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spk18: Good day and thank you for standing by. Welcome to the Regenexx BIO fourth quarter 2023 earnings conference call. At this time all participants are in a listen only mode. After the speaker's presentation there will be a question and answer session. To ask a question during the session you will need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question please press star 1 1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Patrick Christmas, Chief Legal Officer. Please go ahead.
spk07: Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenix Bio 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.regenixbio.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 sections of Regenexx BIO's annual report on Form 10-K for the full year ended December 31, 2023, and comparable risk factor sections of Regenexx BIO'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 Regenexx Bio.
spk04: 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 Piccola, 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 31st, 2023. At the end of the call, we're going to open the line up for questions. Late last year, Regenexx Bio 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 ABVV, RGX314, program for the treatment of wet AMD and diabetic retinopathy being developed in collaboration with our partner, AbbVie, RGX202 for the treatment of Duchenne, and RGX121 for the treatment of MPS2 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 submissions 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 supracoroidal 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 in two amazing milestones. In Duchenne, we announced the completion of enrollment in cohort two and additional positive interim data from our ongoing trial. We are thrilled to see RGX202 as demonstrating strong microdystrophin expression across a wide range of patients. And for MPS2, 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 neurodevelopmental 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 and 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 two altitude and AVA trials in Q2 and mid-2024, respectively. Overall, we're absolutely thrilled about our status and the progress the company's 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 program.
spk10: 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 routes of administration. 314 utilizes the NAVAVA vector to deliver a gene encoding as 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 supracoital delivery of 314 for the treatment of wet AMD in the AV8 study and diabetic retinopathy or DR in the altitude study. AV8 is an active control dose escalation trial evaluating 314 for the treatment of wet AMD. In January, we presented full six-month results from cohorts five and six at the Hawaii and I 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 supracroidal delivery for treatment of DR. We're very excited about the opportunity in DR, given the size of at AMD, and because we believe this patient population could benefit the most from a potential one-time gene therapy. In November, we presented one-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 RGX202, a potential one-time gene therapy for the treatment of Duchenne. RGX202 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 dystrophins. RGF202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAV AAV8 vector and 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 RGX202 continued to be well-tolerated with no drug-related serious adverse events in five patients at both dose levels. All three patients at dose level 1 showed robust RGX202 microdystrophin expression and reduction from baseline in serum creatinine kinase, or CK, levels. supporting evidence of clinical improvement. RGX202 microdystrophin expression from the third patient at dose level one was measured to be 83.4% compared to normal control at three months, the highest expression seen thus far. Importantly, we have seen RGX202 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 World Symposium, we announced that the campsite pivotal trial of RGX-121 for the treatment of MPS II met its primary endpoint with high statistical significance. Patients treated with RGX121 achieved decreased cerebrospinal fluid, CSF, levels of D2F6, 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 D2F6 as a surrogate endpoint reasonably likely to predict clinical benefits. 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 Bitt to review our financial guidance.
spk02: Thank you, Steve. Eugenics Bio ended the quarter in year-end on December 31, 2023, with 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 31st, 2023, compared to $242 million in 2022. The decrease was primarily attributable to clinical trial and manufacturing expenses for AbbVie RGX 314, resulting in an increase in development cost reimbursement from AbbVie under our iCare collaboration. We expect a balance in cash, cash equivalents, and marketable securities of $314 million as of December 31st, 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 AVI 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.
spk04: Thanks, Vint. 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 one-time 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 supracoroidal 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 RGX202 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 RGX202 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 RGX202 this year. Our recent top-line pivotal data supports that we are meaningfully changing the course of disease in boys with MPS2 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 Regenexx Bio 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. 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.
spk18: As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. In the interest of time, we ask that you limit yourself to one question and one follow-up, then rejoin the queue for any additional questions. Please stand by while we compile the Q&A roster. Our first question will come from the line of Gina Wang with Barclays.
