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spk16: Good morning and welcome to the ivericbio second quarter 2022 earnings conference call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the start key followed by zero. After today's presentation, there will be an opportunity to ask questions. Please note this event is being recorded. I'd now like to turn the conference over to Kathy Galante. Please go ahead.
spk01: Good morning and welcome to ivericbio's conference call. Representing Ivericbio today are Mr. Glenn Slendorio, Chief Executive Officer, Dr. Praveen Dougal, President, Keith Westby, Chief Operating Officer, David Carroll, Chief Financial Officer, Dr. Devil Desai, Chief Development Officer, Chris Sims, Chief Commercial Officer, and Tony Gibney, Chief Business and Strategy Officer. I would like to remind you that today we will be making statements relating to Ivericbio's future expectations regarding operational, financial, and research and development matters. These statements constitute forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. These statements cover many events and matters that are subject to various risks that could cause actual results to differ materially from those expressed or implied in any forward-looking statement. I refer you to our SEC filings and in particular to the risk factors included in our quarterly report on Form 10-Q, filed on May 4, 2022, for a detailed description of the risk factors affecting our business that could cause actual results or events to differ materially from the forward-looking statements that we make. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we disclaim any obligation to do so as required by law. I would now like to turn the call over to Glenn.
spk08: Thanks, Kathy, and good morning, everyone. Thank you for joining us for our second quarter conference call. We're excited to share that today marks the one-year point since we completed patient enrollment of GATHER2, our second Phase III clinical trial for Zamora, a novel C5 complement inhibitor. for the treatment of geographic atrophy, or GA. We look forward to reporting the top line data gathered to in September of this year, approximately one year after enrolling of the last patient, plus the time needed for database lock and analysis. Our team executed well all year as we continue to exceed our expectations for patient retention and injection fidelity, which we believe further de-risk gathers to and is an integral part of the clinical trial outcome. Keith will discuss this important data in a moment. Now let's discuss our expectations for reporting the upcoming GATHER2 top-line data. Once available, we will report the preliminary, the pre-specified primary efficacy endpoint analyzed by the mean rate of GA growth or the slope estimated based on GA area measured by fundus, in at least three time points, baseline, six months, and 12 months, calculated by using the square root transformation of the GA area. This is consistent with our written agreement with the US Food and Drug Administration, or the FDA, under a special protocol announcement, or SBA. In addition, we will present the same data with a point analysis. We will also report a summary of the safety profile including potential cases of choroidal neovascularization, CNV, as reported in the traditional manner, commonly defined in the retinal community as choroidal neovascular membrane, or CNVM. While the FDA did not request potential CNV cases to be reported using the non-traditional, recently defined terms such as exudative versus non-exudative CNV, we plan to also provide these data. For detailed definition of exudated and non-exudated CMV, as defined by the Center for Ocular Research and Evaluation, also known as CORE, at the Cole Eye Institute of the Cleveland Clinic, please see our Form 8K on April 4, 2022. In addition to CMV, we plan to also provide rates of potential inflammation and endophthalmitis, if any. As a reminder, we received a written agreement from FDA under an SPA for the overall design of Gather 2 in July of 2021. For those who may not be familiar, the SPA process is a procedure by which the FDA provides a clinical trial sponsor with an official evaluation and written guidance on the design of a proposed protocol intended to form the basis for a new drug application or NDA. If the results from Gather 2 are positive, our key objective and plan is to make Zmora commercially available to physicians and their patients with GA as quickly as possible, obviously assuming regulatory approval. Therefore, we have already began to assemble an NDA. Following a potential positive outcome of Gather 2, we plan to submit applications with the FDA and the European Medicines Agency for marketing approval of Zamora for GA. We're also very excited to have entered into a license agreement with Delta Tech, providing us a worldwide exclusive license to develop and commercialize the sustained release formulation of Zamora using Delta Tech's silica-based sustained release technology. Praveen will discuss this in more details in a moment. On the corporate front, earlier today, we announced that we have an agreement for up to $250 million in non-dilutive debt financing with Hercules and Silicon Valley Bank under a term loan debt financing facility. This non-dilutive financing further strengthens our balance sheet and provides flexibility as we look to finance the potential launch of Zamora. Dave will provide more details in a few moments. We continue to focus on the execution and bringing Zamora to patients suffering from this horrible disease geographic atrophy as our top priority. I will now turn the call over to Keith.
spk19: Thank you, Glenn, and good morning, everyone. As Glenn mentioned, we are thrilled to have reached the one-year mark since the completion of patient enrollment in GATHER2, in which 448 patients were enrolled across 209 global sites. We are extremely excited to report that patient retention for the GATHER2 clinical trial, as measured by the injection fidelity rate, was 92.5% through month 12, above our month 12 target goal of greater than 90%. As a comparison, the 12-month injection fidelity rate for our GATHER1 trial, in which we observed a statistically significant reduction in GA progression at 12 months, was 87%. We are encouraged to see that our efforts to maximize patient retention in the GATHER-2 clinical trial have resulted in even greater patient retention than was observed in GATHER-1 through the same time period. Injection fidelity is calculated by dividing the total number of actual injections, drug and sham, for all patients by the total number of expected injections, drug and sham, based on the total number of patients enrolled in that trial. We consider injection fidelity to be the most important and stringent measure of patient retention because it reflects the timely administration of study drug into the patient's eye. We believe patient retention is an integral part of the GATHER2 outcome. We focus heavily on injection fidelity, not only to de-risk and protect the integrity of our data, but also to potentially observe the early and increasing reduction in GA growth that we previously observed in Gather 1. We expect top-line Gather 2 data to be available in September of this year, approximately one year after the enrollment of the last patient, plus the time needed for database lock and analysis. We are actively working internally and with our third-party vendors to prepare for the Gather 2 database lock to be as efficient as possible. Patient enrollment in STAR our Phase IIb screening clinical trial of Zymora for the treatment of autosomal recessive Stargardt disease is ongoing. The results of this trial are expected after the top-line results of GATHER2. Turning to IC500, our HTRA1 inhibitor, we initiated a number of preclinical tolerability and pharmacokinetic studies last year, and we are planning for IND-enabling toxicology studies. We expect to submit an Investigational New Drug Application, or IND, to the FDA for IC500 during mid-2023. Thank you for your time. I will now turn the call over to Double. Thank you, Keith.
