Regenxbio Inc
NASDAQ:RGNX
Earnings Call Analysis
Q4-2023 Analysis
Regenxbio Inc
REGENXBIO Inc., in its recent earnings call, appears to have embarked on a strategic pivot focusing on a prioritization plan aimed at maximizing value from potential commercial opportunities with large-scale implications. The company is zeroing in on three priority programs: ABBV-RGX-314 for wet AMD and diabetic retinopathy in collaboration with AbbVie, RGX-202 for Duchenne muscular dystrophy, and RGX-121 for Hunter Syndrome. These selections underscore REGENXBIO's confidence in these products as differentiators in the marketplace, providing a clear path to expedite development and generate substantial value in the near and long term.
Amidst the excitement surrounding these priority therapies, the company is steering towards pivotal trials for wet AMD using both subretinal and in-office suprachoroidal delivery methods. The RGX-314 program, exhibiting multibillion-dollar potential, is currently enrolling for pivotal trials with the aim to sustain vision health and become the standard therapy for AMD and diabetic retinopathy. The company is working towards global regulatory submission slated from the end of 2025 through the first half of 2026. Furthermore, with substantial interim data regarding Duchenne and MPS II already announced, upcoming data presentations at conferences and new trial updates are on the horizon, marking critical milestones for REGENXBIO.
Financially, REGENXBIO ended 2023 with a considerable decrease in cash reserves, from $565 million at the end of 2022 to $314 million by the close of 2023. This change is largely attributable to investments in operating activities, particularly research and development for advancing its clinical trials. Nonetheless, the current reserves are anticipated to sustain the company's operations well into the second half of 2025 .
Looking ahead to the rest of 2024, REGENXBIO's management has conveyed a message of optimism, emphasizing the company's strong position for success. By allocating resources efficiently to advance their candidates' development aggressively, they remain focused on enhancing shareholder value. The company is also highlighting the approach of reaching several pivotal stages within the pipeline or filing for BLAs by the end of the year, reinforcing expectations of a year marked with significant growth opportunities.
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Good day and thank you for standing by. Welcome to the REGENXBIO Fourth Quarter 2023 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Patrick Christmas, Chief Legal Officer. Please go ahead.
Good afternoon and thank you for joining us today. Earlier this afternoon, REGENXBIO released financial and operating results for the fourth quarter and full year ended December 31, 2023. 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 31, 2023, and comparable Risk Factors sections of REGENXBIO's quarterly report 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, February 27, 2024, and we undertake no obligation to update any forward-looking statements we may make on this call and account 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 would now like to turn the call over to Ken Mills, CEO of REGENXBIO.
Thank you very much, Patrick. Good afternoon, everyone, and thanks for joining us. I'm pleased to begin today's call with a recap of our recent business highlights as well as an update on our corporate goals. Steve Pakola, our Chief Medical Officer, will then provide an update on clinical programs; and Vit Vasista, our Chief Financial Officer, will provide an overview of financial results for the fourth quarter and the full year ended December 31, 2023. At the end of the call, we're going to open the line up for questions.Late last year, REGENXBIO began work on a pipeline prioritization plan that enables us to focus our capabilities and resources on large commercial opportunities where product candidates are differentiated, can be expedited and support meaningful value generation soon and for the long-term. Our priority programs are ABBV-RGX-314 program for the treatment of wet AMD and diabetic retinopathy being developed in collaboration with our partner, AbbVie; RGX-202 for the treatment of Duchenne, and RGX-121 for the treatment of MPS II or Hunter Syndrome.Early on, in 2024, we've experienced exciting progress for each of these programs. We believe there's a multibillion-dollar potential for the 314, a single injection treatment to become a first-in-class gene therapy in wet AMD and the standard of care to treat and prevent progression of diabetic retinopathy. Enrollment remains on track with our subretinal delivery program for wet AMD currently in pivotal trials with an expectation to support global regulatory submission by the end of 2025 through the first half of 2026. We hosted calls recently with leading retina experts to review our new positive clinical data from our treatment for wet AMD and diabetic retinopathy using in-office suprachoroidal delivery.These events were exciting for us. And today, we're going to be talking about additional upcoming data and events that we're giving guidance on. Three weeks ago, we focused attention on our rare disease pipeline and two amazing milestones. In Duchenne, we announced the completion of enrollment in Cohort 2 and additional positive interim data from our ongoing trial. We are thrilled to see RGX-202 is demonstrating strong microdystrophin expression across a wide range of patients.And for MPS II, we achieved what I