spk21: Thank you for taking my questions. 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 later 24. So could you please lay out additional data points that we will be able to see?
spk04: Yeah, thanks, Gina. 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 a 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 superchoroidal, you know, we're just Continuing to share the data and the progress that we see happening with both wet AMD and diabetic retinopathy, we 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 super-croidal 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 supracoroidal.
spk18: Thank you. Our next question will come from the line of Vikram Purohit with Morgan Stanley.
spk14: Hi, everyone. This is Gaspol. We have one question for the 202 program. Since the last update, do you have any updated commentary on the baseline characteristic, patient characteristic for patient three that may have contributed to the higher level of micro dystrophin expression and reduction in CK levels for patient one and two?
spk04: Hi, Gaspol. Thanks for the question. 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, four to 11, than I think what people have been used to seeing from different data sets. This particular patient was a six and a half year old. And, you know, I think we were really enthusiastic about this being the largest increase in microdystrophin. I think we attribute it to, you know, 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, you know, the robustness of the treatment. And we're going to be excited as we get into dose level two to be able to continue to reinforce that RGX202 is highly expressive and also contributes meaningfully to hopefully improvement in these boys.
spk00: Thank you very much.
spk04: Thanks.
spk18: Thank you. Our next question will come from the line of Alex Stranahan with Bank of America.
spk13: Hey, guys. Thanks for taking our questions. 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 Advia as your launch partner, wealth of data from the Pivotal program, or maybe something specific to 3.1.4 itself? Any thoughts here would be great, and then I've got to follow up.
spk04: Maybe all of the above, Alec. I think the real emphasis for us with 3.1.4 is 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, 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, you know, 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, you know, more than overcoming. That is with patients who have never needed an injection since they received RGX314 in some circumstances. you know, that addresses the overcoming the sort of, you know, 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.
spk10: Yeah, I think the durability, as you mentioned, and certainly the opportunity to have this big of a 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.
spk04: 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 stage as we complete enrollment in pivotal trials for atmosphere and ascent, especially XUS, have been phenomenal. I mean, they're just, they're obviously a great tool. 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 RGX314.
spk13: Okay, great. That's helpful. And then maybe one quick one just on the cash runway. Some big events anticipated that 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? Thanks.
spk04: 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, you know, reduction in burden. We've been seeing early on this year that we've been achieving those goals and continue to be on track to, you know, 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, you know, having just reported the top line data for RGX121 pivotal and seeing that, you know, being able to share that for the first time and some of the other observations like the reduction and changes in enzyme replacement therapy continuation. 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 a PRV. And talking today about the notion of updated data and updated progress on superchoroidal positions us for the ability to achieve some of those additional milestones as well as part of the AbbVie partnership. So, you know, 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. Thank you.
spk18: Thank you. Our next question will come from the line of Ellie Merle with UBS.
spk16: Hi, this is Sarah for Ellie. Thanks so much for taking our question. 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 three, or potentially we could start a phase three before we see that data? Thanks so much.
spk04: Thanks, Sarah. You know, with respect to strength and 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. You know, I think with the microdystrophin expression that we've been seeing to date with dose level 1, we continue to be, you know, really enthusiastic about the fact that, you know, there's an approvable endpoint that has been supported by the FDA. 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. No, I think we're on track. You know, the guidance that we're giving is still to progress through with, you know, microdystrophin updates, you know, additional data about how we're going to be making sort of pivotal dose decision, which is really going to be weighted towards microdistrophin 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 and motor function data will be more mature and will be something that really will start to cross-communicate not only with, you know, pivotal plan, because that's really going to be an accelerated approval strategy based on microdistrophin, but it'll it'll start to set up the conversation about confirmatory evidence as well. So I think everything's on track as we've expected it could be by now. And again, we're gonna 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.
spk09: Yeah, so thanks, Sarah.
