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spk04: 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 Regenics Bio's annual report on Form 10-K for the full year ended December 31, 2022, and comparable risk factors section of Regenics Bio's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, August 2nd, 2023, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not report 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. Ken?
spk27: Thank you, Patrick. Good afternoon, everyone. Thanks for joining us. I'm pleased to begin today's call with a recap of some recent business highlights, as well as an update on our corporate goals. Dr. Steve Pecola, our Chief Medical Officer, will then provide an update on our clinical programs, and Vic Pesista, our Chief Financial Officer, will provide an overview of financial results for the second quarter ended June 30th, 2023. At the end of the call, we will open up the line for questions. At Regenexx Bio, our mission is to improve lives through the curative potential of gene therapy, and we're focused on developing therapies for diseases that have significant unmet needs. We continue to be a leader in gene therapy, with thousands of patients who have been dosed with AAD therapeutics derived from our proprietary NAV technology platform. Recently, it's been a significant time of growth for the AAD gene therapy industry and at Regenexx Bio. We're developing a deeper understanding of gene therapy market access models and digesting regulatory approvals, including the FDA's support of biomarkers as surrogate endpoints to support accelerated approvals. There are now five FDA-approved AAV therapeutics. And I'm pleased how Regenexx Bio remains a leader in the gene therapy space, as our five-by-25 strategy is on track for advancing five AAV therapeutics from our internal pipeline and licensed programs into pivotal stage or commercial products by 2025. What distinguishes Regenexx Bio as a leader in AAV therapeutics? It's our platform, pipeline, and products. There are thousands of patients who have been dosed with AAV Therapeutics derived from our NAV technology platform and hundreds more are receiving treatment every quarter. We estimate approximately two children per day are receiving Zolgensma, which uses our NAV AAV9 vector. We believe that we have a strong pipeline of AAV Therapeutics ourselves with the potential to deliver one-time treatments to address significant unmet need for patients living with common and rare diseases. At Regenexx Bio, we are conducting over 12 active clinical trials using six different forms of delivery devices in three therapeutic areas, retinal, neuromuscular, and neurodegenerative diseases. In 2023, our team is executing on two pivotal phase programs that include over 1,000 subjects to support a goal we have to file our first BLAs in 2024 and 2025. We're observing that, on average, one new patient is being dosed in Regenexx bioclinical trials daily. Our work in retinal disease primarily centers around the strategic partnership we entered into with AbbVie at the end of 2021 to develop and commercialize ABBV-RGX314, or 314, and investigational gene therapy. AbbVie is a strong and complementary partner for Regenexx Bio. We expect to leverage AbbVie's global development and commercial infrastructure within eye care with our expertise in AAV gene therapy clinical development and deep in-house knowledge of manufacturing. Together, we're developing 314 to be the first one-time therapeutic option in major retinal vascular diseases to address significant unmet need for patients. Overall, our pipeline of AEB therapeutic candidates is addressing high unmet need for millions of patients in diseases that represent current market opportunities of over $20 billion. Just a few weeks ago, at our investor day in July, we introduced some new clinical trial data from our retina programs using suprachoroidal delivery and our Duchenne microdystrophin candidate, and we provided specific guidance about additional upcoming interim trial updates From our aviate and altitude trials, we reported that mild to moderate intraocular inflammation previously observed with suprachoroidal delivery is mitigated with short-course topical steroid eye drops. And we reported safety updates from the initial dosings in cohort one of the Affinity Duchenne study to support a well-tolerated profile of our candidate RGX202 to date. Now I'll turn the call over to Steve so that he can review in detail a bit more about the clinical progress and pipeline updates.
spk07: Thanks, 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 our NAVAVA 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. We recently announced the expansion of these studies to enroll a total of 1,200 patients in the US, Europe, Japan, and Israel to support global development of the program. We also recently initiated a fellow eye treatment study as part of the pivotal program using subretinal delivery. This study is evaluating the safety, efficacy, and immunogenicity of subretinal 314 administration in the fellow eye of patients with bilateral disease from atmosphere and ascent who previously received a subretinal injection of 314. Overall, we plan to complete all these trials in time to support global regulatory submissions in late 2025 through the first half of 2026. Additionally, earlier this week, we presented new interim results from our phase two pharmacodynamics study designed to evaluate the same dose levels being used in the two pivotal trials. The updated interim data demonstrated that 314 manufactured using our NavXRest platform process was well-tolerated, and in both the low-dose and high-dose cohorts through six months, patients achieved expected protein levels, along with stable to improved BCVA and CRT, as well as meaningful reductions in anti-VEGF burden, with most subjects remaining injection-free. This study is now fully enrolled. We also have two ongoing phase two trials that fall under our collaboration with AbbVie, assessing in-office supracoroidal delivery of 314 for treatment of wet AMD in the AVIATE trial and treatment of diabetic retinopathy in the ALTITUDE study. AVIATE is an active control dose escalation trial evaluating 314 for the treatment of wet AMD. We recently presented safety data at our investor day from cohort six evaluating dose level 3, 1E12, GC per eye, that included short-course prophylactic ocular steroids following administration of 314. The initial data presented continues to support the safety profile of 314 and highlighted the inclusion of short-course prophylactic steroid eye drops, which resulted in zero cases of intraocular inflammation, or IOI, in all patients. We plan to present full six month results from cohorts five and six at the Hawaii and I meeting in the beginning of 2024. Altitude is the active controlled dose escalation study of 314, suprachoroidal delivery for treatment of DR. We're very excited about the opportunity in DR given the size of the market which exceeds that of wet AMD and because we believe this patient population can benefit the most from a potential one-time gene therapy. During our investor day, we presented initial interim data from cohorts four and five at dose level three with short course prophylactic steroid eye drops following 314 administration. The data demonstrated that 314 was well tolerated with no drug-related serious adverse events in 29 patients from these cohorts. And just as observed in wet AMD, the inclusion of short-course prophylactic steroid eye drops resulted in zero cases of IOI in all patients. We look forward to presenting full 12-month results from cohorts one to three at the American Academy of Ophthalmology meeting later this year. Moving to Duchenne, as Ken mentioned in his remarks, At our investor day, we were pleased to announce our new exon skipping program to complement RGX202. Duchenne patients face high unmet need, and we are committed to bringing multiple treatment options for these boys. Our first program, RGX202, is a potential one-time gene therapy for the treatment of Duchenne, being developed as a highly differentiated product designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the CT domain found naturally in occurring dystrophin. RGX202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAVAV8 vector and a well-characterized muscle-specific promoter. During our investor day, we reported safety data from the Phase 1-2 Affinity Duchenne trial The data we presented on the two patients, ages 4 and 10, showed that RGX202 was well-tolerated in both patients with no drug-related serious adverse events. Time of post-administration follow-up was 45 days and more than three months. We continue to actively recruit patients in this trial, and we look forward to presenting additional data at the World Muscle Society Congress later this year that will include longer-term safety data and initial microdystrophin protein expression levels in muscle at three months. We also continue to enroll patients in Affinity Beyond, an observational screening study that is evaluating the prevalence of AAV8 antibodies in patients with Duchenne. Moving to our other rare disease programs, we are developing two programs for mucopolysaccharide OCs, MPS-2 and MPS-1. RGX-121 is an investigational one-time AAV therapeutic for the treatment of MPS-2, also known as Hunter syndrome, being evaluated in the ongoing Phase 1-2-3 campsite trial. In May, we announced that we received regenerative medicine, advanced therapy, or RMAT designation from the FDA. Recognizing the preliminary data we have presented to date indicates its potential to address the unmet medical need for patients with Hunter syndrome. We completed enrollment of 10 patients for our campsite trial in the first half of 2023 and remain on track to support a BLA filing in 2024 using the accelerated approval pathway. Now on to RGX111, an investigation on one-time AAV therapeutic for the treatment of severe MPS1. We have completed enrollment of the Phase 1-2 trial, and we remain on track to share additional updates on plans for this program later this year. In addition to these two programs, we also are developing RGX181 to treat the neurodegenerative manifestations and RGX381 to treat the ocular manifestations of CLM2 or Batten disease. Physician investigators in Brazil continue with follow-up for the first child with CLN2 disease dosed with RGX181 under a single-patient investigator-initiated study, and we expect investigators to report initial interim data from the single patient, including six-month results at the Society for the Study of Inborn Errors of Metabolism annual symposium later this year. We are also happy to report the recent dosing of our first patient with RGX381. To conclude, we have made significant progress with data updates and trial advancements across all our programs as we continue toward our goal of 5 by 25. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who are involved in and support all these trials. And with that, I turn the call over to Vit to review our financial guidance.
spk25: Thank you, Steve. Regenexx Bio ended the quarter on June 30, 2023, with cash, cash equivalents, and marketable securities totaling $415 million, compared to $565 million as of December 31, 2022. The decrease was primarily driven by cash used to fund operating activities during the first half of 2023. R&D expenses were $60 million for the second quarter of 2023, compared to $61 million for the second quarter of 2022. The decrease was primarily attributable to an increase in developmental cost reimbursement from AbbVie under our iCare collaboration. We expect a balance in cash, cash equivalents, and marketable securities of $415 million as of June 30th, 2023 to fund our operations into 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.
