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spk01: look 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 BIOS annual report on Form 10-K for the full year ended December 31, 2020, and comparable risk factors sections 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 9th, 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 Mills.
spk05: Thank you, Patrick. Good afternoon, everyone. Thanks for joining us. I hope you're all having a safe and nice summer. On today's call, we'll begin with a recap of recent business highlights. Steve will provide an update on our clinical programs, and Vit will provide an overview of financial results for the second quarter of 2021. At the end of the call, we'll open the line for questions. I'm pleased to report that 2021 has been productive for Regenexx Bio. We've made important progress across our clinical development programs and anticipate a busy second half of 2021. Our dedicated team remains focused on bringing the therapeutic potential of our pipeline programs to patients in need, and we look forward to continuing our leadership in AAV-based gene therapy development and manufacturing. Our focus this year continues to be on execution across our pipeline programs. Our clinical programs evaluating RGX314 for the treatment of wet AMD and diabetic retinopathy have expanded and continue to be on track. The first trial in our pivotal program evaluating subretinal delivery of RGX314 in patients with wet AMD, Atmosphere, continues to enroll patients, and our second pivotal trial is expected to initiate in the fourth quarter of 2021. In addition, we continue to advance our two phase two trials evaluating the superchoroidal delivery of RGX314 using the SCS microinjector. The first interim data from cohort one of AVA, our phase two trial in wet AMD, will be presented at the Retina Society 54th Annual Scientific Meeting that begins in September in Chicago, Illinois. We're on track to report initial data in diabetic retinopathy later this year in the fourth quarter. For RGS121, our one-time gene therapy for the treatment of MPS2 or Hunter syndrome, we were pleased to share additional positive interim data from our clinical program at ASGCT in May. We continue to drive this program forward, enrolling additional patients at a higher dose and enrolling pediatric patients over the age of five years old. Finally, our work on RGX202 also continues. We now expect to file an IND for the treatment of Duchenne muscular dystrophy by the end of this year. I will now turn the call over to Steve for an even more detailed clinical and regulatory update.
spk09: Thanks, Ken. As Ken mentioned, our pivotal program evaluating the subretinal delivery of RGX314 for the treatment of wet AMD continues to be on track. We are enrolling patients in the Atmosphere, the first of two planned PIDRAL trials expected to support a VLA in 2024. As a reminder, Atmosphere is expected to enroll approximately 300 patients and evaluates RJX314 compared to repeated Ranavizumab intraocular injections, a standard treatment option for patients with wet AMD. We also expect to initiate the second of two randomized well-controlled clinical trials as part of our pivotal program in the fourth quarter of 2021, and we look forward to sharing additional details. Beyond our pivotal program for RGX314, we've made progress in our two Phase II trials evaluating RGX314 when delivered to the suprachoroidal space. We have completed dosing of patients in the third cohort of our Phase II trial for the treatment of wet AMD, known as AV8. This is the cohort of patients that received the same dose of RGX314 as patients in the second cohort, that is 5E11 genome copies per eye. But the patients in the third cohort are neutralizing antibody or NAB positive at entry. This may provide us additional information about the effects of RGX314 in NAB positive patients. potentially broadening the patient population that could be treated with this in-office delivery approach. I am also pleased to announce that we plan to present initial data from cohort one at the lower dose of 2.5 E11 GZ per eye at the Retina Society 54th Annual Scientific Meeting, which runs from September 29th to October 2nd. Additionally, we plan to report initial data from cohort two in the fourth cohort sorry, the fourth quarter of 2021. For altitude, our phase two trial to evaluate RGX314, suprachoroidal delivery in patients with diabetic retinopathy, we have completed enrollment of cohort one, and we expect to report initial data in the fourth quarter of 2021. We have also begun enrolling patients in cohort two at a higher dose, and are pleased to announce that we will be expanding into a third cohort of patients in this trial. As with AV8, cohort three of altitude will evaluate