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spk07: Good morning and welcome to the AGTC Financial Results Conference call for the second quarter of fiscal year 2022. Today's call is being recorded. Before we get started, I would like to remind everyone that during this call, AGTC may make forward-looking statements, including statements about the company's financial results, financial guidance, its future business strategies and operations, and its product development and regulatory progress, including statements about the timing, and outcomes from data expected in its Skyline and VISTA trials and the type of data that may support registration and potential approval. Actual results could differ materially from those discussed in these forward-looking statements due to a number of important factors, including uncertainty inherent in the clinical development and regulatory process, the extent and duration of the impact of the COVID-19 pandemic, and the other risks described in the risk factor section of AGTC's most recent filed annual report on Form 10-K and other periodic reports filed with the SEC. AGTC undertakes no obligation to update any forward-looking statements after the date of this call. For introductions and opening remarks, I'd like to turn the call over to Sue Washer, Chief Executive Officer of AGTC. Please go ahead.
spk02: Good morning, and thank you all for joining us. With me on today's call are Susan Schneider, our Chief Medical Officer, and John Lieber, our Chief Financial Officer. During today's call, I'll review our recent accomplishments before Susan reviews the recently reported data from the achromatopsia B3 trial. She will then discuss our plans for reporting data from the X-linked retinitis pigmentosa, or XLRT, phase two Skyline trial, and provide guidance on how we intend to measure this trial's success. John will provide an update on the build out of our manufacturing facility, review our financial results for the second quarter of fiscal year 2022, and discuss our upcoming milestones. After our prepared remarks, we'll take your questions. In the second quarter, we made significant progress in our lead clinical programs and met important business objectives. Key accomplishments in our XLRP program included reporting additional data from the ongoing Phase I-II clinical trial of AGTC501, our XLRP gene therapy candidate, and completing enrollment in the Skyline trial. Last week, we reported data from the highest-dose pediatric group in our ongoing Phase I-II achromatopsia trials. These data are consistent with the previously reported adult data. Importantly, based on the data generated to date, we intend to advance our AGTC-401, our product candidate for patients with a CNGD3 gene mutation that causes achromatopsia, into the next stage of clinical development pending feedback from an end of Phase II meeting with the U.S. Food and Drug Administration, or FDA, expected in the first half of this year. With respect to the dose, we believe that the 1.1e to the 12 vector genome per mil dose, which is the dose group five in the Phase I-II trial, is an appropriate dose to move to the next stage of clinical development. Specifically, two pediatric patients in this dose group were responders based on improvements in visual sensitivity. Therefore, of the three adults and four children for a total of N equals 7 in that dose group, and including the two adult responders, four patients are greater than 50% are visual sensitivity responders. These patients also had improvements in quality of life as measured by a patient-reported outcome survey, or PRO, developed specifically for patients with achromatopsia. During the quarter, we also added several talented individuals to our leadership team in order to support advancement of our clinical and preclinical programs. We welcomed Hope Doiley-Gay as General Counsel and Dr. Abraham Scaria as Chief Scientific Officer. Hope has more than 25 years of legal experience with the majority of her career spent in the healthcare industry and deep knowledge of pharmaceutical gene therapy and life science companies. Abraham also has more than 25 years of experience in the biotech and pharmaceutical industries with extensive knowledge in discovery research and early stage development and a focus on gene therapies to treat rare diseases. Most recently, he was the Senior Vice President and Chief Scientific Officer of Iverick Bios, where he was responsible for preclinical research and development for retinal disease therapies. Having recently welcomed John and Sue, who are participating in the call today, and Janet Ray, our Senior Vice President of Regulatory and Quality, the appointments of Hope and Abraham complete the newly expanded management team that has both the expertise and passion to continue developing our clinical programs and preclinical pipelines. We also appointed James Robertson, President and Chief Executive Officer of Eurovant Sciences, to our Board of Directors. James has nearly three decades of experience in the biopharmaceutical industry and has successfully led commercial operations at multiple companies. His insights will be invaluable as we move toward late-stage development and commercialization of our lead clinical programs. The combination of our expanding body of clinical data supporting the potential of our XLRP and achromatopsia B3 candidates and our seasoned and dedicated leadership further increases confidence in our ability to develop transformative gene therapies for patients that currently have no alternative treatment options. I'll now turn the call over to Susan for a discussion of our XLRP and achromatopsia B3 clinical programs.