spk27: Thanks, Steve and Vit, for those important updates about our clinical progress and our financial performance. Regenexx Bio continues to perform at a high level as we execute on our mission of improving lives for the curative potential of gene therapy. In addition to our platform and pipeline, our end-to-end capabilities also set us apart as a leader, with our manufacturing innovation center here in Rockville running scalable, commercial-ready batches of AAV therapeutics. And our research and early development team continues to advance what's possible in gene therapy. We provided clear examples of these capabilities at our Investor Day when we presented data from the Manufacturing Innovation Center performance, including on product quality and yields, and when we introduced plans for a new IND for a candidate with Exxon skipping science to expand our commitment to Duchenne. Looking ahead for the remainder of the year and early into next year, we anticipate a number of important clinical pipeline milestones Let me summarize. Next month, as Steve mentioned, investigators at the Society for the Study of Inborn Errors of Metabolism will report the first initial data, six-month follow-up from the first patient dose with RGX181 for the treatment of CLN2 form of Batten disease. This is a five-year-old child, and this is part of the data from our third neurodegenerative program. In October at World Muscle Society, We expect to share additional interim data from patients in cohort one of Affinity Duchenne, including longer-term safety and the first microdystrophin expression protein levels in muscle at three months. In November, we plan to report additional interim data from the Phase II altitude trial of 314 superchoroidal delivery for the treatment of diabetic retinopathy at the American Academy of Ophthalmology meeting being held. This will include full 12-month results from cohorts 1 through 2 and 3. And finally, in January of next year, investigators will report on additional interim data from the Phase II ABA trial of RGX314 suprachoroidal delivery for the treatment of wet AMD, including full six-month results from cohorts 5 and 6. And this will be at the Hawaiian Eye and ResNet meeting. So we have a lot of important value-driving catalysts ahead of us this year. And with a balance sheet place to continue to fund our mission and operations into 2025 as it described. We have the focus and high-performing team, strong collaborators, and the trust of the clinical and patient community partners. It's a clear and definable path for us to achieve our 5 by 25 vision and continue to lead what's possible with AAV Therapeutics. We want to thank all of you for your Listening today, we look forward to providing you additional updates as we continue on this path for the remainder of this year and into next year. And with that, operator, we'll turn the call over for questions.
spk03: Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star 1-1 on your telephone. If your question has been answered, you wish to move yourself from the queue, please press star 1-1 again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Dane Leon with RJF. Your line is open.
spk08: Hi. Congratulations on all the progress, and thanks for taking some questions for us. Two questions kind of have been percolating with investors recently. One, it seems like you've given us more detail around what efficacy data we could expect from both AV8 and Altitude. Just one question regarding AV8. Should we expect 12-month data from cohorts one through four at Hawaii and I, or will it be just a full look across all cohorts up to month six? And then secondly, can your team elucidate what actual assays around protein expression of microdystrophin we could see at Worlds and whether you would expect some method of comparability to your peers that have ongoing DMD programs as well? Thank you.
spk27: Thanks, Dane, for the good questions. Steve, do you want to take the Hawaiian eye piece? Sure.
spk07: So, hi, Dane. Thanks for the questions. So, for the AV8 wet AMD update, we have discussed the latest results that we have for six-month follow-up. We haven't said more as far as longer-term follow-up, in part because of the later cohorts and the dynamic nature in these interim updates of ongoing studies. as well as really seeing when we might be able to do a data cut. And we always have the overhang of also reaching alignment with Appy as we get closer to these type of meetings. So that's the type of thing that we can update as we get a little closer.
spk27: And on the microdystrophin protein expression, Dane, we are working with methods that we think will be able to be used for comparisons to methods that have been used by others in clinical investigation of the microdystrophin class of products. So I think that as we come into world muscle, you know, I think we all know that, you know, forms of Western blot assays as well as liquid chromatography, mass spec, have been, you know, used in assessments of other patients. We think that we will have methods to support interpretation of that and some forms of comparison, keeping in mind that, you know, there are always nuances in assays, but I think things that the community will be familiar with from us.
spk02: Excellent. I look forward to seeing the data. Thank you.
spk24: Thanks a lot. Appreciate it.
spk02: One moment for our next question.
spk03: Our next question comes from Gina Wagner with Barclays. Your line is open.
spk10: Hi, it's Tony on for Gina. I have two questions. I guess first, briefly, can you remind us of the IP and royalty status for some of your partner programs, including with Rocket for Dan and Z's and Ultragenyx for GSD1A, as well as any IP rights to RH74? And then another one on DMD, with updates expected from Sarepta and Pfizer later this year, what kind of bar would you be looking for in terms of efficacy for protein expression and NSAID?
spk27: Sure, Tony. Thanks a lot for the question. Yeah, with respect to programs that are part of our NAV technology licensee universe, certainly Rocket's Danone program and the Ultragenyx GSD1A programs are under license for two different vectors, Rocket using AAV9, NAV AAV9, and Ultragenyx using NAV AAV8 in the case of GSD1A. These are licenses that we entered into several years ago. We tend to have royalties that are in the range or similar to the type of compensation that we're receiving, for example, on the Zulgensma royalty, so starting in the high single digits and going up on a tiered basis up into double-digit ranges. With respect to IP as it relates to your second question, we currently have two lawsuits that are involving patents relating to the manufacturing of Sarepta's product. as well as patents that involve the composition of Sarepta's product, both of which use AAV RH-74 that they refer to. And so we updated recently on the second lawsuit. The first lawsuit that involves the patents relating to manufacturing of the product is actually scheduled for trial in the beginning of 2024. With respect to your second question, I think this builds off of Dane's question about microdistrophin data and expression and where the program for RGX202 is going, which we're very encouraged about some of the initial safety data that we provided just a few weeks ago. When it comes to microdystrophin expression, we think that RGX314 is within the class of treatments candidates that have been explored clinically so far including both Sarepta and Pfizer and some others like SOLID. We're at a 1E14 dose currently in our trial, and I think that is, again, adjusting for understanding that there can be sometimes differences in assays and quantitation of different AAV products. It's similar to where Pfizer is in its pivotal program, and my understanding of Sarepta's accelerated approved product is that they're slightly above that 1.3E14 in terms of dose level. We'd be coming into observations of some of the first clinical data that we'd see at 90 days looking to achieve similar protein expression with respect to RGX202 to what others are achieving now. The key there is that we believe that once we express microdystrophin in the muscle of children, that our microdystrophin has the potential to be more potent or more efficacious because we're the first clinical candidate to design into the AAV microdystrophin that's being expressed. a substantial component of the C-terminus, as Steve alluded to, the C-terminal domain, which we've established pre-clinically, both in AAV experiments and in other work, to be meaningful in terms of improving the strength and the biological function of a microdystrophin. And so it's actually something that's more akin to what I would consider to be attenuated forms of Duchenne, like Becker muscular dystrophy that was sort of alluded to in the recent FDA ADCOM in discussions about microdystrophin and the possibility of microdystrophin being similar to things occur in nature ours is the first product that includes something that is most similar to things that occur in nature and so we think that will have an amplification of potential efficacy outcomes now the measurement of the efficacy outcomes will not be something that we'll be able to assess at the 90-day point on those considerations of course will be at later time points maybe nearer to nine or twelve months but that's when we would begin to get the type of responses like you were referring to in NSSA, et cetera. But for the update at World Muscle Society, this will be longer-term safety data and our first expression of microdystrophin in cohort one at the 1E14 dose.
spk03: One moment for our next question. Our next question comes from Gaspol Asindey with Morgan Stanley. Your line is open.
spk11: Hi, everyone. This is Gaspol for Vikram Purehead. So our question is, what is your current view on where RGX202 could fit for some competing DMD therapies in the real world setting?
spk27: Yeah, Gospel, it's a great question. You know, the design of RGX202 and the target product profile is multi-threaded for us. First is we believe strongly that there continues to be an unmet need in AAV gene therapy for boys when just a single product would be available or even two products. And that's because, as you all know, of preexisting immunology that can exist. in boys that may not allow them to access AAVs because of zero prevalence or preexisting neutralizing antibodies. So we estimate that the potential market for an AAV8-based capsid, which is what RGX202 is based on, on an incidence basis and on a prevalence basis, could include 15 or maybe up to 30% of the population that might not be able to access other capsids that are currently in development. That's the first point. Second point is what I was just alluding to in my answer to Tony, which is we're the first, RGX202 is the first reagent to be brought forward scientifically and clinically that includes a domain of full-length microdystrophin that doesn't exist in other microdystrophin products, the C-terminus. which, again, evidence to support preclinically that there's an improved effect of biological activity and strength of muscle when that C-terminal domain is present in truncated forms of dystrophin. So that, we think, sets us up potentially for a form of best-in-class when later in development we can assess more clinical data. We'll be more clear on that, but I think the preclinical data points in that direction today. evidence of the C-terminus is something that we strongly emphasize as our focus in development. And then the last piece is, I think, on quality and yields when it comes to manufacturing. This is something that we just highlighted at our Investor Day a few weeks ago. We think that the purity and the quality of the AAV products that are being manufactured here at the Rockville Manufacturing Innovation Center, as well as the yields we're achieving with our NAVexpress process, will allow us to be competitive in a market when it comes to everything from showing improvement in things like potential safety profiles and as well as potentially on cost.
