Regenxbio - Earnings Call - Q4 2024
March 13, 2025
Executive Summary
- Q4 2024 revenue was $21.2M, down 4% year over year and 12% sequentially; GAAP diluted EPS improved to ($1.01) from ($1.43) in Q4 2023 and from ($1.17) in Q3 2024, with operating loss narrowing on lower R&D and credit loss recoveries.
- Guidance: cash, cash equivalents and marketable securities of $244.9M at 12/31/24 plus $110M upfront from Nippon Shinyaku fund operations into the second half of 2026 (raised vs prior “into 2026”).
- Catalysts: RGX-121 BLA submitted; potential FDA approval 2H 2025; RGX-202 pivotal trial nearly 50% enrolled with BLA targeted mid‑2026; AbbVie retinal programs targeting topline wet AMD data in 2026 and planning DR Phase III in 2025.
- Key stock reaction drivers ahead: regulatory milestones (RGX‑121 approval, PRV monetization), nondilutive capital (AbbVie DR milestone), and pivotal RGX‑202 biomarker/functional data flow in 2025–2026.
What Went Well and What Went Wrong
What Went Well
- BLA for clemidsogene lanparvovec (RGX‑121) submitted; potential approval 2H 2025; management: “We’ve submitted our first BLA and expect our first FDA approval in the fourth quarter [2025]”.
- RGX‑202 pivotal advancing rapidly; nearly 50% enrolled; management emphasized manufacturing readiness: “can produce 2,500 doses of RGX‑202 per year… purity levels >80% full capsid”.
- Retinal franchise progressing: DR pivotal planning with AbbVie in 2025; wet AMD pivotal topline expected in 2026; fellow‑eye data showed 97% reduction in anti‑VEGF burden with durable control and no intraocular inflammation.
What Went Wrong
- Revenue decline driven by lower Zolgensma royalties (FY 2024 $81.5M vs $85.3M FY 2023), pressuring top line in Q4 and full year.
- Continued operating losses: Q4 loss from operations ($51.4M), though improved YoY; interest expense rose to ($9.4M) in Q4 2024.
- Cash declined to $244.9M at year‑end from $314.1M prior year, reflecting funding of operations despite March 2024 offering proceeds.
Transcript
Operator (participant)
Welcome, everyone, to the fourth quarter and year-end 2024 REGENXBIO earnings 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 one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one 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 REGENXBIO. Please go ahead.
Patrick Christmas (CLO)
Good afternoon, and thank you for joining us today. Earlier this afternoon, REGENXBIO released financial and operating results for the fourth quarter and year-ending December 31st, 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. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties.
These risks are described in the risk factors and the management's discussion and analysis section of REGENXBIO's annual report on Form 10-K for the full year ended December 31st, 2024, and comparable risk factor sections of REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, March 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 purport to project financial positions or operating results of the company, actual results may differ materially.
I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran.
Curran Simpson (President and CEO)
Thank you, Patrick, and thank you, everyone, for joining us today. 2025 is a transformational year for REGENXBIO, 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 boys with Hunter 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 RGX-202 for Duchenne muscular dystrophy and ABBV-RGX-314 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 a result of 15+ 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. Our Chief Medical Officer, Dr. Steve Pakola, 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 clemidsogene lanparvovec, under the accelerated approval pathway and partnered with Nippon Shinyaku for both of our MPS programs. This partnership marries our collective strengths: REGENXBIO's development and manufacturing expertise with Nippon's experience in successfully commercializing rare disease products.
Our teams are planning for potential approval of RGX-121 for MPS II 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 REGENXBIO. 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 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 RGX-202 as a valued option.
Input from our growing investigator community supports our belief that RGX-202 has the potential to be a preferred and differentiated treatment option. I'll remind you that RGX-202 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-202 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 capacity. Our Manufacturing Innovation Center can produce 2,500 doses of RGX-202 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-RGX-314, or surabgene lomparvovec. 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 suprachoroidal delivery of 314, we held a successful end-of-phase II 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 value 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?