efficacy, safety, and tolerability in up to 20 patients who are NAV positive. And the same dose evaluated in cohort two will be evaluated in cohort three. As in previous cohorts, patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX314. In addition, we are making great strides in our rare disease portfolio and are well positioned to provide key clinical updates in the second half of 2021 and beyond. From our ongoing Phase 1-2 trial of RGX121 in MPS II patients up to five years old, we were pleased to share additional positive interim data from cohorts one and two at ASGCT in mid-May. As reported, RGX121 continued to be well-tolerated with no drug-related serious adverse events. Biomarkers and measures of neurodevelopmental function indicated CNS activity following RGX121 administration, with continued evidence of systemic enzyme expression and biomarker activity observed. We also began dosing patients in cohort three at an increased dose level of 2E11 GC per gram brain mass in the second quarter of 2021. We continue to enroll patients in this cohort. Our phase one two trial of RGX121 for the treatment of MPS2 in pediatric patients over the age of five years old also continues to enroll patients. and we look forward to keeping you updated across both of our RGX121 Phase 1-2 trials. Enrollment is ongoing in Cohort 2 of our Phase 1-2 trial of RGX111 for the treatment of MPS1 at a dose of 5E10 GC per gram brain mass as we are focused on realizing the therapeutic potential of RGX111 for MPS1 patients in need. Our team is preparing to submit the IND for RGX202, a potential one-time gene therapy for the treatment of Duchenne. We plan to submit this IND package by the end of 2021. Lastly, we remain on track to provide program updates for RGX181 for the treatment of CLN2 disease and RGX381 for the treatment of ocular manifestations of CLN2 disease by the end of 2021. Our team has made significant progress in the first half of this year, and we look forward to driving this momentum throughout the second half of 2021. With that, I turn the call back over to Ken.
spk05: Thanks for the great overview, Steve. I'm excited to share just a few more business updates In July, we officially moved into our new headquarters in Rockville, Maryland. It's been tremendous to watch this lab and office space come online, and I'm glad to have our team move into this space. The headquarters includes a GMP facility, which is expected to allow for production of NAV vectors that scales up to 2,000 liters, and we're focused on integrating our capabilities to ensure adequate supply is available across all of our programs. We anticipate that the manufacturing facility in this space will be fully operational starting in the first half of 2022. Our proprietary NAV technology platform also continues to be the foundation of the development of gene therapies outside of the walls of Regenexx BIO. Our licensee partners have made significant advancements in their respective programs utilizing NAV AAV delivery, with several in late stages of development. Our partners at Novartis have reported they've treated more than 1,400 patients with IV intravenous sulgensma, which uses the NAV-AAV9 for the treatment of SMA. We've also been pleased to see the initiation of Novartis' new pivotal study of intrathecal delivery in patients with type 2 SMA. In addition, Ultragenyx recently reported plans to begin dosing patients in two pivotal studies, for DTX301 for the treatment of OTC deficiency, and DTX401 for the treatment of GSD1A. We also note the reinitiation by Astellas of the pivotal trial for AT132 for the treatment of X-linked myotubular myopathy. All of these candidates use our NAV AAV8 vector. Coreleaf Therapeutics is a company that we helped form in 2020. And in June 2021, CoreLeave announced definitive agreement for Unicure to acquire CoreLeave in its lead program for the treatment of temporal lobe epilepsy, now known as AMT260. This utilizes Regenexx Bio's NAV-AEV9 vectors. This transaction closed in July of 2021. Under the license and collaboration agreement, Regenexx Bio received equity in core leaves and is eligible to receive milestones as well as royalties on net sales of AMT-260. As a result of the acquisition, Regenexx Bio received a portion of the 46.3 million euros in upfront cash Unicure paid to acquire core leaves, and is eligible to receive a portion of the over 200 million in additional milestones, 200 million euros of additional milestones that may be paid to CoreLeaf shareholders by Unicure. We look forward to the continued collaboration with all of our licensee partners to bring AAV gene therapies forward using our proprietary NAV technology platform to patients in need. With that, I'd like to turn the call over to Vit for a review of our financials.