spk10: As Keith mentioned, we expect Topline Gather 2 data to be available in September of this year. Following the Topline announcement, we are thrilled to have the opportunity to present the top-line data at the American Academy of Ophthalmology meeting on Friday, September 30th of this year. Earlier this month, we were excited to share the results of a post-hoc analysis from GATHER-1, evaluating response based on location of GA lesions at baseline. We observed that 84.4% of GA lesions were within 500 microns of the foveal center point at baseline, and that 28.3% of GA lesions were within 100 microns of the foveal center point at baseline. These findings were generally balanced across all three treatment arms and their corresponding sham control groups in this study. The GATHER-1 results in which Zamora was observed to have a greater reduction of GA lesion growth as compared to sham occurred with the vast majority of patients having lesions close to the foveal center point. The post hoc analysis was presented at the American Society of Retina Specialists annual meeting earlier this month after David Lally of New England . These data are consistent with previous post hoc analysis of the GATHER-1 trial, which were presented at the angiogenesis meeting and the Retinal World Congress earlier this year. Data from this post-hoc analysis are also consistent with the results of our previously reported pre-specified analysis of Zamora from the GATHER-1 trial, demonstrating a reduction in GA lesion growth compared to Shan observed regardless of lesion size or distance to the foveal center point. Thank you for your time. I will now turn the call over to Praveen.
spk18: Thank you, Devil. The multiple post-hoc analyses from GatherOne, which have been presented at medical conferences around the world, continue to provide consistent results, which gives us a great deal of confidence in the robustness of the GatherOne data. Nice work by you and your team. Turning to our lifecycle expansion for Zamora, we previously reported post-hoc analyses from GatherOne suggesting that Zamora may have the potential to impact age-related macular degeneration, AMD, earlier stages before atrophy occurs in patients. As part of this plan, we are pursuing multiple sustained release technologies for Zamora for the treatment of GA and earlier stages of AMD. A few weeks ago, we entered into a license agreement with Delsatec, a Finnish company with a platform of silica-based drug delivery technologies under which we obtained a worldwide exclusive license to develop and commercialize new formulations of Zmora using Deloxilica-based sustained release technology. These technologies potentially could address patients being treated for GA in potentially earlier stages of AMD, such as intermediate AMD. We believe Zmora, which is a chemically synthesized RNA aptamer, is amenable to injectable sustained release formulations. This agreement underscores our commitment to invest in the lifecycle initiatives for Zmora. We are excited about the possibilities to expand Zmora into earlier stages of AMD and potentially allow for a next generation treatment to help patients with GA. Looking ahead, potential of Zmora. we plan to continue to invest in additional lifecycle initiatives for Zamora to expand the patient population with additional indications and continue to evaluate multiple technologies for Zamora. Furthermore, we plan to explore the potential for Zamora in earlier stages of AMD by initiating a clinical trial studying the current formulation of Zamora in patients with intermediate AMD in the fourth quarter of this year. The development strategy in this indication is subject to regulatory feedback from the FDA and other regulatory authorities, which we plan to obtain before initiating this trial. Thank you all for your time and support. I will now turn the call over to Dave.
spk20: Thank you, Praveen, and good morning, everyone. I'd like to highlight a few items from our press release of this morning and provide some guidance on our new credit facility and our expected year-end cash balance. For the quarter, our net loss totaled $49.3 million, or $0.41 per share, compared to a net loss of $30.1 million, or $0.32 per share, for Q2 2021. This increase in net loss was driven by increases in both R&D and G&A expenses. R&D expenses increased primarily due to the continued progress of the Gather 2 trial, increased manufacturing activities for Zamora, and increases in personnel costs, including share-based compensation associated with additional R&D staffing. G&A expenses increased primarily due to increases in personnel costs, including share-based compensation associated with increased staffing for a potential commercial launch. Turning to our balance sheet and our expected year-end cash balance, as of June 30th, we had cash, cash equivalents, and available-for-sale securities of approximately $312 million. Under terms of our new credit facility, the company is borrowing $50 million today. We now estimate that our year-end cash, cash equivalents, and available-for-sale securities will range between $260 and $270 million. The credit facility provides us with access to up to an additional $150 million in total, subject to our achievement of specified development and regulatory performance milestones for Zamora. An additional $50 million is available to us subject to Lenders' approval. We would view this additional $50 million as a potential source of working capital, again, assuming approval. We believe that this credit facility provides us with additional financial flexibility tied to major de-risking milestones at a lower cost of capital than equity. We intend to provide further details about our financing strategy to support launch following data release. Thank you for your time, and I'll now turn the call back over to Glenn.
spk08: Okay, thanks, Dave. And before we open up the lines for questions, I wanted to recap a very productive quarter. First, today is the one-year point for Gather 2. Over the coming weeks, we will analyze the data and lock the database, and we'll report Gather 2 data to you in September. We have also outlined what top-line data will be available in September. Second, we have entered into an exclusive license agreement with Delta Tech to develop and commercialize a sustained release technology. And finally, as Dave just mentioned, we entered into a credit facility that provides us with up to $250 million of non-dilutive capital, with $50 million coming today in the balance that is tied to de-risking milestones. So I want to thank you all for listening, and operator, I'd like to ask you to open up the line for questions.
spk16: Thank you. We'll now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. At this time, we'll pause momentarily to assemble our roster.
spk25: Our first question comes from Mike Oltz from Morgan Stanley.
spk16: Please go ahead.
spk06: Hey, guys. Thanks for taking the question, and congrats on all the progress here. Just in terms of the top line results, thanks for providing all the color and the detail on what we should expect. Just curious, the primary endpoint you mentioned providing both the slope and point analysis. If we think about that, should we expect those two analyses to be meaningfully different? Thanks.
spk10: Hey, Mike, this is Double. So if you look back on the GATHER1 data, and when we did the point in the slope analysis, you saw that there wasn't really a big difference between the two. And we think that's mainly due to the fact that the growth is pretty linear on these lesions. And so we don't expect there to be a big difference between the two analyses in GATHER2 either.