Steve Pakola (CMO)
Thank you, Curran. I'll start with RGX-202, a potential one-time gene therapy for the treatment of Duchenne. RGX-202 is the only microdystrophin construct to include the C-terminal domain, making it closest to naturally occurring dystrophin. In preclinical studies, microdystrophin with the C-terminal 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 I/II portion of the study. The data disclosed in November included positive functional outcomes from the first five participants in the phase I/II portion at nine 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 nine 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 eculizumab, combined with our novel micro-dystrophin 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 on to our retina franchise, ABBV-RGX-314, 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 II ALTITUDE Trial using in-office suprachoroidal 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 II meeting with the FDA and are now working actively with AbbVie on plans for our phase III 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 suprachoroidal. Within subretinal, we have two ongoing pivotal trials, Atmosphere and Ascent, in the U.S., Europe, and Japan. These trials continue to progress well. 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 REGENXBIO and the Hunter syndrome community with the submission of our BLA for RGX-121. This filing is based on data from the CAMPSIITE Trial, which met its primary pivotal endpoint with high statistical significance. Patients treated with 121 achieved decreased CSF levels of heparan 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?
Mitchell Chan (CFO)
Thank you, Steve. REGENXBIO 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 31st, 2024, compared to $232 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 31st, 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-dilutive financing, we expect the cash runway to potentially extend meaningfully beyond 2026. For instance, some examples of our non-dilutive financing options include our expected DR milestone payment from AbbVie, development milestone payments from Nippon Shinyaku, reversion of our Zolgensma royalty income, and the potential monetization of our priority review voucher on RGX-121, if approved. Collectively, we have many non-dilutive financing optionalities 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.
Curran Simpson (President and CEO)
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. We look forward to a potential FDA approval of RGX-121 this year. The pivotal study of RGX-202 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. 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 AbbVie 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 everyone for your time today. I'll turn the call over for questions. Operator?
Operator (participant)
As a reminder, if you'd like to ask a question at this time, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one 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.
Judah Frommer (Senior Equity Research Analyst)
Hi. Can you hear me now?
Curran Simpson (President and CEO)
Yep.
Judah Frommer (Senior Equity Research Analyst)
Hi. Congrats on the progress here. Just one on cash runway and one clinical question. 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 DR. Just on the clinical side, another question we've been getting is expectations around potentially going to an AdCom for 202 once you have the full data set. Thanks.
Patrick Christmas (CLO)
Yes. Thank you, Judah, for the question. 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. Steve and Curran could definitely speak to the clinical program timings and so forth. That is really the potential risk to it. It is 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 is when we are eligible to receive our priority review voucher, and we could then choose to monetize it at our discretion.
I think that's, I would 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. The other non-dilutive financing option really is on the potential Zolgensma 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. Again, it's hard to predict future revenues from Zolgensma, given that it's promoted by a third party, Novartis here. Once we reach the cap, that revenue stream will revert back to us, royalty revenue stream.
Curran Simpson (President and CEO)
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. 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 over time, MPS II and therapies like ours have been referred to as perfect fits for an accelerated approval pathway. I do expect this to be a high probability event in terms of receiving both an approval and the PRV. 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 the events that are occurring for DR 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 II meeting with FDA and related that that meeting was very positive in terms of our approach. We've also discussed that they're also seeking regulatory advice, XUS, and that's an ongoing process. 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 DR pivotal this year. Steve, I don't know if you have anything to add to that.
Steve Pakola (CMO)
Sure. Hi, Judah. Yeah, I think, as Curran mentioned, we're very happy with the end of phase II 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. Not surprisingly, for a global diabetic retinopathy plan, they do want to get EMA and feedback from Japan. Those are some of the aspects that we want to tidy up before we give any more details on the plan. 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 BLA submission. We do not know. It is not the kind of thing we can say with 100% certainty either way. We, as of now, do not see a significant issue anywhere that would suggest one is needed. If one comes our way, we will be ready for it. I think with any development program at this stage, you plan in case you may need it. If we have one, we would 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. As of now, we do not know.
