REGENXBIO (RGNX) Q4 2025 Earnings Call Transcript

Image source: The Motley Fool.

DATE

Thursday, March 5, 2026 at 8 a.m. ET

CALL PARTICIPANTS

• President and Chief Executive Officer — Curran Simpson
• Chief Medical Officer — Steve Pakola
• Chief Financial Officer — Mitchell Chan

TAKEAWAYS

• Cash position -- $241 million in cash, cash equivalents, and marketable securities at year-end, a decrease of $4 million from the prior year, reflecting $110 million from Nippon Shinyaku and $145 million from HealthCare Royalty Partners, offset by operating use.
• Revenue -- $170 million total annual revenue, including upfront license revenue from the Nippon Shinyaku collaboration and increased royalty revenue from Zolgensma and Evrysdi, both included in the HealthCare Royalty monetization.
• R&D expenses -- $228 million in research and development expenses for the year, up from $209 million the previous year, primarily for pivotal trial execution and manufacturing for RGX-202 and Cirovec.
• Runway guidance -- Mitchell Chan said, "We expect the December 31 cash balance reported today to fund our operations into early 2027," not including a potential $100 million milestone from AbbVie or further royalty proceeds.
• RGX-202 (Duchenne muscular dystrophy) -- Enrollment completed in the pivotal AFFINITY DUCHENNE trial, with confirmatory trial enrollment ongoing; 18-month Phase 1/2 NSAA data showed a 7.4-point improvement versus CTAP at 18 months. No reported serious adverse events or adverse events of special interest, including "no thrombocytopenia or liver injury" in treated patients, with more than 80% full capsids in product composition.
• Regulatory pathway (RGX-202) -- The pivotal and confirmatory trials’ protocols were "prospectively reviewed by FDA," with the company intending to pursue an accelerated approval pathway and a pre-BLA meeting midyear 2026.
• Cirovec (wet AMD and diabetic retinopathy) -- Enrollment is complete in the ATMOSPHERE and ASCENT pivotal trials for subretinal wet AMD, with topline data expected in Q4 and site activation for the NAVIGATE pivotal study in diabetic retinopathy progressing; first patient dosing in NAVIGATE is expected next quarter and will trigger a $100 million milestone from AbbVie.
• Cirovec efficacy (ALTITUDE trial) -- Cirovec recipients at dose level 3 demonstrated "a 93% reduction in annualized anti-VEGF injection need at 12 months, with 60% of recipients remaining injection-free" and a ">70% risk reduction in vision-threatening complications."
• MPS programs (RGX-111/121) -- The company received clinical hold letters for RGX-111 and RGX-121; requirements to lift holds are considered "addressable" as per management, with a Type A meeting and BLA resubmission planned for Hunter syndrome (MPS II).
• AAV integration event (RGX-111) -- Independent analysis confirmed AAV vector genome integration at PLAG1 in a tumor, supporting the hypothesis of AAV vector integration contributing to tumor formation; the patient shows above-average neurocognitive outcomes post-therapy.

RISKS

• The company disclosed receipt of clinical hold letters for RGX-111 and RGX-121 and stated ongoing work to meet requirements on these programs, explicitly noting they are responding to a Complete Response Letter (CRL) for RGX-121.
• Steve Pakola said, "Clonal integration of AAV vector elements into the PLAG1 gene was detected in the tumor tissue" of an RGX-111 patient, raising the risk of rare AAV-mediated oncogenic transformation, though considered very rare following more than 6,000 patient treatments across the field.

SUMMARY

REGENXBIO(NASDAQ:RGNX) provided operational updates highlighting late-stage clinical, regulatory, and financial developments that may influence investor sentiment and near-term strategy. The RGX-202 Duchenne pivotal trial reached full enrollment, with management emphasizing data indicating both functional and biomarker improvements, and advanced FDA interactions ahead of an anticipated accelerated approval pathway. Company leadership outlined Cirovec’s topline data readout schedules, a potential $100 million milestone upon first dosing in diabetic retinopathy, and noted durable efficacy and significant anti-VEGF injection reduction in prior dose cohorts. Management acknowledged ongoing regulatory challenges in the MPS franchise, reporting active engagement with the FDA following a clinical hold and a single observed AAV integration event temporally associated with tumor formation. Financially, the company cited partnership-based revenues, committed R&D investments, and a multi-year cash runway, noting further extension potential with upcoming milestones.

• Management stated that in the pivotal Duchenne program, all patients exceeded their expected functional outcomes when compared to CTAP, as well as matched external controls at 12 months.
• Mitchell Chan confirmed, "This cash runway guidance does not include the $100 million development milestone we expect to receive from AbbVie or additional HealthCare Royalty funds."
• Site activation and first dosing in the NAVIGATE pivotal diabetic retinopathy study, anticipated next quarter, is expected to provide the largest single milestone payment in the company’s collaboration agreement with AbbVie.
• Leadership stated the approach and endpoints for regulatory filings were subject to prior FDA review and have not changed, indicating a well-defined regulatory strategy.
• AAV integration with subsequent tumor development in an RGX-111 patient was reported directly and will be published in a peer-reviewed journal, with the affected child’s neurocognitive function noted as above average post-treatment.

INDUSTRY GLOSSARY

• NSAA: North Star Ambulatory Assessment — a validated tool for evaluating motor function in Duchenne muscular dystrophy clinical trials.
• CTAP: Collaborative Trajectory Analysis Program — a natural history model used to benchmark clinical outcomes against expected disease progression in Duchenne studies.
• SAE/AESI: Serious Adverse Event/Adverse Event of Special Interest — categories used in clinical trials to track significant or targeted medical events.
• DRSS: Diabetic Retinopathy Severity Scale — a categorical scale to assess severity and improvement in diabetic retinopathy clinical trials.
• ICV: Intracerebroventricular — a delivery method involving direct infusion into the brain’s ventricles, referenced regarding sampling in MPS II studies.
• BLA: Biologics License Application — the regulatory submission required for marketing approval of biologic products.
• CRL: Complete Response Letter — an FDA communication detailing deficiencies preventing approval and guiding subsequent resubmissions.
• RMAT: Regenerative Medicine Advanced Therapy designation — an FDA program to expedite development and review of eligible regenerative medicine products.
• PDUFA: Prescription Drug User Fee Act — the legislative framework governing FDA review timelines, referenced regarding competing MPS II programs.

