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spk01: Thank you for joining Q4 2021 RegenXBio, Inc. Earnings Conference Call. At this time, your lines have been placed on mute. Later in the call, there will be a Q&A session and instructions will be given at that time. If you need operator assistance, please press star zero. As a reminder, today's call is being recorded. And if you wish to ask a question, please press star one. I'll now turn to call over to your host today, Patrick Christmas, Chief Legal Officer with GenX Bio. Sir, please go ahead.
spk09: Good afternoon, and thank you for joining us today. With us today are Ken Mills, for GenX Bio's President and Chief Executive Officer, Dr. Steve Bacola, our Chief Medical Officer, and Vipa Sista, our Chief Financial Officer. Earlier this afternoon, Regenexx Bio released financial and operating results for the fourth quarter and full year ended December 31, 2021. The press release reporting our financial results 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 discussion and analysis sections of Regenexx BIO's annual report on Form 10-K for the full year ended December 31, 2021, and comparable risk factor sections of Regenexx 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, March 1, 2022, 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 purport to project financial positions or operating results of the company. Actual results may differ materially. I would now like to turn the call over to Ken. Ken?
spk03: Thank you, Patrick. Good afternoon, everyone, and thanks again for joining us. I'm pleased to begin today's call with a Quick recap of business highlights as well as an update on our corporate goals. Steve will then provide an update on our clinical programs and Vint will provide an overview of financial results for the fourth quarter and year ended 2021. At the end of the call, we will open up the line for questions. I want to start off by saying how pleased I am with our performance as an organization over this past quarter and this past year. Against the challenging backdrop in 2021, Regenexx Bio has continued to perform at a very high level. And I'd really like to take this time to thank our Regenexx Bio team, our investigators, and the patient communities for their commitment to the development of our innovative AAV therapeutics. One of the more important events for our company this past year was the signing and recent closing of our eye care collaboration agreement with AbbVie for the development and commercialization of RGX314. We're really pleased to be working with AbbVie, an industry leader in eye care, as we advance RGX314, a potential one-time treatment, in clinical trials for the treatment of wet AMD and diabetic retinopathy, and consider development in other chronic eye disorders. Aside from AbbVie's significant financial investment that we believe validates our innovative gene therapies and provides significant cash runway, the collaboration allows us to leverage AbbVie's leading development and commercial expertise. We plan to take full advantage of this collaboration as we work together to advance RGX314 in multiple billion-dollar eye care markets. Yesterday, at Regenexx BIO, we recognized Rare Disease Day as we brought focus to this event and sought to generate change for the more than 300 million people worldwide living with a rare disease, their families, and caregivers by participating in a number of awareness and stakeholder engagement exercises. Our 2021 momentum has continued in this new year with a number of recent announcements that we believe raise the profile of our pipeline of AAV therapeutic for rare diseases. For instance, we made significant progress advancing RGX202, our gene therapy for the treatment of Duchenne. Importantly, RGX202 is our first homegrown program leveraging our proprietary NAV AAV8 vector to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-terminal domain of dystrophin. We believe that RGX202 has the potential to address the limitations of other treatment approaches for patients suffering from this severe degenerative disease. With the recent clearance of our investigational new drug application, we're excited to get our clinical trial started, which we expect to take place in the first half of this year. Today, we also announced that the FDA has granted rare pediatric disease designation for RGX202, which makes this program eligible for obtaining a priority review voucher in the future. Last month, we presented positive interim data at the World Symposium for RGX121 being developed for the treatment of Hunter syndrome and RGX111 for the treatment of Hurler syndrome. We believe the data updates highlighted the potential of both programs to alter the course of these debilitating neurodegenerative diseases and deliver improved patient outcomes. As you may know, we have moved into and begun utilizing our new headquarters building in Rockville, Maryland that has our internal GMP facility located within our headquarters. This facility is on