spk09: Thank you, Sue. First, I will briefly review the data presented last week from our ongoing Phase 1-2 clinical trials of AGTC401 for achromatopsia due to mutations in the CNGB3 gene and AGTC402 for achromatopsia due to mutations in the CNGA3 gene. As Sue noted, In both achromatopsia clinical studies, we continue to observe a well-tolerated safety profile in all adults through the full 100-fold dose range with no dose-limiting toxicities. In pediatric patients, both achromatopsia product candidates show a similar well-tolerated safety profile as in adults, except at the very highest dose the 3.1e to the 12 vector genomes per ml dose group, where there was significant inflammation resulting in one suspected unexpected serious adverse reaction, or SUSAR, for AGTC401 and two SUSARs for AGTC402, all previously reported. Each of these patients have responded well to an adjusted steroid regimen, with intraocular inflammation resolved for two patients and significantly improved in the third. Importantly, at the second highest dose, the 1.1e to the 12th vector genomes per mL dose, or group five dose, no SUSARs, endophthalmitis, or drug-related serious adverse events have been reported in either the pediatric or the adult patients many of whom are past the 12 month time point. This generally safe and well tolerated profile is also consistent with earlier data out to as long as 24 months for the AGTC501, our XLRP product candidate. Of note, in our AGTC401 clinical trial, we have observed several adult responders out to 12 months based on visual sensitivity, light discomfort, and a quality-of-life questionnaire designed specifically to assess light sensitivity that impacts a chromatopsia patient. The most consistent responses are in dose group 5, which is a dose of 1.1e to the 12 vector genomes per mL. Importantly, for the AGTC401 pediatric patients, we also saw responders for visual sensitivity at this dose. For responders, the improvement in visual sensitivity was robust and durable in both adult and pediatric patients. Interestingly, this is also the dose with the best response in our XLRP clinical trial. This slide focuses on the seven group five patients. Importantly, four of the five patients in group five who were able to complete the perimetry testing, two adults and two children, had robust and durable responses, and several had improvements in one or more additional endpoints, including a measure of quality of life. We also observed that the two very young children, both five years of age, who were unable to complete the visual sensitivity test, had improvements in their quality of life survey, and one of them had improvements in best corrected visual acuity, or BCVA. Here you can see the visual sensitivity data as graphs over time for the two adult and two pediatric responders in group five that illustrate durable and robust improvements. In the graph on the left, the four responders averaged a six decibel improvement in mean visual sensitivity compared to baseline, which represents a 16 to 24-fold increase versus the contralateral untreated eyes that showed relatively little change over time. The graph on the right shows an even larger improvement in those responders that also met the hurdle of five loci increasing by seven decibels. Based on these data, we believe that AGTC401 has best in class potential for the treatment of achromatopsia B3, and we look forward to sharing information in the first half of this year on the next steps in clinical development following our end of phase two meeting with the FDA. Let's now shift our focus to our XLRP clinical program. As Sue mentioned, We reported additional data from the ongoing XLRP Phase 1-2 trial in the second quarter of calendar year 2021. Consistent with previously reported data, these additional results demonstrated a 50% response rate for Groups 5 and 6 based on micro-perimetry assessments and with best corrected visual acuity outcomes. we continue to show evidence of a biological response at month 12. Improvements in visual sensitivity also correlate with improvements in retinal structure. Furthermore, we are seeing evidence of a continued durability of response up to 24 months after treatment based on data from a subset of patients in the Phase I-II trial who have reached this time point. These data reinforce our belief that AGTC501 is a differentiated product candidate with best-in-class potential, and we look forward to reporting the full two-year data later in calendar year 2022. As announced last month, we completed enrollment in the Skyline trial. We exceeded the enrollment target for this trial, which we believe reflects the strong interest in our XLRP candidate among patients and physicians. As many of you are aware, Skyline is a multi-site masked phase two expansion of the ongoing phase one study in which patients are randomized to either a high or low dose of AGTC501 with the primary objective to identify the proportion of treated eyes that demonstrate improvement from baseline in measures of visual sensitivity and visual acuity as well as the patient's ability to navigate a mobility maze with changing obstacles and under varying light conditions. Importantly, this is our first clinical trial that has the potential to demonstrate a correlation between visual sensitivity and or visual acuity with maze outcomes, a new functional endpoint also added to the VISTA Phase 2-3 clinical trial. Skyline and VISTA use the same inclusion and exclusion criteria, which are based on baseline characteristics identified in the Phase 1-2 clinical trial utilized to predict responders. We are on track to report interim masked three-month data from Skyline in the second quarter of calendar year 2022. And today, I will provide guidance on our expectation for these data and review key clinical assessments performed in this clinical trial. Anticipated key takeaways for the Skyline Monthly Interim Analysis are summarized here. Based on the body of safety data from our Phase 1-2 clinical trial, we have confidence that Skyline safety outcomes will continue to show that our XORP candidate is generally safe and well tolerated. We also plan to report on the proportion of patients showing improvement in visual sensitivity in their treated eye. Based on the data cutoff time point for this interim analysis, we intend to evaluate data from the first 13 of a total of 14 patients enrolled in the Skyline trial. Data to date from the Phase 1-2 trial have demonstrated a 50% response rate in higher dose groups when including patients who meet the entry criteria for the Skyline and VISTA trial. And the VISTA trial is powered to show a statistically significant difference at a 50% response rate. I want to emphasize that at the time we present the three-month Skyline data, the trial will be masked. This means that while we will be able to report on responders in two groups, we will not know the specific dose group assignments. Outcomes