spk16: Got it. Thank you. The next question comes from Annabelle Simimi from Stiefel. Please go ahead.
spk04: Hi, and thanks for taking my question. So I just want to go back to some of the data that you mentioned had been presented at the Retina World Congress as well as ASRS regarding the, I guess, the distance from the phobia. So clearly natural history indicates faster progression the further you get from the center of the phobia, and Zymora has also consistently shown more efficacy you know, the further you move from the center as well, I think probably because of the metabolic rate of these lesions. So, can you share with us whether the enrollment criteria for GATHER-1 is, or GATHER-2 is the same as GATHER-1, and what are your suspicions about how you might be able to replicate this data given what you know about the slopes analysis now?
spk08: So, Annabelle, it's Glenn. Good morning, and thank you for the question. So, we have Double here today and also Praveen. I'll let Double take the first part of that, and then I'll ask Praveen to comment as well.
spk10: Yeah, Annabelle, so maybe just I'll take the first one first. So in terms of enrollment criteria, nothing different in terms of Gather 1 and Gather 2, specifically as it relates to lesion distance. Just to recap for you, you know, the two main criteria here are, one, disease cannot touch the center point of the fovea, and then second, some part of the lesion needed to be within 1.5 millimeters of the foveal center. That was the enrollment for GRAVID 1. It's the same thing for GATHER 2. In terms of whether or not 1 and 2 are going to look similar, we haven't seen the data for GATHER 2, so it's hard to kind of make a judgment call on that. What I can tell you is that if you look at the types of patients that typically hang around retina offices that are referred from tertiary care, they typically tend to be the ones that look like GATHER 1, and we would expect that to be the same case in GATHER 2.
spk27: Praveen?
spk18: Annabelle, good morning. This is Praveen. So thanks for the question again. So here are the take-home points from these post-hoc analyses that you refer to, I think. One is that Zamora works regardless of the location of the lesion, but it will work better in earlier lesions as witnessed by lesions that are further away. So that's take-home point number one. Take-home point number two, I think, is that in GATHER1, the lesions that were there were fairly severe. Most of these patients, as Avil said, had lesions that were right near the center point. So perhaps our idea of saying extra foveal should be recapitulated now. Maybe we should start saying non-center point because these lesions were really quite close to the center of the fovea. And also realize that most of these patients had bilateral lesions. So These lesions were really quite severe and the patients were quite severe. So although the inclusion criteria is exactly the same in GATHER2 as in GATHER1, we're also hoping that if we can get lesions that are a little bit of an earlier stage, that delta will be even higher. As you've seen in that ASRS analysis, there's a very clear difference between the delta of treatment versus sham the further you go and the earlier lesion that you get. So we're hoping that lesions will be a little bit earlier. Again, We have no way of knowing that because we're completely masked. But at the end of the day, the main point here, I think, is that lesion, the more that works, regardless of where the lesion is. But in GATHER1, the vast majority of the lesions were right next to the center point.
spk04: Great. That was helpful for the color. And just to go back to the question about the points analysis versus the slips analysis, I guess part of the reason why there wasn't such a difference is because you didn't have a tremendous amount of variability in the patient. So if we look at GATHER-2, is it possible the earlier you go, the more variability you might have and the points analysis might be different from the slopes analysis? So how should we think about variability versus, you know, in terms of these points and slopes analysis, analyses?
spk10: Yeah, so Annabel, this is Double. So what I'd say is that I don't think we're going to see much of a difference, as I mentioned previously, from the population in Gather 2 that we saw in Gather 1 to begin with. So, again, I think the full expectation amongst the folks at the company is that the results between those two analyses shouldn't differ very much based on what we saw in Gather 1. Praveen, any additional comment?
spk18: Yeah, I would agree with you. I'd say the same thing, Annabelle. The variability really comes from the patient population as opposed to the lesion location. And what we've done is to really limit the variability in the patient population. As you know, as has been shown earlier and by others as well, the patients that we picked, which now we'll call non-centrophobia involving, were exactly the right patients to pick. And those are the same patients that we expect in GATHER2 that will be the same patients in GATHER2 as GATHER1. So the variability, again, comes from the patient selection, not so much from the lesion. So we don't expect really any difference.
spk03: Okay, great. Thanks so much.
spk16: The next question comes from Greg Harrison from Bank of America. Please go ahead.
spk17: Good morning. Thanks for taking our questions. So when we see the data for Gather 2, is there a percentage change that you feel would correlate well with clinical benefit? Just trying to think if any statistically significant benefit is sufficient, not only for approval, but also for your competitive position in the market.
spk08: Greg, thanks for the question. Praveen, you want to take that one?
spk18: Yeah, sure. Greg, good morning and thank you for the question. I think the main thing to do is to keep two silos very, very clear. One silo is the regulatory pathway and the other silo would be, I think, what you're asking, which is what would be the functional benefit to the patient and to payers and to physicians that one can communicate with. So let's keep those two a little bit separate at this point, although I realize that they're interrelated. As far as the regulatory pathway is concerned, it couldn't be clearer. We have a SPA agreement with the FDA So all we have to do is to hit the primary endpoint for purposes of submission. So the regulatory pathway via the SPA agreement, I think, is absolutely clear. The second question, which is also quite important and germane, which is what about the functional benefit for patients? How do payers react to this? What is it that physicians are going to say? Having practiced retina for over 26 years, I'll tell you, patients are not necessarily going to understand or care about the percentages relating to function or the square root transformation or anything else. What they are going to understand is they're going to understand preservation of central vision and time. And what I mean by that is that we know from extensive studies that once you start getting geographic atrophy, within a matter of two years, over 60% of patients lose driving vision. Now, we know that in four or five years, most of these patients will have completely obliterated central vision. So the currency of language that everybody understands is that of time. So what we'll be able to show data for, because of the patients who we've selected who are non-central point involving, what we can say is if you take this treatment, you'll be able to drive for X years longer. You'll be able to read for X years longer or work for X years longer. And I think that's the currency of language that patients will understand, payers will appreciate, and certainly physicians will use as a currency of communication.
spk17: Got it. That's helpful. And then one other, how much of the filing has been completed at this point and can be completed ahead of having the final Gather 2 data? And how would the timing here compare with a typical timeline after phase three.