track to be fully operational in the first half of 2022 and is expected to allow for the production of NAV vectors that scales up to 2,000 liters. Importantly, with the new headquarters and CGMP manufacturing facility, we are continuing to expand our capabilities from basic research and development to commercial scale infrastructure. As a result of this and all of our achievements, we're excited to be introducing a new arm of the Regenexx Biostrategy called 5x25. that will be a clear and definable plan to advance AAV therapeutics. With a number of license and collaboration agreements in place, as well as a growing internal pipeline, the purpose of 5x25 is to identify the key programs that treat very high unmet needs in areas where we, our partners and licensees, can use our NAV technology platform to develop and potentially commercialize AAV therapeutics as soon as possible. We believe this will help us focus as an organization on key value creating assets where we have the expertise to develop and enable the development of these programs in an efficient way. Specifically, we intend to progress five AAV therapeutics from our internal pipeline and licensed programs into pivotal stage or commercial products by 2025. The leading candidates to meet our five by 25 strategy include our internal programs such as RGX314 for the treatment of wet AMD and diabetic retinopathy, RGX202 for the treatment of Duchenne, and RGX121 for the treatment of Hunter syndrome. But in addition, we will draw from other programs that we plan to advance internally into development and programs being developed through our NAV technology licensees to achieve this strategic goal. What this signifies for me is that we're steering Regenexx Bio in the direction of supporting more late-stage development and commercialization of AAV therapeutics. I view this as a natural evolution for the company that has been foundational in the progress in the field of AAV therapeutics and has made over 10 plus years of foundational commitment. With that, I'd like to turn the call over to Steve. He's going to go into greater detail about our internal programs. Steve?
spk08: Thanks, Ken. I'll begin with an update on RGX314, which is being developed in collaboration with AbbVie to treat multiple ocular indications, including wet AMD and diabetic retinopathy. RGX314 uses the NAV AAV8 vector to deliver a gene encoding a therapeutic antibody fragment to inhibit vascular endothelial growth factor, or VEGF. Wet AMD is the leading cause of vision loss in people over 60, affecting more than 2 million patients in the U.S., Europe, and Japan. The current standard of care for wet AMD is anti-VEGF treatments, which require patients to receive injections into the eye every 4 to 12 weeks for the duration of the disease. Real-world evidence shows that patients with wet AMD are severely undertreated due to the unsustainable treatment burden of these frequent injections required with currently approved anti-VEGF therapies. As a result, the majority of wet AMD patients experience significant vision loss over time. RGX314 is being developed as a one-time treatment for wet AMD that have the potential to reduce the frequency of anti-VEGF treatments and preserve vision for wet AMD patients. In our Phase I-II clinical trial of RGX314 for the treatment of wet AMD, using the subretinal delivery approach and its long-term follow-up study, we have observed a durable treatment effect over three years, including mean improvement in vision and stable retinal thickness and reduction in anti-VEGF treatment burden. We believe RGX314 represents a significant potential advancement for the treatment of wet AMD. We continue to enroll patients in the atmosphere trial, the first of two pivotal trials to evaluate the efficacy and safety of RGX314 in patients with wet AMD using the subretinal delivery approach. We also recently announced in January the initiation of the ASCENT trial, our second of two pivotal trials evaluating the efficacy and safety of subretinal delivery of RGX314 in patients with wet AMD. Importantly, the ASCENT trial is the first trial to be initiated under our eye-care collaboration agreement with AFI. These two trials are expected to support BLA submission for RGS314 in 2024. We are also developing RGS314 using an in-office superchoroidal delivery approach. In November 2021, we presented interim six-month data from cohort two of the Phase II AVA trial at the American Academy of Ophthalmology meeting. The data presented continues to demonstrate evidence of the emerging clinical profile of RGX314, with patients in cohort 2 showing stable visual acuity and retinal thickness, as well as a 72% reduction in anti-VEGF treatment burden compared to the mean annualized injection rate during the 12 months prior to receiving RGX314. Looking at the safety profile across all cohorts, As of November 4th, 2021, RGS 314 was reported to be well-tolerated in 50 patients from cohorts one to three with no drug-related serious adverse events. Mild intraocular