will be reported only as dose group A and dose group B. We also expect that best corrected visual acuity will continue to show supportive evidence of a biological response with a difference between each patient's treated versus untreated eye. We plan to present these data as the number of eyes in dose group A and in dose group B with improvement over baseline of five ETDRS letters or more compared to the untreated eye. We consider this to be a response to treatment. While we have previously reported visual sensitivity and visual acuity data, the Skyline trial is the first that utilizes a visual navigation challenge, or VNC, which is a mobility maze used to assess functional vision. We believe that improvements in maze performance have the potential to correlate with improvements in visual sensitivity and or visual acuity. Finally, while we are assessing changes in macular structure in the Skyline trial, we do not believe, based on data from the Phase 1-2 study, that we will see any consistent changes in structure at the three-month interim analysis, as this time point is too early to capture these changes. If the three-month interim data achieve these expectations, we believe we will have significantly de-risked the VISTA clinical trial, which together with data from both the Phase I-II study and the Skyline Phase II expansion study is intended to support a BLA filing. I'd now like to briefly review the key Skyline efficacy endpoints. To start, We can look at vision and function in two ways, visual function and functional vision. Visual function describes how well the eyes and basic visual system can detect a target stimulus. In other words, how information is transmitted through the eye to the brain. Micro-parametry and best corrective visual acuity are tests used to assess visual function. We are utilizing macular integrity assessment system, or MIA, microperimetry, to measure light sensitivity of the retina in the Skyline and VISTA trials, as we believe it can appropriately measure functional changes of visual sensitivity to treatment in XLRP patients. Functional vision refers to how well a patient performs while interacting with the visual environment. That is, how the brain processes information to perform tasks of daily living. The mobility maze, which is a new endpoint for the AGTC 501 clinical program, assesses functional vision. These are the key ways we plan on evaluating outcomes for Skyline to potentially show a positive response to treatment in a clinically meaningful way and with endpoint second support registration. We also believe that it is important to show structure-function relationships in support of a treatment effect. Ellipsoid zone, or EZ width, is used to assess changes in macular structure. As we have previously discussed, EZ degeneration and loss over time is a hallmark of XLRP, and we've shared data from the Phase I-II trial demonstrating a significant association between improvements in visual sensitivity measured by Maya and improvements in retinal health measured by improvement in EZ in groups four to six. However, since EZ changes occur more slowly than changes in visual sensitivity or visual acuity, we do not expect to see evidence of structural improvements in the three-month skyline interim analysis. The mobility maze is a new endpoint for the AGTC501 clinical program. A mobility maze was validated as an endpoint for the approval of Luxturna, the first gene therapy approved for inherited retinal disease. Therefore, there is regulatory precedent for this measurement as a clinically meaningful and accepted endpoint for registration. We are using the AURA Visual Navigation Challenge, or VNC. This slide shows an example of the type of outputs and data that will be evaluated using the maze and how we currently plan to report the outcomes for the Skyline three-month interim analysis. The AURA VNC has multiple possible configurations that create varying levels of challenge conditions with respect to maze path and obstacles. In addition, patients are tested over a range of lighting conditions from dim to bright interior light. Patient performance is assessed by both the time taken to traverse the maze as well as accuracy in navigating the course and avoiding obstacles. To pass at a given light level, the patient must navigate the maze within both a defined time and accuracy rate. The ability to pass the maze challenge at lower light levels is consistent with a response to treatment. The FDA has previously provided feedback to us that it considers a clinically meaningful change to be a patient's ability to pass the test in two illumination levels lower than baseline A key benefit to the mobility maze is that it has the potential to capture improvements in multiple functional endpoints as the ability to successfully navigate the maze, a function of both visual sensitivity and visual acuity. In addition to assessing the ORAVNC results for efficacy, we plan to also evaluate potential correlations between changes in mobility maze scores and improvements in microperimetry and best corrected visual acuity assessments in the Skyline three-month interim analysis. Now let's turn our attention to the XLRP VISTA clinical trial. This slide summarizes the VISTA study design. As previously discussed, VISTA is a Phase 2-3 trial with two treatment arms that correspond to the doses used in groups two and five in the phase one-two trial, as well as an untreated control group. The primary endpoint is improvement in visual sensitivity based on the percent of responder patients. A responder is a patient that has at least five predefined loci improved by at least seven decibels. However, as we have stated previously, we believe that given this is an ORCN indication, that an approval will likely be based on the totality of the data, including the mean improvement in visual sensitivity over the entire treated area, supportive improvements in visual acuity and structure, a favorable risk benefit profile, and improvement in patient reported outcomes, or PROs. At the time of the first VISTA interim analysis, we expect to have 12-month skyline data and 24-month data from the Phase I-II clinical trial, which will enable us to have a robust data package to review. We believe that AGTC501 has best-in-class potential for the treatment of XORP and look forward to sharing additional data from all three clinical trials with you in the months ahead. In summary, we have generated a significant body of clinical and preclinical data to date. While these data are important to the development of our achromatopsia and XLRP product candidates, they also provide further evidence that our preclinical approach to product development and our technology platform are robust and supportive of our broader portfolio of gene therapy candidates. I'll now turn the call over to John for a brief update on our manufacturing facility and review of second quarter 2022 financial results.