Judah Frommer (Senior Equity Research Analyst)
Thanks.
Operator (participant)
Our next question comes from a line of Gena Wang with Barclays.
Gena Wang (Managing Director of Biotech Equity Research)
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. I have two questions. One is regarding the NDA update. Just wondering how many patient data from one to three years old should we expect to see? Also, given the younger patient age, should we expect to see higher protein expression? Related questions, any thoughts regarding lower age to zero, given, I think, as mentioned, they will start a cohort between zero and 18. My second question is regarding the ALTITUDE DME cohort. Just wondering, what will be the timing of data update? In terms of also number of patients and type of data you will share with us?
Curran Simpson (President and CEO)
Great. I'll take the first one, and then I'll let Steve answer the second one. We're planning to update at MDA likely one patient in the one to four cohort in terms of their microdystrophin value. 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. Obviously, we'll save that specific for the conference itself. 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.
Steve Pakola (CMO)
Yeah. Hi, Gena. Thanks for the question. ALTITUDE, our 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. In DME, you care about visual acuity, and you also care about disease activity assessed by retinal thickness on OCT.
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? Basically, treatment burden. We would report on all three of those as well as safety.
Gena Wang (Managing Director of Biotech Equity Research)
Thank you.
Operator (participant)
Our next question comes from a line of Mani Foroohar with Leerink.
Ryan McElroy (Biotechnology Equity Research Associate)
Hey, guys. Yeah, I have Ryan on from Mani. Thanks for taking our question. 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 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? 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 I/II trial? Thanks.
Curran Simpson (President and CEO)
Yeah, I think it's safe to say that we're seeing really encouraging enrollment in terms of the Duchenne study. 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 there's a significant amount of interest and a significant number of patients that are going through screening. The second part is, yes, we do expect it to accelerate primarily because we're increasingly adding sites to the study. The overall productivity of the study will just continue. It'll be a non-linear enrollment curve, if you will. 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.
Steve Pakola (CMO)
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. I think having the nine and 12-month data has really bolstered our case across our clinic. 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 microdystrophin in that age range.
We do know, by the way, harkening back to Gena's question, that younger, we have seen with other programs that you have higher microdystrophin levels. I think one of the massive unmet needs is in the older patients where you do not see with other programs high microdystrophin levels. We are really excited about that. We really want to treat broadly across the entire age range. That is why we are 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 account for pivotal. We are very excited to enroll across the age range, that one to three years, four to seven, and also eight and older.
Curran Simpson (President and CEO)
We are particularly interested in that cohort because, as you know, there is no approved therapy for patients in the one to four age category. That is a key element of our pivotal plan. These patients will be included in that.
Ryan McElroy (Biotechnology Equity Research Associate)
Thanks, guys.
Operator (participant)
Our next question comes from a line of Luca Issi with RBC Capital Markets.
Lisa Walter (VP of Biotech Equity Research)
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 ejection fraction or cardiac biomarkers like troponin I as part of the AFFINITY study? If so, could these be a meaningful way to differentiate your program further from Allovidis? I have one question on wet AMD on the subretinal study. I'm just curious if you are considering maybe cutting the enrollment a bit short in order to accelerate the readout timelines. 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. As we know from Zolgensma's launch, being first to market does matter.
Any color here on DMD or the subretinal pivotals, that would be appreciated. Thanks so much.
Curran Simpson (President and CEO)
Great. Thanks. I think I'll let Steve comment certainly on the retina discussion. In terms of cardiac, Steve can describe what we're measuring in the clinic. 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 is represented well in studies that we did preclinically, like the treadmill test for MDX mice. 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 a 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's something we'll certainly be monitoring. Maybe I'll let Steve cover how we're doing that.