inflammation was observed on slurt lamp examination at similar incidents across both levels, those levels in cohorts one and two, with four out of 15 patients in cohort one and three out of 15 patients in cohort two and resolve quickly with topical corticosteroids. We're also pleased to announce the completion of enrollment in Cohort 4 and the expected completion of Cohort 5 in the first half of 2022. Cohorts 4 and 5 are evaluating RGX314 at a third dose level of 1E12 genome copies per eye, and we look forward to sharing additional data from these cohorts. Moving to RGX314 for the treatment of diabetic retinopathy, or DR. DR is a complication of diabetes and is the leading cause of blindness in adults between the age of 24 to 75 worldwide. An estimated 27 million patients are affected by this debilitating disease worldwide, making it a large opportunity for Regenexx Bio. Unlike what AMD, DR does not present itself to caregivers with a set of acute morbidities early on. Instead, it is a progressive disease, and while a large proportion of DR patients develop vision-threatening complications, including diabetic macular edema, or DME, and neovascularization that can lead to blindness, many with this condition do not receive anti-VEGF treatment. a proven therapy to reduce the risk of developing these vision-threatening complications, and that's because of the unsustainable treatment burden required with today's available treatments. A product profile like RGX314's that has the potential to be a one-time in-office treatment could potentially overcome this hurdle and provide an important therapy for patients with diabetic retinopathy. We recently presented six-month data from our phase two altitude trial at the Angiogenesis Conference in February that demonstrated a clinically meaningful, that is, an at least two-step improvement from baseline on the diabetic retinopathy severity scale, or DRSS, after a single RGX314 administration in 47% of the 15 patients treated in cohort one compared to zero percent of patients in the observational control. Importantly, this was an increase from the 33 percent observed at three months. We are encouraged by what we are seeing at this stage. The data demonstrate comparability as well, using the same endpoint to the outcome seen in the other trials that were the basis of approval for the current approved anti-VEGF treatments for DR. Furthermore, as of January 2022, RGX314 was reported to be well-tolerated in the 15 patients dosed with RGX314 in cohort one with no drug-related SAEs and no intraocular inflammation observed. Shifting to our rare disease portfolio, our team has made significant progress advancing RGX202 our potential one-time gene therapy for the treatment of Duchenne. We are developing RGX202 to be a highly differentiated product and have designed it to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-terminal or CT domain found in naturally occurring dystrophin. In preclinical studies, the presence of the CT domain has been shown to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice models. Additional design features, including codon optimization and reduced CPG content, have the potential to improve gene expression, increase translational efficiency, and reduce immunogenicity. is designed to support the delivery and targeted expression of genes throughout the skeletal and heart muscle using our NAVAV8 vector and a well-characterized muscle-specific promoter, SPC512. This product has now received both orphan and rare pediatric disease designation, which mark important milestones and acknowledgment of the need for new treatment options for patients with Duchenne. In January, we announced our IND was cleared by the FDA, and we are now on track to initiate our Phase 1-2 Affinity Duchenne trial in the first half of the year. We provided other key updates to our rare genetic disease portfolio at this year's World Symposium, highlighting Phase 1-2 data for both RGX121 and RGX111, are one-time gene therapies for the treatment of MPS2, or Hunter syndrome, and severe MPS1, or Hurler syndrome. For RGX121, we presented updated data from all three cohorts. Importantly, we observed dose-dependent reductions in CSF biomarkers with cohort 3 patients approaching normal levels of the D2S6 biomarker, along with demonstration of meaningful improvements in neurodevelopmental function and caregiver-reported outcomes, observed up to two years after RGX121 administration. For RGX111, data at world was our first reveal, and while the patient numbers are small, we did observe emerging evidence of CSF biomarker activity along with neurodevelopmental assessments indicating an encouraging potential CMS profile. We plan to enroll additional patients in cohort two, and in both updates as of December 20, 2021, RGX-121 and RGX-111 were well tolerated with no drug-related SAEs. Overall, we have already made significant progress in 2022, and we look forward to providing further updates throughout the year. Now, I'll turn the call back over to Ken.