spk03: All right. Thank you very much.
spk27: Thanks.
spk03: One moment for our next question. Our next question comes from Alex Serenahan with Bank of America. Your line is open.
spk09: Hey, guys. Thanks for taking our questions. Just a couple from us. First, actually, on MPS II, just curious, your interactions with the FDA around the RMAT designation, if you could give a sense of, you know, what it would take to show clinically for accelerated approval, and if you intend to update the markets with the top-line data prior to filing. And secondly, it's just around the ABD milestones. I appreciate this is not in the runway guidance, but any additional color around the scope and timing around any additional milestone triggers over the next year or two would be great. Thank you.
spk27: Hey, Alec. Thanks for those questions. On MPS II, yeah, we just announced today that we've completed The goal of enrollment of 10 patients with respect to the campsite study to support our plans for accelerated approval. And it was great timing with respect to the RMAT designation from FDA as well to support our continued execution here on the regulatory front. I think that, look, RMAD is something that's a designation that only comes from FDA's acknowledgement of clinical data. There are other types of designations that sometimes can rely exclusively on preclinical data for support, but in this case, RMAD is something where the FDA has already assessed clinical data that's been generated from our trials and provided input that it believes that there's a potential status here for moving quickly. And that's been consistent with our dialogue with FDA, you know, in the last several years with respect to how we've been thinking about transitioning from some of the first patients we've reported findings on all the way through to getting to that third dose level in our dose escalation and starting this phase of pivotal enrollment in the last year so I think that you absolutely can expect on a going forward basis from us additional data before the time of the filing of the BLA that would include top-line data that would go to support the BLA filing but at this phase sitting here today. We've just completed enrollment in the second quarter of the 10 patients and we're going to compile the timeline for not only completing the work to support the BLA but also for those data updates. So look out for us on those updates going forward. When it comes to AbbVie, you're bringing me back. I think when we first reported on this partnership in iCare with AbbVie, we highlighted in our filings that in addition to the total number of milestones that may be earned out by Orogenics Bio for development, regulatory and commercial, a big portion of that, I think it was over $750 million, is actually associated with the development and regulatory milestones. And I guess what we can say today is that, you know, the guidance that we can provide is that a substantial portion of that 780 is associated with the execution and advancement of suprachoroidal development. And so, as Steve is alluding to, as we come into updates later this year with respect to altitude and aviate as we progress from 23 into 2024, we're certainly learning a lot more about the potential for the advancement and the regulatory advancement and the development advancement of the supracoroidal programs for both wet AMD and diabetic retinopathy. And that starts to bring those development and regulatory milestones as potential earnouts for us into focus.
spk03: Thanks, Ken. I appreciate the call. One moment for our next question. Our next question comes from Ellie Merle with UBS. Your line is open.
spk15: Hey, guys. Thanks so much for taking the question. For DMD, I guess, can you maybe provide more color on when you expect to move to the second dose level? And I know you said we'll get data on the first dose level at World Muscle, but maybe what are the timelines for us seeing data from the second higher dose? And then just your expectations around expression level differences between the second dose and the first dose level. Thanks.
spk27: Thanks, Ellie. A few layers there. You know, we haven't given any guidance or any sort of specific kind of plan around dose escalation or, you know, and this trial is also designed for the potential of dose expansion at the first dose level as well. That'll be something that will be happening in the phase where we have the opportunity to sort of complete and evaluate the first cohort level and take into account the different types of variables, including the initial measures of microdystrophin at dose level one. With respect to dose level two, though, I mean, preclinically, we certainly have seen, and it's designed into the study because we've seen evidence of higher microdystrophin expression. We've seen evidence of improvement in outcomes with respect to functional assessment in the animal models. But, of course, you know, we want to understand how this could be recapitulated in human. And, frankly, we've also seen really strong expression and functional outcomes at the 1E14 dose level as well. So there's definitely still an opportunity here for us to decide that expansion of 1E14 is the direction that we want to go. And it's sort of an and-or function, perhaps, whether dose escalation to 2E14 occurs. I think we'll begin to talk about microdystrophin expression in more detail at World Muscle Society when we have some of the data to be able to present. And as I alluded to, I think in Dane's question, Ellie, you know, there's variability, of course, in different assay methods that people are using to assess microdystrophin. But, you know, we believe that we have really well-characterized, validated methods for specifically quantifying microdystrophin that's coming from RGX202. I expect to bring that forward and put it into context for all the stakeholders, of course investors, but also physicians and families when it comes to things that they've seen before from other programs. And I think our team has done an excellent job at working on methods that we understand and view are reliable, that regulators are going to view are reliable as well and are going to allow everyone to contextualize. You know, we're at the same dose as where Pfizer is and where Pfizer and Emergenix Bio from a, you know, sort of stated dosing perspective are slightly below where Sarepta is. I think that, you know, the preclinical data and the clinical data all says that, you know, all of these are in sort of relative similar ranges. So, We're expecting our initial microdystrophin data to be within the range of what sort of microdystrophin dose levels are from other programs at similar dose levels. I can't emphasize enough that important benefit of the same molecule that we express versus what someone expresses without the C-terminal domain is going to have a different effect functionally. The C-terminus is something that enhances the potency, enhances the functionality of a microdystrophin that's being expressed in gene therapy. So while we may achieve similar protein levels of microdystrophin as others, we think that our microdystrophin is going to be something on a molecule-by-molecule basis that is more effective.
spk16: Great. Thanks so much for all the color.
spk03: One moment for our next question. Our next question comes from Luka Issy with RBC. Your line is open.
spk14: Oh, great. Thanks for taking our questions. This is Lisa on for Luka. Just a couple questions on DMD. I just want to ask a more specific question on the microdystrophin expression levels and what the expectations are. So Sarepta has a 40 to 50% new change in microdystrophin expression from baseline on the label. Is that what we should expect to see as the bar for success when we get more data in October? And also on DMD, You know, despite setting a favorable regulatory precedent on the biomarker and gaining accelerated approval, Pfizer yesterday mentioned that their interim look for efficacy later this year will be on function and not on the surrogate biomarker. I know it's still early days, but just wondering what's your strategy for gaining approval and wondering if you are in the biomarker camp or the functional camp. Thanks for taking the question.
spk27: Um. Sure. Thanks, Lisa. You know, digging into it a bit, you know, I think, I mean, referencing the product approval label for Sarepta, I would say, you know, we can look at means. We should also look at medians and distributions of patients. And we'll have small numbers. And in certain cases, when they had small numbers, you know, there was quite a distribution of microdystrophin expression. So I think for us, we definitely view that we're going to be in the territory of things that have been reported by both Sarepta and Pfizer with respect to microdystrophin expression. And I think that, you know, that does for me, I mean, I wouldn't go as far as to say something like the median of the first patients that were enrolled on the basis of Sarepta, which I think was anything from like nearly zero up to like over 100%, because that would be ridiculous. But I think what we've seen when it comes to median and means of things reported by Sarepta and Pfizer is that there's sort of a range of like 20 to 40 percent, and that would be something that for us would be adjusted for the heterogeneity of the disease, the different types of methods, and sort of the assessments that have been done, something that I think would feel comfortable for us in terms of similarity. You know, with respect to, you know, the regulatory approach here, you know, I mean, I think, you know, my observations, well, I mean, let me just say that I think, you know, Regenexx Bio, both through our neurodegenerative franchise as well as since we've entered the you know, development of products for Duchenne muscular dystrophy have been very much focused on discussions with regulators and stakeholders about the use of the accelerated approval pathway. And I think that, you know, we continue to sort of approach our development and, you know, sort of regulatory execution on that basis. And we think that the validation of, you know, the first AAV therapeutic to be approved on the basis of accelerated approval is a great milestone to continue to support that. confirmatory data and other people taking approaches of trying to establish different avenues to show more longer-term functional data I think are also valid and different and I think that you know we'll continue to sort of process all of the information that comes in from both our own trials and our own development experience that of sort of stakeholders and patients as well as the FDA but from where we sit right now There's an urgent need, and especially with the approval on an accelerated basis of this first product, I think we all know that there's limited labeling that's supported the accelerated approval. At Regenexx Bio, we're developing, based on a clinical trial that's enrolling in boys from all the way up to age 11, there's still significant unmet need here and there's a significant urgency here. And so that's where I think we anchor ourselves to the patient need and the regulatory understanding that accelerated approval is something that all the stakeholders are supportive of and that we think that we want to contribute to as well.
spk14: Thanks for taking our questions.