spk10: So you mentioned long-term data. How much do we need in suprachoroidal before we're thinking about phase three? 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 one-year time point. And we know, as Ken mentioned, we fortunately late last year were able to present one-year data from dose levels one and two where they both were well tolerated. And we were seeing not only proof of concept, but exactly what we'd 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 Abby 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 information or any kind of timeline on it other than to just give you that sense of how we can assess this data both from a safety and efficacy standpoint.
spk17: Great. Thanks, guys.
spk03: Thanks.
spk18: Our next question will come from the line of Annabel Cimini with Stifel. Hi. Thanks for taking my question.
spk22: Just to follow up on the GMD program in terms of the dose selection between dose one and two for moving into the phase three, you just mentioned microdistrict 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 microdistrict expression that correlates better with potential functional benefit that you're looking for or just trying to determine whether you can probably reach a broader swath of the population with as high districting levels as possible as long as that safety stays intact. So that's my first question.
spk04: Yeah, I mean, it's a great question, Annabelle. We're in You know, I think we're drawing on several different resources, right, at this point in terms of how we're thinking about, you know, pivotal dose determination. And we've guided to the fact that that's a mid-year decision for us. First, you know, we're clearly impacted by microdystrophin levels that we've seen at dose level one. And we're excited. I mean, we're seeing signal in a wide range of boys, in all boys, age range-wise. And, you know, we're seeing differences, but I think that they're, you know, 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 an over 10-year-old that had a lower level of microdystrophin, and in that particular case, you know, 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. You know, 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 one is very high. And, you know, we look at our preclinical data, and we brought this forward, you know, last year as well. We re-ran some preclinical studies directly comparing dose level one and dose level two. in mdx mice and we see separation we see better results with those level two and so to the extent that that data directs us as well if those level two 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 you know, dose level two expression and, you know, other observations are going to be important contributions to that. And that's why, you know, starting next week and into, you know, the middle of the year, we have expectations that we'll be getting more data to sort of help shape that entire decision.
spk22: Okay. And is there any chance that you move forward with two doses or is that not something that's done in gene therapy? Okay.
spk04: No, it's not something that I think we, you know, of course we've done that in atmosphere, in a sense, in retina, you know, as well as anyone that can be more commonplace 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 MPS2, 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, you know, it will be two or one. And, you know, the preclinical evidence says it's two, but the clinical evidence right now, you know, says one 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, you know, look at what we achieved with respect to the pivotal result there. I think we're following a similar playbook here.
spk22: Great. Thanks very much. Appreciate the caller.
spk03: Yep. Thank you.
spk18: Our next question comes from a line of Brian Scorny with Baird.
spk11: Hey guys, this is Charlie on for Brian. I was just, I wanted to ask a question about 121. I was wondering, you know, looking at the difference between the patients who are less or greater than two standard deviations below the mean at age equivalent skills, how do you think about the, you know, 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. Thanks.
spk04: Yeah, it's also a great question because I think we brought forward this really interesting data in terms of stratification. You know, we had a call today. We've had calls recently with, you know, rare disease families and parents and investigators and partners. And I think 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, you know, usually that's age-correlated, but we've decided to step out a little bit under, you know, the spotlight of just saying it's about age and getting kids younger. I mean, that's certainly true, but it's not exclusively it. 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, you know, I mean, we've shown the Bailey's and we're very transparent about what we're seeing in terms of, you know, 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, you know, 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, you know, engagement with the boys among their families? And those things are not to be discounted in any way, shape, or form. You know, they are more caregiver and patient reported outcomes different than the, you know, sort of analyses that we do in these structured forms of evaluating behavior and neurodevelopment. So, you know, I think we We've also, even in this program for 121, had a trial publicly available that we've those kids over the age of five 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. But 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. 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.
spk11: Yeah, definitely. Yeah, the data is great, so thank you for providing that extra color.
spk18: Our next question will come from the line of Danielle Brill with Raymond James.