spk03: Thanks, Steve, for the really good updates, and especially to the team for the progress over the past quarter and this past year. Let's see. Before turning the call over to Vit, I wanted to circle back to discuss our manufacturing a bit more and its importance to our overall strategy. We have over 21,000 square feet of our corporate headquarters that's dedicated to our in-house GLP pilot plans, advanced analytic labs, multiple 2,000-liter bioreactor suites for CGMP manufacturing of bulk drug substance, and a new flexible and state-of-the-art fill-finish suite to support all of our multiple programs focused. And we've been talking about our investment in an in-house GMP facility is an important next step to have better control over our manufacturing process and supply. But specifically, I want to highlight that there's a real close alignment that exists between our research team and our manufacturing team. We believe that this is a key differentiator for GenX-Bio in two ways. First, it allows for us to move quickly from candidate selection to production of clinical grade material, which supports accelerating the early development of our AAV therapeutics. And second, we believe that our approach focuses early on product quality and process control, which lessens the need for changes during clinical development to enable efficient transition from clinical trials into that commercial readiness. And another piece to add is that our manufacturing team has also formulated AAV therapeutics to be used in a number of different innovative delivery device solutions and techniques, including the pioneering work in clinical use of suprachoroidal and inter-cisternal interventions. So we believe being a leader in innovative device delivery of AAV therapeutics is a distinguishing competency of Regenexx BIO as we progress our new 5 by 25 strategy. With that, I will turn the call over to Vit to review our financial guidance.
spk07: Thank you, Mr. President. Regenexx BIO ended the quarter and year on December 31st, 2021, with cash cash equivalents, and marketable securities totaling $849.3 million, compared to $522.5 million as of December 31st, 2020. The increase was primarily the result of the $370 million upfront payment recognized upon the closing of the AbbVie Eye Care collaboration and $216.1 million of aggregate net proceeds received from our follow-on public offering of common stock completed in January 2021. The increase was partially offset by cash used to fund operating activities and capital expenditures during the year-ended December 31st, 2021. Based on our current operating plan, we expect a balance in cash, cash equivalents, and marketable securities of $849.3 million as of December 31st 2021 to fund our operations, including the completion of our internal manufacturing capabilities and clinical advancement of our product candidates into 2025. With that, I will turn the State of Regenexx by-way address back to President Mills to provide final thoughts.
spk03: President Mills Much appreciated, as always, Vit, and thanks for the highlights of the financial position of the company. So as you've heard from Steve and Vit in our update today, we've had important progress across our pipeline of AAV therapeutics. Furthermore, we look forward to steering in the direction of supporting more late-stage development and commercialization of AAV therapeutics through our 5 by 25 strategy and utilizing our internal GMP facility to support the acceleration and the development of our AAV therapeutics. We're confident that we have the right team in place across all key business levels, including science, manufacturing, and commercial. We believe that our science has been validated both by our own growing body of clinical data as well as key collaborations like our eye care collaboration with AbbVie and the numerous other license agreements with leading biotechnology companies who use our nav technology. We believe truly that we have the end-to-end capabilities in place to support our plans to efficiently and successfully advance our exciting pipeline. And as Vit noted, we have capital in a balance sheet to support our strategy. I'm more confident than ever in our science and our people to support our ability to develop AAV therapeutics for diseases that have the potential to significantly impact patients' lives. We look forward to continued progress in the coming year. I'm particularly excited about advancing our new 5x25 strategy within the company and progressing our eye care collaboration with AbbVie and dosing the first participants in our RGX202 clinical trial for the treatment of Duchenne. For now, I'll turn the call over to the operator for questions.
spk01: Thank you. At this time, if you would like to ask a question, please press star 1 on your telephone keypad. Again, to ask a question, simply press star 1 on your telephone keypad. Your first question is from the line of Gina Wong from Barclays. Your line is now open.
spk00: Hi. Thanks for taking the question. This is Tong for Gina. Thanks for the update as well. We have three questions. The first question is about the bridging study following your comment on manufacturing. Just want to get a bit more color on current status of the study and estimate the time of completion. and also do plan to present data sometime later this year. The second one is for 315 supercloto wet AMD study, cohort three. As we know, the total dose was the same as cohort two, but delivered only by one injection versus two injections in cohort two. Is there any reason to expect one could potentially lead to better visual acuity or better safety? And lastly, for the Duxin trial design, how should we think about the patient baseline, age, an assay score, and what would be the initial dose? Thank you.
spk03: Thanks, Tong, for the question. Steve, I'll start with the bridging study, and maybe you can follow up on the two additional questions. I think, Tong, with respect to the bridging study, it's part of our overall pivotal program, which we announced last year with respect to providing guidance on a BLA date of 2024. We're right now operating all three studies in parallel and enrollment is ongoing in all the studies atmosphere as well as the bridging study. We don't have any additional guidance beyond that. All of this is on track and we continue to including on the Other side of the announced collaboration with AbbVie with respect to the eye care collaboration continue to support the 2024 plan for BLA for the subretinal approach. So that's our answer to that question. With respect to superchoroidal 314, Steve, do you want to take that one?