Full Conference Call Transcript

Patrick Christmas: Good morning, and thank you for joining us today. Earlier this morning, REGENXBIO Inc. released financial and operating results for the fourth quarter and year ending 12/31/2025. The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties.

These risks are described in the Risk Factors and the Management's Discussion and Analysis section of REGENXBIO Inc.'s Annual Report on Form 10-K for the full year ended 12/31/2025, and comparable Risk Factors section in REGENXBIO Inc.'s Quarterly Reports on Form 10-Q, which will be 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, 03/05/2026. We undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast.

In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I will now turn the call to Curran Simpson, President and CEO of REGENXBIO Inc. Curran?

Curran Simpson: Thank you, Patrick. Good morning, everyone, and thank you for joining our call today. 2026 is set to be a pivotal year for REGENXBIO Inc. With great focus on advancing our late-stage pipeline in 2025, we enter the year with near-term topline Phase 3 readouts and ongoing commercial readiness activities in Duchenne muscular dystrophy and wet AMD. Last but not least, we are also entering the pivotal Phase 2b/3 program, named NAVIGATE, for diabetic retinopathy being developed in collaboration with our eye care partner AbbVie. Our clear focus on execution in 2025 has led to a robust set of important catalysts to transform REGENXBIO Inc. from a late-stage development organization to a commercial entity.

Today, I am joined by Steve Pakola, our Chief Medical Officer, who will walk through the ongoing clinical advancement of our programs, and Mitchell Chan, our Chief Financial Officer, to provide our financial updates.

With that, let me start with RGX-202, our late-stage Duchenne program. I am pleased to report that momentum for RGX-202, our potential best-in-class gene therapy for Duchenne, remains strong. We completed dosing in our pivotal study last fall and are seeing robust enrollment in our confirmatory trial, reflecting continued enthusiasm from the Duchenne community. Our growing clinical dataset, including the 18-month Phase 1/2 NSAA results shared in January, demonstrate meaningful differentiation from the known natural history of Duchenne across multiple validated measures. Combined with a favorable safety and biomarker profile to date, we believe RGX-202 has the potential to deliver durable, clinically meaningful benefit.

With less than 1% of the global Duchenne population having received an approved gene therapy and no approved option for patients aged 1 to 3, the unmet need remains significant. We look forward to sharing additional Phase 1/2 data next week at the Muscular Dystrophy Association's annual meeting and topline data from our pivotal study early in the second quarter as we advance towards a BLA submission.

We look forward to engaging with FDA midyear to discuss our planned BLA submission using the accelerated approval pathway. We have FDA engagement planned ahead of the pre-BLA meeting and intend to support our primary microdystrophin endpoint with significant functional data both in the pre-BLA meeting and at the time of submission. By 2026, we will have 12 months of functional data on the majority of pivotal trial patients. In addition, with the enrollment momentum in our confirmatory study, our safety database continues to expand.

In our retinal disease programs, our partnership with AbbVie continues to progress. Topline data for subretinal Cirovec in wet AMD are expected in Q4 this year. ATMOSPHERE and ASCENT represent the largest global gene therapy program in this indication, and if approved, Cirovec would be the first gene therapy for wet AMD. I am also pleased to share that site activation plans are also underway in the NAVIGATE pivotal study in diabetic retinopathy, with first patient dosing expected next quarter, triggering a $100 million milestone from AbbVie.

Finally, turning to our MPS programs, since receiving the CRL for RGX-121 two weeks ago, we have also received the clinical hold letters for both RGX-111 and RGX-121. We believe that the requirements to remove the holds are addressable and, in fact, had already been in the process of addressing them. We continue to work on the CRL response and are working towards a Type A meeting with the goal of resubmitting the BLA. We remain committed to the MPS community, the Hunter syndrome patients waiting for a treatment for this devastating disease.

As we enter 2026, our focus is clear: execute against our key milestones and bring the hope for transformative gene therapies closer to patients in need. With that, I will turn it over to Steve.

Steve Pakola: Thank you, Curran. I will start with the RGX-202 program for the treatment of Duchenne. As Curran mentioned, we are incredibly excited that enrollment in the AFFINITY DUCHENNE pivotal trial completed in October 2025. As a reminder, this study enrolled ambulatory patients aged 1 and older and is the most advanced clinical-stage gene therapy program for Duchenne. RGX-202 has demonstrated a highly differentiated safety and efficacy profile with consistent, robust microdystrophin expression in the Phase 1/2 study. This includes the positive NSAA data we disclosed in January. As Curran referenced, the 7.4 average improvement compared to the recognized CTAP model observed at 18 months is striking.

These results are generally consistent with the October 2025 data showing all patients exceeded their expected functional outcomes when compared to CTAP, as well as matched external controls at 12 months. It is important to note the majority of these patients were 8 years and older at dosing, an age when functional decline is expected, making these functional outcomes even more impressive.

The Duchenne patient and physician communities continue to highlight the excellent safety profile of RGX-202 to date. As reported in the Phase 1/2 study, we have seen no SAEs or AESIs, including no thrombocytopenia or liver injury. We attribute this to our proactive immune suppression regimen, our novel construct, and our field-leading product purity, with more than 80% full capsids. We are very pleased with how these differentiated elements enable us to deliver 202 at a 2e14 dose and maximize the potential for efficacy without compromising safety. Next week at MDA, we are thrilled to share additional new Phase 1/2 data on podium, including functional and safety outcomes.

With this momentum in our pivotal study, and results to date in the Phase 1/2 study, we look forward to sharing topline data from the pivotal study in early second quarter this year.

Turning now to our Cirovec franchise, which is advancing one-time treatment for wet AMD and diabetic retinopathy, or DR. Enrollment is complete in ATMOSPHERE and ASCENT, our two large pivotal studies intended to support global regulatory submissions for subretinal wet AMD starting next year. The data from the subretinal program have been excellent, with durable outcomes reported through four years in the Phase 1/2 trial. Additionally, Cirovec recipients in the fellow eye bilateral dosing study demonstrated a 93% reduction in annualized anti-VEGF injection need at 12 months, with 60% of recipients remaining injection-free through that timeframe. We look forward to sharing topline results from ATMOSPHERE and ASCENT with AbbVie in Q4.