spk03: One moment for our next question. Our next question comes from Brian Scorney with Bayard. Your line is open. Hi.
spk13: Thanks for taking our questions. This is Charlie on for Brian. We wanted to ask, it seems like suprachoroidal delivery for what AMD, what it's going to take to progress into Phase III is going to be fairly straightforward for what AMD, but for diabetic retinopathy, we wanted to get a little more color on how you're thinking about the interim results you'll be presenting later, and what the kind of bar is in terms of efficacy. And we'd also just kind of like a reminder on what kind of conversations you've had with the FDA so far regarding the NAVExpress manufacturing platform. Thank you.
spk22: Do you want to take the DR question?
spk13: Sure.
spk07: Thanks, Charlie. As you mentioned, we have the opportunity to look at readouts for both wet AMD and DR. On DR, it's interesting. There's the precedent of looking at two-step improvement on diabetic retinopathy severity. That's largely a technical consideration and a powering consideration for what's been done with prior repeat injection anti-VEGF agents. But what patients and their doctors really care about is preventing progression. So really having a proportion of patients that can have improvement of a certain level is a proxy for, okay, then you're more likely to not have patients progress to vision-threatening or blinding complications, which is the ultimate goal. So the reason I give that context is both of those are clinically meaningful. If you can have patients improving and if you can have a lower proportion of patients that worsen. And what we've seen to date with six-month results from our earlier cohorts is we really see both. The overall trajectory of these patients is going in a better, not a worse direction. And that's in contradistinction to what we know happens in patients' natural history and also in our negative control arm with observation. And what we also know is the bar that one thinks of for repeat injections indefinitely is something totally irrelevant for us with a one-time in-office treatment. Because we know that with repeated injections, you can actually stave off vision-threatening complications, but the treatment burden for these asymptomatic patients is just too much, and patients aren't signing up for this, as I think it's fair to say many predicted initially. But if you could have a one-time in-office treatment, that is a much lower bar for a benefit-risk consideration. When we talk to clinicians, experts, and investigators, really any clear reduction in clinically meaningful worsening is a very viable clinically and commercially target to shoot for. So on top of looking for proof of concept, That's really the way we're thinking about a target product profile. So we in AbbVie definitely look forward to seeing results that come later. The other thing I'd say is durability. So we've seen very good results at six months. It's going to be great to have an opportunity to assess durability out to a year later this year.
spk27: On the NavXpress side of it, I think that, you know, we have started the process in 2023 of creating, you know, process qualification lots around the planning of PLAs for both RGX121 and RGX314. And so we've had the opportunity to have a lot of dialogue with FDA. Again, we're running, you know, over 12 clinical trials. But, you know, for two late-stage studies, 1-2-1 and 3-1-4 with the subretinal approach, We've had more advanced discussions with FDA. We've also had the opportunity, you know, conveniently being here in Rockville, to have had people visit the facility. And we feel like we have one of the strongest capabilities when it comes to high-quality, high-yield, commercial-ready CGMP facilities that exist.
spk03: Great. Thank you. One moment for our next question. Our next question comes from Andreas Argarides with Wedbush Securities. Your line is open.
spk05: Yeah, thanks for taking our questions here. Just two from us. For RGX121 and PS2, can you elaborate on your interactions with the FDA and how they came to support the shorter timeframe for accelerated approval versus the competitors? And then, you know, what additional data do you or ABDI, sorry, this is probably the second part of the question to it, need to collect to feel comfortable advancing a 314 into pivotal trials for what NB and DR, and whose decision is it at the end of the day? Thanks.
spk07: So, I, hey, Andres, I can take the second one first. I guess the generic answer is we obviously take into account all data updates that we give and look at traditional aspects like dose response, safety and tolerability always come first if we're going to consider a potential dose. And I think the good news is in both indications, we have very clear non-invasive ways to assess for response and also potential dose response and There's not one Line in the sand I'd say that you can give in these cases because it really is looking at the overall results other than the suggestion I gave in terms of at least efficacy on on diabetic retinopathy and And to your related question of who makes the decision, we work very closely and collaboratively with AbbVie and we have the traditional joint committees like joint development and joint commercial committees that work together and cross-functionally evaluate all the data and really compare that against our target product profile to make such decisions.
spk27: Yeah, and with respect to the first question about 121, there really is not a close competitor to the target product profile of RGX121, which is a one-time therapy to address strictly the CNS components of Hunter syndrome. So we think we sort of stand in a unique class here, both with the one-time nature and standing on top of the unmet need for CNS features of MPS II because of the existing standard of care treatments in the U.S. like Alipraze not being able to address those features. And I think that the FDA designation of the RMAT is supportive of the fact that they're encouraged by the clinical data that has been reported so far. such that they want it designated as a program that has the type of status that is meant to be accelerated. So I think that we feel really good about our data. We feel good about the unique one-time profile of a treatment that addresses CNS manifestations of Hunter, and we feel good about the data that we've reported and the support that we're seeing from stakeholders and regulators.
spk05: Great. Thanks for the color there, and congrats on all the progress. We can't wait to see what's coming up.
spk03: One moment for our next question. Our next question comes from Manny Fruhar with Lyric. Your line is open.
spk20: Hi, good afternoon. This is Lillian Nisango on for Manny. I know earlier you had touched a little bit on the infringement lawsuit, and I was wondering if you could provide or if there were any updates that were available in terms of the timing for the second lawsuit, as well as kind of the potential level of damages that is sought out and the potential division between the company and the University of Pennsylvania.
spk18: So we don't have any update on the timing of the second lawsuit.
spk27: As I alluded to, the first case is scheduled to go to trial in early 2024. And that's the, otherwise the exact timing of the second lawsuit is not yet known.
spk20: Thank you. And in terms, so for the Duchenne program, so What do you expect to the CERB-CAS LVDS recent approval? What do you expect that impact to be on potential recruitment or enrollment in your study, as well as the potential impact from the UNBARC study results that are expected later this year?
spk27: And again, I think an important feature that everyone understands in AAV gene therapy is that there continue to be boys, kids in some of our trials and in other trials that aren't able to access therapy for a variety of reasons, even sometimes commercial therapies because of the pre-existing immunology. They can maybe achieve treatment from a certain type of therapy. vector because of serology, but not another. And Duchenne is a, you know, a rare disease, but is a larger incidence and prevalence than other areas that we operate in, in clinical development. So we have not seen, nor do we really expect to see any impingement on our ability to enroll with respect to the RGX202 program at clinical stage right now. As we go forward, I think additional data for microdystrophin class of products on the basis of the fact that our product is of that class, when we have the opportunity to show our microdystrophin data, emphasizing that our microdystrophin is a potentially better form of and more similar to full-length dystrophin or more naturally biologically active forms of truncated dystrophin, I think should be really exciting because it could show that there's evidence of, you know, incremental improvement with existing technology, but really I think we should be thinking about RGX202 as an improvement to the first generation of microdystrophins both on the basis of inclusion of the C-terminal domain, as well as the potential to bring some of the benefits of the Manufacturing Innovation Center into focus. And all of that's in addition to, look, there's just going to be boys that aren't going to be able to access the other treatments.
spk20: Thank you. And actually, speaking of the potential differentiation in terms of potency, Should we expect to see impacts on muscle function or muscle strength maybe earlier than other programs, say, you know, at the six-month readout?
spk27: I think that it's hard to assess that from the animal models because they're very different in certain forms than the human aspects of the disease as you get later in the progression. The animal models can be fragile in different types of ways, and so you can't always collect that same longitudinal data. I think on the basis of our understanding, I think, you know, we would expect to see more clear separation at something like the one-year time point, but I think it could be possible for certain types of measures to distinguish themselves between the six- and 12-month time points as well. We certainly wouldn't expect it would be something that would accompany the, you know, microdystrophin measures from the biopsies at three months.
spk19: Thank you so much for your clarifications.
spk03: Thanks. Again, ladies and gentlemen, if you have a question or a comment at this time, please press star 1-1 on your telephone. One moment for our next question. Our next question comes from Caroline Palomecu with Birkenberg Capital Markets. Your line is open.
spk17: Hi. Thanks for taking the question. So on RGX 314 for subretinal wet A and B, Are there any updates in enrollment from AbbVie on the Pivotal Trials Ascent atmosphere, especially since they increased the number of patients as well as the trial sites in the study? Thanks.
spk07: Hi, Carolyn. We don't have any change in our guidance. Everything's going very well post the expansion, the global expansion of the Pivotal Program. And we continue on track to complete these studies so that we can achieve BLA and European regulatory submissions in late 2025 through the first half of 2026. And yeah, we're trucking along.
spk01: Great. Thanks.
spk03: And I'm not showing any further questions at this time, and this does conclude today's presentation. You may now disconnect and have a wonderful day. you Thank you. Thank you. Thank you. Good day and thank you for standing by. Welcome to the Q2 2023 RegenX BioEarnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll 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 today's conference is being recorded. I would now like to turn the conference over to your speaker today, Patrick Christmas, Chief Legal Officer. You may begin.