spk05: Thanks, Susan. I'll first provide an update on the construction progress of our manufacturing facility, followed by a summary of our financial results and near-term milestones. Construction of our new lease manufacturing and quality control facility is in process with initial operations at the facility expected to begin in the fourth quarter of calendar year 2022. The facility is a key part of our strategy to expedite the potential BLA filing and commercial launch subject to FDA approval of AGTC 501 for the treatment of XLRP and support the manufacturing and supply of materials for AGTC 401 and our early pipeline programs. As seen here, the facility is well underway. Now I'll turn to our financial results. Net loss for the three and six months ended December 31st, 2021 was 19.1 million and 36.3 million respectively compared to 15.5 million and 30.8 million respectively during the comparable 2020 periods. As of December 31st, 2021, we had cash, cash equivalents and investments of 72.8 million. We believe these funds will be sufficient to allow us to generate data from our ongoing and planned clinical programs and fund currently planned research and discovery programs into calendar year 2023. Importantly, as you will see on the next slide, we have multiple upcoming milestones which we believe have substantial potential for creating significant value for patients and shareholders. This is a milestone-rich time for AGTC That includes multiple clinical data readouts and additional preclinical milestones. These include reporting the Skyline three-month interim data in the second quarter of this year and 12-month Skyline and interim VISTA trial results in the first half of calendar year 2023. In our Chromatopsia B3 program, we reported the three-month pediatric data from both trials last week and expect to report end of phase two feedback from the FDA in the first half of 2022. We also expect to continue advancing our earlier stage and partner programs, which provides significant pipeline potential across multiple disease indications with unmet medical needs. That concludes our remarks today. Operator, you may now open the line for a question and answer period.
spk07: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions. Our first questions come from the line of Joe Pangenis with HC Wainwright. Please proceed with your questions.
spk01: Everybody, good morning. Thanks for taking the question. A couple questions, if you don't mind. So first, I guess, John, based on your manufacturing facility comments, I mean, the company has always been doing a lot of early preparations, you know, regarding manufacturing and having things in-house. I guess, you know, with all the management that you've just brought in, how should we view the company's growth with regard to future hirings and employees for the manufacturing facility as well?
spk05: Yeah, that's a good question, Joe. Thank you for joining us this morning and thanks for the question. So I would say we certainly don't provide specific guidance on headcount, et cetera, but we had a lot of hiring in the back half of the last calendar year, 2021, and our hiring for the manufacturing facility for this year going forward is going to be focused on, obviously, folks who can help get the facility ready to be GMP certified, and then ultimately a focus on people who then can operate the operators who work inside the facility to actually start making the material. So I think, um, we should be thinking about more hiring this year, um, uh, at a slower pace than perhaps it was last year. But again, all of that is factored into our cash runway that we've given us to the time.
spk01: Absolutely. Thanks. That's helpful. And then I guess just sort of going back to the expectations around, um, skyline, um, Sue, I'm hoping you can either remind us and, or give a little color, with regard to the maze challenge. Obviously, the endpoints are pretty laid out there as you did it. I guess the question that I have is maybe a little more color around the time points that you're testing and is it a different configuration at each time point? You talk about multiple configurations at each time point, so hopefully getting a little more color there.
spk02: Good morning, Joe. Thank you for that question. Actually, I'm going to let Susan address this. She has all of the information on the maze in her head. And so we'll let her give you that color, Susan.