spk05: Hey, guys. This is Alex. I'm for Danielle. Just kind of a big picture question, again, on BMD. Curious to know how you interpreted some of the regulatory comments made last week in an 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. You know, might that imply that the Levitas label expansion may be limited to just four to seven years old, considering that's the population that they studied in their placebo-controlled trials?
spk04: It almost feels like a loaded question. I think we have, you know, look, we are in a mode right now with 202 where, you know, 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 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 precedents in ways that I think are 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, you know, a lot of work that's going on in gene therapy. So I think that You know, 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, you know, that evidence and that information is useful to contribute to conversations within the community and all stakeholders, including regulators, about how to help steer, you know, 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.
spk15: Fair enough. Thanks for the call.
spk18: Our next question will come from the line of Luca Isi with RBC Capital Markets.
spk23: Oh, great. Thanks for taking our question. This is Lisa for Luca. Just a couple on MPS II. So, first, the question on your regulatory strategy, I know you have reiterated that biomarker reduction at four months is sufficient for accelerated approval. However, we know it not only has to run a head-to-head trial versus ERT as the Phase III study, which is five times bigger and six times longer than your campsite Phase II. Is there any chance that the FDA opts to hold RGX121 to the same standard as Denali? And I have a follow-up. Thanks.
spk04: Hi, Lisa. Thanks for the question. The target product profile for RGX121 is specifically focused on addressing the neurological complications of MPS2 in kids with known neuronopathic mutations. And that's where we focus all of our clinical development that has led to the selection of a pivotal dose and the execution of the pivotal phase of the campsite trial. And in that case, it means we've enrolled a 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 known neuronopathic genotypes that are basically a certainty of their progression and 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 L-aprase to address the high unmet need for the kids with neuronopathic mutations while they still have benefits from things like IV L-aprase. 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 and development or stabilized growth and development. And I think FDA has expressed with us and publicly a real openness to the use of what is, you know, really well characterized biochemical marker, which is the 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 MPSs, and I think in the same way that I see the constituents at those places pulling for us and pulling for RGX121. 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 MPS2 we think RGX121 can show the most benefit. design a therapeutic candidate and a set of trials to achieve that. And, you know, 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, you know, 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, you know, we're really encouraged about where our program's going and hope that that also is, frankly, you know, something that's an observational change for other programs as well.
spk23: Got it, got it. Super helpful. And just a follow-up, from Campsite, do you have any plans to share additional biomarker data, such as systemic reduction of GAGs or NFL? Any color would be helpful. Thanks.
spk04: 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 maybe we get into the second half of the year, and as we start to talk more about You know, 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 the second half of this year.
spk18: Got it. Thanks so much. Our next question will come from the line of Manny Ferruhar with Learing Partners.
spk20: Hey, guys. Thanks for taking the question. 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 on the way. It looks like it's the back half of 25. But you do delineate in the press release a number of NAV technology platform licensees. that you define as having meaningful milestones throughout 2024. I think you call it Ultragenyx, Rocket, Novartis specifically, if 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.
spk04: I think the things we've pointed most to, Mani, in terms of potential impact on balance sheet are the milestones, certainly, that are associated with the transition of super-croidal into pivotal phase with AbbVie. Those have been the, you know, major priorities, and then the potential to achieve, you know, a pediatric review voucher upon the approval of RGX121. And I think our guidance on all of those things have been, you know, 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 on the press release and the history of the company around our NAV technology platform licensees, it's a great and interesting question. I mean, obviously, you know, the impact of Novartis as we continue to report quarterly sales and annual sales, you know, has to this point not really changed our balance sheet since we did the monetization of the Zulgensma 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. You know, we're seeing some evidence of, you know, regulatory progress, for instance, on the intratechal Zolgensma approach, which could change the labeling or change the product availability of the AV9 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 rockets and Ultragenyx. I think we've identified that, you know, 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, you know, 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, you know, 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, you know, combined half a billion dollars in milestones associated with AbbVie partnerships, suprachoroidal progress, you know, would be in the same range. They might be, though, I don't know, five to ten times less than some of those things on a generalized basis when you look at the historical benefit of, you know, our licensee milestones. Is that helpful?
