patients treated in office, we're seeing a differentiated safety profile particularly in the setting of short course seven weeks prophylactic steroid eye drops. A significantly shorter regimen than those used in other gene therapy trials. This continues to support the potential of three fourteen as a meaningful treatment option for patients and physicians.

Finally, on to our MPS programs. It's an incredibly exciting time for REGENXBIO and the Hunter Syndrome community with the submission of our BLA for 21. This filing is based on data from the campsite 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 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 eighty percent of patients who received the pivotal dose discontinued enzyme replacement therapy or remain treatment naive, as well as neuro developmental 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. 01/2021 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 the second half of twenty twenty five. 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. REGENXBILE ended the quarter on 12/31/2024 with cash, cash equivalents and marketable securities of $245,000,000 compared to $314,000,000 as of 12/31/2023. The decrease was primarily driven by cash used to fund operating activities during the twelve months ended 12/31/2024, partially offset by $131,000,000 in net proceeds received from an upsides public offering of common stock and pre funded warrants completed in March 2024. R and D expenses were $2.00 $9,000,000 for the year ended 12/31/2024, compared to $232,000,000 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 $245,000,000 as of 12/31/2024, to fund our operations into the second half of twenty twenty six. DISH cash runway guidance is based on the company's current operational plans and excludes the impact of any future potential commercial revenue associated with 21. If we include additional non dilutive 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 Doctor milestone payment from AbbVie development milestone payments from Nippon Shinjaku, conversion of our sojournment royalty income and the potential monetization of our priority review voucher on RGX-one hundred and twenty one if approved.

Collectively, we have many non dilutive financing optionality that could extend our cash runway well beyond the second half of twenty twenty six. In summary, we feel we are in a strong financial position as we 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 Shinyaku for our MPS programs. [indiscernible] We look forward to a potential FDA approval RGX-one hundred and twenty one this year. The pivotal study of RGX-two zero two 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 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 twenty twenty six. 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 AbbVie on a pivotal study in diabetic retinopathy in 2025. [indiscernible] 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?

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

Hi. Can you hear me now? [indiscernible] [indiscernible] 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 AbbVie milestone coming through for Doctor And then just on the clinical side, another question we've been getting just expectations around potentially going to an ad com for for 02/2002 once you have the full data set? Thanks. Yes. Thank you, Judette, 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 Doctor milestone that we expect 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 we'll move forward Regarding the PRV, I think the question here is when do we receive a potential regulatory approval.

Upon regulatory approval, that's when we're eligible to receive our priority review voucher and we could then choose to monetize it at our discretion. So I think that's will 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 Sogren's Bell royalty stream that may revert back to us. Once we hit the HGR cap, of $300,000,000 that royalty stream does revert back to us. So again, it's hard to predict future revenues from Zargensma given that it's promoted by a third party Novartis here? But once that we reach the cap, that revenue stream will revert back to us royalty revenue stream. Hi, Judah, it's Karen. I can talk a little bit about just the PRV and probabilities success. I think the fact that we've had a a pre BLA meeting with FDA and reviewed the pivotal data, really helps in terms of derisking. They've seen the data. They've seen our approach. And while, of course, it's a regulatory review and that has risk associated with it like any. We feel like we're in a really good place particularly because I think in 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 open approval and the PRV. And that's in line with all the discussions we've had with FDA I'll let Steve comment a bit on Doctor, but I think the events that are occurring for Doctor now are really just regulatory discussions with AbbVie 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 U. S. And that's an ongoing process. But we feel like two key things, the data is strong and so far the feedback is strong. Again pointing towards a positive movement towards the the Doctor pivotal this year. And Steve, I don't know if you have anything to add to that.

Sure.

Hi.

Judah. Yes, I think as Karan mentioned, we're very happy with the end of Phase II meeting with the FDA Happy has always been very interested in global advancement and really getting access to three fourteen globally. That's one of the reasons we struck the deal with Appvie. 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 [indiscernible] 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. So we feel this is pretty darn derisked based on our regulatory discussions to date. You also Judah had a question on 121 since we announced completion of the BLA submission. We don't 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 Gena Wang with Barclays.

Thank you for taking my questions. I apologize if this question already being asked. My phone got dropped, so I missed 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 to see? And also giving the younger patient age, should we expect to see higher protein expression And related questions, any thoughts regarding lower age to zero? Given I think as Solih mentioned, they will start a cohort between zero and 18. And then my second question is regarding the altitude DME cohort. Just wondering what will be the timing of data update? And then in terms of also number of patient and type of data you will 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 one to four cohort in terms of their microdystrophin value. And would suggest based on the the emerging database that we're gaining on age versus micro dystrophin that it's a fair expectation to expect a high number in terms of micro dystrophin 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 microdystrophin numbers both in our study and other studies that we're able to see in the public domain.