spk08: Yeah, Greg, hi. It's Glenn. So, as we mentioned in the past, the regulatory team has been working on the data that they have available, which is Gather 1. Having that, I think, gives us a real good head start on completing the following once we see the data from Gather 2. So, we haven't specified timing. It really will be dependent on what the Gather 2 data looks like. you know, which will, you know, kind of round out our strategy on the regulatory path forward. So, when we have that data, we'll consider giving guidance on the filing strategy. It's very important. It is a competitive situation, so we know timing for investors is important. But right now, to answer that question, we really need to see the Gather 2 data. Male Speaker 1 Great.
spk12: Thanks for taking the question.
spk16: The next question comes from Ken Cacciatore from Cowan & Company. Please go ahead.
spk15: Hey guys, real exciting time. Excited to see the data in September. Just wanted to ask about the extended release formulation. Real potential commercial advantage that you might have if you're able to move this forward. Obviously be real beneficial for patients. Praveen, I know you talked about some of the unique characteristics of Zamora. Maybe you could flush it out just a little bit more. that you think make it real amenable for an extended release. If you would like, it would be interesting if you could compare to Apellis. We've not heard of them moving forward with an extended release. So if you were willing to maybe compare and contrast why they may be behind, that would be interesting. And also, maybe you could bring Delsa Tech to life a little bit, how long you all have been working with them. Clearly going to be a very important partner to you all. Can you talk about them and maybe a little bit of their history and success in developing extended release formulations? And then maybe timing to get into clinic would be interesting. Thanks so much.
spk26: Praveen, you want to start?
spk18: Sure. Ken, good morning and thank you for the questions. So first of all, regarding our molecule, it's an RNA aptamer and there's a really big advantage to an RNA aptamer. Not only is it a small molecule, so the capacity for loading is going to be greater, but But being an RNAptimer as opposed to a protein, it can be completely denatured and renatured and be fully functional. So that's a huge advantage for a sustained delivery type strategy. We believe that this has advantages over our competitors. Again, I'd rather not speculate about the competitors. You can certainly ask them, but I do believe that we have a significant advantage here because of our molecule. In regards to Delsatec and other strategies that we're looking at, there are certain characteristics that were important for us. First of all, it had to be loadable to a capacity that allowed for a sustained release, and it certainly checked that box. It had to be tunable, and what I mean by that is that in the natural history of macular degeneration, depending on where we target the disease, the release characteristics may need to be different. In other words, the way that the release characteristics would be optimal for drusen, for instance, may be a little different than for more advanced geographic atrophy. So the release characteristics have to be tunable. Obviously, it had to be safe, and then it had to be scalable. So with Delsatech, with the preliminary studies that we did, we were quite confident that this fit all the boxes and that this would be a very, very good strategy. Having said that, I must also say that it's not going to be the only strategy. Obviously, we're looking at other strategies as well. Our intention, as I've stated many times and as Glenn has as well, is to be the retina company for all of macular degeneration and other retinal diseases. So not just geographic atrophy, but for earlier stages of macular degeneration. And what this sustained delivery strategy allows us to do is it opens up a new target of patients with earlier stages of macular degeneration and certainly allows for us to make the geographic atrophy patients be treated in a way that's much more sustainable as well. Thank you for the question, Ken.
spk16: The next question comes from Eddie Hickman from Guggenheim Securities. Please go ahead.
spk05: Good morning, and congrats on all the progress. I'm looking forward to seeing the data soon. Just two from me. Can you confirm what the SPA agreement says specifically about GATHER-1? Does it confirm that it sees it as a supportive study, or have they agreed to analyze them together as co-registrational studies? Does the SPA say anything about that? And then secondly, based on your physician feedback and experience with monthly anti-VEGF, is there sort of an expected rate of inflammation or endo-optimitis that might be expected just for monthly intravitreal injections, and has the FDA ever commented on what those acceptable levels may be from a safety perspective? Thank you.
spk08: Eddie, thank you. Maybe we'll work backwards. We have some logistics we're trying to manage today, so Dub will take the second question first, and then Praveen will take your initial question.
spk10: Yeah, Eddie, thanks for the question. So in terms of physician feedback on rates of endophthalmitis and inflammation, you know, the easy answer to that is they want it to be zero. But if you look at, you know, kind of commonly prescribed retina therapeutics that are out there, you know, roughly in that one to less than 1% range is kind of where we see inflammation and less than 1% certainly for endophthalmitis is where we typically look. um for for safe drugs and so so that's kind of the number that we have in our mind and at the end of the day the number is going to be the number whatever it's going to be but that's what we're generally understanding in terms of um the physician feedback on inflammation and and ophthalmitis i will give it back to glenn for the spa agreement ravine you want to take that i mean you had first-hand conversations with the regulators sure glenn i'll be happy to do that and eddie good morning and thank you for the question
spk18: So what I would say regarding SPA agreement is there are a couple of take-home messages that are really important here. First of all, the FDA advised us to apply for a SPA agreement. And this was done when the GATHER-2 study was half-recruited. So what that should tell us is the level of alignment and the level of confidence the FDA had in the earlier discussions we had with them, albeit all informal. So that's the first take-home message. The second one is after having gone through the entire spa process, which, as you know, involves an army of statisticians and clinical trialists and so forth, they agreed on everything that was there. The only thing that they wanted slightly changed was they wanted a slope analysis. In other words, they wanted us to assume a constant rate of growth. We hadn't assumed anything at all. nothing else was commented upon they agreed with the with the endpoint they agreed with the mixed random effects model as well as a sample size all of those things and as you know we're happy to do that that really didn't change anything as for a gather one however the spa agreement really is for one study only and that was gathered to the FDA had really no obligation to comment on gather one however they went out of their way to comment on gather one and what they said is was that they were in agreement that our pre-specified analysis was absolutely valid. They also thought that their preferred analysis was absolutely valid. And when the application is made, they will look at GATHER-1 and GATHER-1 in both ways with the pre-specified analysis as well as the preferred analysis. So we are very confident, because the FDA has commented on Gather 1 and given us a for Gather 2, that they're very well aware of the entirety of the program. And both the programs together will be certainly valid for submission.