spk08: Sure. So as you pointed out, cohort three is a single injection of 100 microliters The same total dose, though, in terms of GC per eye as cohort two, and cohort two had two separate injections of each 100 microliters. Our plan is that one injection is better than two from an overall feasibility and patient and doctor delivery standpoint. We have no reason to expect one approach would be better than another, though on a safety tolerability standpoint, certainly a single injection is much preferred. And, you know, I'll take that opportunity to say all our other cohorts are, going forward, are with the single injection with 100 microliters in both our AVH study and our altitude supercroidal delivery study. Regarding And then you also asked about when we could have the status or when we could have results. We're excited about the agreement we have with the FDA from the end of Phase 2 from our overall bridging plan. As Ken mentioned, we're very excited about our global partnership with AbbVie, so we're very excited with collaborating closely with Abby on talking about our future plans for other disclosures, but we don't have any other updates to give in terms of that program, in terms of what we've already discussed. Your third question on our Affinity Duchenne study, so as as we've disclosed, we're starting with 1E14 GC per kg, and this is a dose that we're excited about based on our overall preclinical package and the findings that we have there, where, of course, in one-time gene therapy for Duchenne, it's important to start at a dose that you believe you will see some effect and potential for benefit. So we're excited about starting that study the first half of this year.
spk03: Yes, Steve, I think the question was to do with inclusion criteria. Tong, as we're starting up the study, we have disclosed that we're going to be focused on males in the age range of, I think it's 4 to 11, with ambulatory function, including mutations in the DMD gene that are between certain exons, and we will be excluding patients on the basis of anti-AAV antibodies. So that's some flavor for the inclusion and demographic criteria for the study. Thanks for the question.
spk00: Thank you.
spk01: Thank you. And your next question comes from the line of Alex from Bank of America. Your line is now open.
spk11: Hey, guys. Thanks for taking our questions. Just a couple from us. First, in the supracoroidal DR patient that had a sustained four-step improvement, are there any characteristics unique to that patient that you can point to for the outsized response? And given the anticipated pace of enrollment for a couple of the higher-dose cohorts in the first half of this year, is it safe to assume we could see three-month data from both the wet AMD and DR supracoroidal studies maybe later this year, or would you prefer to wait for a more mature six-month data update. And then just on your 5x25 plan and use of cash going forward, good to see runway into 2025. I guess, would you consider maybe bringing in any external technologies to supplement the NAV platform, or is the plan really to support the later stage development and maybe add to it de novo? Thanks.
spk03: Thanks, Alex. Steve, do you want to jump on the 314DR question?
spk08: Sure. So, Alex, you pointed out the four-step improver that we included in our presentation from cohort one. And the nice aspect of the diabetic retinopathy severity score is the ability to actually see the evidence of disease and what ultimately progresses and eventually leads to bad outcomes for these patients. So we don't go into, you know, the granularity of the specific changes, but the consistency that we see across the data set in terms of being able to see a significant a meaningful proportion of patients able to achieve at least two-step improvement and also have some cases where you get more than two-step. The more step changes you have, the more evidence, the stronger the improvements are in the underlying evidence of disease when you actually look at the retinal disease. So we're excited that we have... cohort one, that we have a six-month data and that we can continue to follow those patients longer. Similar to the answer to the prior question, we're not in a position to give specifics on when we'd have data coming out from later cohorts, but we and our partner, AbbVie, are excited about advancing not only with longer-term follow-up for cohort one, but also being able to do the same at a higher dose. in cohorts two and three where we also get to look at NAB negative as well as NAB positive patients.