We are very excited to be advancing Cirovec into pivotal stage for DR using in-office suprachoroidal delivery with AbbVie. This progressive vision-threatening disease is a public health priority globally. It remains a leading cause of vision loss among working age in the U.S., and a one-time treatment could change the way this disease is treated for millions of people. Site activation activities are underway in the Phase 2b/3 NAVIGATE trial. This is a double-masked, sham injection-controlled trial evaluating Cirovec at 1e12, which is the same as dose level 3 in the Phase 2 ALTITUDE trial. The Phase 2b portion of the study will enroll 136 patients with nonproliferative DR, or NPDR.

The primary endpoint is a two-step or greater improvement on the Diabetic Retinopathy Severity Scale, or DRSS, at one year. As a reminder, in the Phase 2 ALTITUDE trial, at two years post-treatment, with dose level 3 and short-course prophylactic topical steroids, no intraocular inflammation was observed. The majority of subjects achieved DRSS improvement, with 50% achieving at least a two-step improvement without any additional DR treatment. Cirovec at dose level 3 also reduced the risk of disease progression, demonstrating a greater than 70% risk reduction in vision-threatening complications compared to historical control.

As Curran mentioned, we are working towards addressing the clinical holds for RGX-111/121. And in the interim, we have received the final genetic analysis from the SAE in the RGX-111 study. The analysis of the resected tumor was conducted by an independent third-party lab and, as we reported, detected an AAV vector genome integration event associated with overexpression of a proto-oncogene, PLAG1. Clonal integration of AAV vector elements into the PLAG1 gene was detected in the tumor tissue. Analyses supported classification as a PLAG1 family neuroepithelial tumor and are consistent with the hypothesis that AAV vector integration at the PLAG1 site contributed to tumor formation.

Of note, this participant had a background of factors that could have contributed to risk of oncogenic transformation. This child underwent an unsuccessful stem cell transplant at four months of age with loss of donor chimerism, and he received chemotherapeutics that may have contributed to DNA damage. Notably, the report concludes, based on formal neuropsychological testing and developmental pediatrician assessment, that the patient's neurocognitive development is above average, which indicates mitigation of MPS I disease. We anticipate the analysis will be published in a peer-reviewed journal this year, and we are pleased that the patient continues to do well.

Finally, I would like to express my sincere gratitude to all the patients, families, clinicians, site staff, and patient advocacy representatives who have supported these trials. With that, I will turn the call over to Mitchell to review our financial guidance. Mitchell?

Mitchell Chan: Thank you, Steve, and good morning, everyone. REGENXBIO Inc. ended the quarter on 12/31/2025 with cash, cash equivalents, and marketable securities of $241 million, compared to $245 million as of 12/31/2024. This year-end figure reflects the $110 million upfront payment from Nippon Shinyaku in 2025 and the $145 million in net proceeds received from the royalty monetization with HealthCare Royalty Partners in 2025, offset by cash used to fund operating activities through the year.

We continue to invest in de-risking our late-stage program in 2025. R&D expenses were $228 million for the year ended 12/31/2025, compared to $209 million in 2024, with much of this cost going to pivotal trial execution and manufacturing of RGX-202 and Cirovec. We also continue to bring meaningful revenue recognition in 2025, with total annual revenue being $170 million. This includes the upfront license revenue under our Nippon Shinyaku collaboration as well as an increase in royalty revenue for Zolgensma and Evrysdi, both of which are included in our royalty monetization agreement with HealthCare Royalty. We expect the December 31 cash balance reported today to fund our operations into early 2027.

This cash runway guidance does not include the $100 million development milestone we expect to receive from AbbVie upon first patient dose in the NAVIGATE study or any additional funds from the May 2025 HealthCare Royalty agreement, which together could extend our runway into 2027. This guidance also does not include any future revenue from our MPS programs. In all, we find ourselves in a strong position to leverage multiple funding options as we advance towards multiple product launches.

Curran Simpson: Thank you, Mitch. As you heard today, our strong execution has positioned us for an exciting and transformational year ahead as we share pivotal readouts and look to enhance the treatment landscape in Duchenne, wet AMD, and diabetic retinopathy, representing large indications and commercial opportunities. Our investment in-house manufacturing and co-development with world-class partners keeps us in a strong position as we approach commercialization. Last week, we joined the rare disease community in recognizing Rare Disease Day, and I would like to take a moment to acknowledge these patients, families, and community leaders.

We know they are counting on us to deliver innovative new medicines, and we greatly appreciate the support they have shown us, particularly on our rare programs recently. Their needs are significant and urgent, and we are inspired by their commitment to raise awareness and give voice to the critical need for new therapies. With that, I will turn the call over for questions. Operator?

Operator: Thank you. To remove yourself from the queue, you may press 11 again. We ask that you please limit yourself to one question and one follow-up to allow everyone the opportunity to participate. Please standby while we compile the Q&A roster. Our first question comes from the line of Mani Foroohar of Leerink Partners. Please go ahead, Mani.

Mani Foroohar: Hey, guys, thanks for taking the question. So as we get closer to data and regulatory clarity in terms of submission around DMD, obviously, there is a lot of debate and concern around whether a controlled trial or an appropriate control arm could be; obviously, there are both Sarepta and Elevidys have seen that in the confirmatory and pivotal studies, respectively. What gives you confidence on your path to accelerated approval and on the design of your confirmatory study, which is a little bit different than both of those competitors? That is helpful.

And as a clarifying question, when you talked about reaching alignment, submitting the protocol, including the confirmation study protocol, can you give a sense of when that happened and if those interactions were with FDA and CBER under the current leadership, or under the prior leadership preceding Dr. Peter Marks?

Curran Simpson: Thanks, Mani. I think there are a number of aspects to that give us confidence. I think, number one, the fact that the protocol was prospectively reviewed by FDA. We received comments on the design of the study and the stats plan around comparison to external controls. We feel like we have, and none of that has changed. We have not altered the pivotal protocol through execution. I think the second pillar of that is there is not a narrow difference between the results we are seeing on functional outcomes versus natural history comparatives, and this is matching many patients against the patient treated.