spk08: And Eddie, what I'll add to that is you can go back to our prior press release where we did both calculations for Gather 1, the pre-specified plus the FDA preferred analysis. and what you will see is consistency in the rates of efficacy there. And happy to provide that if you don't have access to it.
spk05: Joshua, thanks. And actually, one final one. When it comes to the CNV versus sort of exudations, do you plan to have at the top line release any data from the Cole Eye Institute, or are you expecting the primary readers in the study to be evaluating CNV in the way that it was done in a post-hoc manner by the Cleveland Clinic, or will it be done by Duke?
spk08: Great question, Eddie. Praveen, do you want to cover that?
spk18: Sure, I'll be happy to. So, Eddie, the fact of it is that I don't know if there'll be much difference at all because our definition is very, very clear, but our plan at this point is to continue to use the Duke Reading Center as the primary point of analysis for a core neovascular membrane formation as per the definition that is traditional and as they defined it in Gather 1. Now, we also had the Gather 1 analysis done by the Core Reading Institute, and the reason for that is because the Duke was no longer masked to that data. And we wanted to make sure that the reading center that defined and will look at the exudation rates remains completely masked. Therefore, I don't think that analysis plan is going to change at all for Gather 2.
spk23: Great. Thank you so much.
spk16: The next question comes from Kambi Yazdi from Jefferies. Please go ahead.
spk14: Hi, team. Good morning. Kambi's on for Chris. A few questions for me. Do you plan to do an EMA filing as well as an FDA filing? What are kind of the differences in those two agencies' stances on GA therapies? Second question, what was the relative performance of DeltaTek sustained release technology versus some of the other options you considered? Third question, what IMD endpoints are you going to propose to the FDA for intermediate IMD? And I'll pause there. Thank you.
spk08: Okay, great question. So I'll ask, we'll go backwards. Keith, do you want to talk a little bit about the DeltaTek technology first, and then we'll address the other questions.
spk19: Sure, happy to do that. Thanks, Camby, for the question. So in terms of Delsatec, I know Praveen talked a little bit about it, but there were a number of factors that we looked at in terms of feasibility. But really, the silica-based gel is really important for us because the Aptimer, again, is very compatible with that. So the number of things that we looked at in terms of loading, in terms of tunability, you know, and we've also done a number of other feasibility studies with a number of other companies. So as we continue to move on, I'm sure we'll put out additional data here, but this, again, won't be our only, this is not our only plan here. We're looking to do additional drug delivery efforts around Zamora.
spk08: Thanks, Keith, and I'll take the next two questions. First, on the regulatory filing strategy, as mentioned this morning in our conversation, we do plan to submit a filing to the EMEA that will follow the NDA that we file. We have engaged experts and advisors in Europe to help us through that process and that planning for EMEA, but it is our expectation that we will have a filing We have not defined the timing just yet. The question related to endpoints for intermediate AMD, also a very good question. As you know, we had said we will engage with FDA prior to starting any trial with intermediate AMD. We believe the strategy may be a collection of different endpoints. And I think the best way to handle that is we need to have the discussion with the regulators first. and then get back to you on the results of those discussions. It's a little bit hard to put bookends around that right now, but obviously the team has many ideas, and we're looking forward to our discussion with FDA.
spk14: Awesome. Thank you so much, Glenn. And then maybe as one final follow-up, from a functional perspective, going back to that kind of distance from fovea analysis, How does, can you help us understand how a patient with GA lesions about like, you know, 100 microns from the center is different than, you know, 500 microns from the center versus, of course, foveal and then kind of the time it would take to progress from 500 microns to 100 microns and then all the way to the central vision? Thank you. That's my final question.
spk08: Sure, thanks. Again, very good question. I'm going to ask both Dovel and Praveen to comment on that. Dovel will begin.
spk10: Yeah, thanks for the question. So if you think about distance from the foveal center and kind of how a patient perceives that, you just think about, you know, kind of looking into a kaleidoscope, right? And then the closer that lesion is to the foveal center, just imagine not seeing black spots right near the middle. And then if they're further away, you kind of see it more out in the periphery. So obviously, the closer it gets to that center point, the more of your functional vision gets impaired. In terms of the progression of those lesions, it's highly variable. And that's one of the things about this disease that really leaves us to think we need to treat it early and we need to get after it as aggressively as possible. Because depending upon the size of your lesion at baseline, the distance, what kind of banding pattern, they can all grow at different rates. So it's hard to say on average, what will a lesion grow, how fast will it go from 500 to 100 microns away? Praveen?
spk18: Yeah, you know, what I would say is I think there's very good evidence now that what we traditionally think of as an endpoint, which is visual acuity, is not a good endpoint for visual function. What we have, what you can have, for instance, is excellent visual acuity, but still have terrible visual function. And If you think of how visual acuity works, you're in a dark room with a bright light at the end. And, you know, life is rarely like that. And if you think about your day today, you're really not going to have that situation at all or very little if at all. So the regulatory agencies and other agencies do recognize that. there are other functional parameters that are really important. And if you wonder how it affects a patient's day-to-day life, if you wear glasses, all you have to do is take a little scotch tape and put it a little bit off-center, in the bottom or on the sides, and what you'll realize is that you simply can't function. So even if you're 500 microns away or further, what you'll find is that there are lots of patients out there who are visually dysfunctional with lesions even though it seems further away. It could, for instance, be an architect that may not be able to see a straight line in the upper corner. It could be a lawyer who may not be able to read a sentence because of a dark spot. So there are lots of patients out there that are visually dysfunctional. These patients are quite desperate to stop that lesion from progressing. And how fast is it progressing? Well, you know, we know from studies, as I mentioned earlier on, that in a matter of time, two years to lose driving vision, about five or six years to lose complete oveal vision. So what we can offer with Zumora version one in the GA patients is to be able to say, look, if you take this treatment, this is how much time you will have to continue to function and do your functional activity. And hopefully what we can do is go even earlier and not just slow down the rate of death, but to prevent death altogether. And that really would change the trajectory of the disease.
spk02: Awesome. Thank you so much.
spk16: We have time for one more question, and that's from Colleen Cussey from Baird. Please go ahead.