spk10: Thank you, Ken. Regenexx Bio ended the quarter on June 30th, 2021 with cash, cash equivalents, and marketable securities totaling $593 million compared to $522.5 million as of December 31st, 2020. The increase was primarily due to the $216.1 million of aggregate net proceeds received from our follow-on public offering of common stock completed in January 2021, including the full exercise of the underwriter's option to purchase additional shares in connection with the offering. The increase was partially offset by net cash used in operating activities of $71 million, cash used to purchase property and equipment of $50.9 million, and Zulgenzimo Royalty's paid healthcare royalty management of $22 million during the six months ended June 30th, 2021. Based on our current operating plan, we expect the balance in cash, cash equivalents, and marketable securities of $593 million as of June 30th, 2021 to fund our operations, including the completion of our internal manufacturing capabilities and clinical advancement of our private candidates into the second half of 2023. With that, I will turn the call back to Ken to provide final thoughts on Anthony Rizzo and Regenexx 5. Thanks, Ben.
spk05: The hard work, experience, and commitment of our entire team has enabled significant progress across our entire gene therapy portfolio. We're focused on building on our momentum from the first half of 2021 to execute on clinical and preclinical development for the remainder of this year and beyond. With that, we'll open up the call operator for questions.
spk03: As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound or hash key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Josh Mitra from BOFA. Your line is now open.
spk06: Hey, guys. This is Alec on for Jeff. Thanks for taking our questions. Just a few from us. Since cohort one from the supercorral study is comparable in terms of the dose level to cohort five from the subretinal study, I guess could you just remind me the thought process behind starting at this dose and whether sort of the bioavailability is expected to be comparable between the two administrative techniques, or could it maybe be a little bit less just in terms of, you know, expectations for the data? As a follow-up to that, I'm just trying to frame the update at the conference in terms of the length of follow-up. Is it safe to say that it could be somewhere in the six-month range, given the study opened about a year ago? Obviously, maybe not enough to reach the 40-week BCVA endpoint. And then just lastly, a quick one. Do you think it would be appropriate to apply read-through to what we might see in the DR update in 4Q, given it's obviously different patient populations? Thanks.
spk05: Thanks, Alec. Steve, would you like to handle this?
spk09: Sure, great. Thanks, Alec, for those questions. So why start cohort one dose level with supracoroidal with the same GC per eye that we had in our phase one, two cohort five? Basically, we had the benefit of a full dose range that we had gone through with the subretinal delivery, plus the overall preclinical package, including GLP tox studies, where we had the ability to start that high and also to be able to go higher. So we felt it was important to already right out of the gate, start with the dose where there could be equipoise of actually being able to look for some type of pharmacodynamic signal. To your second question of how might we think of that translating, I think the reality is these are, and we've always said this, these are different routes of administration. Fortunately, we chose superchoroidal because Like subretinal, it allows us to administer locally where we're, unlike with intravitreal administration, we can give that dose where it spreads close to the target retinal tissue. But it is a different route where you get a broader spread than, say, the more intense transduction in a smaller area that you expect with subretinal delivery. So It's really hard, Alec, to say more than that, and that's why we do the dose ranging with a different route of administration. But here we have the benefit, because of all the experience we have, to be able to start a little higher. As far as the data that we're going to be able to look at at Retina Society and what we're going to be able to come out, again, very consistent with what we've said from the beginning, where in the wet AMD disease setting, we've always felt, even in our subretinal phase 1-2 study, and we've signaled the same in our suprachoroidal wet AMD study, AV8, that six months is a more fulsome time point to really evaluate the key biomarkers that we care about, including functional outcomes. So the typical outcome measures that we've talked about in the past and that we have experience looking at at six months are what we're going to look for and what we'll be able to present at Retina Society. Your question on diabetic retinopathy, yes, you're spot on. That's a different patient population. However, we do have the body of evidence across many different anti-VEGF repeated injection programs that have looked at treatment of different patient populations including diabetic retinopathy as well as wet AMD where there is the general belief of a range of doses that has effect in one disease setting of VEGF-driven retinopathies that by targeting VEGF with similar doses in other VEGF-driven retinopathies that you have the potential to detect the signal. It's just in that patient population where the signal is something different, albeit just as important, it's just that in diabetic retinopathy we have the ability to look at the severity of the underlying diabetic retinopathy and actually grade that and actually see can we improve the diabetic retinopathy severity with one-time administration in the office with RGX314. Operator?
spk03: Next question comes from the line of Jenna Wong from Berkeley. Your line is now open.