So I think that the fact that we have such compelling data specifically in the older patients, where they are typically in a decline phase, I feel will sort of trump the concept of a placebo arm, which we do not think is ethical. And I think the other aspects of how that relates to the confirmatory study: the confirmatory study was included in the original protocol as in addition to the pivotal design. So, again, that was reviewed by FDA. We are really pleased with how the enrollment is going there.

And one thing that enrolling as quickly as we have on the confirmatory study does in a positive way is it increases the number of safety exposures that we have at the time of filing. We are talking about roughly 50 total rather than the 30 that were in the pivotal group. So a broader safety database at the time of review, which will be very helpful. Because in our end-of-Phase 2 meeting, one of the things that we heard as a ticket to accelerated approval was similar efficacy but improved safety, and that was pre–black box warning for Elevidys.

So I think we are in an even stronger position now around our dataset, and we look forward to discussing that with FDA in our pre-BLA meeting. Yeah. I can comment on the latter part of the question. It was under the prior leadership. This was roughly 2024 that these discussions took place. But I would say the review team that we spoke to and that this was reviewed by is pretty largely intact from what we can tell to date. Steve, if you want to discuss just the prospective nature of the data plan.

Steve Pakola: Sure. Thanks for the questions, Mani. So, highlighting what Curran mentioned, the importance of prospective design. This was all set as of those discussions that Curran met. So, for example, the primary—this is accelerated approval—so we were very clear in our design of the primary being microdystrophin. We were also very clear in the secondary functional endpoints that we were looking at and the methodology for assessing that. So this is not a case where midstream we changed something or we looked at data and adjusted how we were looking at the data. And, Mani, one thing I would add in general is we understand the environment and where people are trying to assess FDA's position.

From the very beginning of the study, we knew about the controversy around microdystrophin as a biomarker reasonably capable of predicting clinical benefit or functional benefit. And I think that is why the way we have designed the study and in the way we are approaching FDA, we are maximizing the functional data that we bring to the review. And I think that is an incredibly important aspect of how we are approaching this, because we feel like the functional data really supports the improved biomarker data that we have over current therapy.

Operator: Thank you. Our next question comes from the line of Judah Frommer of Morgan Stanley. Please go ahead, Judah.

Judah Frommer: Yes, hi, good morning, guys. Thanks for taking the question. Maybe just a follow-up on 202 to start. If FDA does end up wanting potentially longer duration follow-ups, specifically for safety, and you go down the path of a traditional approval, what would that entail? What would the trial's role be in that scenario? And then just on the Hunter's program, there is an approval decision coming up for Denali. What would you hope to learn from that program as you go back to FDA to discuss once you are well with them? Thanks. Do you have those heparan sulfate assays, if it is a relatively simple addition to the submission?

Curran Simpson: Sure. Hi, Judah. I think if FDA expects longer-term functional data, the time points I would keep in mind is we completed enrollment of the pivotal study in October. So at that point this year, we will have 12-month data on the full pivotal dataset. And then, of course, there is time for QC of the data and then incorporating that into a filing. But it is a near-term event that we would have functional data on the full pivotal dataset. And then if you consider that maybe there is a larger sample size required, the fact that we immediately went into enrollment of the confirmatory study just keeps working towards more data as we go through the year.

So I feel like there is no discontinuity between our pivotal and our confirmatory dataset, but we feel like the data we have seen in the Phase 1/2 is already strikingly different from natural history, and so more is not always better in that case, given the unmet need that we are seeing, the prevalent market continuing to grow. So we feel like we are in a good place, notwithstanding as well the safety profile that we are showing. We have investigators clamoring for something where they do not have to worry post-treatment of these events that have been seen in high-dose AAV.

On the outcomes for 121, we certainly will pay a lot of attention to Denali's PDUFA decision, and in particular, the fact that part of that submission—and significant element of that submission—is heparan sulfate–based biomarker. If you go on ChatGPT and pull up D2S6, it clearly says that it is a subcomponent of heparan sulfate. So we see them as the same. But in the event that FDA continues to not necessarily see them the same but endorses heparan sulfate, we will be in a great position with our data to pivot to that if that is what is necessary.

But we feel really strongly that our dataset using D2S6 shows really good biomarker reduction, very consistent across patients who we know are neuropathic from external reviews. And so we look forward to the Type A. But I think to your point, it will be helpful to see decisions on Ultragenyx's program and Denali's program to see how that may or may not affect ours. We do.

Operator: Thank you. Our next question comes from the line of Annabel Samimy of Stifel. Your line is open, Annabel.

Annabel Samimy: Hi, thanks for taking my question. I am going to be original and ask about 314. So I noticed that you were moving forward with dose level 3, and I know also that you had agreed with AbbVie to conduct a Phase 2 trial to test the higher dose, but you are going with dose level 3. So I guess the question is, why is it not going straight into a Phase 3? Does the Phase 2/3 also count as part of that pivotal? And just curious about what you found with the L4 that made you go with the L3, and what does this mean for wet AMD? Thanks.

Just to follow up, are—like, I know that you are exploring deals for in wet AMD. Are you not going to move forward with that one, given the profile for DL3? I guess I am just trying to understand if there is any safety question with the L4.

Curran Simpson: Great, Annabel. I will comment a bit on the trial and what is coming, and Steve can comment a little bit on the dose selection. Keep in mind for the Phase 2 studies on diabetic retinopathy, it is a relatively small sample size, but strikingly good results in terms of what we were seeing on two-step improvement, etc., that we have published. The goal really of the Phase 2b, as it stands now, is to expand that dataset to a higher number of patients and confirm that result. But it is sequenced to be off an interim look and then directly into a larger pivotal study.

And I think that is just prudent risk management as we develop the program and move forward. The patients that are treated in the Phase 2b will certainly contribute to the safety database that will be created for DR. So they are helpful in some ways managing the size of the pivotals that we have to run. Now I will let Steve talk a little bit about the dose selection.

And on wet AMD, wet AMD is just a trickier indication in terms of reading the tea leaves and looking for a signal in terms of efficacy compared to DR, where there is no other treatment, and you are really looking at pretty binary assessment of things like actual improvement in DR. So I think it is just more straightforward to make a decision on DR as compared to wet AMD. So we and AbbVie are continuing to evaluate the data.