spk09: Okay. Thank you, Sue. So the maze that we're utilizing by Aura actually is standardized and developed with keeping in mind that patients won't be able to learn the course in subsequent utilization of the course. It actually uses four different courses with varying levels of difficulty and navigation capabilities, et cetera, and really focusing on low contrast visual navigation challenge as well as high contrast visual navigation challenge. So hopefully that answers your question. The patients will be assessed per visit and will be assessing the change from baseline as outlined in a pastel fashion.
spk01: Nope, that's helpful. I guess maybe just an add-on there is just remind us the frequency of visits.
spk09: We're still working through what those are. They will be the same visits as we have for the study itself.
spk01: Got it. Thank you very much.
spk07: Thank you. Our next questions come from the line. Please proceed with your questions.
spk06: Great. Good morning. Thanks very much for taking our questions. I had two related to the studies that are ongoing. So with regards to the XLRP, recognizing a lot of these studies are kind of coming in fast and furious. Sue, I think in our prior conversation you talked about perhaps approaching the FDA or the VISTA endpoint discussion should you try to pursue the mobility maze. Today, Susan talked about the totality being important. So how are you kind of currently thinking about approaching the FDA to think about the two or the primary endpoint designation or switch of the primary endpoint designation, if you will? Is there a certain date that you need to kind of approach them by to get to an agreement or is it pretty much at any time point? And then second question, perhaps more for Susan, as we think about the achromatopsia B3 and the phase two discussion, maybe a housekeeping question, has that meeting been calendared or penciled in to the calendar? And two, what are sort of the outcomes if you want to think about, or how should we think about the outcomes of recognizing that go forward would be good, but what are sort of the scenarios that you guys are contemplating as we anticipate that update? Thanks.
spk02: Morning, Dagon. It's nice to talk to you today. As far as the XLRP and when we might interact with the FDA, I think it's important to understand, like with a lot of orphan indications and new modalities like gene therapy, we have a wide range of opportunities to have interaction with the FDA in different types of meetings over time. And if we ever see anything that we feel warrants us to have an interaction, we will definitely reach out. In a more formal way, what we have signaled and guided to is at the time we have the first interim analysis for VISTA, we will also have 12-month data for Skyline and 24-month data for our Phase I-II. So that is three sets of data, three different sets of patients, very robust information that we'll be able to analyze. And at that time, if there are things that we want to interact with the FDA, we do think that we'll have the body of data to do it. But it will all be a reaction to what the data tells us and what meeting we can take advantage of with the FDA. And then I'll pass it off to Susan about the end of Phase II and and what various outcomes we might have in that discussion. But we have mentioned before that we do have that meeting on the books. We haven't guided to a specific date, but we have received a meeting. So we're quite confident that we'll be able to provide feedback to the public by the end of June.
spk09: Susan? Thank you, Sue. And as Sue said, we do have a meeting date, and we are preparing for that. as we speak and are excited to be able to interact with the FDA. Basically, at an end-to-phase two meeting, we propose clinical questions that will give us additional guidance on the plan phase three and the path forward to be able to file and be successful in that light. And so the endpoints that we have in the phase one-two study that showed us a response as well as some additional questions about how we're going to move forward to phase three, consistent with the study design that we will be proposing. We'll be looking for guidance from the FDA about adequacy of that program.
spk02: And I'll just jump in real quickly. I think that maybe what you were getting to, we would consider success from the end of phase two to get to agreement on a protocol. And that may involve a lot of back and forth. It generally does, as the FDA is learning the specifics of our program and our construct and the data we have. And we're learning their intent. And we would expect to have that back and forth. and make adjustments. And success is to have a trial that can be executed and go forward, such as what we got out of the end of phase two interaction with the FDA for our XLRP program.
spk06: Awesome. Thank you very much. Look forward to that second quarter update.
spk07: Thank you. Our next questions come from the line of Yann and Zhu with Wells Fargo. Please proceed with your questions.
spk04: Thanks for taking my questions and for the update today. I have kind of three groups of questions for each of the endpoints to be reported for Skyline. For the visual sensitivity, first of all, would you mind talking about what is the bar for success in terms of response rate, responder rate for each of the endpoints? And specifically for the visual sensitivity, would it be a 7-5 analysis or a sensitivity across the retina analysis? For the BCVA, I think you mentioned 5 later as the response criteria. Is that one line of improvement above the test retest threshold for XLRP in this specific indication? And for the VNC, is it a binocular or single eye test? And are the low contrast and high contrast setting going to be reported separately as two different responses, or are they somehow incorporated into one response? Thanks.