spk02: Thank you. I have one question with three parts on RGX314 supercorridor programs. The first one is a clarifying question. Across all the cohorts in AVIET and ATTITUDE trials, is the volume the same for each injection? And my second question is for aviate cohort one data at the Retinal Society. Should we expect meaningful information from the abstract release? And also for the full presentation, will you include the protein level in addition to visual acuity, retinal thickness, and injection frequency data? And third, the last part of the question is you started cohort three for both aviate and attitude. Any concerns on safety since you increased the concentration and also any concern or efficacy since you enrolled the patient with existing neutralizing antibody?
spk05: Hi Gina, this is Ken. I'll start and then maybe Steve can provide more color if needed. In terms of the volume question, and thanks for your questions by the way, especially in August. The 100 microliters is the standard volume that's injected with our suprachoroidal device that we've selected for delivery of RGX314. And that's been the dose volume that we've used in the initial cohorts of both of the studies. When we dose escalated in the AV8 study, the first transition was with Going from 2.5E11 to 5E11 was to go from one single injection of 100 microliters of volume to two separate injections in the same visit. So, in that case, we were using two different injection sites, two different injectors. So, we were technically injecting 200 microliters into those patients. continue to move forward with altitude. We've standardized, though, on the 100 microliter volume for higher concentrations now, and we would expect to continue to do that in cohorts three and cohorts that we would plan to move forward for further study. On the data, I think I heard the back end of your question, maybe not the front end, so we're approaching We're a month or so away from bringing together data with investigator on podium at the Retina Society meeting. Our approach here is similar to, if not identical to, our approaches that we've had on our study of the subretinal data, which is to bring the full package of information that we're collecting from the study forward. And I think Steve mentioned in response to Alex's question that we've always used the cutoff of six months as the time point that's been important to us to collect all the different measures. The things we're measuring are the same as what we've measured in the past when it comes to these outcomes, including safety, of course, and the functional outcomes Steve referred to and protein levels. We haven't done the data cut right now. We'll be transitioning into that in the next you know, 30 to 60 days to prepare for that announcement. And, you know, we'll bring as much data as we can to that podium presentation based on what we have from the clinical study. And the final question was about cohort three. And it had to do with, yeah, safety and efficacy. Steve, do you want to make a comment?
spk09: Sure, I can. Yeah, I can. Jump in there. Hi, Gina. Yeah, so the aspect of increased concentration by being able to go to a single 100 microliter injection that Ken referred to that we're able to do in C3 of AB8 and also in C3, cohort 2 and cohort 3 of altitude whether we have any safety concerns there. We felt comfortable to advance to using that higher concentration in both NAV negative, but then also NAV positive patients based on the data we have, and also the higher concentration data that we have from our preclinical package that was included in our IND. And all of that was what made us feel comfortable to go there. Your second related question was what about efficacy issues of evaluating in NAB-positive patients as we're doing now in both AB8 and we'll be doing in altitude. Here, this is why we do these cohorts. Here again, from the beginning, even before starting the initial cohorts in NAB-negative patients, our plan had always been and we'd always communicated that we were going stepwise. First, looking in NAB negative patients, and these were the first ever studies looking at supracoroidal gene therapy. But now that we have done that at two different doses in the wet AMD population, that's what gave us the comfort to advance there. And this is why we're so excited to make these significant milestones for this space to not only be able to assess NAB-negative patients, but also to look at both safety and efficacy in patients who are NAB-positive.
spk03: Okay, next question comes from the line of Dane Leon from Raymond James. Your line is now open.
spk07: Thank you for taking the questions. I guess the first question for me, when do you think you would consider getting a bilateral study for RGX314, either supracroidal or a subretinal procedure? And then secondly, can you maybe give some color in terms of the idea around DMD, if there's I think originally you had that slated to begin in the mid part of the year. It's now back towards the latter part of the year. Any color there would be appreciated as well. Thank you.
spk05: Sure, Dana. I'll take the second part of that question, which is, you know, for 202, the IND deliverables in the process for sort of finalizing and starting to, you know, author and prepare the IND is what's ongoing right now within the company, and I think we had given guidance at the beginning of the year that we thought we could have that all prepared by mid-year, and what we're seeing is a little bit of change to that into the fourth quarter of this year, but nothing in terms of the process internally that has changed materially for us in terms of getting that IND filed and the study up and running, just been a little bit of adjustment to the original plan based on the work that needed to be done and has been done. Maybe with respect to the bilateral consideration, I'll ask Steve to weigh in there.