Steve Pakola: Sure. First, Annabel, thanks for raising certainly one of our big priorities, which is DR, given what a massive unmet need that is where we certainly believe a one-time treatment is really what is needed for this disease to make the ultimate impact. And the other thing I say is on the dose selection and the Phase 2b/3 concept is it is a real validation of not only our commitment but also AbbVie's to embark on a Phase 2b/3 program. So, as in any program, we do the dose escalation to really look at safety and efficacy.

I think one of the aspects was with the time that we took to evaluate dose level 1, dose level 2, dose level 3, the longer we look, the more compelling dose level 3 became. And it really reached a point of pretty remarkable results where we were definitely hitting our target product profile, where the durability to actually see 50% of patients not only be stable but actually have at least a two-step improvement in diabetic retinopathy was really quite compelling. And I think, clinically, even more meaningful for clinicians is the fact that there was a dramatic reduction in vision-threatening complications—over 70%—compared to what you would anticipate without treatment based on natural history data.

So I think this constellation was really what drove the decision for us and AbbVie. If you are already at your target product profile, and meaningfully with short-course topical steroids, zero cases of IOI, which is really the big sensitivity in the retina community when it comes to safety, we really had what we needed to go forward. And, you know, once you hit your target product profile and you are really, frankly, plateauing in terms of the results that you would anticipate, and you are seeing durability, that made it a clear decision for us and happy to move forward.

Curran Simpson: Yeah. So wet AMD is just a trickier indication in terms of reading the tea leaves and looking for a signal in terms of efficacy compared to DR where there is no other treatment, and you are really looking at pretty binary assessment of things like actual improvement in DR. So I think it is just more straightforward to make a decision on DR as compared to wet AMD. So we and AbbVie are continuing to evaluate the data.

Operator: Thank you. Our next question comes from the line of Alec Stranahan of Bank of America. Please go ahead, Alec.

Alec Stranahan: Hey, guys, thanks for taking our questions. Two for me as well. I guess, first, just on the functional data, could you just remind us how much of this you will be providing at the topline? I guess, how many patients you expect you will have at that point for the 12-month functional data. And then just on MPS I, curious how the neoplasm in the MPS I patient maybe shifts benefit-risk discussion with the FDA, and I guess what kind of mitigation measures you are considering here, given it sounds to be AAV-related? Thank you. Got it. Very helpful. Thank you.

Curran Simpson: Thanks, Alec. I can speak a bit on the topline data plans. So I think as we have previously discussed, we will have, obviously, a safety data update on the full cohort, which is n=30. We will have biomarker topline data for the primary endpoint for the full pivotal dataset as well. In terms of functional data, we have not set a specific time for the release of the topline data, so it is a little bit in flux, but I would set an expectation of roughly seven or so patients at 12 months for functional data. And then, of course, throughout the remainder of the year, we will consider updating that as additional data comes in.

Historically, we did report some nine-month data early in the Phase 1/2 studies. I think we are going to try to avoid that because that really does not work well with most of our natural history comparisons that we would like to make. And I think on top of it, we just feel nine months is too early to judge stability of effect on function. But as we go past 12 months, then I think we get to a meaningful level of functional data, and they are well past the removal of immune suppression agents.

Steve Pakola: And I can jump in as well, Alec, on the MPS I neoplasm. So you, of course, hit the nail on the head of, well, what does this mean in terms of the overall benefit-risk? And our view, and what we hear from clinicians as well, is that on one hand, you have the risk of a rare event such as tumor, which is not completely unanticipated given the fact that we know that integration can happen with AAVs. And, in fact, it is even included in AAV gene therapy labels for that reason: the potential risk. So fortunately, it does seem to be a very rare event.

We have over 6,000 patients treated with AAVs of different sorts by different sponsors, and here is a case where an integration happened at a proto-oncogene. So the clinical community, if we raise this with the investigators and KOLs in the space, almost instinctively, their first response is, okay, there is a rare risk of a tumor versus a 100% risk of inexorable decline and irreversible brain damage. So it really comes down to that context for this devastating disease with such unmet need that the clinicians—it has not changed their view of the favorable benefit-risk. So, from our view going forward, as far as mitigations that you raised, just as in this patient, we can look at periodic MRI.

We have already looked at that in the other patients, not only in the 111 program, but also 121, and not seen any other evidence. And, of course, full disclosure in the investigator brochure and informed consent. And with that knowledge, clinicians and the patient families are able to make that assessment about benefit-risk.

Operator: Thank you. Our next question comes from the line of Paul Choi of Goldman Sachs. Please go ahead, Paul.

Paul Choi: Hi, thank you, and good morning. Thank you for taking our questions. I have two on RGX-202, please. First, with regard to the data you will have next week at MDA, can you just clarify what patient numbers you will have and additional duration of follow-up, or should we just think of—or will it just be additional details on the 18-month data that you previously presented? And my second question is, you have, in your press release, talked about the functional data to date in the context of a CTAP analysis. Can you comment on whether, in terms of your FDA interactions, there is alignment on using these kinds of analysis versus sort of conventional North Star analysis?

Any clarity there on the FDA's acceptance of that evaluation framework would be helpful. Thank you.

Curran Simpson: Thanks, Paul. I think, because the MDA manuscript is in deep editing mode with Steve, I will let Steve cover the expectations for MDA next week. But it will be, I think, a pretty substantial update—maybe the last update, if you will—in terms of Phase 1/2 data as we transfer over to our pivotal program. But, Steve, maybe you want to comment on what to expect. I think one thing I would add on MDA is we have a poster that will accompany the podium presentation.

We have not talked a lot about benefit to cardiac in Duchenne, and part of the reason for that is that we expect those types of outcomes to be much more long term in terms of seeing that in the clinical setting. So what we are providing at MDA is a preclinical model specifically showing the differentiation of our construct using the C-terminus in potentially preventing cardiac deterioration, if you will. Just something to have a look at as part of the total dataset. Some additional preclinical data that we think really supports what we have known from our preclinical work, where we saw good biodistribution in the MDX model in cardiac muscle. So stay tuned there.