spk28: Great. Good morning. Thanks so much for taking our questions, and congrats on the progress. So in the 8K, it says the criteria for the next tranche of debt financing is meeting the primary endpoint and the data are supportive of filing. Can you talk about whether those are actually two different things? And anything else you can say on what will be considered sufficient clinical data package to support submission? And can you just confirm that the SPA says p-value of 0.05 would be the threshold for significance? Thank you.
spk08: Well, thanks, Colleen. I'll let Dave take the first question. So thanks for the question, Colleen.
spk21: Yes, it is. That's our position there.
spk08: That's an easy answer. Colleen, on the SPA agreement, double .05, can you confirm that? Yeah. Yeah, it is. And, Colleen, there was one other question mixed in there, I think. Did we hit it all?
spk28: So I think the question was if those are two different things, me and the primary endpoint, and the data are supportive of filing. And the response was yes, those are two different things.
spk07: Just a quick question. Okay. Thanks, Colleen. Appreciate the question.
spk16: There are no more questions in the queue. This concludes our question and answer session. I would like to turn the conference back over to Glenn Splendorio for any closing remarks.
spk08: Well, thank you, Operator, and thank you, everybody, for listening to the call this morning. As I mentioned before, great progress in the last quarter, and we're quite excited that we have reached the one-year point with Gather 2. And we look forward to a conversation in September about that data. Have a great day everybody. Bye bye.
spk16: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect. © transcript Emily Beynon you Thank you. Thank you. Thank you. Thank you. Good morning and welcome to the ivericbio second quarter 2022 earnings conference call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the start key followed by zero. After today's presentation, there will be an opportunity to ask questions. Please note this event is being recorded. I'd now like to turn the conference over to Kathy Galante. Please go ahead.
spk01: Good morning, and welcome to iVericBio's conference call. Representing iVericBio today are Mr. Glenn Slendorio, Chief Executive Officer, Dr. Praveen Dougal, President, Keith Westby, Chief Operating Officer, David Carroll, Chief Financial Officer, Dr. Devil Desai, Chief Development Officer, Chris Simms, Chief Commercial Officer, and Tony Gibney, Chief Business and Strategy Officer. I would like to remind you that today we will be making statements relating to ivericbio's future expectations regarding operational, financial, and research and development matters. These statements constitute forward-looking statements for purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. These statements cover many events and matters that are subject to various risks that could cause actual results to differ materially from those expressed or implied in any forward-looking statement. I refer you to our SEC filings, and in particular to the risk factors included in our quarterly report on Form 10-Q, filed on May 4, 2022, for a detailed description of the risk factors affecting our business that could cause actual results or events to differ materially from the forward-looking statements that we make. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we disclaim any obligation to do so as required by law. I would now like to turn the call over to Glenn.
spk08: Thanks, Kathy, and good morning, everyone. Thank you for joining us for our second quarter conference call. We're excited to share that today marks the one year point since we completed patient enrollment of GATHER2, our second phase three clinical trial for Zamora, a novel C5 complement inhibitor for the treatment of geographic atrophy or GA. We look forward to reporting the top line data GATHER2 in September of this year, approximately one year after enrolling of the last patient plus the time needed for database lock and analysis. Our team executed well all year as we continue to exceed our expectations for patient retention and injection fidelity, which we believe further de-risk gathers too and is an integral part of the clinical trial outcome. Keith will discuss this important data in a moment. Now let's discuss our expectations for reporting The upcoming Gather 2 top line data, once available, we will report the preliminary, the pre-specified primary efficacy endpoint analyzed by the mean rate of GA growth or the slope estimated based on GA area measured by fundus hortofluorescence in at least three time points, baseline, six months, and 12 months, calculated by using the square root transformation of the GA area. This is consistent with our written agreement with the US Food and Drug Administration, or the FDA, under a special protocol announcement, or SBA. In addition, we will present the same data with a point analysis. We will also report a summary of the safety profile, including potential cases of choroidal neovascularization, CNV, as reported in the traditional manner, commonly defined in the retinal community as choroidal neovascular membrane, or CNVM. While the FDA did not request potential CNV cases to be reported using the nontraditional recently defined terms such as exudative versus nonexudative CNV, we plan to also provide these data. For detailed definition of exudated and nonexudative CNV, as defined by the Center for Ocular Research and Evaluation, also known as CORE, at the Cole Eye Institute of the Cleveland Clinic, please see our form 8K on April 4th, 2022. In addition to CNV, we plan to also provide rates of potential inflammation and endophthalmitis, if any. As a reminder, we received a written agreement from FDA under an SPA for the overall design of GATHER2 in July of 2021. For those who may not be familiar, the SBA process is a procedure by which the FDA provides a clinical trial sponsor with an official evaluation and written guidance on the design of a proposed protocol intended to form the basis for a new drug application or NDA. If the results from Gather 2 are positive, our key objective and plan is to make Zmora commercially available to physicians and their patients with GA as quickly as possible, obviously assuming regulatory approval. Therefore, we have already began to assemble an NDA. Following a potential positive outcome of Gather 2, we plan to submit applications with the FDA and the European Medicines Agency for marketing approval of Zamora for GA. We're also very excited to have entered into a license agreement with Delta Tech providing us a worldwide exclusive license to develop and commercialize the sustained release formulation of Zamora using Delta Tech's silica-based sustained release technology. Praveen will discuss this in more details in a moment. On the corporate front, earlier today we announced that we have an agreement for up to $250 million in non-dilutive debt financing with Hercules and Silicon Valley Bank under a term loan debt financing facility. This non-dilutive financing further strengthens our balance sheet and provides flexibility as we look to finance the potential launch of Zamora. Dave will provide more details in a few moments. We continue to focus on the execution and bringing Zamora to patients suffering from this horrible disease, geographic atrophy, as our top priority. I will now turn the call over to Keith.