spk02: Good morning, Ann, and it's nice to talk to you and address these questions. I'm just going to provide an overview and then let Susan provide some more color. So I think that we've had many discussions about visual sensitivity and that the bar sets do precedence to older machines and into the glaucoma space for visual sensitivity is the idea of having at least a seven decibel change and at least five loci. And that is the bar for success. We've set that at 50% because that is what we saw in the phase one, two for that bar. But we have always stated that we feel in a disease where patients are going blind and will be blind, legally blind in their 40s and totally blind probably in their 60s, that we think it's a totality of data. And so we'll report that visual sensitivity as the mean over the entire area, because we think that is what patients care about, is what is the improvement they see in their vision over the entire area, especially in a normal situation, their vision would just be declining. For BCVA, it is not the primary endpoint, it's the secondary endpoint. And we feel, again, that in an indication where they're losing vision every day and will become completely blind, that an improvement of five letters is meaningful to them. That is what we saw in a statistically significant way in the Phase I-II. So meeting the same criteria that we saw in the Phase I-II for visual sensitivity and BCVA would be what we consider successful. On the maize, I'll just provide an overview. In the maize, I'd really like Susan to provide some more data. But we will be testing each eye, so each eye separately, to be able to show the treated eye versus the untreated eye. And we are testing in both of those contrast situations. And I'll let Susan speak to more of the details of the assessment and reporting on that.
spk09: Thank you, Sue. And just going back to the BCVA, what we consider as a response is change from baseline in five letters or more. That puts us outside of the level of noise. Again, as Sue said, that is supportive data for the primary endpoint. The BCVA will not be the primary endpoint for us. With respect to the microprimitary, We are using the macular integrity assessment system, or MIA, which is a standardized way of measuring light sensitivity of the retina. We're looking at central sensitivity. And as Sue said, the FDA has suggested that we should have a minimum of a seven decibel change as the threshold from baseline there with the loci pre-specified. With respect to the maze, as Sue also said and I support, we will be testing one eye separately and then both eyes together. There are two courses proposed, the low luminance and the high contrast one. And the subject will test at all of the available light levels. There's a range of levels. again, on the various eye combinations, right eye, left eye, both eyes, on all available courses. They'll start at screening. And then based on where their baseline is, they will be tested throughout the study at the subsequent visits that are in the Skyline study and then in VISTA. And they would need a pass to need to stop testing at the various eye combinations.
spk02: And one thing that I'll add here, and Susan mentioned it during the first part of the call, but I think it's very important, is that what we saw in the Phase 1-2 was improvements in visual sensitivity supported by visual acuity, further supported by structural stabilization and improvement. functional vision, you know, vision function changing, vision function changing, structure changing, and then we saw that the PROs supported that their functional vision, their quality of life was improving. And that is what we would say was the basis for the success of the trial. And moving forward, what we want to see out of Skyline is the same kind of results, improvements in visual sensitivity and supportive improvements in visual acuity and We won't quite have structured data at three months, but we'll report what we do see. And then the maze then becomes a much more powerful tool to look at those quality of life, ability to navigate, and show support of functional vision.
spk04: Great. Thanks for all the comments.
spk07: Thank you. Our next questions come from the line of Kristin Kluska with Cantor Fitzgerald. Please proceed with your questions.
spk10: Hi, good morning, everybody. Thanks for taking my questions. The first is that I don't believe there are any specific natural history studies that include specific maize assessments. I could point to some pastel rates, but I wanted to ask what you believe expectations would be without any treatment. So including areas also where the most errors are most likely to take place as well as time to completion.
spk02: Yeah, thank you, Kristen, and good morning to you. As far as natural history studies that show the maze over time, there have been some studies with different kinds of mazes. So the Luxterna approval, you can walk through the ADCOM for that. indication and they provided data over a greater than one year timeframe in a maze in RPE65, which is a different indication, but it is a retinitis pigmentosa indication, and they didn't see any change over time in maze performance. So there was no spontaneous improvement. They again did change up their maze at each visit, so there wasn't the capability for learning, and we think that that's important. And then also the contractor we're working with, the vendor Aura, they have developed this visceral navigation challenge and shown for retinitis pigmentosa and have shown consistently that it doesn't spontaneously improve. But you're right, there hasn't been a formal, fulsome natural history study conducted. And then, Susan, do you want to comment on the second half of Kristen's question?
spk09: Sure. Could you repeat that second half, please?
spk10: Yeah, so I was interested in knowing a little bit more specifically about the maze. Again, this is the question pertains to assuming no treatment. Like, are there specific obstacles in the maze perhaps where you might expect more errors to take place?
spk09: I guess the best answer for that is we will see with the data that we have. This is a new endpoint for us, and part of this will be related to the visual function of each patient. So this will be per patient measurements, and it may depend on how advanced their visual field is at the time that they're screened and therefore baseline for the study.
spk02: I would add, Kristen, there's no specific part of the maze that's supposed to be more difficult than another part of the maze. The maze is supposed to be just very challenging, and the amount of time it takes the patient to try and figure out their way through, and if they make any errors, like stepping off of the course or bumping into the obstacles, that shows that their vision is poor, but there's no specific obstacle that's meant to be significantly more challenging than any other obstacle, if that's what you were asking.