spk03: And on the five by 25 questions, Alec, I think, yeah, I hope that, you know, this strategy emphasizes several points. One is absolutely our focus on our medical and our operational including our GMP capabilities to enable the development of current and emerging late-stage programs towards commercialization is absolutely a focus. I think it also places emphasis on our research and early development team to bring forward new innovations and connect with the types of things we've evidenced that we can do in the past, bring forward new biology, bring forward new focus for AAV therapeutics on targets, and make that up potentially you know, either organically or in partnership with new devices and new routes of administration. So, you know, I think the next few years are for us about getting into later stages of development, establishing the company, having capabilities for late-stage development as well as commercialization, but bringing forward that continued innovation that's been there all along, in my view. And, you know, as you alluded to, and I think we feel that we're in a strong financial position to be able to make those types of investments on an end-to-end basis through 2025. And, you know, with evidence of a BLA in 2024 and other things emerging, I feel really, you know, encouraged that we're in a really good place for shareholders and stakeholders.
spk01: Thank you. Thank you. Your next question comes from the line of Vikram Paru. It's from Mark and Stanley. Is that open?
spk05: Thanks for taking our call. This is Gospel on Fort Bikram. So we have one question. So for the subrocoroidal delivery of IGX314, you have observed some intraocular inflammation in wet AMD, but not in DR. Do you have a current hypothesis as to what could be driving this difference?
spk03: Thanks, Gospel. Steve, would you like to provide an answer here?
spk08: Yes, I can. Thanks for the question. Keeping in mind it's relatively small numbers across the different groups, but as you pointed out, we haven't seen any intraocular inflammation in cohort one in the DR patient population, and we see low rates and easily managed rates in the data that we've presented for the wet AMD population. We don't conjecture that there's directionally a greater likelihood to have an inflammatory response. Some have wondered, could DR patients be more prone to an inflammatory response? There's no evidence of that from our historical epidemiology and all the interventions that exist with biologics that have been used to treat both wet AMD and DR. But certainly from our data, there continues to be no suggestion of an increased risk. So we're just very glad to see across both platforms, the wet AMD patient population and the DR population, that we don't see any signs of concerning inflammation. And that's particularly key since this is in the backdrop of no prophylactic steroids, unlike other programs out there. So we're very pleased with the overall safety and tolerability that we're seeing to date in superchoroidal in-office delivery for both wet AMD and DR. Thanks, Gospel. Thank you.
spk01: Thank you. Your next question comes from the line of Dan Leon from Raymond James. Your line is now open.
spk10: Thanks for taking the questions. Just two simple ones from me. Regarding the ABA study and next follow-up on the clinical data, is it possible that we're going to get the 12-month data from cohort one during back half of 22? And would it be possible to get six-month data from cohorts two or three before year end? And then the second question I have is, could you just remind us of how the economics work now that you have this SEND study open with 314 and when some of the costs of the trial and program for atmosphere and the SEND transfer to AbbVie from your P&L. Thanks.
spk03: Thanks, Dane. So I think as we've talked about with everyone since the announcement and closing of the AbbVie collaboration, we have a partner here in AbbVie, and we've been aligning with them and sort of setting in place a lot of important structures for us to continue to leverage one another's experience and expertise. to accelerate as quickly as possible all the work that's going on around RGX314. In terms of plans for updates, while we don't have any specific guidance right now, what we are saying is that we continue to use the intervals that we've been updating on with respect to the program. So in the case of WET-AMD, we view that things at the six-month and 12-month time points for cohorts are, you know, meaningful and contributory in terms of making decisions about programs. As well, on the diabetic retinopathy side, you know, we've seen evidence of intervals on the order of three months and six months. We plan to continue to use those as mileposts to establish communication with all stakeholders, including investors, and we plan to continue to do that at major medical conferences with investigators who are involved in our studies making presentations. So I think that what we're able to do right now is show everyone where we are with respect to enrollment and talk about the fact that, you know, we look forward to in the future being at medical conferences with similar intervals of updates as we have in the past. And as we get closer to those dates like we did with respect to angiogenesis just I think a few weeks ago, you know, then we're able to get more clarity when things are actually accepted by these, you know, submissions of these investigators for these presentations. And with respect to the economics, Dane, thanks for bringing that up because, you know, it's something that starts this year with respect to transition of costs, and I think we said out of the gate that, you know, this was a partnership particularly in the U.S. You know, we have economics of sort of 50-50 profit share, and we are going to continue to be involved in the execution of clinical trials as well as things like clinical supply and ultimately commercial supply, especially in the U.S. But this is also a year in 2022 where we start to see the impact of ex-U.S. costs as well as transition overall in cost sharing with respect to Regenexx and AbbVie. So, you know, I would say, you know, and I think it's even evident in the financials for 2021, we were still bearing, of course, most of the costs, you know, because we announced the closing of the deal in November, although obviously our balance sheet was strengthened by the one-time upfront payment of $370 million. This is a year where transition of costs certainly begin to occur where the cost sharing starts to set in. And I think what I remember about the deal on the initial side is that that continues all the way through 2023 until we get to a steady state that I think is, you know, fairly representative of where geographically AbbVie has a responsibility and also the fact that we have sort of 50% of the profit and commercialization involvement on the U.S. side. So I think we're, you know, going from paying for mostly everything in 2021 to by the time we get to 2023, something that's more representative of the sort of global geographic share in terms of commercial control.