think is a major breakthrough with statistically significant results for our pivotal trial on which we are filing a BLA. Patients receiving this treatment have continued to show improvement in their neuro-developmental skill acquisition up to four years, and we recently observed discontinuation standard of care intravenous enzyme therapy. Our recent milestones demonstrate how our new plan is supporting the acceleration of the development of gene therapies and the expansion of value for our shareholders.And today, we're providing some new guidance, as I mentioned, on near-term milestones for Duchenne and our treatments for wet AMD and diabetic retinopathy using in-office delivery. Next week, we have plans to share new Duchenne trial update at the Muscular Dystrophy Association Conference being held in Orlando, Florida. Also, we expect to share new program and data updates for the Phase II ALTITUDE and AVA trials in Q2 and mid-2024, respectively. Overall, we're absolutely thrilled about our status and the progress the company has made and with the way things have started off in 2024. I'm going to circle back in a bit and talk more about next steps for us.But for now, I'm going to turn it over to Steve, so he can do a deeper dive on the review of the clinical progress for our prioritized programs.
Thank you, Ken. I'll begin with 314, which is being developed in collaboration with AbbVie to treat wet AMD and diabetic retinopathy, via subretinal and suprachoroidal route of administration. 314 utilizes the NAV AAV8 vector to deliver a gene encoding a therapeutic antibody fragment to inhibit VEGF. The anti-VEGF market opportunity is poised to grow significantly as the population ages. 314 for the treatment of wet AMD via subretinal delivery is being evaluated in two ongoing pivotal trials, ATMOSPHERE and ASCENT, which are expected to enroll a total of 1,200 patients in the U.S., Europe and Japan, and we anticipate global regulatory submissions in late 2025 through the first half of 2026.In addition to our Phase II pharmacodynamic study that is evaluating the same dose levels being used in the two pivotal trials, we also have two ongoing Phase II trials that fall under our collaboration with AbbVie, assessing in-office suprachoroidal delivery of 314 for the treatment of wet AMD in the AAV8 study in Diabetic Retinopathy or DR, in the ALTITUDE study. AAV8 is an active controlled dose escalation trial evaluating 314 for the treatment of wet AMD. In January, we presented full 6-month results from Cohorts 5 and 6 at the Hawaiian Eye Meeting. Consistent with previous updates, the data presented continued to support the safety profile of 314 and showed a meaningful reduction in anti-VEGF treatment burden.ALTITUDE is the observation controlled study of 314 suprachoroidal delivery for treatment of DR. We're very excited about the opportunity in DR given the size of this market, which exceeds that of wet AMD and because we believe this patient population could benefit the most from a potential onetime gene therapy. In November, we presented 1-year data from dose levels 1 and 2, showing 314 to be well-tolerated with patients demonstrating clinically meaningful improvements in disease severity with reductions in vision-threatening events. We look forward to providing additional updates on this program in the second quarter of this year.Moving to RGX-202 a potential onetime gene therapy for the treatment of Duchenne; RGX-202 is a highly differentiated product designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-terminal or CT domain found in naturally occurring dystrophin. RGX-202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAV AAV8 vector in a well-characterized muscle-specific promoter. Our AAV capsid also represents an alternative for boys who may not be eligible for other AAV mediated microdystrophin therapies due to age or presence of preexisting neutralizing antibodies.In February, we presented exciting interim data from the Phase I/II AFFINITY DUCHENNE trial, demonstrating that RGX-202 continued to be well-tolerated with no drug-related serious adverse events in 5 patients at both dose levels. All three patients at dose level 1 showed robust RGX-202 microdystrophin expression and reduction from baseline in serum creatinine kinase or CK levels, supporting evidence of clinical improvement. RGX-202 microdystrophin expression from the third patient at dose level 1 was measured to be 83.4% compared to normal control at three months, the highest expression seen thus far.Importantly, we have seen RGX-202 activity in every patient and across a broad age group of both younger and older boys. Coming up next week at the MDA Conference, we're excited to share new program and data updates from the Phase I/II Duchenne trial. We also look forward to sharing initial strength and functional assessment data later this year. Also in February, at the WORLDSymposium, we announced that the CAMPSIITE pivotal trial of RGX-121 for the treatment of MPS II met its primary endpoint with high statistical significance.Patients treated with RGX-121 achieved decreased cerebrospinal fluid, CSF levels of D2S6, a key biomarker of brain disease activity to below maximum attenuated disease levels. We remain on track to file a BLA in 2024 under the accelerated approval pathway using CSF-D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. To conclude, we have made 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 supported all of these programs.And with that, I turn the call over to Vit to review our financial guidance.