spk09: Sure. Hi, Dane. It's a good question. It's actually one we get anecdotally, not surprisingly, from, for example, patients in our Phase I-II subretinal study who've had good success with treatment in one eye and an interest in wouldn't this be great if I could have both my eyes treated. So I'll take each route separately. For subretinal delivery, the benefit of all the experience that we have here, both in terms of the relative immune privilege status of the subretinal space and also the precedent of Luxterna bilateral administration, it does make sense that going forward we would consider the potential to treat the fellow eye of patients who had one eye treated as a study eye in our trial. So we haven't announced plans there, but that is something that we think makes a lot of sense from a clinical development standpoint and also of course, in the real world going forward to fully realize the value proposition for RGX314 gene therapy treatment. For suprachoroidal delivery, as we've often said, that's in much earlier innings in terms of evaluation. So first things first, we evaluate how steady eye treatment goes in terms of safety and efficacy and overall tolerability. And based on the results that we see there and the accumulated data also that we have from subretinol, as of that time point, we'd also be in a better position to evaluate treatment of the fellow eye of study patients.
spk03: Okay, next question comes from the line of Manny for Ruhar from SVB Learing. Your line is now open.
spk04: Hey, good afternoon. This is Rick on the line for Manny. Congrats on all the progress and just two questions from us. First, so the data in the Hunter program has been pretty impressive to date. I was hoping you could just share some of your most recent thoughts on the pathway to approval here and if you can comment specifically on Approvable endpoints in Hunter syndrome and expectations for a single-arm registrational trial versus placebo-controlled. And then the second question is just around financials. I know the CGMP facility is expected to be fully operational during the first half of 2022. If you could just elaborate on some of the expected changes in distribution of CAPEX versus OPEX as the facility is completed, and if we should expect any meaningful increases in spend as the vector manufacturing scales up.
spk05: Thanks, Rick. I'll start with the first one. On Hunter, we've also, as you mentioned, been very encouraged by some of the outcomes that we've seen from the initial study work. The first two doses in particular have, to us, shown evidence of changes in biochemistry that represent that the gene therapy is working the way that it is designed and is tracking towards having a meaningful effect in these kids. We're always wanting to reconcile that with, you know, other functional data and clinical assessment data, which we know historically can, you know, take longer to reconcile from baseline. But we like and we've been able now to collect from cohorts one and cohorts two, you know, what we think are meaningful understandings of relationships between some of those early biochemical changes and some of the longer-term progress of the assessments. And so I think that's our plan as we continue to steer this program forward is to bring that evidence forward with all the stakeholders, including regulators, show evidence of the connection between early biochemical changes and long-term changes in clinical outcomes. And we're also going to a higher dose, which we think should even further power and amplify that strategy, because I think we are expecting and have seen evidence of increased dose effect while we maintain a good safety profile. So for us, like in any rare disease program, we're We're patient enough to want to take in all the data, but our team is really focused on pathways towards acceleration where there's this great unmet need. So, you know, we will look at this program going forward as leaning as heavily as we can on early evidence of biomarker changes to justify, you know, the clinical changes that we want for these kids and their families and that I think, you know, regulators should fairly expect as well. On the financial side, I'll start, if you have any more color, I think we have the CapEx investment, as you mentioned, has been ongoing across the spectrum of this year. When we finish and have the manufacturing suite operational, it'll complete that phase of investment. We'll also be bringing additional programs online over the next several months and into the middle of next year, including our RGX202 program. As we talk about expanding our RGX314 program with additional dose levels and an additional study, the requirements are still there operationally for increased utilization of any GMP space overall, I think that more what we're going to see is some reduction of CapEx in the transition from 21, 22, and beyond, at least as it relates to the GMP facility. but probably a steady continued increase in the operational expenses associated with an expanding platform of clinical studies, including and especially DMV, later stages of RGX314 with more patients coming on to the second pivotal, and potentially new programs as well.