Steve Pakola: Sure. So, all patients with the primary endpoint, I think, is obviously a key aspect for what we would anticipate. We are almost there, actually, in what we have disclosed before. I think function—the key thing is more patients and longer follow-up. We are really excited about the fact that we have already disclosed previously last year and early this year several different cuts of functional data. We are really happy with what we have seen at dose level 1 and dose level 2, even out to 18 months with dose level 2 for the CTAP. So it is just really a great chance to keep building on that base of functional data.

The consideration on the different ways of looking at function and what to compare to—CTAP—I think it is important to note that the program does not hinge on CTAP. It is really a supportive analysis. So our view is the totality of the data is important, that in looking at control data from external databases, it is very comforting and very validating if—and that is what we have seen to date—by different ways of looking at it, you see very consistent results. But certainly, our primary approach from a functional basis, and this is what we have prespecified as well, is the traditional approach separate from CTAP. Where that includes, as well, the propensity score weighting.

So I think that is going to give audiences also a sense to see how the results are looking compared to what one would anticipate based on prior analysis. So we are going to be looking at all this, and I think you can anticipate seeing several different ways of looking at comparison to expected trajectory without treatment. And the other key thing is continued safety. So to the earlier question about how much long-term safety—each update is not just the functional, but a chance to show continued differentiation on safety.

Operator: Our next question comes from the line of Luca Issi of RBC. Please go ahead, Luca.

Luca Issi: Oh, great. Thanks so much for taking my question. Maybe, Steve, any update on safety for DMD? You obviously have a very strong scientific hypothesis around sirolimus and eculizumab and, you know, empty-to-capsid ratio, etc. But, you know, we have seen obviously more setbacks for the field on the safety side from Pfizer and Sarepta than we would have liked. So I guess what percentage of your patients have ALT and AST elevations at this point, and how are the kinetics of those curves in terms of both, like, peak and area under the curve, compared to Sarepta and Pfizer? I do not think we have seen those curves before, so any context there would be much appreciated.

And maybe quickly, Steve, also on the CRL for MPS II, now public, why do you measure heparan sulfate at baseline versus after therapy using two different routes of access? I think the CRL notes that you used ICV at baseline versus spinal tap after therapy, which obviously created some variability. So we are just curious for why you decided to do that. Thanks so much.

Steve Pakola: Sure. So, on the safety aspect, there are several reasons why we anticipated having a differentiated safety profile: the higher purity, the specific construct, and our immune modulation regimen. And I think the key factor is we have not changed our immune modulation at all since the beginning of the study. So I think that gives comfort in how to analyze the type of safety data that we are seeing. Phase 1/2, we continue to see no cases of liver injury. So it is 13 patients, but zero out of 13 is clearly different from existing therapy, where that rate is 40%.

So we look forward to showing some more details on that from the Phase 1/2 study at MDA as well. Also on thrombocytopenia, no cases of thrombocytopenia as well, which is one of the key complement-mediated signals of complement activation that could signal potential risk for other more serious events. So we continue to see the differentiation that we would like to see and look forward to showing more data going forward. And, of course, we will have the topline results in the first half of the second quarter, which will be another cut for you to get more comfort on the data.

So onto the CRL, there was, yes, some comment about the potential impact of route of taking the sample. There was consistency, actually, in the vast majority of patients utilizing the same approach. We actually have the benefit of screening and baseline measurement where we have total consistency of ability to match like-for-like or apples-to-apples in terms of the same method of sampling, and we see really the same results in terms of change from baseline. So that will be part of our response—showing that analysis more clearly and more upfront so that they can get comfort around that difference.

Operator: Thank you. Our next question comes from the line of Brian Skorney of Baird. Please go ahead, Brian.

Brian Skorney: Hey, good morning, team. A couple of questions from me. Maybe going back to some questions around the D2S6 subunit discussion on the Hunter application. There is a lot of talk about it, and I think references this was a discussion point in the mid- and late-cycle review meetings. I guess at any point were measures of regular heparan sulfate discussed and submitted in the application process? Seems like something that could have been addressed during the review. And can you share what the HS data look like in the CSF and the other organs with us?

And then on DMD, given what you have been through in the Hunter review, what sort of dynamics and questions are you looking to have answered in the pre-BLA meeting with the agency? And, you know, I guess the bottom line is, does anything coming out of your BLA meeting matter if it is not coming directly from the division head?

Curran Simpson: Thanks for the question. I will take the DMD one, and then maybe have Steve talk through the heparan sulfate data, which we did provide limited heparan sulfate data during the review, but it was quite late in the review cycle. But I think in terms of what are the outcomes we are looking for in the pre-BLA meeting, I think that is the point at which, if you recall all the way back to the original protocol and our end-of-Phase 2 meeting, one of the things that we discussed with FDA was correlation of the microdystrophin results to functional outcomes was something that was an expectation of FDA.

Now, importantly, there was no specified number of patients of data that had to be provided to make that correlation. I think that was something that everyone considered would be a review issue at the time. I think as we have seen in our Phase 1/2 data, there is a very strong correlation that we are seeing to date: all of our patients above the 10% threshold, and we are seeing the majority of patients having not just sustained function or lack of disease progression, but improvement in age groups where you would not expect it.

So I think we have really compelling data, which at the time of the BLA discussion, pre-BLA discussion, I think will be very helpful—hopefully to encourage we are ready to file the BLA. The timing of the pre-BLA meeting is optimized now to provide maximum functional data at the time of discussion. So we have moved it out slightly, but it does not really alter, I think, the overall speed at which we can file, which we could file immediately after that meeting. Typically, a pre-BLA meeting will incorporate feedback from FDA leadership. So I think that is why that is an important event for us.

And obviously, ahead of that, we are going to do as much as we can informally outside of that process to assure ourselves of a positive outcome. Is that helpful? Yeah. Thank you. That is helpful.

Steve Pakola: Yeah. Thanks for the question, Brian. So, to start off, D2S6, it is important to note that biologically, it is the substrate that directly would link to the enzyme that we are reconstituting with treatment. So that is why, prospectively, that is what we put forward throughout the program. We do measure heparan sulfate, and likewise, we see, not too surprisingly, a dramatic reduction in heparan sulfate. And I guess similar to the earlier question about different routes of sampling, in our response to the CRL we will certainly lay out, in greater detail, our heparan sulfate results. The other thing is we really have an opportunity to clarify a lot of the factors, not just the biomarker.