Thank you, Steve. REGENXBIO ended the quarter and year end on December 31, 2023, with cash, cash equivalents and marketable securities totaling $314 million compared to $565 million as of December 31, 2022. The decrease was primarily driven by cash used to fund operating activities in 2023. R&D expenses were $232 million for the year ended December 31, 2023, compared to $242 million in 2022.The decrease was primarily attributable to a clinical trial and manufacturing expenses for AbbVie RGX-314, resulting in an increase in development cost reimbursement from AbbVie under our Eye Care Collaboration. We expect the balance in cash, cash equivalents and marketable securities of $314 million as of December 31, 2023, to fund our operations into the second half of 2025. This cash runway guidance is based on the company's current operational plans and excludes the impact of any payments that may be received from AbbVie upon the achievement of development or commercial milestones under our 314 collaboration.With that, I will turn the call back to Ken to provide final thoughts.
Thanks, Vit. Thanks, Steve. 2024, our plans are intended to generate significant value for our shareholders as we ensure that resources are allocated to our most valuable product candidates and to accelerate the development of these candidates. As outlined here today and supported by the press release announcements, we're motivated to expand value by addressing important unmet need in patients. We plan to achieve this in our Eye Care partnership with AbbVie using our potential onetime treatments by sustaining vision health long-term and overcoming clinical challenges of managing retinal disease.Our operational goals with AbbVie are directed at completing work and assessments needed to support initiation pivotal trials for 314 using in-office suprachoroidal delivery and completing enrollment of our ongoing pivotal trials for 314 using subretinal delivery, which underpins our filing strategy for global regulatory submission by the end of 2025 through the first half of 2026. Initial efficacy data from the first patients treated with RGX-202 is enabling us to accelerate this program. Duchenne is a market where there's a large unmet need for new therapies and that is capable of supporting multiple gene therapies, and we believe RGX-202 has a unique differentiating set of features that support its potential to be a best-in-class product.We're taking steps to initiate a pivotal trial for RGX-202 this year. Our recent top line pivotal data supports that we are meaningfully changing the course of disease in boys with MPS II by restoring their missing gene function. Based on these data, we're working to file a BLA as quickly as possible. By the end of this year, everything in our pipeline should be initiating pivotal stage, fully enrolled at pivotal stage or under a filed BLA. As a result of these recent updates and upcoming near-term milestones and milestones throughout 2024 announced today, we believe REGENXBIO is well-positioned for success this year and in the long term.So thanks, everybody, for your time today. We hope that you share our enthusiasm about these recent updates, about the impact that our treatments and treatment candidates are having on patients. And we also ask that you join us later this week in honoring Rare Disease Day. With that, I will turn the call over to questions. Operator?
[Operator Instructions] Our first question will come from the line of Gena Wang with Barclays.
Also congrats on the clinical progress here. So regarding the data update for both 202 and 314, one is next week and the other two is the later '24. So could you please lay out the additional data points that we will be able to see?
Yeah. Thanks, Gena. We're not able to give that level of fidelity here today with respect to the MDA conference next week. We plan to have new data and updates about the program, and we're also under an embargo status with respect to the conference. So there is currently scheduled, though an investigator presentation at the conference next week. And also some posters that we have submitted previously as part of anticipated updates. And now we're able to give more clarity that there will actually be new updates next week on 202.With respect to 314 suprachoroidal, we're just continuing to share the data and the progress that we see happening with both wet AMD and diabetic retinopathy. Just a few weeks ago, about a month ago, made the Hawaiian Eye update. And at the end of last year at AAO, we had the diabetic retinopathy, suprachoroidal update. So more time has gone by, more work by the program teams. So there's going to be updates that include new data and new program updates we anticipate Q2 and mid-2024 with respect to suprachoroidal.