spk10: Anything to add to it? Yeah, thanks, Rick. Yeah, we expect that from a CapEx perspective, will have to continue spending just to get to the final completion of the manufacturing suite. And then in 2022, a lot of the work will be more focused on just standing up the suite and a lot less focused on additional CapEx. And then to echo Ken's point, there will be a change in OpEx, but the change in OpEx a shift from using external CMOs once our facility is up online to bringing more of that in-house. With the expanded programs and expanded need for drug product in the clinical stages, we assume that it's going to be a little bit higher than what we currently see.
spk03: Okay, next question comes from the line of Matthew Harrison from Morgan Stanley. Your line is now open.
spk08: Hey, great. Good afternoon. I guess two follow-up questions, one on 314 and one on Hunter. So on Hunter, I guess my question here is can you just help or let us think about a little bit how you compare and contrast your programs which obviously is the gene therapy versus some of the antibodies that are in development, especially the ones that seem to cross the blood-brain barrier better, and how you think about the relative gag reductions between those two treatments and just the competitiveness of development there. And then secondly, on 314, I know there's been a lot of questions people have asked about that. I guess what I was really hoping for was, You have a couple cohorts here. We're only going to see the first dose. I mean, as you think about developing superchoroidal, do we need to wait for all three cohorts? Or if you see data that you think is good enough from this first cohort, could you move that forward quickly? Maybe you could just give us sort of the scenarios on how you might develop that, given the first set of data we're going to see.
spk05: Yeah, Matthew, thanks for the question. Look, we've always, I think, you know, established that we're disciplined and we're focused on building good pharmacological understanding of product candidates. And product candidates include, you know, a treatment candidate with a new route of administration. You know, we tested five different doses with our subretinal route of administration and working through an understanding of safety, pharmacology, functional clinical responses, and protein levels, made a very educated and, I think, thoughtful decision about how to move that into pivotal phase. We'll take the same type of disciplined approach with respect to a superchoroidal, except, and an important exception here, we're starting, obviously, already with a baseline of pharmacological understanding that we can relate, you know, and correlate some to subretinol. especially on safety. We've had evidence already. We've talked about with all of you that we're starting at higher dose levels, and we're able to continue to dose escalate based on the preclinical data and our clinical understanding overall. The true answer is we... We will know when we're able to accelerate when we see the entirety of data from the cohorts that we choose to start to enroll and escalate to. You know, and I think that when, you know, we certainly want to have a dose curve before moving on to a later stage of development with any route of administration and any pharmacological candidate profile. You know, typically when we have conversations with regulators and groups like FDA, you know, more and better, especially when you're moving into a patient population that's about hundreds of thousands, if not millions of patients. It can be a very different conversation when you're talking about a rare disease or an ultra-rare disease with an unmet need that is so severe that warrants different type of thinking. I think that's why we've been so encouraged overall so far this year. We're basically on track with enrollment. We've been on track with including expansion of our Phase II studies to higher doses into NAB-positive patients. We're on track to report that first data at six-month time points for cohort one and 88. I think as important, we're on track because of that enrollment and expansion for relatively fast follow-on with respect to those additional cohorts as well. So that's going to be our approach. We'll keep sharing the data at the time points that we think are important and meaningful to all of you and all of the stakeholders here as we get it, and make sure that we have the right amount of data to make decisions about where the program can go next, which You know, we have always wanted our programs to move as quickly as possible and into late stages of development, especially with wet AMD and DR. Let's see, on the Hunter program side of it, You know, I think we're very conscious and excited about the landscape of interest that people have in lysosomal storage diseases like Hunter to bring something, especially to these diseases that have enzyme replacement therapy to treat systemic or peripheral symptoms, but nothing that is addressing the central nervous system disease here that exists in these kids that we all know exist. You know, what's unique for us about gene therapy and our approach is I kind of characterize it often as an inside-out approach, right? So when we see changes in biomarkers, when we see evidence of biochemistry changing in the CSS of kids, it symbolizes, represents, doesn't symbolize, it tells us a scientific story that we have transduced, transcribed, and expressed protein intracellularly. And that's where the problem is. And so when we see that change happening with something like a substrate of the enzyme in the CSF, and we've seen that correlation in animals to those intracellular changes, for us, that's very meaningful and very important in why we've done a lot of characterization of these substrates and their direct correlation to those gene therapy changes, those intracellular changes that could only occur if our treatment is transducing cells and transcribing proteins. Other treatments, other mechanisms of action show and have shown changes in biochemistry. They have different mechanisms of how they operate. They're often outside-in approaches using proteins that are bound to the enzyme or, as you mentioned, antibodies or antibody fragments or things that can help those proteins, those enzymes, transport across the blood-brain barrier, etc. That's not our area of expertise. I don't want to speak beyond what we focus on and where our science has taken us. But I think that we view that a one-time treatment for gene therapy that is showing changes that preclinically and clinically are meaningful and correlate to the fact that the gene has gotten into the brain cells and is on is about as meaningful a data set as we can show in these important diseases. And now we need to back it up with the clinical evidence as well. So that's what gets us excited about one-time gene therapy for things like Hunter syndrome.