spk19: Thank you, Glenn, and good morning, everyone. As Glenn mentioned, we are thrilled to have reached the one-year mark since the completion of patient enrollment in GATHER2, in which 448 patients were enrolled across 209 global sites. We are extremely excited to report that patient retention for the GATHER2 clinical trial, as measured by the injection fidelity rate, was 92.5% through month 12, above our month 12 target goal of greater than 90%. As a comparison, the 12-month injection fidelity rate for our GATHER1 trial, in which we observed a statistically significant reduction in GA progression at 12 months, was 87%. We are encouraged to see that our efforts to maximize patient retention in the GATHER2 clinical trial have resulted in even greater patient retention than was observed in GATHER1 through the same time period. Injection fidelity is calculated by dividing the total number of actual injections, drug and sham, for all patients by the total number of expected injections, drug and sham, based on the total number of patients enrolled in that trial. We consider injection fidelity to be the most important and stringent measure of patient retention because it reflects the timely administration of study drug into the patient's eye. We believe patient retention is an integral part of the gathered true outcome. We focus heavily on injection fidelity, not only to de-risk and protect the integrity of our data, but also to potentially observe the early and increasing reduction in GA growth that we previously observed in GATHER1. We expect top line GATHER2 data to be available in September of this year, approximately one year after the enrollment of the last patient, plus the time needed for database lock and analysis. We are actively working internally and with our third-party vendors to prepare for the GATHER2 database lock to be as efficient as possible. Patient enrollment in STAR, our Phase IIb screening clinical trial of Zamora for the treatment of autosomal recessive Stargardt disease, is ongoing. The results of this trial are expected after the top-line results of GATHER2. Turning to IC500, our HTRA1 inhibitor, We initiated a number of preclinical tolerability and pharmacokinetic studies last year, and we are planning for IND-enabling toxicology studies. We expect to submit an investigational new drug application, or IND, to the FDA for IC500 during mid-2023. Thank you for your time. I will now turn the call over to Double. Thank you, Keith.
spk10: As Keith mentioned, we expect top-line GATHER2 data to be available in September of this year. Following the top line announcement, we are thrilled to have the opportunity to present the top line data at the American Academy of Ophthalmology meeting on Friday, September 30th of this year. Earlier this month, we were excited to share the results of a post hoc analysis from GatherOne. evaluating response based on location of GA lesions at baseline. We observed that 84.4% of GA lesions were within 500 microns of the foveal center point at baseline, and that 28.3% of GA lesions were within 100 microns of the foveal center point at baseline. These findings were generally balanced across all three treatment arms. and their corresponding sham control groups in this study. The GATHER-1 results in which Zamora was observed to have a greater reduction of GA lesion growth as compared to sham occurred with the vast majority of patients having lesions close to the foveal center point. The post-hoc analysis was presented at the American Society of Retina Specialists annual meeting earlier this month after David Lally of New England These data are consistent with previous post hoc analysis of the GATHER-1 trial, which were presented at the angiogenesis meeting and the Retinal World Congress earlier this year. Data from this post hoc analysis are also consistent with the results of our previously reported pre-specified analysis of Zamora from the GATHER-1 trial, demonstrating a reduction in GA lesion growth compared to Shan observed regardless of lesion size or distance to the foveal center point. Thank you for your time. I will now turn the call over to Praveen.
spk18: Thank you, Devil. The multiple post-hoc analyses from GATHER1, which have been presented at medical conferences around the world, continue to provide consistent results, which gives us a great deal of confidence in the robustness of the GATHER1 data. Nice work by you and your team. Turning to our life cycle expansion for Zamora, we previously reported post hoc analyses from Gather One suggesting that Zamora may have the potential to impact age-related macular degeneration, AMD, earlier stages before atrophy occurs in patients. As part of this plan, we are pursuing multiple sustained release technologies for Zamora for the treatment of GA and earlier stages of AMD. A few weeks ago, we entered into a license agreement with Delsatech, a Finnish company with a platform of silica-based drug delivery technologies under which we obtained a worldwide exclusive license to develop and commercialize new formulations of Zumora using DELC silica-based sustained release technology. These technologies potentially could address patients being treated for GA and potentially earlier stages of AMD, such as intermediate AMD. We believe Zamora, which is a chemically synthesized RNA aptamer, is amenable to injectable sustained release formulations. This agreement underscores our commitment to invest in the lifecycle initiatives for Zamora. We are excited about the possibilities to expand Zmora into earlier stages of AMD and potentially allow for a next generation treatment to help patients with GA. Looking ahead potential of Zmora, we plan to continue to invest in additional lifecycle initiatives for Zmora to expand the patient population with additional indications and continue to evaluate multiple technologies for Zmora. Furthermore, we plan to explore the potential for Zmora in earlier stages of AMD by initiating a clinical trial studying the current formulation of Zmora in patients with intermediate AMD in the fourth quarter of this year. The development strategy in this indication is subject to regulatory feedback from the FDA and other regulatory authorities, which we plan to obtain before initiating this trial. Thank you all for your time and support. I will now turn the call over to Dave.
spk20: Thank you, Praveen, and good morning, everyone. I'd like to highlight a few items from our press release of this morning and provide some guidance on our new credit facility and our expected year-end cash balance. For the quarter, our net loss totaled $49.3 million, or $0.41 per share, compared to a net loss of $30.1 million, or $0.32 per share, for Q2 2021. This increase in net loss was driven by increases in both R&D and G&A expenses. R&D expenses increased primarily due to the continued progress of the Gather 2 trial, increased manufacturing activities for Zamora, and increases in personnel costs, including share-based compensation associated with additional R&D staffing. G&A expenses increased primarily due to increases in personnel costs, including share-based compensation associated with increased staffing for a potential commercial launch. Turning to our balance sheet and our expected year-end cash balance, as of June 30th, we had cash, cash equivalents, and available-for-sale securities of approximately $312 million. Under terms of our new credit facility, the company is borrowing $50 million today. We now estimate that our year-end cash, cash equivalents, and available-for-sale securities will range between $260 and $270 million. The credit facility provides us with access to up to an additional $150 million in total, subject to our achievement of specified development and regulatory performance milestones for Zamora. An additional $50 million is available to us subject to Lenders' approval. We would view this additional $50 million as a potential source of working capital, again, assuming approval. We believe that this credit facility provides us with additional financial flexibility tied to major de-risking milestones at a lower cost of capital than equity. We intend to provide further details about our financing strategy to support launch following data release. Thank you for your time, and I'll now turn the call back over to Glenn.