spk10: Yes, that's perfect. Thank you. And just to follow up on that, I wanted to ask, I know there's a couple of different Could you talk about the work that goes into supporting the idea that these separate configurations are all equivalent, given that patients will be running the maze more than once? And then also other changes to, again, make sure that patients are also not memorizing the course either. Thank you.
spk02: So I'll start with that. I mean, we have worked with Aura on this maze because of their expertise. in this type of measurement and they've worked with many other groups and with experts in the space and there's a complete science to how they set it up and a manual as to how to change it up and they've worked very hard to make sure that the different configurations were equivalent and that there were enough different configurations that the patient could not memorize it because I do think that that's important. And so how they've set up this maze, they're really working hard to minimize any ability of the patient over time to memorize it. And you have to remember that in some cases there's three to six months between visits. So to memorize... you know, different configurations of a maze you did under different light conditions and be able to remember it, you know, three to six months later, because it changed in between, I think is going to be a de minimis issue.
spk10: Thanks again.
spk07: As a reminder, if you would like to ask a question, please press star 1 on your telephone keypad. Our next questions come from the line of Yun Zhang with BTIG. Please proceed with your questions.
spk03: Hi. Good morning. Thanks very much for taking the questions. So my questions are on the Phase 2-3 VISTA study. And first, I wanted to confirm the status of the study. Has the study started patient enrollment? And if not, is there anything that you're waiting for before you start patient enrollment, for example, the three months data from Skyline study? And also from the diagram of the study design, looks like the interim data analysis is somewhere between month three and month six. And so is that a specific, sorry, in terms of the time point, is that something different from a three-month interim data analysis?
spk02: Thank you for joining us today and I'll address these questions. So we have not provided detailed guidance on VISTA except when we will be releasing data. And so that's in the first half of 2023. We've also historically guided and stand by the guidance that we don't need anything specifically out of Skyline to be able to proceed with VISTA. We've also guided that VISTA has significantly more sites activated and being activated than Skyline did. And now that Skyline has completed enrollment, the Skyline sites are being activated to move into VISTA. So those are the pieces of specific guidance that we've provided.
spk03: Okay. So no matter what the outcome will look like from the lower dose cohort from Skyline, the design of the VISTA study is now going to be changed and still will proceed with a high dose plus a low dose?
spk02: Yeah, that's a very important point to bring up is that the reason we have two active arms in the VISTAs trial as well as an untreated control is that from a regulatory perspective, the FDA was very much supportive of having two active arms to try and eliminate as much bias as possible in how the patients were thinking about the trial and whether they were highly motivated and focusing really hard to try and get better results if they knew they were treated. So the patients don't know which active arm they're in, And that's just as important for the Skyline trial, where they're also masked to low and high, as it is for VISTA. And for a registration-facing trial, the FDA would still want to have there to be two arms to eliminate that bias as much as possible. So that is one aspect of the trial that would not change as we move forward.
spk03: OK. And last question. So I believe you talked about this possibility of modifying the study design of VISTA based on the interim data analysis. So I just wanted to confirm if that's still the case. And if so, what could potentially be changed based on the interim data analysis?
spk02: Yes, I think we talked about this during the first portion of the call and later on in that What we want to be able to do is as data comes forward, and we're a very data-driven company, we always have the opportunity to have interaction with the FDA and make sure that we're all still comfortable we're moving forward. We would never want to get to the 12-month endpoint, which is the addressable endpoint, and wish we'd had interactions with the FDA. Okay. And as I said earlier, at the interim analysis of VISTA, we'll also have 12-month data from Skyline and 24-month data from the Phase I-II. So it's a robust set of data. And so if there's anything that we feel we would need to adjust or anything we could accelerate, such as dosing the contralateral eye earlier, such as, you know, slightly adjusting the number of patients, maybe our statistical power is stronger than we thought going in, we would have that interaction. But it's all going to be based on the data, and there's nothing specific that we would be looking to change. It would be based on the data, and then, as I said, at any time, based on that data, we would have interactions with the FDA.
spk03: Okay. Thank you very much.
spk07: Thank you. Our next questions come from the line of Zegba Chala with Roth Capital. Please proceed with your questions.
spk08: Good morning. Thanks for taking my questions. I think the first one is just to follow up to the previous question, and that's just regarding the potential to actually change the patient number for the VISTA study. I just want to know, is it possible to get any insights as to whether or not you will need that from any of the previous readouts, specifically maybe the Skyline 3-month or 12-month data? Could that be informative as well as to whether or not you may have the right power currently?