spk03: Okay, your next question comes from the line of Esther Rajarvalu from UBS. Your line is now open. Esther, your line is now open. Esther is not responding, so let's open the line for Luca Eze from RBC Capital. Your lines are open.
spk00: Oh, thanks so much. Appreciate you taking the question and congrats on the progress. Maybe just a few here. So maybe on the phase three for WET-AMD, I think you mentioned in the past that your rescue injection criteria was going to be more stringent in the phase three versus prior trial. Wondering if that is still the case and maybe if they can expand a little bit more on it. And then the second, on the bridging study, do you have any update there? I know you're pivoting from adherence aligned, suspension aligned, so wondering if you have started that trial. And probably most importantly, if that trial is gating to start the second phase three or any other trial, And then every third, any update on the clinical hole for Batten disease, that would be great. Thanks so much.
spk05: Thanks, Luca. I'll start back to front there. No, we don't have any updates on the Batten study. We're expecting to provide more updates on that program between now and the end of the year. Overall, for the RGX314 pivotal program, we announced that we are initiating the second pivotal study, that we expect that to start in the fourth quarter of this year. We have announced that we have continued to enroll in the atmosphere study, and that overall enrollment is occurring across all of the studies, including the bridging study. So we're on track with respect to atmosphere, the bridging study, and and the plans that we have for initiation of the second pivotal study. There's not an interrelationship between the staging of the bridging study and the start of the second pivotal. Those were things that we had planned already and are happening according to the timeline and are on track. I guess with respect to the first part of your question, I'll put this back in Steve's court to talk about the criteria for retreatment in atmosphere.
spk09: Yeah. Thanks, Ken. Thanks, Luca. Yes, you're exactly right. We have taken advantage of the learnings from the Phase 1-2 study, which was the first in human study where we had a very low bar for retreatment where investigators could retreat based on any amount of fluid without any requirement for increase in fluid or a decrease in visual acuity. And as we presented before, we were still able to show a dramatic reduction in treatment burden in those patients, though a lot of the injections that were even given were given for very little fluid or even in some cases no increase in fluid. So for our pivotal studies, we are incorporating a stricter rescue or re-treatment criteria where we use objective data that is requiring either a reduction in best corrected visual acuity and or a certain amount of increase in the central retinal thickness. And these criteria are very much in line with the precedent of what's out there in terms of other studies that are looking at increasing the treatment interval or treatment duration. So we're in that same basic range. It's just that in our case, we're looking at a potential one-time treatment in these trials.
spk10: Thanks, Luca.
spk03: Okay, and once again, to ask a question, you will need to press star 1 on your telephone. Your next question comes from the line of Dean Leon from Raymond James. Your line is now open.
spk07: Thanks for taking the follow-up question. Just one specifically. We have gotten questions and a good amount of questions given the issues with the peer company and patients experiencing severe reactions that had diabetic macular edema to their gene therapy. Just wanted to give you guys the chance to comment in terms of having the first cohort that you expect to report out in diabetic retinopathy, which is a different indication in the fourth quarter. Just maybe compare and contrast your expectations for the biology of these diabetic retinopathy patients versus a diabetic macular edema patient and then any specific points of interest that AIM may be able to make around how you view the safety of your program. Thank you.