Our next question will come from the line of Vikram Purohit with Morgan Stanley.
Hi everyone. This is Gospel on for Vikram. We have one question for the 202 program. Since the last update, do you have any updated commentary on the baseline characteristics, patient characteristic for patient 3 that may have contributed to the higher level of microdystrophin expression and reduction in CK levels for patient 1 and 2?
Hi Gospel. Thanks for the question. I think no new information since we updated last time and all the patients enrolled in the trial are meeting inclusion criteria, therefore, have backgrounds that are sufficiently similar. Obviously, we've got a wider age range here in terms of enrollment 4 to 11, then I think what people have been used to seeing from different data sets. This particular patient was sort of 6.5-year-old. And I think we're really enthusiastic about this being the largest increase in microdystrophin.I think we attribute it to just some of the natural heterogeneity that can exist in the progression of the disease. And we certainly see this at the high end of the range of expression in terms of things that have been reported in general, including by other sponsors. But I think it really, for us, reflects the robustness of the treatment, and we're going to be excited as we get into dose level 2 to be able to continue to reinforce that RGX-202 is highly expressive and also contributes meaningfully to hopefully improvement in these boys.
Our next question will come from the line of Alec Stranahan with Bank of America.
Just two from me. First on 314, we've obviously seen increasing focus recently on other companies developing gene therapies for wet AMD, but obviously, you guys are still furthest ahead. Maybe thinking beyond an approval, and I realize there's a lot of uncertainty to get to that point, but assuming 314 gets approved, what kind of competitive moat do you see being formed? Is this a scale advantage, having AbbVie as your launch partner, wealth of data from the pivotal program or maybe something specific to 314 itself? Any thoughts here would be great. And then I've got a follow-up.
Yeah, maybe all of the above, Alec. I mean, I think the real emphasis for us with 314 both in terms of how far along we are in development and the partnership with AbbVie and the investment that's being made in its development is particularly on the long-term outcome side. I mean, we have evidence of sustaining vision in patients and vision health long-term out to four years. And with that, we've even seen improvement in vision in some patients at three years and beyond four years from a single injection and that is with more than overcoming -- that is with patients who have never needed an injection since they received RGX-314 in some circumstances.So that addresses the overcoming sort of day-to-day challenges that physicians and patients have with respect to managing retinal disease. I think that evidence of durability and that focus on vision is going to be incredibly important in the clinical and commercial setting. Steve, I don't know if you want to comment about how you're thinking about that with the medical teams and how that translates?
Yeah. I think the durability, as you mentioned, and certainly the opportunity to have this big of a database of patients and patient exposures combined with the durability that we can show. And when you throw in the VA stability and even improvement in the setting of a dramatic reduction in treatment burden, that's really unparalleled compared to any of the competitors out there when you think of the combination of durability reduction in treatment burden with the VA findings. So our investigators repeat this over and over again when they refer to the kind of results that we've seen to-date.
And AbbVie's partnership and thoughtfulness and views that have come to bear on thinking about how to influence clinical development, clinical development decisions and the positioning of things late stages. We complete enrollment in pivotal trials for ATMOSPHERE and ASCENT, especially ex-U.S., have been phenomenal. I mean they're just -- they're obviously a great global partner with a global footprint and an unbelievable engine for really tuning into the patient and in this case, the retinal specialist experience to reinforce what they need. But I really believe it's about long-term vision health and that's the differentiation that we see with RGX-314.
Okay, great. That's helpful. And then maybe one quick one just on the cash runway. Some big events anticipated that it could trigger milestones from AbbVie over the next 12 to 18 months, let's say. But are there any other levers you guys can pull to push this past second half '25 if needed or are you pretty comfortable with the setup in regards to the runway?