Steve Pakola (CMO)
Sure. 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 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. It is really as the boys advance into the teen years that you see the unfortunate cardiac deterioration. That is one of the reasons we are so excited that we are seeing very high and consistent microdystrophin expression in these older boys. That also bolsters our confidence. How can we look at this? Certainly, ejection fraction, as you mentioned, is one of the measures you can look with echo, which is not as accurate and sensitive as looking with MRI.
We do incorporate both of these. We're going to have the ability to look at that. We do also look at troponin levels. Again, I think the key aspect is it's not going to be really meaningful to look at these while patients' cardiac function is normal. 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. 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. We have patients already out nine and 12 months and further as we go out further.
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 and our pivotal trials for subretinal delivery, whether we've considered 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. 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. This is a unique opportunity to compare to two established, approved treatment regimens to really inform the clinical community, not just the regulatory body. Our view would not be to cut these short.
As Curran has summarized, we look forward to completing enrollment this year and being able to have results next year. 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 injection. We are seeing that as a strong differentiator. That is, again, why we are pleased that we're going to be able to complete enrollment this year.
Curran Simpson (President and CEO)
One thing I would add too, just we are certainly cognizant of timing and moving as quickly as we can to a BLA filing. 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. This is 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. That's something to follow in the next year. We're with you in terms of going as fast as possible. As Steve mentioned, we want to do it the right way.
Lisa Walter (VP of Biotech Equity Research)
Got it. Thanks so much for taking the questions.
Curran Simpson (President and CEO)
Thanks.
Operator (participant)
Our next question comes from a line of Annabelle Samimy with Stifel.
Annabel Samimy (Managing Director of Equity Research and Biopharmaceuticals)
Hi. Thanks for taking my questions. Just following on the regulatory discussions for DR, 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. 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 you've already disclosed, or will we see new patients of the 11 that had already been treated? Finally, for DMD, the 50% enrollment, 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 I/II study? Thanks.
Curran Simpson (President and CEO)
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 I/II study, likely at nine months. Also, long-term data on the dose level one patients that'll be out at least to 18 months, depending on the specific timing of the update. 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.
We're just incrementally adding, hopefully, meaningful updates, not patient-by-patient, enriching that dataset 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. Also, some of the patients that were dosed, actually the majority of them that were dosed in the phase I/II study, would also be eligible as part of the pivotal dataset. Just recall that's an N of 30 that we're driving for to complete that study.
Steve Pakola (CMO)
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 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. 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. That means it still opens the ability to use a negative control. For example, in our case, the potential to use a sham control arm where we know that those patients don't magically get better. In fact, they on average get worse.
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. That is one of the reasons we want to work with the EMA and also in Japan. We think there is a very solid case for use of the diabetic retinopathy severity scale. In fact, the more years that go by and the more studies that are done, we think that case gets stronger. We look forward to in the future giving an update on discussions that we have had with regulators around the world.
Annabel Samimy (Managing Director of Equity Research and Biopharmaceuticals)
Thank you.
Operator (participant)
Our next question comes from a line of Brian Skorney with Baird. Brian, you may be on mute.
Brian Skorney (Managing Director of Biotechnology)
You're right. Off mute now. Thanks for taking the question, everyone. You've now submitted a BLA for Hunter with SIBR, had discussions going into the pivotal program for DMD and planning a program for diabetic retinopathy. We get a lot of questions about continuity at SIBR given the change of guard at HHS and FDA. I don't really know anyone who's probably had more interaction with SIBR than you guys over the last couple of months. I just wondered, with Celia Witten departing a couple of weeks ago, if you could give us a sense as to how up-to-date your discussions with SIBR and OTP are, and if you're seeing significant change within the review division, the Office of Therapeutic Products, and how much that could potentially impact future gene therapy reviews.