Yes. Hi, Gina. Thanks for the question. So Altitude are diabetic retinopathy. Study where we've already shown very solid data in terms of diabetic retinopathy patients without DME and that's why we're so excited with AbbVie 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 injections. 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 Farooqar with Leerink.

Hey, guys. You have Ryan on for Montney. Thanks for taking our question. So maybe just two. Can you talk about what you're seeing in terms of pace of enrollment for the DMD pivotal trial? And whether you expect this to accelerate as the year goes on? 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 in enrolling that separate cohort from the Phase onetwo trial?

Thanks. Yes, 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 and what we're seeing at sites as sites are activated that there's a significant number of there's significant amount of interest and 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. So So 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 twelve 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 initial data in terms of microdystrophin in that age range. And we do know, by the way, harkening back to to Gina's question that younger, we have seen with other programs that 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 microgistro 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. Your question, any patients that come in now that are one and above are going to count for Pivotal. 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 Easi with RBC Capital Markets.

Great. Thanks so much for 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 study. And if so, could these be a meaningful way to differentiate your program further from elovitis? And I have one question on what AMD On the sub retinal study, I'm just curious if you are considering maybe cutting the enrollment a bit too short in order to accelerate the readout time lines. 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 FABISMA's launch being first to market does matter. So any color here on DNB or the subretinal pivotal that would be appreciated?

I think I'll let Steve comment certainly on the retina discuss describe what we're measuring in the clinic. But certainly from our preclinical data, when we looked at biodistribution in our early preclinical studies, [indiscernible] certainly have reason to expect good biodistribution not just to the peripheral muscle, but to the heart and to the lung section. So 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 differ differentiate on that, of course, that'll come down to what we consider 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 how we're doing that. Sure.

Hi.

Hi, Lisa.

Yes, for the reasons Karen 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 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 microdystrophin 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 you're it's not going to be really meaningful to look at these while patients 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 twelve 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 potential drug effect. Your other question about wet AMD in our pivotal trials, for subretinal delivery, whether we 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 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 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 Karen 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 a potentially a majority of patients prevent the need for injection. 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 of timing and moving as quickly as we can.

To a BLA filing. And that's one 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 these are 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 my questions.

Thanks.

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

Hi, thanks for taking my questions. Just following on the regulatory Are there any specific key areas of difference between The U. S. And the OUS regulators that we should be thinking about? I know that the pathway is pretty clear for The U. S. I'm curious about OUS And then on DMD, for the 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 fifty percent enrollment, can I just can you just clarify that this includes whether this includes new patients that were enrolled into the pivotal or does it also include the patients from the Phase onetwo study?

Thanks.

Yes, I'll take the MD 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 up 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 onetwo study, likely at nine months. And then also long term data on the dose level one patients that will be out at least to eighteen months depending on the timing specific timing of the 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 onetwo study would also be eligible as part of pivotal data set. And just recall that's an N of 30 that we're driving for to complete that study. [indiscernible] 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 indication for treatment of diabetic retinopathy from drugs like Lucentis and EYLEA 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 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 [indiscernible] 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 Skorney with Baird. [indiscernible] You're right.

Thanks for taking the question everyone. You now submitted BLA for Hunter with Seabird, had discussions going to the program for DMD and planning a program for diabetic retinopathy. We get a lot of questions about continuity at CBER given the change of guard at and FDA and I don't really know anyone who's probably had more interaction than Zebra than you guys over the last couple of months. So just wondering with Celia Wetten's departure a couple of weeks ago, if you could give us a sense as to how up to date you're discussions with CBER and OTPR, and if you're seeing significant [indiscernible] Cyber Peter products and how much that could potentially impact future gene therapy reviews?

Yes. I think our general comment is from our perspective, it's business usual in terms of submissions that we're making. We're on a pretty frequent basis providing amendments to protocols, amendments to INDs and those are we're getting questions back and forth on certain things. So we're really not seeing a significant difference either in timing of responses or availability of of the teams. And I think we were encouraged by some of the comments, especially on the rare disease side around accelerated approval from MacKerry 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 maybe if I could ask a follow-up on DMD. Now that you're about 50% enrolled into the two zero two 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 mean, in particular, wondering if like the availability of 11S and 11S is data, but if it's sort of left, I think, or four to five year old favoring coming in? To be screened for gene therapy or because the data strongest for a lot of SDC sort of in that age group do you see patients coming outside of that four to five year old on a demand basis?