spk04: Good afternoon, and thank you for joining us today. Earlier this afternoon, Regenexx Bio released financial and operating results for the second quarter ended June 30, 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 Regenic Bio's annual report on Form 10-K for the full year ended December 31, 2022. and comparable risk factors section of Regenexx BIOS quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, August 2, 2023, and we undertake no obligation to update any forward-looking statements we may make on this call and account new information in 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 report 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. Ken?
spk27: Thank you, Patrick. Good afternoon, everyone. Thanks for joining us. I'm pleased to begin today's call with a recap of some recent business highlights, as well as an update on our corporate goals. Dr. Steve Pecola, our Chief Medical Officer, will then provide an update on our clinical programs. And Vic Pesista, our Chief Financial Officer, will provide an overview of financial results for the second quarter ended June 30th, 2023. At the end of the call, we will open up the line for questions. At Regenexx Bio, our mission is to improve lives through the curative potential of gene therapy, and we're focused on developing therapies for diseases that have significant unmet needs. We continue to be a leader in gene therapy, with thousands of patients who have been dosed with AAV therapeutics derived from our proprietary NAV technology platform. It's been a significant time of growth for the AAD gene therapy industry and at Regenexx Bio. We're developing a deeper understanding of gene therapy market access models and digesting regulatory approvals, including the FDA's support of biomarkers as surrogate endpoints to support accelerated approvals. There are now five FDA-approved AAV therapeutics. And I'm pleased how Regenexx Bio remains a leader in the gene therapy space, as our five-by-25 strategy is on track for advancing five AAV therapeutics from our internal pipeline and licensed programs into pivotal stage or commercial products by 2025. What distinguishes Regenexx Bio as a leader in AAV therapeutics? It's our platform, pipeline, and products. There are thousands of patients who have been dosed with AAV therapeutics derived from our NAV technology platform, and hundreds more are receiving treatment every quarter. We estimate approximately two children per day are receiving Zolgensma, which uses our NAV AAV9 vector. We believe that we have a strong pipeline of AAV therapeutics ourselves, with the potential to deliver one-time treatments to address significant unmet need for patients living with common and rare diseases. At Regenexx Bio, we are conducting over 12 active clinical trials using six different forms of delivery devices in three therapeutic areas, retinal, neuromuscular, and neurodegenerative diseases. In 2023, our team is executing on two pivotal phase programs that include over 1,000 subjects to support a goal we have to file our first BLAs in 2024 and 2025. We're observing that, on average, one new patient is being dosed in Regenexx bioclinical trials daily. Our work in retinal disease primarily centers around the strategic partnership we entered into with AbbVie at the end of 2021 to develop and commercialize ABBV-RGX314, or 314, and investigational gene therapy. AbbVie is a strong and complementary partner for Regenexx Bio. We expect to leverage AbbVie's global development and commercial infrastructure within eye care with our expertise in AAV gene therapy clinical development and deep in-house knowledge of manufacturing. Together, we're developing 314 to be the first one-time therapeutic option in major retinal vascular diseases to address significant unmet need for patients. Overall, our pipeline of AEB therapeutic candidates is addressing high unmet need for millions of patients in diseases that represent current market opportunities of over $20 billion. Just a few weeks ago, at our investor day in July, we introduced some new clinical trial data from our retina programs using suprachoroidal delivery and our Duchenne microdystrophin candidate, and we provided specific guidance about additional upcoming interim trial updates From our aviate and altitude trials, we reported that mild to moderate intraocular inflammation previously observed with suprachoroidal delivery is mitigated with short course topical steroid eye drops. And we reported safety updates from the initial dosings in cohort one of the Affinity Duchenne study to support a well-tolerated profile of our candidate RGX202 to date. Now I'll turn the call over to Steve so that he can review in detail a bit more about the clinical progress and pipeline updates.
spk07: Thanks, 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 our NAVAV8 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. We recently announced the expansion of these studies to enroll a total of 1,200 patients in the U.S., Europe, Japan, and Israel to support global development of the program. We also recently initiated a fellow eye treatment study as part of the pivotal program using subretinal delivery. This study is evaluating the safety, efficacy, and immunogenicity of subretinal 314 administration in the fellow eye of patients with bilateral disease from atmosphere and ascent who previously received a subretinal injection of 314. Overall, we plan to complete all these trials in time to support global regulatory submissions in late 2025 through the first half of 2026. Additionally, earlier this week, we presented new interim results from our phase two pharmacodynamics study designed to evaluate the same dose levels being used in the two pivotal trials. The updated interim data demonstrated that 314 manufactured using our NavXRest platform process was well-tolerated, and in both the low-dose and high-dose cohorts through six months, patients achieved expected protein levels, along with stable to improved BCVA and CRT, as well as meaningful reductions in anti-VEGF burden, with most subjects remaining injection-free. This study is now fully enrolled. We also have two ongoing phase two trials that fall under our collaboration with AbbVie, assessing in-office supracoroidal delivery of 314 for treatment of wet AMD in the AVIATE trial and treatment of diabetic retinopathy in the ALTITUDE study. AVIATE is an active control dose escalation trial evaluating 314 for the treatment of wet AMD. We recently presented safety data at our investor day from cohort six evaluating dose level 3, 1E12, GC per eye, that included short-course prophylactic ocular steroids following administration of 314. The initial data presented continues to support the safety profile of 314 and highlighted the inclusion of short-course prophylactic steroid eye drops, which resulted in zero cases of intraocular inflammation, or IOI, in all patients. We plan to present full six month results from cohorts five and six at the Hawaii and I meeting in the beginning of 2024. Altitude is the active controlled dose escalation study of 314, suprachoroidal delivery for treatment of DR. We're very excited about the opportunity in DR given the size of the market which exceeds that of wet AMD and because we believe this patient population can benefit the most from a potential one-time gene therapy. During our investor day, we presented initial interim data from cohorts four and five at dose level three with short-course prophylactic steroid eye drops following 314 administration. The data demonstrated that 314 was well-tolerated with no drug-related serious adverse events in 29 patients from these cohorts, And just as observed in wet AMD, the inclusion of short course prophylactic steroid eye drops resulted in zero cases of IOI in all patients. We look forward to presenting full 12-month results from cohorts one to three at the American Academy of Ophthalmology meeting later this year. Moving to Duchenne, as Ken mentioned in his remarks at our investor day, we were pleased to announce our new exon skipping program. to complement RGX202. Duchenne patients face high unmet need, and we are committed to bringing multiple treatment options for these boys. Our first program, RGX202, is a potential one-time gene therapy for the treatment of Duchenne, being developed as a highly differentiated product designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the CT domain found naturally in occurring dystrophin. RGX202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAVAV8 vector and a well-characterized muscle-specific promoter. During our investor day, we reported safety data from the Phase 1-2 Affinity Duchenne trial. The data we presented on the two patients, ages 4 and 10, showed that RGX202 was well-tolerated in both patients with no drug-related serious adverse events. Time of post-administration follow-up was 45 days and more than three months. We continue to actively recruit patients in this trial, and we look forward to presenting additional data at the World Muscle Society Congress later this year that will include longer-term safety data and initial microdystrophin protein expression levels in muscle at three months. We also continue to enroll patients in Affinity Beyond, an observational screening study that is evaluating the prevalence of AAV8 antibodies in patients with Duchenne. Moving to our other rare disease programs, we are developing two programs for mucopolysaccharide OCs, MPS2 and MPS1. RGX-121 is an investigational one-time AAV therapeutic for the treatment of MPS II, also known as Hunter syndrome, being evaluated in the ongoing Phase 1-2-3 campsite trial. In May, we announced that we received Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA. Recognizing the preliminary data we have presented to date indicates its potential to address the unmet medical need for patients with Hunter syndrome. We completed enrollment of 10 patients for our campsite trial in the first half of 2023 and remain on track to support a BLA filing in 2024 using the accelerated approval pathway. Now on to RGX111, an investigation on one-time AAV therapeutic for the treatment of severe MPS1. We have completed enrollment of the Phase 1-2 trial, and we remain on track to share additional updates on plans for this program later this year. In addition to these two programs, we also are developing RGX181 to treat the neurodegenerative manifestations, and RGX381 to treat the ocular manifestations of CLN2 or Batten disease. Physician investigators in Brazil continue with follow-up for the first child with CLN2 disease dosed with RGX181 under a single-patient investigator-initiated study, and we expect investigators to report initial interim data from the single patient including six-month results at the Society for the Study of Inborn Errors of Metabolism Annual Symposium later this year. We are also happy to report the recent dosing of our first patient with RGX381. To conclude, we have made significant progress with data updates and trial advancements across all our programs as we continue toward our goal of 5 by 25. Lastly, I'd like to thank the patients, families, clinicians, and patient advocacy representatives who are involved in and support all these trials. And with that, I turn the call over to Vit to review our financial guidance.