I think we said after we introduced our updated strategic plans last year and the cost reductions that we were as a company and our Board of Directors very focused on enhancing value for shareholders and that meant focusing on very high potential opportunities with differentiation, commercial opportunities that were meaningful. It involves some hard choices. And some of those choices were reduction in burn.We've been seeing early on this year that we've been achieving those goals and continue to be on track to not only maintain that guidance but continue to be confident in it. And I think with respect to yeah, that basket of milestones, I mean, having just reported the top line data for RGX-121 pivotal and seeing that being able to share that for the first time in some of the other observations like the reduction and changes in enzyme replacement therapy continuation. We're feeling really confident about the BLA filing, really working as quickly as possible to get that on track.Of course, with the BLA approval, we've expected that we could be eligible for PRV. And talking today about the notion of updated data and updated progress on suprachoroidal positions us for the ability to achieve some of those additional milestones as well as part of the AbbVie partnership. So I just think a few months removed from the updated strategic plan and the focus, we're really enthusiastic about the momentum that we have with the science and with this plan right now. I think the capital is in a good place.
Our next question will come from the line of Ellie Merle with UBS.
This is Sarah on for Ellie. I guess two quick ones from us. Can you talk about your most recent thoughts on expectations into initial strength and functional data from 202 later this year? And then also, can you remind us, is longer-term data from the superchoroidal 314 program gating to starting Phase III or potentially we could start a Phase III before we see that data?
Thanks, Sarah. With respect to strength in motor function data over the course of 2024, we've guided that we expect to be able to achieve that and share that for both dose level 1 and dose level 2. I think with the microdystrophin expression that we've been seeing to-date with dose level 1, we continue to be really enthusiastic about the fact that there's an approvable endpoint that has been supported by the FDA. It's therefore, been labeled as a surrogate that's reasonably likely to predict clinical benefit.And the clinical benefit that we're all looking for here is improvement in strength and motor function in these boys and daily activity things as well as routinized assessments for those. So no, I think we're on track. The guidance that we're giving is still to progress through with microdystrophin updates, additional data about how we're going to be making sort of pivotal dose decision, which is really going to be weighted towards microdystrophin data and safety data.And then by the second half of the year, as we've migrated towards our final plan for initiation of pivotal trial, I think then that strength in motor function data will be more mature and will be something that really will start to cross communicate not only with pivotal plan because that's really going to be an accelerated approval strategy based on microdystrophin, but it will start to set up the conversation about confirmatory evidence as well. So I think everything is on track as we've expected it could be by now. And again, we're going to have another update just announced today with some new data at the Muscular Dystrophy Associated Conference next week to continue to let this story breathe throughout 2024. Steve, on the second question?
Yes. So thanks, Sarah. So you mentioned long-term data, how much do we need in suprachoroidal before we're thinking about Phase III. I think it's important to mention that, for example, with diabetic retinopathy, we know what is an acceptable pivotal endpoint and its use of the validated DRSS scale. And we know that, that's at a 1-year time point. And we know, as Ken mentioned, we -- fortunately, late last year, we're able to present 1-year data from dose levels 1 and 2, where they both were well-tolerated, and we were seeing not only proof of concept, but exactly what we want to see in terms of improvement on diabetic retinopathy severity and a dramatic reduction in vision-threatening events. So that really puts us and AbbVie in a good position as far as assessing the potential to move into later-stage development. But we're not in a position to give any more details or any kind of time line on it other than to just give you that sense of how we can assess this data, both from a safety and efficacy standpoint.
Our next question will come from the line of Annabel Samimy with Stifel.
Just a follow-up on the DMD program in terms of the dose selection between dose 1 and 2 for moving into the Phase III. You just mentioned microdystrophin levels and safety data. But I guess to get a little bit more granular, is there a level you're aiming for as far as microdystrophin expression that correlates better with potential functional benefit that you're looking for? Just trying to determine whether you can probably reach a broader swath of the population with as high dystrophin levels as possible as long as that stays intact. So that's my first question.