spk19: No, that's really helpful. Thank you.
spk25: Yeah, good question.
spk18: Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect. you Thank you. I'm sorry. Thank you. Good day and thank you for standing by. Welcome to the Regenexx BIO fourth quarter 2023 earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Patrick Christmas, Chief Legal Officer. Please go ahead.
spk07: Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenexx Bio 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.regenexxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook, in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors and the management's discussion and analysis sections of Regenexx BIO's annual report on Form 10-K for the full year ended December 31, 2023, and comparable risk factor sections of Regenexx BIO'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 Regenic Spike.
spk04: 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 31st, 2023. At the end of the call, we're going to open the lineup for questions. Late last year, Regenexx Bio 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 ABVV-RGX314, program for the treatment of wet AMD and diabetic retinopathy, being developed in collaboration with our partner, AbbVie. RGX202 for the treatment of Duchenne, and RGX121 for the treatment of MPS2 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 submissions 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 supracoroidal 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 two and additional positive interim data from our ongoing trial. We are thrilled to see RGX202 as 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 VLA. Patients receiving this treatment have continued to show improvement in their neurodevelopmental 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 and 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's 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.
spk10: 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 routes of administration. 314 utilizes the NAV-AVA vector to deliver a gene encoding as 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 supracoidal delivery of 314 for the treatment of wet AMD in the ABA study and diabetic retinopathy, or DR, in the altitude study. AV8 is an active controlled dose escalation trial evaluating 314 for the treatment of wet AMD. In January, we presented full six-month results from cohorts five and six at the Hawaii and I 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 burdens. Altitude is the observation-controlled study of 314 supercoital delivery for treatment of DR. We're very excited about the opportunity in DR, given the size of this market, which exceeds that of what AMD, and because we believe this patient population could benefit the most from a potential one-time gene therapy. In November, we presented one-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 RGX202, a potential one-time gene therapy for the treatment of Duchenne. RGX202 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. RGF202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAVAVA vector and 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 RGX202 continued to be well-tolerated with no drug-related serious adverse events in five patients at both dose levels. All three patients at dose level one showed robust RGX202 microdystrophin expression and reduction from baseline in serum creatinine kinase or CK levels, supporting evidence of clinical improvement. RGX202 microdystrophin expression from the third patient at dose level one was measured to be 83.4% compared to normal control at three months the highest expression seen thus far. Importantly, we have seen RGX202 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 1-2 Duchenne trial. We also look forward to sharing initial strength and functional assessment data later this year. Also in February at the World Symposium, we announced that the campsite pivotal trial of RGX121 for the treatment of MPS2 met its primary endpoint with high statistical significance. Patients treated with RGX121 achieved decreased cerebrospinal fluid, CSF, levels of D2F6, 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 D2F6 as a surrogate endpoint reasonably likely to predict clinical benefits. 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 Bitt to review our financial guidance.
spk02: Thank you, Steve. Eugenics Bio ended the quarter in year end on December 31, 2023, with cash equivalents and marketable securities totaling $314 million. compared to $565 million as of December 31st, 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 31st, 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 iCare collaboration. We expect a 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 AVI 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.
spk04: Thanks, Vint. 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 one-time 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 supracoroidal 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 RGX202 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 RGX202 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 RGX202 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 Regenexx Bio 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. 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.
spk18: As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1 1 again. In the interest of time, we ask that you limit yourself to one question and one follow-up, then rejoin the queue for any additional questions. Please stand by while we compile the Q&A roster. Our first question will come from the line of Gina Wang with Barclays.
spk21: Thank you for taking my questions. 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 later 24. So could you please lay out additional data points that we will be able to see?
spk04: Yeah, thanks, Gina. 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 superchoroidal, you know, we're just Continuing to share the data and the progress that we see happening with both wet AMD and diabetic retinopathy, we 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 super-croidal 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 supracoroidal.