spk07: Thank you.
spk03: Thanks for the question. Hope you're well.
spk01: Thank you. Your next question comes from the line of Manny from SVD Learing. Your line is now open.
spk02: Yes, thanks for taking the question. Regarding 5 by 25, just as we think about modeling it and timing, obviously there's the pretty straightforward way to think about what the metrics are to consider in 2025, but can you give us a sense of how to think about ramp of investments and specific events that you think we should be focused on in the interim between here and 2025 in terms of timing and moving certain things in the clinic, the late stages, and tempo of relevant late-stage data sets, et cetera?
spk03: Yeah, Mani, thanks for the question and the focus on that strategy. I think We've outlined and identified that we view that, you know, RGX314 is obviously a major contributor to the 5x25 strategy. We're, you know, looking at obviously the continuation of the pivotal program for subretinal and, you know, have given guidance for a BLA in 2024. I think that communicates that, you know, this is obviously a lead program that we're looking to make that transition into, you know, late stages of development and beyond and from 24 into 25. Superchoroidal, you know, are phase two studies that are being run both in wet AMD as well as diabetic retinopathy, and we view the kind of runway in front of those programs as having, you know, the types of experiences and decisions that we had when we were sort of in the phase two stages of, you know, the subretinal program. So seeing those transition into later stages of development would be considered to be options for sort of a base plan of achieving metrics. And RGX121 is already obviously clinical phase. We've talked about that, you know, we've recently shown data that we believe is supportive of really good outcomes for some of the children that have enrolled in these studies. We've done significant dose ranging in the clinical trials. We've seen evidence of biomarker changes that are dose dependent. We've seen correlations to outcomes when it comes to cognition and other things that are both measurable and important. So, you know, we're feeling really good about clinical data there, putting us on track to make advancements with respect to 121. And frankly, RGX202 as a program, you know, we continue to be really encouraged by the science we've seen preclinically, the safe to proceed, and capabilities that we have in place, especially on the quality of product manufacturing. we are giving guidance to dosing, you know, first patients in the beginning of this year, and we have in mind that RGX202 is going to be a contributor to the 5x25 strategy, which would mean that it would be a program that would be, you know, in our view, eligible and consistent with getting into that range of pivotal stage or, you know, commercial through 2025. So, you know, those are things that are in focus today. I think, obviously, there are, you know, a number of partnered programs or licensed programs that are, you know, in earlier stages or even, you know, heading into later stages of development that we think could become a part of the metrics that meet that. And we have things that we think we could be bringing forward scientifically or through partnership that may meet that well. You know, we're putting forward what we think is an important, meaningful, you know, strategy that also has a sense of urgency about it. One that I think is A strategy that, as a company, I think it's unique. The capabilities we have, the experiences, the position that we are in with respect to different stages of assets, to be able to put ourselves on the line for achieving metrics like that, I think is a meaningful and important step for us as a company. I hope that touches on a few different elements that we have in mind for achieving that strategy, although You know, I think there are a number of different ways to compile a positive outcome here, and we want to help as many patients as possible.
spk02: No, that was really very useful.
spk03: Thanks, Monique.
spk01: Thank you so much. And your next question comes from the line of Luca E.C. from RBC. Your line is now open.