Yeah. I mean it's a great question, Annabel. I think we're drawing on several different resources, right, at this point in terms of how we're thinking about pivotal dose determination. And we've guided to the fact that that's a midyear decision for us. First, we're currently impacted by microdystrophin levels that we've seen at dose level 1. And we're excited. I mean, we're seeing a signal in a wide range of boys in all boys, age range wise. And we're seeing differences, but I think that there -- in some cases, they're explainable.I mean in older kids, I think there's some evidence of additional progression in disease. So we have over a 10-year old had a lower level of microdystrophin in that particular case. That may be something where a dose level 2 will be important in the other boys, the 4-year-old and the 6-year old to-date. We're seeing things that are well within the range of the product that's already approved on the basis of accelerated approval and evidence that in other cases with other sponsors, they've seen forms of improvements in boys in terms of strength and motor function at these types of levels.So again, the enthusiasm at dose level 1 is very high -- and we look at our preclinical data, and we brought this forward last year as well. We reran some preclinical studies directly comparing dose level 1 and dose level 2 in MDX mice, and we see separation. We see better results with dose level 2. And so to the extent that, that data directs us as well, if dose level 2 is safe, which it has been reported to-date and continues, in our view to be, it's going to be hard to want to step away from that because I think we're just naturally going to expect more is going to get us more expression, more expression is going to get us improvement in function.So I think we'll keep playing that out in the first evidence of dose level 2 expression and other observations are going to be important contributions to that, and that's why starting next week and into the middle of the year, we have expectations that we'll be getting more data to sort of help shape that entire decision.
Okay. And is there any chance that you move forward with 2 doses or is that not something that's done in gene therapy?
No, it's not something that I think we -- of course, we've done that in ATMOSPHERE and ASCENT in retina as well as anyone that can be more common place and for masking purposes and other reasons, probably good reasons to do that in some of the retina settings. But for rare diseases, and with respect to MPS II, I think as well as Duchenne, I think we've been focused on single-dose trials with the doses that can provide the greatest evidence of not only the gene turning on, the proteins themselves expressing, but in these phases of development, the strongest evidence of both safety and functional benefit.And so it will be 2 or 1. And we -- the preclinical evidence says it's 2, but the clinical evidence right now says 1 is really good. So I find for us -- that's actually not dissimilar to things we observed with 121 where we were seeing expression dose-escalated, ultimately took the highest dose into pivotal that was a safe dose and look at what we achieved with respect to the pivotal result there. I think we're following a similar playbook here.
Our next question comes from the line of Brian Skorney with Baird.
This is [ Charlie ] on for Brian. I was just -- I wanted to ask a question about 121. I was wondering, looking at the difference between the patients who are less -- or greater than two standard deviations below the mean age equivalent skills. How do you think about the difficulty of showing gain of skills in those patients in terms of could this affect the label? And will this affect your commercial plan? Do you expect those patients to be treated as well? It would just be great to get some color on that.
Yeah, it's also a great question because I think we brought forward this really interesting data in terms of stratification. We had a call today. We've had calls recently with rare disease families and parents and investigators and partners. And I think what -- one way to answer that, Charlie, is disease stabilization is improvement for families and for children. And I think that's not all kids depending on progression of disease, age, what their journey is for diagnosis and when they present right now in Hunter and in Duchenne are going to be able to be finding access to things like gene therapy and other care at a point in time where you can expect to see the type of improvement that we're seeing in the kids that are within two standard deviations of the mean.And that -- usually, that's age-correlated, but we've decided to step out a little bit under the spotlight of just saying it's about age and getting kids younger. I mean, that's certainly true, but it's not exclusively yet. It is about progression as well. When it comes to thinking about the commercial benefit and the clinical benefit in the commercial setting rather, I have to say, I mean, we've shown the [ bay leaves ] and we're very transparent about what we're seeing in terms of the different functional indices in the assessments that we do clinically and that there can be differences.What we sometimes talk about less and though I think is going to be a part of the conversation with payers and in the commercial setting is when we are seeing stabilization, what impact is that having at home, what impact is that having on family, what impact is that having on sleep patterns, on toileting, on engagement and with the boys among their families and those things are not to be discounted in any way, shape or form. They are more caregiver and patient reported outcomes different than the sort of analysis that we view in these structured forms of evaluating behavior and neurodevelopment.So I think we -- we've also, even in this program for 121 had a trial publicly available that we dose kids over the age of 5 that are much older than any place that you would even expect to even potentially see the type of stabilization that we've shown in the setting so far. And there are things to take away from that that are valuable for patients and families. So look, overall, I think getting kids earlier in the progression of the disease and younger is going to result in some of, I think, the strongest outcomes when it comes to the literal interpretations of neurological development, behavioral development, fine motor skills and so forth.But there's a lot of kids, I think that also can benefit from gene therapy on the basis of that stabilization comment. And those are also some of the kids that may benefit from the discontinuation of enzyme replacement therapy, which -- while it may not be something that is part of the label initially, I think it's going to creep into the clinical and commercial consciousness over time. So I feel like 121 is a very strong clinical data set to support high unmet need across a lot of boys with Hunter.