Yes. 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, our 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'd look at evaluating different treatment options. I think that's where our differentiation comes into play So I think certainly the microdystrophin 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 the most evidence for Alevitus. 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 LFT elevations, no thrombocytopenia. And these are findings that have been seen in other programs and with ELEVITIS I think upwards of forty percent 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, that's 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 microdystrophin 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 So 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 the goal given the broad patient population we want to have safety and efficacy in I think particularly if you think about it ninety five percent of the prevalent market is still available.

For these studies. So I think that plus 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.

I want to ask on Afiniti and how you're thinking about your post trial or post approval commitments and just your thoughts on the sort of requirements, I guess, down the road for confirmatory study or other regulatory requirements and just your thoughts there?

And second, based on the data you're seeing to date, in the ambulatory population, I wanted to see if you what's the current appetite to potentially explore two zero two 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 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 [indiscernible] towards the end of completing a confirmatory study as quickly as possible. And we'll have further discussions with FDA and pre BLA meeting about what exactly that will mean. [indiscernible] the second question just remind me.

So on non ambulatory Yes. So we are considering yes, we're certainly considering strongly conducting studies in non ambulatory patients. But right now, not at the expense of going as fast as possible. 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 microdystrophin levels and also functional results that we're seeing in eight and above including a 12 year old. It's It's an interesting dilemma really like Karin said, we got to focus on the population for our pivotal, but more and more once we showed that data investigators and also patient are 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.

Great. One thing I would add just to the 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 Merl with UBS.

Hey guys. Thanks for taking the question. Just a little bit more on the 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 stop 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. Yes, 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 two in our Phase onetwo study. Will be specific about the number of patients more around when their visits occur and when the data is updated. We'll also report twelve month data on patients that we previously reported. There were two at nine months. In that release. And also we will update patients dosed at dose level one that were at twelve months who are now likely out to about eighteen months, maybe two years on some longer term data, but of course that's not a 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 twelve months, but that will be much later in the year. [indiscernible] as far as what we we'd see or what we'll look at, it will be the usual suspects Ellie, as far as time function test 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 to 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 [indiscernible] in terms of whether individual patients 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.

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

Hey, guys. Thanks for the question. One for me on NPDR. Steve, to your point, we've seen a some reticence from patients receive anti VEGF therapies due to that high period of frequent injections. And you've shown some meaningful decreases in vision threatening events up to twelve months in altitude at the higher dose. In line or better than the Panorama study of Flivircept. 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 distinct for a gene therapy versus say 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 and Happy are so excited about the Doctor indication because of suprachoroidal 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 eighty nine percent reduction in vision threatening a year So that really was the impetus for us in AbbVie accelerating the end of Phase two 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 INFINITI Duchenne. I guess how long after completion of enrollment do you think we could see data? Would twelve 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 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 things [indiscernible] the addressable market at launch would be great.

Thank you. [indiscernible] In terms of the second question, I think I'll take first. I think one of the 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-twenty twenty six BLA filing. So that could lead to an approval essential approval in early twenty twenty seven. 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 a launch.

So 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 twelve week time point, that is our accelerated approval endpoint time point for microdystrophin. 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.

And I think if you think about what functional data would we have in hand at the time of filing, Certainly, the full Phase onetwo dose level two cohort would be past twelve months at that point. And a good proportion of the patients treated in the pivotal study will have at least nine month, if not twelve 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 one hundred and twenty day safety update as well. Got it. Makes sense.

Appreciate the color.

Our next question comes from Yi Chen Thank you for taking my question.

Could you comment on Yifeng Shinaki, Shinaki's sales team presence in The U. S. Many of them will be promoting ArgX-one 21? And do you expect to do you expect that any sales related milestone could be triggered within twelve 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 audio is just a little rough.

The sales team presence of the Bone Shenayaku in The U. S. How many of them will be promoting RGX 121? [indiscernible] Yes. Nepentheiyahu has a significant U. S. Presence in rare disease. They have an existing sales force that services their Duchenne launch. And we expect that majority of those that same team would be applied towards commercialization of RGX-one 21.

Given the timeline now that we filed the BLA, we're we're pointing towards 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 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, the 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 700,000,000 total potential milestones, but some of those could be realized in first or second year of launch.

Thank you.

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