spk25: Thank you, Steve. Regenexx Bio ended the quarter on June 30, 2023, with cash, cash equivalents, and marketable securities totaling $415 million compared to $565 million as of December 31st, 2022. The decrease was primarily driven by cash used to fund operating activities during the first half of 2023. R&D expenses were $60 million for the second quarter of 2023 compared to $61 million for the second quarter of 2022. The decrease was primarily attributable to an increase in developmental cost reimbursement from AbbVie under our iCare collaboration. We expect a balance in cash, cash equivalents, and marketable securities of $415 million as of June 30th, 2023 to fund our operations into 2025. This cash runway guidance is based on the company's current operational plans and exclude 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.
spk27: Thanks Steve and Vit for those important updates about our clinical progress and our financial performance. Regenexx Bio continues to perform at a high level as we execute on our mission of improving lives for the curative potential of gene therapy. In addition to our platform and pipeline, our end-to-end capabilities also set us apart as a leader, with our manufacturing innovation center here in Rockville running scalable, commercial-ready batches of AAV therapeutics, and our research and early development team continues to advance what's possible in gene therapy. We provided clear examples of these capabilities at our Investor Day when we presented data from the Manufacturing Innovation Center performance, including on product quality and yields, and when we introduced plans for a new IND for a candidate with Exxon skipping science to expand our commitment to Duchenne. Looking ahead for the remainder of the year and early into next year, we anticipate a number of important clinical pipeline milestones Let me summarize. Next month, as Steve mentioned, investigators at the Society for the Study of Inborn Errors of Metabolism will report the first initial data, six-month follow-up from the first patient dosed with RGX181 for the treatment of CLN2 form of Batten disease. This is a five-year-old child, and this is part of the data from our third neurodegenerative program. In October at World Muscle Society, We expect to share additional interim data from patients in cohort one of Affinity Duchenne, including longer-term safety and the first microdystrophin expression protein levels in muscle at three months. In November, we plan to report additional interim data from the Phase II altitude trial of 314 superchoroidal delivery for the treatment of diabetic retinopathy at the American Academy of Ophthalmology meeting being held. This will include full 12-month results from cohorts 1 through 2 and 3. And finally, in January of next year, investigators will report on additional interim data from the Phase II ABA trial of RGX314 superchoroidal delivery for the treatment of wet AMD, including full six-month results from cohorts 5 and 6. And this will be at the Hawaiian Eye and ResNet meeting. So we have a lot of important value-driving catalysts ahead of us this year. And with a balance sheet, place to continue to fund our mission and operations into 2025 as Vint described. We have the focus and high-performing team, strong collaborators, and the trust of the clinical and patient community partners. It's a clear and definable path for us to achieve our 5 by 25 vision and continue to lead what's possible with AAV Therapeutics. We want to thank all of you for Listening today, we look forward to providing you additional updates as we continue on this path for the remainder of this year and into next year. And with that, operator, we'll turn the call over for questions.
spk03: Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star 1-1 on your telephone. If your question has been answered, you wish to move yourself from the queue, please press star 1-1 again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Dane Leon with RJF. Your line is open.
spk08: Hi. Congratulations on all the progress, and thanks for taking some questions for us. Two questions kind of have been percolating with investors recently. One, it seems like you've given us more detail around what efficacy data we could expect from both AV8 and Altitude. Just one question regarding AV8. Should we expect 12-month data from cohorts one through four at Hawaii and I, or will it be just a full look across all cohorts up to month six? And then secondly, can your team elucidate what actual assays around protein expression of microdystrophin we could see at Worlds and whether you would expect some method of comparability to your peers that have ongoing DMG programs as well? Thank you.
spk27: Thanks, Dane, for the good questions. Steve, do you want to take the Hawaiian eye piece?
spk07: Sure. So, hi, Dane. Thanks for the questions. So, for the AV8 wet AMD update, we have discussed the latest results that we have for six-month follow-up. We haven't said more as far as longer-term follow-up, in part because of the later cohorts and the dynamic nature in these interim updates of ongoing studies. as well as really seeing when we might be able to do a data cut. And we always have the overhang of also reaching alignment with Appy as we get closer to these type of meetings. So that's the type of thing that we can update as we get a little closer.
spk27: And on the microdystrophin protein expression, Dane, we are working with methods that we think will be able to be used for comparisons to methods that have been used by others in clinical investigation of the microdystrophin class of products. So I think that as we come into world muscle, you know, I think we all know that, you know, forms of Western blot assays as well as liquid chromatography, mass spec, have been, you know, used in assessments of other patients. We think that we will have methods to support interpretation of that and some forms of comparison, keeping in mind that, you know, there are always nuances in assays, but I think things that the community will be familiar with from us.
spk02: Excellent. I look forward to seeing the data. Thank you.
spk24: Thanks a lot. Appreciate it.
spk02: One moment for our next question.
spk03: Our next question comes from Gina Wagner with Barclays. Your line is open.
spk10: Hi, it's Tony on for Gina. I have two questions. I guess first, briefly, can you remind us of the IP and royalty status for some of your partner programs, including with Rocket for Dan and Z's and Ultragenyx for GSD1A, as well as any IP rights to RH74? And then another one on DMD, With updates expected from Sarept and Pfizer later this year, what kind of bar would you be looking for in terms of efficacy for protein expression and NSAID?
spk27: Sure, Tony. Thanks a lot for the question. Yeah, with respect to programs that are part of our NAV technology licensee universe, certainly ROCKET's Danone program and the Ultragenyx GSD1A programs are under license for two different vectors, ROCKET using AAV9, NAV AAV9, and Ultragenyx using NAV AAV8 in the case of GSD1A. These are licenses that we entered into several years ago. We tend to have royalties that are in the range or similar to the type of compensation that we're receiving, for example, on the Zulgensma royalty, so starting in the high single digits and going up on a tiered basis up into double-digit ranges. With respect to IP as it relates to your second question, we currently have two lawsuits that are involving patents relating to the manufacturing of Sarepta's product. as well as patents that involve the composition of Sarepta's product, both of which use PAV RH74 that they refer to. And so we updated recently on the second lawsuit. The first lawsuit that involves the patents relating to manufacturing of the product is actually scheduled for trial in the beginning of 2024. With respect to your second question, I think this builds off of Dane's question about microdistrophin data and expression and where the program for RGX202 is going, which we're very encouraged about some of the initial safety data that we provided just a few weeks ago. When it comes to microdystrophin expression, we think that RGX314 is within the class of treatments, candidates that have been explored clinically so far, including both Sarepta and Pfizer and some others like SOLID. We're at a 1E14 dose currently in our trial, and I think that is, again, adjusting for understanding that there can be sometimes differences in assays and quantitation of different AAV products. It's similar to where Pfizer is in its pivotal program, and my understanding of Sarepta's accelerated approved product is that they're slightly above that 1.3E14 in terms of dose level. We'd be coming into observations of some of the first clinical data that we'd see at 90 days looking to achieve similar protein expression with respect to RGX202 to what others are achieving now. The key there is that we believe that once we express microdystrophin in the muscle of children, that our microdystrophin has the potential to be more potent or more efficacious because we're the first clinical candidate to design into the AAV microdystrophin that's being expressed. a substantial component of the C-terminus, as Steve alluded to, the C-terminal domain, which we've established preclinically, both in AAV experiments and in other work. to be meaningful in terms of improving the strength and the biological function of a microdystrophin. And so it's actually something that's more akin to what I would consider to be attenuated forms of Duchenne, like Becker muscular dystrophy that was sort of alluded to in the recent FDA ADCOM in discussions about microdystrophin and the possibility of microdystrophin being similar to things that occur in nature. Ours is the first product that includes something that is most similar to things that occur in nature. And so we think that we'll have an amplification of potential efficacy outcomes. Now, the measurement of the efficacy outcomes will not be something that we'll be able to assess at the 90-day point. Those considerations, of course, will be at later time points, maybe nearer to 9 or 12 months. But that's when we would begin to get the type of responses like you were referring to in NSSA, et cetera. But for the update at World Muscle Society, this will be longer-term safety data and our first expression of microdystrophin in cohort one at the 1E14 dose.
spk03: One moment for our next question. Our next question comes from Gaspol Asindey with Morgan Stanley. Your line is open.
spk11: Hi, everyone. This is Gaspol for Vikram Purehead. So our question is, what is your current view on where RGX202 could fit for some competing DMD therapies in the real world setting?