Yes, definitely. Yes, the data is great. So thank you for providing that extra color.
Our next question will come from the line of Danielle Brill with Raymond James.
This is [ Alex ] on for Danielle. Just kind of a big picture question again on DMD. Curious to know how you interpreted some of the regulatory comments made last week at a FDA biomarker workshop about needing to think about subsequent therapies and impact on patients, potentially not being able to get a better gene therapy in the future. Might that imply that [indiscernible] label expansion may be limited to just 4 to 7 years old, considering that the population that they studied in their placebo-controlled trials?
Almost sounds like a loaded question. I think we have -- look, we are in a mode right now with 202, where we're just beginning to see what the potential is here. And I think with additional updates and additional data, I think then we can really feel like we can move ourselves into the conversation. We're there. We have differentiated biology.We have something that I think is an opportunity for a variety of different stakeholders to pause and think about what's the innovation of adding the C-terminal domain to an AAV therapeutic can mean, what can it mean from a kind of surrogate endpoint perspective but also from the longer-term outcomes perspective. And I think we appreciate the complexity that in AAV development and in the regulation of AAV, you're setting things up as precedence in ways that I think our important and need to continue to support innovation.And that's what we hear, and that's what we see from the approaches that have been taken by the agency in the case of a lot of work that's going on in gene therapy. So I think that yes, we think that innovation continues to be important. We think that when we're showing data in older boys, for instance, that we think that that evidence and that information is useful to contribute to conversations within the community and all stakeholders, including regulators about how to help steer our development plan and our approach and things that may come after us as further improvements. So we like to hear that those thoughts are happening and that those conversations are happening, and we feel it as well in our direct interactions.
Our next question will come from the line of Luca Issi with RBC Capital Markets.
Great. This is Lisa on for Luca. Just a couple on MPS II. So first, a question on your regulatory strategy. I know you have reiterated that biomarker reduction at 4 months [ is a physician ] for accelerated approval. However, we know Denali has to run a head-to-head trial versus ERT as the Phase II/III study, which is 5x bigger and 6x longer than your CAMPSIITE Phase II. Is there any chance that the FDA opts to hold RGX-121 to the same standard as Denali? And I have a follow-up.
Hi Lisa. Thanks for the question. The target product profile for RGX-121 is specifically focused on addressing the neurological complications of MPS II in kids with non neuronopathic mutations. And that's where we focused all of our clinical development that has led to the selection of a pivotal dose and the execution of the pivotal phase of the CAMPSIITE trial. And in that case, it means we've enrolled the demographic of kids that are pretty young, in some cases, just months old and not always as progressed in the disease, but sometimes they have siblings or have no neuronopathic genotypes that are basically a certainty of their progression in their characterization.And that's the label we're looking for. We're looking for the treatment that comes forward with this accelerated approval exercise to be something that is delivered on top of ELAPRASE to address the high unmet need for the kid who with neuronopathic mutation, while they still have benefits from things like IV ELAPRASE they're dying from the brain disease, and we're looking to address that and reconstitute function at the gene level to not only look to achieve to save them from dying, but also to get them back on the path of either normal growth in development or stabilized growth in development.And I think FDA has expressed with us and publicly a real openness to the use of what is really well characterized biochemical marker, which is a natural substrate of the enzyme that's deficient in boys with Hunter syndrome. And just last week, we were at a meeting, including Denali and Ultragenyx and others lobbying for the use of that biomarker in the setting of accelerated approval. And I saw real meaningful advancements and conversation occurring there. And we're all working together on this, I should add.I'm pulling for Denali and I'm pulling for treatments for other MPS' and I think in the same way that I see the constituents at those places pulling for us and pulling for RGX-121. So we don't control what the FDA does across all the different sponsor programs. I think all we can communicate is that we've tried to be very focused on what part of the disease in MPS II, we think 121 can show the most benefit, design a therapeutic candidate in a set of trials to achieve that. And with feedback all along, I think we're in an excellent position with our approach to file a BLA as quickly as possible here.So look, there are differences between the different types of approaches and different products, and they have different product profiles, and they're looking to achieve different things. But when it comes to things like using a biomarker to support accelerated approval, when it comes to using that biomarker to assess it as a surrogate endpoint, we're on the same page with a lot of other people, and we're really encouraged about where our program is going and hope that, that also is, frankly, something that's an observational change for other programs as well.