spk21: Thank you.
spk18: Our next question will come from the line of Vikram Purohit with Morgan Stanley.
spk14: Hi, everyone. This is Gaspol on . We have one question for the 202 program. Since the last update, do you have any updated commentary on the baseline characteristic, patient characteristic for patient three that may have contributed to the higher level of micro dystrophin expression and reduction in CK levels for patient one and two?
spk04: 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, four to 11, than I think what people have been used to seeing from different data sets. This particular patient was a six-and-a-half-year-old. And I think we were 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 two to be able to continue to reinforce that RGX202 is highly expressive and also contributes meaningfully to hopefully improvement in these boys.
spk00: Thank you very much.
spk04: Thanks.
spk18: Thank you. Our next question will come from the line of Alex Stranahan with Bank of America.
spk13: Hey, guys. Thanks for taking our questions. 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 Advia as your launch partner, wealth of data from the Pivotal program, or maybe something specific to 3.1.4 itself? Any thoughts here would be great, and then I've got to follow up.
spk04: Maybe all of the above, Alec. I think the real emphasis for us with 3.1.4 is 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, 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, you know, 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, you know, more than overcoming. That is with patients who have never needed an injection since they received RGX314 in some circumstances. you know, that addresses the overcoming the sort of, you know, 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.
spk10: 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.
spk04: 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 XUS, 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 RGX314.
spk13: Okay, great. That's helpful. And then maybe one quick one just on the cash runway. Some big events anticipated that 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? Thanks.
spk04: 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. That meant focusing on, you know, very high potential opportunities with differentiation, commercial opportunities that were meaningful. It involved some hard choices. And some of those choices were, you know, reduction in burden. We've been seeing early on this year that we've been achieving those goals and continue to be on track to, you know, 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 RGX121 pivotal and seeing that, you know, being able to share that for the first time and some of the other observations like the reduction and changes in enzyme replacement therapy continuation, 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 a PRV. And, you know, talking today about the notion of updated data and updated progress on superchoroidal positions us for the ability to achieve some of those additional milestones as well as part of the AbbVie partnership. So, you know, 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.
spk13: Thank you.
spk18: Thank you. Our next question will come from the line of Ellie Merle with UBS.
spk16: Hi, this is Sarah. I'm for Ellie. Thanks so much for taking our question. 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 three or potentially we could start a phase three before we see that data? Thanks so much.
spk04: Thanks, Sarah. You know, with respect to strength and 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. You know, I think with the microdystrophin expression that we've been seeing to date with dose level 1, we continue to be, you know, really enthusiastic about the fact that, you know, there's an approval endpoint that has been supported by the FDA. 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. No, I think we're on track. You know, the guidance that we're giving is still to progress through with, you know, microdystrophin updates, you know, additional data about how we're going to be making sort of pivotal dose decision, which is really going to be weighted towards microdistrophin 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 and motor function data will be more mature and will be something that really will start to cross-communicate not only with, you know, pivotal plan, because that's really going to be an accelerated approval strategy based on microdistrophin, but it'll it'll start to set up the conversation about confirmatory evidence as well. So I think everything's on track as we've expected it could be by now. And again, we're gonna 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.
spk09: Yeah, so thanks, Sarah.
spk10: So you mentioned long-term data. How much do we need in suprachoroidal before we're thinking about phase three? 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 one-year time point. And we know, as Ken mentioned, we fortunately late last year were able to present one-year data from dose levels one and two where they both were well-tolerated. And we were seeing not only proof of concept, but exactly what we'd 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 Abby 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 information or any kind of timeline on it other than to just give you that sense of how we can assess this data both from a safety and efficacy standpoint.
spk17: Great. Thanks, guys.
spk03: Thanks.
spk18: Our next question will come from the line of Annabel Cimini with Stifel. Hi. Thanks for taking my question.