Curran Simpson (President and CEO)
Yeah, I think our general comment is, from our perspective, it's business as usual in terms of the submissions that we're making. We're on a pretty frequent basis providing amendments to protocols, amendments to INDs. 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. I think we were encouraged by some of the comments, especially on the rare disease side around accelerated approval from McCarry and just the overall sentiment. 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.
Therefore, we don't see any change in sort of the risk profile of our pending BLA now and ongoing discussions for Duchenne.
Brian Skorney (Managing Director of Biotechnology)
Maybe if I can 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 to screen them? In particular, wondering if the availability of ELEVIDYS and ELEVIDYS' data, if it's sort of like four to five-year-olds favoring coming in to be screened for gene therapy, or because the data is strongest for 11S, 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?
Curran Simpson (President and CEO)
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, our screening logs and patients testing for neutralizing antibodies, it's a significant number of people, of patients being screened. 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?
Steve Pakola (CMO)
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. 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 most evidence for 11S. I think one aspect that is a differentiator across the spectrum is safety. Safety first, that's certainly how investigators think about it, and that's how patient families, of course, think about it. We believe with various aspects of our program, both our proactive immune suppression transient approach, our high purity levels that are very differentiating. Overall, what we're seeing is very good safety.
We have seen no SAEs, no AEs of special interest. That includes no LFT elevations, no thrombocytopenia. These are findings that have been seen in other programs. With ELEVIDYS, I think upwards of 40% have LFT elevations. That is 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 are excited about in our program is some of the not just microdystrophin expression, but also vector genome copies per cell that we are actually seeing, which are much higher than has been reported by any other program. We think that gives added confidence when you think of that younger age group where there still may be some muscle cell division.
In short, in summary, we see good differentiation aspects that are compelling for doctors and patient families to consider. That is 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.
Curran Simpson (President and CEO)
I think particularly if you think about it, 95% of the prevalent market is still available for these studies. I think that plus the focus on next-generation therapies is really helping with enrollment. We are excited where we are this early in the year. I can guarantee we are pushing to go as quickly as we can on all fronts for the BLA submission.
Brian Skorney (Managing Director of Biotechnology)
Great. Thank you.
Operator (participant)
Our next question comes from a line of Paul Choi with Goldman Sachs.
Paul Choi (Biotechnology Analyst)
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 sort of requirements, I guess, down the road for a confirmatory study or other regulatory requirements and just your thoughts there. 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 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.
Curran Simpson (President and CEO)
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. I think in general, we intend to continue to enroll post-enrollment of our pivotal N equals 30 dataset towards the end of completing a confirmatory study as quickly as possible. We'll have further discussions with FDA in our pre-BLA meeting about what exactly that will mean. I think the second question, just remind me.
Steve Pakola (CMO)
On non-ambulatory?
Curran Simpson (President and CEO)
Yeah. We are considering.
Paul Choi (Biotechnology Analyst)
Non-amplification?
Curran Simpson (President and CEO)
Yeah. We're certainly considering strongly conducting studies in non-ambulatory patients. 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. It is definitely a consideration given the size of the prevalent market there. 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.
Steve Pakola (CMO)
Given the excellent microdystrophin levels and also functional results that we're seeing in eight and above, including a 12-year-old, it's an interesting dilemma, really. Like Curran said, we got to focus on the population for our pivotal. More and more, once we show that data, investigators and also patient advocacy are asking about non-ambulatory because it's quite logical given the results we've seen. It is something we'll be looking at, but not acutely adding to the pivotal.
Curran Simpson (President and CEO)
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. I think that's really important that we can seamlessly move into a confirmatory study with existing drug supply.
Operator (participant)
Our next question comes from a line of Ellie Merle with UBS.
Ellie Merle (Biotech Equity Research Analyst)
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? 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? If so, is this something that you've discussed at all with the FDA? Thanks.
Curran Simpson (President and CEO)
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 two in our phase I/II 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. Also, we will update patients dosed 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. Of course, that's not at the pivotal dose.
It'll be just informational at that point. That's what you should expect to see near-term. 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.