Got it. Got it. Super helpful. And just a follow-up. From CAMPSIITE, do you have any plans to share additional biomarker data such as systemic reduction of GAGs or [ NFL ]? Any color would be helpful.
We don't have any specific guidance right now on MPS II other than filing of the BLA. And I think that's really where all of the focus, resource, energy effort and having achieved the primary endpoint based on the trial design, that's where we are. I mean I think we -- maybe we get into the second half of the year and as we start to talk more about post filing, what's happening with respect to the commercial setting and what additional data may be useful to sort of frame out things that get described or defined in label or in terms of things that are helpful. That may be something we focused on. But right now, the focus of the team internally is completing the modules, completing the follow-up of all patients on safety to support the BLA filing in the second half of this year.
Our next question will come from the line of Mani Foroohar with Leerink Partners.
Obviously, there's been a lot of digging in on the pipeline. A quick clarification. You guys laid out in your financial guidance that you've got cash [ runway ]. It looks like the back half of '25, but you do delineate in the press release a number of NAV technology platform license fees that you define as having meaningful milestones throughout 2024. I think you called out Ultragenyx, Rocket, Novartis specifically that memory serves. Could you walk through this year and highlight individual events that would result in cash flows coming to you guys or in you [ changing ] the accounting treatment and value carried on your financial statements for any of these licensee programs? Just trying to understand what that means for you guys financially or from an accounting basis.
I think the things we pointed most to Mani in terms of potential impact on balance sheet are the milestones certainly, that are associated with the transition of suprachoroidal into pivotal phase with AbbVie. Those have been the major priorities and then the potential to achieve a pediatric review voucher upon the approval of RGX-121. And I think our guidance on all of those things have been -- they're event-driven, obviously, but there are things that we see the potential for them to occur over the course of our existing execution timeline. And those are hundreds of millions of dollars of individual events.When we start to look at the section in the press release in the history of the company around our NAV technology platform licenses, it's a great and interesting question. I mean, obviously, the impact of Novartis as we continue to report quarterly sales and annual sales. As to this point, not really changed our balance sheet since we did the monetization of the Zolgensma royalty and we continue to see the impact of that being limited over the course of the next year, certainly into 2025. That might change.We're seeing some evidence of regulatory progress, for instance, on the intrathecal Zolgensma approach, which could change the labeling or change the product availability of the AAV9 expressing SMN, but we're not planning to include any additional discussion or guidance in terms of thoughts about that impact in the near-term. When it comes to Rocket and Ultragenyx, I think we've identified that they have two or three programs collectively in pivotal phase and that the approval of those products, the reporting out of pivotal data may give us a bit more evidence and confidence to talk about the likelihood of achieving milestones for product approvals.And so again, those are event-driven things that could occur as they've guided over the course of this year or even into 2025. So I think that's how we've been thinking about identifying and sort of focusing on the NAV technology platform licensees and the drivers of value. I don't think that in our licenses and maybe the intrathecal Zolgensma could be something that would be an exception to this. But I don't think that those types of milestones are necessarily at the same level as a PRV or the types of milestones that combined $0.5 billion in milestones associated with AbbVie partnership suprachoroidal progress would be in the same range, they might be, though, I don't know, 5x to 10x less than some of those things on a generalized basis, when you look at the historical benefit of our licensee milestones. Is that helpful?
No, that's really helpful.
Good question.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.