spk02: Thank you, Segla, and good morning. I think that it's premature to make any definitive statements about that until we have the data. Data is always very informative, but until we have that data, I would not want to predict what it may or may not allow us to do going forward.
spk08: Thanks, Sue. And then just to follow up here on another question, I'm just kind of curious as to why a phase six extension study is not being considered for the achromatopsia program to kind of help bolster the data, especially for the younger pediatric patient population? Or isn't it perhaps like familiarize the sites with the new baseline room of criteria to expedite the phase three study as you date for the XLR pre-program? And then how are you thinking about the robustness of the package for your chromatopoeia program versus the SLRP program ahead of your meeting with the FDA.
spk02: I don't think I understood. I apologize. I don't think I understood the first part of your question. I think there was interference on the line, but I think you were addressing what we are doing with sites and investigators as we prepare for the end of phase two. And so if that was the question, we are absolutely involved with all of our investigators as we plan for the end of phase two meeting. They know that we plan to move the Achromatopsia B3 program forward and are interacting with their patient base in that way. Our patient advocacy and patient enrollment teams are reaching out and working through our patient advocacy group connections to make sure patients are aware that we're planning to move the B3 program forward. And so I think we're moving forward with that in mind. We can't plan anything specific, however, until the end of phase two meeting with the FDA.
spk08: Thanks, Jen. I've got a clarification since my line was breaking up. I was just also wondering why an extension study was not being considered for the chromatopsia program like you did for the ex-op program, since, as you noted, Getting sites on board with the new enrollment criteria could help expedite the phase three study, for example.
spk02: So there's a lot of things that come into that historically. I think that we were less confident in exactly dosing when we decided to expand the Skyline study, and also we were adding the maze as a new endpoint. So we wanted to get some data on the maze as quickly as possible as we were going into the Phase 2-3 VISTA trial. In the case of achromatopsia, it seems very, very clear to us what the appropriate dose is, especially since it's the same dose that looks the best in achromatopsia as XLRT, which is not surprising because it is the same captured, same delivery method, same target cell type. So I think we have fewer questions that we want to gather more additional data on and so feel it's the best use of resources to have that in a phase two meeting and go directly into a phase two three.
spk08: And then the last one here is just about the commercial or pre-commercialization preparations. Can you comment on some additional efforts beyond, you know, obviously executing on the clinical study and preparing the manufacturing facility? And then I think just out of curiosity as well, is it possible that there could be some downtime at the manufacturing facility where you could manufacture products for other companies? I was just wondering how well utilized the space is going to be.
spk02: So on commercialization preparation, we're doing a lot of work with some third-party vendors to make sure that we understand the patient population distribution, we understand the feelings of and getting input from payers and physicians and patients. So we're doing a lot of work to prepare for development of a commercialization plan. As far as the manufacturing facility, you're absolutely correct. We will not. fully utilize the capacity of that facility with our own production. However, we do not want to in any way become a CDMO. That would not be a good utilization of our resources. But if we found some like-minded company that wanted to use some of the capacity We have been looking into that as a possibility, but just want to be clear, we have no change in strategy or any desire to become a CDMO.
spk08: Got it. Thank you so much, and congrats again on all the progress.
spk07: Thank you. There are no further questions at this time. I would like to turn the call back over to Sue Washer for any closing comments.
spk02: Thank you. Completing enrollment in the Skyline trial and reporting additional pediatric data for the achromatopsia program were important milestones that support continued advancement of our two lead clinical candidates. We believe that the data generated to date for both AGTC 501 and AGTC 401 de-risked their continued development and support differentiated product profiles that have been best in class potential. Additionally, while we do not provide an update on our preclinical pipeline programs today, we continue to make progress across the portfolio and are excited about the multiple opportunities these programs provide to address unmet patient need in a broader array of indications, including additional ophthalmic indications and central nervous system indications. Our collaboration with Autonomy on a program targeting non-syndromic hearing loss also continues to advance And we expect Nautonomy to begin toxicology and biodistribution studies this year to support filing of a new drug application IND in the first half of 2023. Our expanded management team has the expertise and dedication to build on our momentum and enhance our ability to realize the clinical and commercial value of our diversified pipeline. We remain grateful to the patients, physicians, and advocacy communities for their enthusiasm and support of our clinical trials. We expect to achieve additional milestones in our XLRP and achromatopsia B3 programs over the next 12 months that will firmly solidify our leadership in the inherited retinal disease gene therapy space, and I look forward to sharing our progress with you as we work to bring these therapies to patients whose lives will truly be brightened by our success. Thank you for joining us on today's call.
spk07: this does conclude today's teleconference we appreciate your participation you may disconnect your lines at this time enjoy the rest of your day
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