And function is another area where our clinicians are very positive about what they are seeing. And, as you would expect, the longer the follow-up, the greater clarity you can anticipate seeing. So we can certainly show longer-term follow-up, which is one of the pathways that the FDA listed as a way to deal with the CRL.

Operator: Our next question comes from the line of Luca Issi of RBC. Please go ahead, Luca.

Luca Issi: Oh, great. Thanks so much for taking my question. Maybe, Steve, any update on safety for DMD? You obviously have a very strong scientific hypothesis around sirolimus and eculizumab and, you know, empty-to-capsid ratio, etc. But, you know, we have seen obviously more setbacks for the field on the safety side from Pfizer and Sarepta than we would have liked. So I guess what percentage of your patients have ALT and AST elevations at this point, and how are the kinetics of those curves in terms of both, like, peak and area under the curve, compared to Sarepta and Pfizer? I do not think we have seen those curves before, so any context there would be much appreciated.

And maybe quickly, Steve, also on the CRL for MPS II, now public, why do you measure heparan sulfate at baseline versus after therapy using two different routes of access? I think the CRL notes that you used ICV at baseline versus spinal tap after therapy, which obviously created some variability. So we are just curious for why you decided to do that. Thanks so much.

Steve Pakola: Sure. So, on the safety aspect, there are several reasons why we anticipated having a differentiated safety profile: the higher purity, the specific construct, and our immune modulation regimen. And I think the key factor is we have not changed our immune modulation at all since the beginning of the study. So I think that gives comfort in how to analyze the type of safety data that we are seeing. Phase 1/2, we continue to see no cases of liver injury. So it is 13 patients, but zero out of 13 is clearly different from existing therapy, where that rate is 40%.

So we look forward to showing some more details on that from the Phase 1/2 study at MDA as well. Also on thrombocytopenia, no cases of thrombocytopenia as well, which is one of the key complement-mediated signals of complement activation that could signal potential risk for other more serious events. So we continue to see the differentiation that we would like to see and look forward to showing more data going forward. And, of course, we will have the topline results in the first half of the second quarter, which will be another cut for you to get more comfort on the data.

So onto the CRL, there was, yes, some comment about the potential impact of route of taking the sample. There was consistency, actually, in the vast majority of patients utilizing the same approach. We actually have the benefit of screening and baseline measurement where we have total consistency of ability to match like-for-like or apples-to-apples in terms of the same method of sampling, and we see really the same results in terms of change from baseline. So that will be part of our response—showing that analysis more clearly and more upfront so that they can get comfort around that difference.

Operator: Our next question comes from the line of Ellie Merl of Barclays. Ellie, your line is open.

Eduardo Martinez-Montes: Hi, this is Eduardo on for Ellie. Thanks for taking our question. I think you mentioned you expect 12 months’ functional data from the majority, if not all, of the pivotal patients in the fall of this year. How should we think of those data in context of the regulatory strategy? Could those be submitted as a supplement? And could that extend the review timeline?

Curran Simpson: That is a good question. I think that it will likely be a result of the discussion that we have at the pre-BLA meeting in terms of what level of functional data is required to submit. There is no point to submit early if we are going to get additional data requests. So I think getting clarity on that with FDA will be very helpful. We will be in a position—and we have already, obviously, completed our nonclinical work in that module well along. We have completed substantially the manufacturing work related to the BLA, and that module will be ready quickly.

So I think, to answer your question, the timing of the full filing for the BLA will be dependent on the clinical data and the functional data that we incorporate into it. The chance to add it is the 120-day safety update that is part of a BLA submission. That has historically been very difficult to include additional clinical data beyond safety as part of it. So I am not confident that we would be able to add at that point more functional data. So I think when we file, we want to be confident that is acceptable with FDA. Yeah. The BLA submission could happen directly after the pre-BLA meeting.

One of the topics in the pre-BLA meeting will be the timing of submission with FDA. So I think post that meeting, we will be in a good position to update on the overall filing timeline. But, yes, it is possible that we can still file within 2026. That is really dependent on these ongoing discussions. Appreciate it. Thank you.

Operator: Our next question comes from the line of Daniil Gataulin of Chardan. Daniil, your line is open.

Daniil Gataulin: Alright. Hey, good morning. Thank you guys for taking my question. On 202, you mentioned a pre-BLA meeting in mid-’26, but also additional planned interactions in the first half. What is the agenda for those meetings? And secondly, what do you expect the regulatory path and timelines to look like for European approval?

Curran Simpson: In terms of the regulatory interactions, we have planned meetings with FDA ahead of the pre-BLA meeting to get at some of the questions we have today around our data analysis methods, some of which are new because we have been able to access additional natural history databases. And as Steve mentioned, and we have published additional CTAP data. So just trying to ensure that when we deliver our pre-BLA package, it is in line with FDA expectations. We have not discussed the timing of those meetings, but they will be interspersed with things like topline data and our pre-BLA meeting as we go forward.

So the whole idea here is to de-risk the pre-BLA meeting with ongoing dialogue with FDA and ensure that we are fully aligned so that we have a high-probability submission in terms of FDA acceptance. And I think, again, that is why we continue to publish our functional data, because that is what we think is the most compelling aspect of this on top of safety. There is a huge unmet need in Duchenne, and we see the prevalent population actually growing.

We see a pretty narrow payer band in terms of patient ages that are being reimbursed, and so we expect there to be a lot of energy around additional therapies being made available, and with our data, we think we have a compelling case to do that quickly. Is that helpful? It is. Thank you. And with respect to the regulatory path and timelines for Europe approval. For European approval, right now, we are getting feedback on designs that include a placebo arm that are feasible to run ex-U.S.

We do not have a specific timeline that we have put out in terms of when that study would start, but we will be more specific about that post that official feedback from EMA. Got it. Okay. Alright. Thank you very much.

Operator: Thank you. Next question comes from the line of Bill Mahon of Clear Street. Bill, your line is open.