spk27: Yeah, Gospel, it's a great question. You know, the design of RGX202 and the target product profile is multi-threaded for us. First is we believe strongly that there continues to be an unmet need in AAV gene therapy for boys when just a single product would be available or even two products. And that's because, as you all know, of preexisting immunology that can exist. in boys that may not allow them to access AAVs because of zero prevalence or preexisting neutralizing antibodies. So we estimate that the potential market for an AAV8-based capsid, which is what RGX202 is based on, on an incidence basis and on a prevalence basis, could include 15 or maybe up to 30% of the population that might not be able to access other capsids that are currently in development. That's the first point. Second point is what I was just alluding to in my answer to Tony, which is RDX202 is the first reagent to be brought forward scientifically and clinically that includes a domain of full-length microdystrophin that doesn't exist in other microdystrophin products, the C-terminus. which, again, evidence to support preclinically that there's an improved effect of biological activity and strength of muscle when that C-terminal domain is present in truncated forms of dystrophin. So that, we think, sets us up potentially for a form of best-in-class when later in development we can assess more clinical data. We'll be more clear on that, but I think the preclinical data points in that direction today. evidence of the C-terminus is something that we strongly emphasize as our focus in development. And then the last piece is, I think, on quality and yields when it comes to manufacturing. This is something that we just highlighted at our Investor Day a few weeks ago. We think that the purity and the quality of the AAV products that are being manufactured here at the Rockville Manufacturing Innovation Center, as well as the yields we're achieving with our NAVexpress process, will allow us to be competitive in a market when it comes to everything from showing improvement in things like potential safety profiles and as well as potentially on cost.
spk03: All right. Thank you very much.
spk27: Thanks.
spk03: One moment for our next question. Our next question comes from Alex Serenahan with Bank of America. Your line is open.
spk09: Hey, guys. Thanks for taking our questions. Just a couple from us. First, actually, on MPS II, just curious, your interactions with the FDA around the RMAT designation, if you could give a sense of, you know, what it would take to show clinically for accelerated approval, and if you intend to update the markets with the top-line data prior to filing. And secondly, it's just around the ABD milestones. I appreciate this is not in the runway guidance, but any additional color around the scope and timing around any additional milestone triggers over the next year or two would be great. Thank you.
spk27: Hey, Alec. Thanks for those questions. On MPS II, yeah, we just announced today that we've completed The goal of enrollment of 10 patients with respect to the campsite study to support our plans for accelerated approval. And it was great timing with respect to the RMAT designation from FDA as well to support our continued execution here on the regulatory front. I think that, look, RMAD is something that's a designation that only comes from FDA's acknowledgment of clinical data. There are other types of designations that sometimes can rely exclusively on preclinical data for support, but in this case, RMAD is something where the FDA has already assessed clinical data that's been generated from our trials and provided input that it believes that there's a potential status here for moving quickly. And that's been consistent with our dialogue with FDA, you know, in the last several years with respect to how we've been thinking about transitioning from some of the first patients we've reported findings on all the way through to getting to that third dose level in our dose escalation and starting this phase of pivotal enrollment in the last year so I think that you absolutely can expect on a going forward basis from us additional data before the time of the filing of the BLA that would include top-line data that would go to support the BLA filing but at this phase sitting here today. We've just completed enrollment in the second quarter of the 10 patients, and we're going to compile the timeline for not only completing the work to support the BLA, but also for those data updates. So look out for us on those updates going forward. When it comes to AbbVie, you're bringing me back. I think when we first reported on this partnership in iCare with AbbVie, we highlighted in our filings that in addition to the total number of milestones that may be earned out by Regenexx Bio for development, regulatory and commercial, a big portion of that, I think it was over $750 million, is actually associated with the development and regulatory milestones. And I guess what we can say today is that, you know, the guidance that we can provide is that a substantial portion of that 780 is associated with the execution and advancement of suprachoroidal development. And so, as Steve is alluding to, as we come into updates later this year with respect to altitude and aviate as we progress from 2023 into 2024, we're certainly learning a lot more about the potential for the advancement and the regulatory advancement and the development advancement of the suprachoroidal programs for both wet AMD and diabetic retinopathy, and that starts to bring those development and regulatory milestones as potential earnouts for us into focus.
spk09: Thanks, Ken. Appreciate the call.
spk03: One moment for our next question. Our next question comes from Ellie Merle with UBS. Your line is open.
spk15: Hey guys, thanks so much for taking the question. For DMD, I guess, can you maybe provide more color on when you expect to move to the second dose level? And I know you said we'll get data on the first dose level at World Muscle, but maybe what are the timelines for us seeing data from the second higher dose? And then just your expectations around expression level differences between the second dose and the first dose level. Thanks.
spk27: Thanks, Ellie. A few layers there. You know, we haven't given any guidance or any sort of specific kind of plan around dose escalation or, you know, and this trial is also designed for the potential of dose expansion at the first dose level as well. That'll be something that will be happening in the phase where we have the opportunity to sort of complete and evaluate the first cohort level and take into account the different types of variables, including the initial measures of microdystrophin at dose level one. With respect to dose level 2, though, I mean, preclinically, we certainly have seen, and it's designed into the study because we've seen evidence of higher microdystrophin expression. We've seen evidence of improvement in outcomes with respect to functional assessments in the animal models. But, of course, you know, we want to understand how this could be recapitulated in human. And, frankly, we've also seen really strong expression and functional outcomes at the 1E14 dose level as well. So there's definitely still an opportunity here for us to decide that expansion of 1E14 is the direction that we want to go. And it's sort of an and-or function, perhaps, whether dose escalation to 2E14 occurs. I think we'll begin to talk about microdystrophin expression in more detail at World Muscle Society when we have some of the data to be able to present. And as I alluded to, I think in Dane's question, Ellie, you know, there's variability, of course, in different assay methods that people are using to assess microdystrophin. But, you know, we believe that we have really well-characterized, validated methods for specifically quantifying microdystrophin that's coming from RGX202. Expect to bring that forward and put it into context for all the stakeholders, you know, of course investors, but also physicians and families when it comes to things that they've seen before from other programs. And I think our team has done an excellent job at working on methods that we understand and view are reliable, that regulators are going to view are reliable as well and are going to allow everyone to contextualize. As I said, We're at the same dose as where Pfizer is and where Pfizer and Emergenics Bio, from a stated dosing perspective, are slightly below where Sarepta is. I think the preclinical data and the clinical data all says that all of these are in relative similar ranges. We're expecting our initial microdystrophin data to be within the range of what sort of microdystrophin dose levels are from other programs at similar dose levels. I can't emphasize enough that important benefit of the same molecule that we express versus what someone expresses without a C-terminal domain is going to have a different effect functionally. The C-terminus is something that enhances the potency, enhances the functionality of a microdystrophin that's being expressed in gene therapy. So while we may achieve similar protein levels of microdystrophin as others, we think that our microdystrophin is going to be something on a molecule-by-molecule basis that is more effective.
spk16: Great. Thanks so much for all the color.
spk03: One moment for our next question. Our next question comes from Luca Issy with RBC. Your line is open.
spk14: Oh, great. Thanks for taking our questions. This is Lisa. I'm for Luca. Just a couple questions on DMD. I just want to ask a more specific question on the microdystrophin expression levels and what the expectations are. So Sarepta has a 40 to 50% new change in microdystrophin expression from baseline on the label. Is that what we should expect to see as the bar for success when we get more data in October? And also on DMD, You know, despite setting a favorable regulatory precedent on the biomarker and gaining accelerated approval, Pfizer yesterday mentioned that their interim look for efficacy later this year will be on function and not on surrogate biomarker. I know it's still early days, but just wondering what's your strategy for gaining approval and wondering if you are in the biomarker camp or the functional camp. Thanks for taking questions.
spk27: Sure. Thanks, Lisa. You know, digging into it a bit, you know, I think, I mean, referencing the product approval label for Sarepta, I would say, you know, we can look at means. We should also look at medians and distributions of patients. And And we'll have small numbers. And in certain cases, when they had small numbers, you know, there was quite a distribution of micro dystrophin expression. So I think for us, we definitely view that we're going to be in the territory of things that have been reported by both. Sarepta and Pfizer with respect to microdystrophin expression. And I think that, you know, that does for me, I mean, I wouldn't go as far as to say something like the median of the first patients that were enrolled on the basis of Sarepta, which I think was anything from like nearly zero up to like over 100%, because that would be ridiculous. But I think what we've seen when it comes to median and means of things reported is by Sarepta and Pfizer is that there's sort of a range of like 20 to 40%, and that would be something that for us would be adjusted for the heterogeneity of the disease, the different types of methods, and sort of the assessments that have been done, something that I think would feel comfortable for us in terms of similarity. With respect to the regulatory approach here, You know, I think, you know, my observations, well, I mean, let me just say that I think, you know, Regenexx Bio, both through our neurodegenerative franchise, as well as since we've entered the, you know, development of products for Duchenne muscular dystrophy, have been very much focused on discussions with regulators and stakeholders about the use of the accelerated approval pathway. And I think that You know, we continue to sort of approach our development and, you know, sort of regulatory execution on that basis. And we think that the validation of, you know, the first AAV therapeutic to be approved on the basis of accelerated approval is a great milestone to continue to support that. confirmatory data and other people taking approaches of trying to establish different avenues to show more longer-term functional data, I think are also valid and different. And I think that, you know, we'll continue to sort of process all of the information that comes in from both our own trials and our own development experience, that of sort of stakeholders and patients as well as the FDA. But from where we sit right now, there's an urgent need, and especially with the approval on an accelerated basis of this first product. I think we all know that there's limited labeling that's supported the accelerated approval. At Regenexx Bio, we're developing, based on a clinical trial that's enrolling in boys from all the way up to age 11, there's still significant unmet need here and there's a significant urgency here. And so that's where I think we anchor ourselves to the patient need and the regulatory understanding that accelerated approval is something that all the stakeholders are supportive of and that we think that, you know, we want to contribute to as well.