Steve Pakola (CMO)
As far as what we see or what we'll look at, it'll be the usual suspects, Ellie, as far as time function tests, so time to stand, 10 m walk, run, time to climb, and NSAA, which traditionally has been viewed as less sensitive than the time function test. Actually, in our November update, we saw encouraging results not just on the time function test, but also on the NSAA. We are 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 will 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. That is really important given disease trajectory is different depending on age and baseline severity.
We match on all those factors to give greater confidence in terms of whether individual patients' trajectory is positive or not. We have discussed this with the FDA. This was certainly a part of the successful end of phase II meeting that we held before starting pivotal. We had no issues getting into the pivotal design.
Ellie Merle (Biotech Equity Research Analyst)
Cool. Thanks.
Operator (participant)
Our next question comes from a line of Sean McCutcheon with Raymond James.
Sean McCutcheon (VP of Biotechnology Equity Research)
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 burden of frequent injections. 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 aflibercept. What do you view as the treatment durability at which we could start to see more utilization in NPDR? How do you view that as distinct for a gene therapy versus, say, a sustained-release TKI? Thanks.
Steve Pakola (CMO)
Sure. That's a great question, Sean. 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. You're basically signing patients up who are currently asymptomatic to get injections the rest of their life, basically. 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. If it's repeated injections, we see that as a major barrier. That's why we in AbbVie are so excited about the DR indication because a suprachoroidal in-office one-time injection is really the way to address this massive unmet need.
That is 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. 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, we're both excited to advance into pivotal this year.
Sean McCutcheon (VP of Biotechnology Equity Research)
Thank you.
Operator (participant)
Our next question comes from a line of Alec Stranahan with Bank of America.
Alec Stranahan (Biotechnology Equity Research)
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 micro-dystrophin 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? 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.
Curran Simpson (President and CEO)
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. If you look at the updated guidance now, we're pointing towards a mid-2026 BLA filing. That could lead to a potential approval in early 2027, which I think is really important. 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. 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.
Steve Pakola (CMO)
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-dystrophin. That is a very significant step. We certainly would be coming out with that data since that is really what is going to drive actually going ahead with the BLA submission by mid next year already. We would also have safety at that time point as well. I think that really puts us in a good position.
Curran Simpson (President and CEO)
I think if you think about what functional data would we have in hand at the time of filing, certainly the full phase I/II dose level two cohort would be past 12 months at that point. A good proportion of the patients treated in the pivotal study will have at least nine month, if not 12-month data. We will have a healthy level of functional data to accompany the primary endpoint of micro-dystrophin at the time of filing and probably be able to update that somewhat at the 120-day safety update as well.
Alec Stranahan (Biotechnology Equity Research)
Got it. Makes sense. Appreciate the color.
Operator (participant)
Our next question comes from Yi Chen with H.C. Wainwright.
Yi Chen (Managing Director of Equity Research)
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 RGX-121? Do you expect that any sales-related milestone could be triggered within 12 months of commercial launch? Thank you.
Patrick Christmas (CLO)
Didn't quite hear the first part.
Curran Simpson (President and CEO)
Could we repeat just the beginning of that question? I got it was a little bit muffled. Yeah, the audio was just a little rough.
Yi Chen (Managing Director of Equity Research)
The sales team presence of Nippon Shinyaku's in the U.S., how many of them will be promoting RGX-121 once it's approved?
Curran Simpson (President and CEO)
Yes. Nippon Shinyaku has a significant U.S. presence in rare disease. They have an existing sales force that services their Duchenne launch. We expect that majority of that same team would be applied towards commercialization of RGX-121. Given the timeline now that we filed the BLA, we're pointing towards PDUFA date somewhere in Q4 of this year. 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. 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.
Yi Chen (Managing Director of Equity Research)
Thank you.
Operator (participant)
I'm showing no further questions in queue at this time. This concludes today's conference call. Thank you for participating. You may now disconnect.