spk05: Thanks, Dane, because we're letting you back in again. We did that. Steve, do you want to answer that?
spk09: Yeah. Yeah, glad to have the follow-up question from you, Dane. Similar to how Ken talked about other programs in another space, we're really not in a position to go into any pontificating of what could be going on in another setting, but we're obviously aware of the findings. That's a different program with a different vector, different transgene and importantly different route of administration where there is obviously known the risk of inflammation that exists with that route of administration and why we've been excited about and selected subretinal initially and then suprachoroidal where unlike with intravitreal administration of any vectors, including AAV2 or modified AAV2 vectors and NAV vectors where with intravitreal you can get inflammation. With supracoroidal in both small animal models and also large animal models including multiple non-human primate studies, we have not seen inflammation. So that's why we were excited to go into both wet AMD and diabetic retinopathy in dose-ranging studies in both those indications without prophylactic steroids and why we're excited based on initial data from the initial cohort in both studies to be able to go up in dose in both wet-AMT and also DR and also importantly felt comfortable to advance also in NAP-positive patients in both settings with that higher dose. You know, we go where the science leads and the data. So we're, you know, again, we can speak to our data. We're aware of the context in the whole field. But each program is specific, you know, based on its vector, transgene, and other factors, and importantly, route of administration.
spk05: Thanks, Steve.
spk03: Your next question comes from the line of Esther from UBS. Your line is now open.
spk11: Hey, thank you for taking my question, and I apologize for missing the queue before. I was jumping between calls. But just kind of touching again on the suprachoroidal delivery, can you help us understand how widely it's used right now and in what context it's used and how much, you know, what the economics could be for supercoroidal delivery versus intravitreal for ophthalmologists. And then I have one other follow-up.
spk09: Yeah. I can... Go ahead, Steve.
spk05: You're good.
spk09: Okay. All right. Yeah, so I'll take the front end of that, Astor. So supercoroidal space... or delivery to that space more broadly than just gene therapy, the most extensive experiences with ClearSide and their SCS microinjector, where they've dosed well over 1,000 eyes, mostly with a steroid preparation, a triamcinolone preparation for treatment of noninfectious uveitis, though it's also been used in other treatment settings. And based on the safety and tolerability and feasibility of administration, they're continuing to advance also in partnership with other companies such as Bausch for their LEAD program. So that's actually one of the reasons we chose to partner with Clearsight to use the most validated clinically device for delivering an infusion to the supracoroidal space for our one-time in-office gene therapy approach and why we're excited to advance on that. We, like Clearside and their partners, have seen very good feasibility in terms of administration of RGX314 utilizing the SCS microinjector. This is a different route of administration with the benefit that you don't have to go to the operating room to perform. And these are retinal surgeon specialists, so this is a very simple and straightforward in-office approach that we've seen. So we're very pleased and excited to continue to advance with supracoroidal delivery. aspect we still need to see is whether neutralizing antibody status is important or not in terms of the potential expansion of the use of the superchoroidal injection route. Ken, did you have anything else to add on the back end of that question?
spk05: No, Steve, just that we're not prognosticating on pricing of SuperCoroidal right now. We're initiating our first inhuman investigation of what we think is an exciting route of administration and approach and have the opportunity to evaluate that and take inventory of it, look more to the future to talk about next steps of the program and ultimately happy to have conversations about commercialization of this high potential approach.
spk03: Okay, there are no further questions at this time. I will turn it over back to Mr. Cangellis for any closing remarks.
spk05: Thanks, Operator, and thanks, everyone, for participating today. For those of you who are still hanging on, I'd say we have an exciting quarter. We have three data updates that we've communicated between now and the end of the year, starting with Retina Society, then Cohort 2 at AMD, and Diabetic Retinopathy Cohort 1. between now and the end of the year for our GX314, an IND filing for our GMD program, and more updates on 121, looking to continue to chart a course for how that program moves forward. So thanks for the great questions. We touched on a lot of these topics. Emphasize that the first half of this year has been a great period of execution at the company and looking forward to more updates for the rest of the year. Have a good afternoon.
spk03: This concludes today's conference call. Thank you for participating. You may now disconnect.
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