spk18: Thanks for taking our questions.
spk03: One moment for our next question. Our next question comes from Brian. It's Courtney with Bayer. Your line is open. Hi.
spk13: Thanks for taking our questions. This is Charlie on for Brian. We wanted to ask, it seems like suprachoroidal delivery for what AMD, what it's going to take to progress into Phase III is going to be fairly straightforward for what AMD, but for diabetic retinopathy, we wanted to get a little more color on how you're thinking about the interim results you'll be presenting later and what the kind of bar is in terms of efficacy. And we'd also just kind of like a reminder on what kind of conversations you've had with the FDA so far regarding the NavXpress manufacturing platform. Thank you.
spk22: Do you want to take the DR question?
spk07: Sure. Thanks, Charlie. As you mentioned, we have the opportunity to look at readouts for both wet AMD and DR. On DR, it's interesting. There's the precedent of looking at two-step improvement on diabetic retinopathy severity. That's largely a technical consideration and a powering consideration for what's been done with prior repeat injection anti-VEGF agents. But what patients and their doctors really care about is preventing progression. So really having a proportion of patients that can have improvement of a certain level is a proxy for, okay, then you're more likely to not have patients progress to vision-threatening or blinding complications, which is the ultimate goal. So the reason I give that context is both of those are clinically meaningful. If you can have patients improving and if you can have a lower proportion of patients that worsen. And what we've seen to date with six-month results from our earlier cohorts is we really see both. The overall trajectory of these patients is going in a better, not a worse, direction. And that's in contradistinction to what we know happens in patients' natural history and also in our negative control arm with observation. And what we also know is the bar that one thinks of for repeat injections indefinitely is something totally irrelevant for us with a one-time in-office treatment. because we know that with repeated injections, you can actually stave off vision-threatening complications, but the treatment burden for these asymptomatic patients is just too much, and patients aren't signing up for this, as I think it's fair to say many predicted initially. But if you could have a one-time in-office treatment, that is a much lower bar for a benefit-risk consideration. When we talk to clinicians, experts, and investigators, really any clear reduction in clinically meaningful worsening is a very viable clinically and commercially target to shoot for. On top of looking for proof of concept, that's really the way we're thinking about a target product profile. We and AbbVie definitely look forward to seeing results that come later. The other thing I'd say is durability. So we've seen very good results at six months. It's going to be great to have an opportunity to assess durability out to a year later this year.
spk27: On the NavXpress side of it, I think that, you know, we have Started the process in 2023 of creating process qualification lots around the planning of BLAs for both RGX121 and RGX314. And so, we've had the opportunity to have a lot of dialogue with FDA. Again, we're running, you know, over 12 clinical trials. But, you know, for two late-stage studies, 121 and 314 with the subretinal approach, we've had more advanced discussions with FDA. We've also had the opportunity, you know, conveniently being here in Rockville, to have had people visit the facility. And we feel like we have one of the strongest capabilities when it comes to high-quality, high-yield, commercial-ready CGMP facilities that exist.
spk03: Great. Thank you. One moment for our next question. Our next question comes from Andreas Argarides with Wedbush Securities. Your line is open.
spk05: Yeah, thanks for taking our questions here. Just two from us. For RGX121 and PS2, can you elaborate on your interactions with the FDA and how they came to support the shorter timeframe for accelerated approval versus the competitors? And then, you know, what additional data do you or ABDI, sorry, this is probably the second part of the question to it, need to collect to feel comfortable advancing a 314 into pivotal trials for what NB and DR, and whose decision is it at the end of the day? Thanks.
spk07: So I, hey Andres, I can take the second one first. I guess the generic answer is we obviously take into account all data updates that we give and look at traditional aspects like dose response, safety and tolerability always come first if we're going to consider a potential dose. And I think the good news is in both indications, we have very clear non-invasive ways to assess forward response and also potential dose response and There's not one Line in the sand I'd say that you can give in these cases because it really is looking at the overall results other than the suggestion I gave in terms of at least efficacy on on diabetic retinopathy and And to your related question of who makes the decision, we work very closely and collaboratively with AbbVie and we have the traditional joint committees like joint development and joint commercial committees that work together and cross-functionally evaluate all the data and really compare that against our target product profile to make such decisions.
spk27: Yeah, and with respect to the first question about 121, there really is not a close competitor to the target product profile of RGX121, which is a one-time therapy to address strictly the CNS components of RGX121. Hunter syndrome so, you know, we think we sort of stand in a unique class here both with the one-time nature and you know standing on top of the unmet need for CNS features of MPS II because of the existing standard of care treatments in the US like Ella praise Not being able to address those features And I think that the FDA designation of the RMAT is supportive of the fact that they're encouraged by the clinical data that has been reported so far, such that they want it designated as a program that has the type of status that is meant to be accelerated. So I think that we feel really good about our data. We feel good about the unique one-time profile of a treatment that addresses CNS manifestations of Hunter, and we feel good about the data that we've reported and the support that we're seeing from stakeholders and regulators.
spk05: Great. Thanks for the color there, and congrats on all the progress. We're looking forward to all your updates coming up.
spk03: One moment for our next question. Our next question comes from Manny Fruhar with Lyric. Your line is open.
spk20: Hi, good afternoon. This is Lili Nisongo on For Money. I know earlier you had touched a little bit on the infringement lawsuit, and I was wondering if you could provide or if there were any updates that were available in terms of the timing for the second lawsuit, as well as kind of the potential level of damages that is sought out and the potential division between the company and the University of Pennsylvania.
spk18: So we don't have any update on the timing of the second lawsuit.
spk27: As I alluded to, the first case is scheduled to go to trial in early 2024. And that's the, otherwise the exact timing of the second lawsuit is not yet known.
spk20: Thank you. And in terms of the Duchenne program, so What do you expect to the CERB-CAS LVDS recent approval, what do you expect that impact to be on potential recruitment or enrollment in your study, as well as the potential impact from the UNBARC study results that are expected later this year?
spk27: Again, I think an important feature that everyone understands in AAV gene therapy is that there continue to be boys, kids in some of our trials and in other trials that aren't able to access therapy for a variety of reasons, even sometimes commercial therapies because of the pre-existing immunology. They can maybe achieve treatment from a certain type of therapy. vector because of serology, but not another. And Duchenne is a, you know, a rare disease, but is a larger incidence and prevalence than other areas that we operate in, in clinical development. So we have not seen, nor do we really expect to see any impingement on our ability to enroll with respect to the RGX202 program at clinical stage right now. As we go forward, I think additional data for microdystrophin class of products on the basis of the fact that our product is of that class, when we have the opportunity to show our microdystrophin data, emphasizing that our microdystrophin is a potentially better form of and more similar to full-length dystrophin or more naturally biologically active forms of truncated dystrophin, I think should be really exciting because it could show that there's evidence of, you know, incremental improvements with existing technology, but really I think we should be thinking about RGX202 as an improvement to the first generation of microdystrophins both on the basis of inclusion of the C-terminal domain, as well as the potential to bring some of the benefits of the manufacturing innovation center into focus. And all of that's in addition to, look, there's just going to be boys that aren't going to be able to access the other treatments.
spk20: Thank you. And actually, speaking of the potential differentiation in terms of potency, Should we expect to see impacts on muscle function or muscle strength maybe earlier than other programs, say, you know, at the six-month readout?
spk27: I think that it's hard to assess that from the animal models because they're very different in certain forms than the human aspects of the disease as you get later in the progression. The animal models can be fragile in different types of ways, and so you can't always collect that same longitudinal data. I think on the basis of our understanding, I think, you know, we would expect to see more clear separation at something like the one-year time point, but I think it could be possible for certain types of measures to distinguish themselves between the six- and 12-month time points as well. We certainly wouldn't expect it would be something that would accompany the, you know, microdystrophin measures from the biopsies at three months.
spk19: Thank you so much for your clarifications. Thanks.
spk03: Again, ladies and gentlemen, if you have a question or a comment at this time, please press star 1-1 on your telephone. One moment for our next question. Our next question comes from Caroline Palomaque with Birkenberg Capital Markets. Your line is open.
spk17: Hi. Thanks for taking the question. So on RGX 314 for subretinal wet A and B, Are there any updates in enrollment from AbbVie on the Pivotal Trials Ascent atmosphere, especially since they increased the number of patients as well as the trial sites in the study? Thanks.
spk07: Hi, Carolyn. So we don't have any change in our guidance. Everything's going very well post the expansion, the global expansion of the Pivotal Program. And we continue on track to complete these studies so that we can achieve BLA and European regulatory submissions in late 2025 through the first half of 2026. And, yeah, we're trucking along.
spk01: Great. Thanks.
spk03: And I'm not showing any further questions at this time. And this does conclude today's presentation. You may now disconnect and have a wonderful day.
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