spk22: Just to follow up on the GMD program in terms of the selection between dose one and two for moving into the phase three, you just mentioned microdistrict 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 microdistrict and expression that correlates better with potential functional benefit that you're looking for or just trying to determine whether you can probably reach a broader swath of the population with as high distribution levels as possible as long as that safety stays intact. So that's my first question.
spk04: Yeah, I mean, it's a great question, Annabelle. We're in You know, I think we're drawing on several different resources, right, at this point in terms of how we're thinking about, you know, pivotal dose determination. And we've guided to the fact that that's a mid-year decision for us. First, you know, we're clearly impacted by microdystrophin levels that we've seen at dose level one. And we're excited. I mean, we're seeing signal in a wide range of boys, in all boys, age range-wise. And, you know, we're seeing differences, but I think that they're, you know, 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 an over 10-year-old that had a lower level of microdystrophin, and in that particular case, you know, that may be something where a dose level two will be important. In the other boys, the four-year-old and the six-year-old to date, you know, 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 one is very high. And, you know, we look at our preclinical data, and we brought this forward, you know, last year as well. We reran some preclinical studies directly comparing dose level one and dose level two in MDX mice, and we see separation. We see better results with dose level two. And so to the extent that that data directs us as well, if dose level two is safe, which it has been reported to date and continues in our view to be, it's going to be hard to, you know, 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, you know, we'll keep playing that out in the first evidence of, you know, dose level 2 expression and, you know, other observations are going to be important contributions to that. And that's why, you know, starting next week and into, you know, the middle of the year, we have expectations that we'll be getting more data to sort of help shape that entire decision.
spk22: Okay. And is there any chance that you move forward with two doses or is that not something that's done in gene therapy?
spk04: No, it's not something that I think we, you know, of course we've done that in atmosphere, in a sense, in retina, you know, as well as anyone that can be more commonplace 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 MPS2, 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, you know, it will be two or one. And, you know, the preclinical evidence says it's two, but the clinical evidence right now, you know, says one 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, you know, look at what we achieved with respect to the pivotal result there. I think we're following a similar playbook here.
spk22: Great. Thanks very much. Appreciate the caller.
spk03: Yep. Thank you.
spk18: Our next question comes from a line of Brian Scorny with Baird.
spk11: Hey guys, this is Charlie on for Brian. I was just, I wanted to ask a question about 121. I was wondering, you know, looking at the difference between the patients who are less or greater than two standard deviations below the mean at age equivalent skills, how do you think about the, you know, 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. Thanks.
spk04: Yeah, it's also a great question because I think we brought forward this really interesting data in terms of stratification. You know, we had a call today. We've had calls recently with, you know, rare disease families and parents and investigators and partners. And I think one way to answer that, Charlie, is disease stabilization is improvement for families and for children. And I think that's You know, 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, you know, 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, you know, usually that's age-correlated, but we've decided to step out a little bit under, you know, the spotlight of just saying it's about age and getting kids younger. I mean, that's certainly true, but it's not exclusively it. 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, you know, I mean, we've shown the Bailey's and we're very transparent about what we're seeing in terms of, you know, 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 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, you know, sort of analyses that we do in these structured forms of evaluating behavior and neurodevelopment. So, you know, I think we We've also, even in this program for 121, had a trial publicly available that we've those kids over the age of five 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. But 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. 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.
spk11: Yeah, definitely. Yeah, the data is great, so thank you for providing that extra color.
spk18: Our next question will come from the line of Danielle Brill with Raymond James.
spk05: Hey, guys. This is Alex. I'm for Danielle. Just kind of a big-picture question, again, on BMD. Curious to know how you interpreted some of the regulatory comments made last week in an 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. You know, might that imply that label expansion may be limited to just four to seven years old, considering that's the population that they studied in their placebo-controlled trials?