Bill Mahon: Hey, good morning, and thank you. So it seems that there is kind of a broad effort to read the 121 CRL and extrapolate that to 202. So I was just hoping that you could point out specific points within the 121 CRL that you expect to differ in 202 and not keep it from approval. And then I know, Steve, you mentioned that 6,000 patients have now been treated with AAV in one form or another. Is there a difference in the rate of AAV-associated neoplasms across different tissue types or serotypes or disease states?

Curran Simpson: Yeah. It is a great question. I think there are some real clear differences between 121 and 202, and some of it goes back to the history of development for both programs. The 121 program really was based on a biomarker premise, meaning D2S6 being reasonably likely to predict clinical benefit, and we felt like we had closed that loop in terms of the RMAT designation we got on the program in 2023. In the case of 121, sometimes you need several years of post-treatment follow-up for those patients to clearly state that they are deviating from natural acquisition of skills and cognitive improvement.

And so going into that filing, we did not have the extent of clinical data supporting the biomarker that we do on 202. So in Duchenne, thinking ahead on that and knowing that there was controversy around microdystrophin within FDA, we leaned in heavily on recruiting as quickly as we possibly could and also putting together the functional data to correspond directly with the biomarker data. And so we know going into the review process that we will need both. So that was not the case on 121. We were really relying on the biomarker premise and that supporting data, but we only had, at the time of filing, six months of clinical data.

In this case, for Duchenne, even going back to dose level 1, we will have beyond two years’ worth of data showing durability of effect, and then for DL2, as we mentioned, several of our patients—maybe half the cohort—out past 12 months. So a much different discussion with FDA that will be armed with clinical data showing correlation to what we think are very positive biomarker results that show benefit. So I think that is probably the main difference between how we see it—between how those programs will go and why we think 202 will be, you know, more successful in providing that kind of data.

Steve Pakola: And from the actual results, we also have the benefit of the safety differentiation again. And I think also the greater your data is, the clearer you can believe that there is an actual difference. So I think the 8-and-older data in particular that Curran mentioned earlier, where patients are not just stable, they are actually improving. So I think that goes into the delineation here as well, where that is definitely not something one would anticipate without treatment and even with existing therapy—to have an actual improvement in those tough-to-treat older boys. Yeah, from preclinical data and clinical data, there does not appear to be any particular difference between different serotypes in terms of the rate of integration.

So I think that is why, across different programs, that issue is raised—that there is the possibility that, given that there is rare integration, at some point you could have the integration basically go where you do not want it to go. But, no, there is no real strong evidence of a particular predilection. Of course, you look at other factors like where do you give the drug, what is the promoter, what is the target tissue, and those are the aspects that give us a lot of comfort in terms of how this is really walled off from our other bigger opportunities of 314 and 202.

Operator: Thank you. Our next question comes from the line of Sean McCutcheon of Raymond James. Please go ahead, Sean.

Sean McCutcheon: Hey, guys, thanks for the question. Now that you have announced NAVIGATE, with the Phase 2b focusing on two-step DRSS improvement, how are you thinking about, if at all, the flexibility on that endpoint on binary or ordinal DRSS going into Phase 3, particularly as it relates to pulling out a benefit at one year versus the two-year timeframe where you saw the clearest benefit on two-step improvement at dose level 3 in ALTITUDE? Thanks.

Curran Simpson: I think I will let Steve take a shot at that.

Steve Pakola: Thanks, Sean. Yeah. We are very pleased with the FDA's openness to looking at different types of endpoints and not just the traditional binary two-step improvement or two-step worsening, and the precedent that is now out there. We and AbbVie decided to stick with the traditional two-step change that has traditionally been used. But I think you raised a great point, and it is one of the positives of the Phase 2b/3 design that we have. Yes, we are starting with the at-least two-step improvement, but we have the flexibility to take into account that data to assess is it more sensitive or, in another way, power per number of patients that you have if you use an ordinal endpoint.

And I think it is reasonable to think that may be the case, because we are seeing benefit on both ends. We are seeing not only a higher rate of patients improving, but also, critically, a higher percent of patients who are not getting worse. So an ordinal endpoint, when we look at things with AbbVie, is certainly an option.

Operator: Our next question comes from the line of Yi Chen of H.C. Wainwright. Please go ahead, Yi.

Eduardo Martinez-Montes: This is Eduardo on for Yi. Just a quick question going back to 202. I am curious if you have used the CTAP method to apply towards placebo arms in the Elevidys study. Obviously, one of the big gripes with the historical competitors is that the placebo arms do not necessarily track with them. So I am curious if you have actually used that method to see if you predict the placebo arms in these other randomized trials.

Steve Pakola: Yeah. So there are different studies out there, of course, and there is always the caveat you have to mention about cross-study comparisons and specifics that might be different. Certainly, when we look at what is out there with Elevidys in terms of CTAP or other models, particularly in the older boys, again, we do not see this evidence of older boys getting better versus just stabilization. So a lot of differentiation tends to be driven by the control data and approach. But, again, I guess I would circle back to it is important to look at CTAP, external matched control, and also the propensity score weighting.

So I think when we have our next data updates, it is going to be easier for the clinicians in the broader community to try to compare what has been seen previously. But, again, what we are seeing so far, if we continue to see that, we feel very confident about the differentiation by whichever method that we will be presenting. Thanks so much for answering the question.

Operator: Thank you. Ladies and gentlemen, that does end the Q&A portion of our call and conclude today's conference call. Thank you for participating. You may now disconnect.

This article is a transcript of this conference call produced for The Motley Fool. While we strive for our Foolish Best, there may be errors, omissions, or inaccuracies in this transcript. Parts of this article were created using Large Language Models (LLMs) based on The Motley Fool's insights and investing approach. It has been reviewed by our AI quality control systems. Since LLMs cannot (currently) own stocks, it has no positions in any of the stocks mentioned. As with all our articles, The Motley Fool does not assume any responsibility for your use of this content, and we strongly encourage you to do your own research, including listening to the call yourself and reading the company's SEC filings. Please see our Terms and Conditions for additional details, including our Obligatory Capitalized Disclaimers of Liability.

The Motley Fool has positions in and recommends Regenxbio. The Motley Fool has a disclosure policy.