spk04: Oh, great. Thanks for taking the question. This is Lisa for Luca. Two from us. Firstly, on the Phase III wet AMD, the pivotal trial, you know, I believe this Phase III for wet AMD is really one of the largest ever to use subretinal injection as a route of administration. And given this is a surgical procedure, I'm just wondering if you can provide us any color on what efforts you have employed to maintain consistency from site to site in order to help limit any variability. And my second question has to do with the bridging studies. I know your bridging study is powered to show non-inferiority on protein concentration as the primary endpoint, but we also see a few secondary endpoints listed, including BCVA. Just wondering if you could also provide more color on whether or not meeting non-inferiority on the secondary endpoints will also be required by the regulators here. Thank you.
spk03: Thanks, Lisa. Steve, you want to? answer both of those questions?
spk08: Sure. Hi, Lisa. Thanks for those two questions. So the first one, yeah, we're really proud of the scale, so to speak, in terms of both the size of the trial and overall advancement for the field in terms of subretinal delivery of gene therapy for a big indication like wet AMD. To your point, one issue is scalability in terms of surgeons and actually training on this, and this is something that we have a lot of experience on over the years, given that we advance first through our Phase 1-2 study and those 42 patients. And as with that study, we carry forward what you might expect a surgical trainer or liaison team that trains new surgeons in performing this procedure. And as we talked about during phase one, two, what we're seeing in action now that we're into two pivotal studies now, atmosphere and ascent, is we actually get to see this real time in terms of training additional surgeons. And As we anticipated, we're seeing that it's fairly straightforward because these are retina specialists and retina surgeons who have experience doing a lot more complicated procedures than this procedure of a standard small-gauge vitrectomy and injection of the gene therapy subretinally. It's something that we're glad to be actually implementing on and actually executing. And we're basically following the same process of training new surgeons and following these, but as anticipated, we're not seeing any issues with new surgeons coming online for this. The second question on the bridging study So we reached agreement with the FDA at our end of phase two on our overall plan. We have primary endpoint looking at protein to show general comparability. The reality is, as we already know, with that number of patients, 15 in a active comparison type approach, there really isn't power to differentiate or show non-inferiority on those other types of anatomic or functional endpoints, but we do obviously measure them and take advantage of having that to continue to learn more about and gather more data. But I think the main answer to your question is the study is empowered to really look at those in any kind of definitive way, so we don't see that as a key aspect.
spk04: Thanks. Very helpful. Thanks for taking the questions.
spk03: Thanks, Lisa.
spk01: Thank you. And your next question comes from the line of Andreas Argyris from Webb Bush. Your line is still open.
spk06: Thanks for taking our question. Just a quick one from us, and apologies if it was asked previously. We had a little connection issue. But so based on the subretinal 314 data, showing that patients with baseline MABS to AAV8 did not impact transduction. How do you expect, or is there any read-through to Cohort 3, the data that we're going to see from AAV8? Thanks.
spk03: Yeah, Steve, you're on it. Okay.
spk08: All right, thanks. So for subretinol, as you mentioned, we – did not see any impact of preexisting neutralizing antibodies to AAV8, nor did we expect to because there's so much known about subretinal delivery, and that's why that's been historically the gold standard, including the relative immune privilege status of the subretinal space. But we still measured a baseline NAP status and confirmed in our Phase I-II that Patients who had preexisting naps did just as well from a safety and efficacy standpoint as patients who were nap negative. For supracoroidal delivery, we're very encouraged that preclinically we don't see inflammation in any type of response, and that's what allowed us to feel confident to go into dose ranging without prophylactic steroids. We did intentionally set up different cohorts so that we could answer the question you're asking of whether, like subretinal delivery, can we deliver RGX314 to the suprachoroidal space and whether neutralizing antibodies matter or not when delivering to that space. So that's why we're excited to be able to look at that in both cohort two compared to cohort three, but then also at the third dose level, cohort four, which we completed dosing in, and cohort five, the NAP positive corollary of cohort four. So we look forward to answering that question.
spk06: Great. Thanks for the call.
spk01: Thank you. There are no further questions at this time. I would now like to turn back the call over to Ken Mills to make any closing remarks.
spk03: Thanks, Operator. I just wanted to say thanks to everyone again for joining us today, and I hope that all of you have a great weekend. We look forward to seeing you all soon. Thanks.
spk01: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.
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