spk04: It almost feels like a loaded question. I think we have... You know, look, we are in a mode right now with 202 where, you know, 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, you know, is an opportunity for a variety of different stakeholders to pause and think about what 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 precedents in ways that I think are 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, you know, a lot of work that's going on in gene therapy. So I think that You know, 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, you know, that evidence and that information is useful to contribute to conversations within the community and all stakeholders, including regulators, about how to help steer, you know, 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.
spk15: Fair enough. Thank you, Nicole.
spk18: Our next question will come from the line of Luca Isi with RBC Capital Markets.
spk23: Oh, great. Thanks for taking our question. This is Lisa for Luca. Just a couple on MPS II. So, first, the question on your regulatory strategy, I know you have reiterated that biomarker reduction at four months is sufficient for accelerated approval. However, we know the NALI has to run a head-to-head trial versus VRT as the Phase III study, which is five times bigger and six times longer than your campsite Phase II. Is there any chance that the FDA opts to hold RGX121 to the same standard as Denali? And I have a follow-up. Thanks.
spk04: Hi, Lisa. Thanks for the question. The target product profile for RGX121 is specifically focused on addressing the neurological complications of MPS2 in kids with known neuronopathic mutations. And that's where we focus all of our clinical development that has led to the selection of a pivotal dose and the execution of the pivotal phase of the campsite trial. And in that case, it means we've enrolled a 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 known neuronopathic genotypes that are basically a certainty of their progression and 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 L-iprase to address the high unmet need for the kids who, with neuronapathic mutations, while they still have benefits from things like IV L-iprase, 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 and development or stabilized growth and development. And I think FDA has expressed with us and publicly a real openness to the use of what is, you know, really well characterized biochemical marker, which is the 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. You know, I'm pulling for Denali, and I'm pulling for treatments for other MPSs, and I think in the same way that I see, you know, the constituents at those places pulling for us and pulling for RGX121. 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 and a set of trials to achieve that. And, you know, 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, you know, 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, you know, we're really encouraged about where our program's going and hope that that also is, frankly, you know, something that's an observational change for other programs as well.
spk23: Got it. Got it. Super helpful. And just a follow-up. From Campsite, do you have any plans to share additional biomarker data, such as systemic reduction of GAGs or NFL? Any color would be helpful. Thanks.
spk04: 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 maybe we get into the second half of the year, and as we start to talk more about You know, 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 the second half of this year.
spk18: Got it. Thanks so much. Our next question will come from the line of Manny Ferruhar with Learing Partners.
spk20: Hey, guys. Thanks for taking the question. 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 on the way. It looks like it's the back half of 25. But you do delineate in the press release a number of NAV technology platform licensees. that you define as having meaningful milestones throughout 2024. I think you call it Ultragenyx, Rocket, Novartis specifically, if 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.
spk04: I think the things we've pointed most to, Mani, in terms of potential impact on balance sheet are the milestones certainly that are associated with the transition of super-croidal into pivotal phase with AbbVie. Those have been the, you know, major priorities, and then the potential to achieve, you know, a pediatric review voucher upon the approval of RGX121. And I think our guidance on all of those things have been, you know, 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 on the press release and the history of the company around our NAV technology platform licensees, it's a great and interesting question. I mean, obviously, you know, the impact of Novartis as we continue to report quarterly sales and annual sales, you know, has to this point not really changed our balance sheet since we did the monetization of the Zulgensma 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. You know, we're seeing some evidence of, you know, regulatory progress, for instance, on the intratechal Zolgensma approach. which could change the labeling or change the product availability of the AV9 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 rockets, And Ultragenyx, I think we've identified that, you know, 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, you know, 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, you know, 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, you know, combined half a billion dollars in milestones associated with AbbVie partnerships, suprachoroidal progress, you know, would be in the same range. They might be, though, I don't know, five to ten times less than some of those things on a generalized basis when you look at the historical benefit of, you know, our licensee milestones. Is that helpful?
spk19: No, that's really helpful. Thank you.
spk25: Yeah, good question.
spk18: Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.
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