spk08: Okay, thanks, Dave. And before we open up the lines for questions, I wanted to recap a very productive quarter. First, today is the one-year point for Gather 2. Over the coming weeks, we will analyze the data and lock the database, and we'll report Gather 2 data to you in September. We have also outlined what top-line data will be available in September. Second, we have entered into an exclusive license agreement with Delta Tech to develop and commercialize a sustained release technology. And finally, as Dave just mentioned, we entered into a credit facility that provides us with up to $250 million of non-dilutive capital, with $50 million coming today in the balance that is tied to de-risking milestones. So I want to thank you all for listening, and operator, I'd like to ask you to open up the line for questions.
spk16: Thank you. We'll now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. At this time, we'll pause momentarily to assemble our roster.
spk25: Our first question comes from Mike Oltz from Morgan Stanley.
spk16: Please go ahead.
spk06: Hey, guys. Thanks for taking the question, and congrats on all the progress here. Just in terms of the top line results, thanks for providing all the color and the detail on what we should expect. Just curious, the primary endpoint you mentioned providing both the slope and point analysis. If we think about that, should we expect those two analyses to be meaningfully different? Thanks.
spk10: Hey, Mike, this is Double. So if you look back on the GATHER1 data and when we did the point in the slope analysis, you saw that there wasn't really a big difference between the two. And we think that's mainly due to the fact that the growth is pretty linear on these lesions. And so we don't expect there to be a big difference between the two analyses in GATHER2 either.
spk16: Got it. Thank you. The next question comes from Annabelle Simimi from Stiefel. Please go ahead.
spk04: Hi, and thanks for taking my question. So I just want to go back to some of the data that you mentioned had been presented at the Retina World Congress as well as ASRS regarding the, I guess, the distance from the fovea. So clearly natural history indicates faster progression the further you get from the center of the fovea, and Zymora has also consistently shown more efficacy you know, the further you move from the center as well, I think probably because of the metabolic rate of these lesions. So, can you share with us whether the enrollment criteria for GATHER-1 is, or GATHER-2 is the same as GATHER-1, and what are your suspicions about how you might be able to replicate this data, given what you know about the slopes analysis now?
spk08: So, Annabelle, it's Glenn. Good morning, and thank you for the question. So, we have Double here today, and also Praveen. I'll let Double take the first part of that, and then I'll ask Praveen to comment as well.
spk10: Yeah, Annabelle, so maybe just I'll take the first one first. So in terms of enrollment criteria, nothing different in terms of Gather 1 and Gather 2, specifically as it relates to lesion distance. Just to recap for you, you know, the two main criteria here are, one, the disease cannot touch the center point of the fovea, and then second, some part of the lesion needed to be within 1.5 millimeters of the foveal center. That was the enrollment for GRAVID-1. It's the same thing for GATHER-2. In terms of whether or not 1 and 2 are going to look similar, we haven't seen the data for GATHER-2, so it's hard to kind of make a judgment call on that. What I can tell you is that if you look at the types of patients that typically hang around retina offices that are referred from tertiary care, they typically tend to be the ones that look like GATHER-1, and we would expect that to be the same case in GATHER-2.
spk27: Praveen?
spk18: Annabel, good morning. This is Praveen. So thanks for the question again. So here are the take-home points from these post-hoc analyses that you refer to, I think. One is that Zamora works regardless of the location of the lesion, but it will work better in earlier lesions as witnessed by lesions that are further away. So that's take-home point number one. Take-home point number two, I think, is that in GATHER1, the lesions that were there were fairly severe. Most of these patients, as Avil said, had lesions that were right near the center point. So perhaps, you know, our idea of saying extra foveal should be recapitulated now. Maybe we should start saying non-center point because these lesions were really quite close to the center of the fovea. And also realize that most of these patients had bilateral lesions. So these lesions were really quite severe and the patients were quite severe. So although the inclusion criteria is exactly the same in GATHER2 as in GATHER1, we're also hoping that if we can get lesions that are a little bit of an earlier stage, that delta will be even higher. As you've seen in that ASRS analysis, there's a very clear difference between the delta of treatment versus sham the further you go and the earlier lesion that you get. So we're hoping that lesions will be a little bit earlier. Again, We have no way of knowing that because we're completely masked. But at the end of the day, the main point here, I think, is that lesion that works regardless of where the lesion is. But in GATHER-1, the vast majority of the lesions were right next to the center point.
spk04: Great. That was helpful for the color. And just to go back to the question about the points analysis versus the slips analysis, I guess part of the reason why there wasn't... such a difference is because you didn't have a tremendous amount of variability in the patient. So if we look at GATHER-2, is it possible the earlier you go, the more variability you might have and the points analysis might be different from the slopes analysis? So how should we think about variability versus, you know, in terms of these points and slopes analysis, analyses?
spk10: Yeah, so Annabel, this is double. So what I'd say is that I don't think we're going to see much of a difference, as I mentioned previously, from the population in Gather 2 that we saw in Gather 1 to begin with. So, again, I think the full expectation amongst the folks at the company is that the results between those two analyses shouldn't differ very much based on what we saw in Gather 1. Praveen, any additional comment?
spk18: Yeah, I would agree with you. I'd say the same thing, Annabelle. The variability really comes from the patient population as opposed to the lesion location. And what we've done is to really limit the variability in the patient population. As you know, as has been shown earlier and by others as well, the patients that we picked, which now we'll call non-centrophobia involving, were exactly the right patients to pick. And those are the same patients that we expect in GATHER-2 that will be the same patients in GATHER-2 as GATHER-1. So the variability, again, comes from the patient selection, not so much from the lesion. So we don't expect really any difference.
spk03: Okay, great. Thanks so much.
spk16: The next question comes from Greg Harrison from Bank of America. Please go ahead.
spk17: Good morning. Thanks for taking our questions. So when we see the data for Gather 2, is there a percentage change that you feel would correlate well with clinical benefit? Just trying to think if any statistically significant benefit is sufficient, not only for approval, but also for your competitive position in the market.
spk08: Greg, thanks for the question. Praveen, you want to take that one?
spk18: Yeah, sure. Greg, good morning and thank you for the question. I think the main thing to do is to keep two silos very, very clear. One silo is the regulatory pathway and the other silo would be, I think, what you're asking, which is what would be the functional benefit to the patient and to payers and to physicians that one can communicate with. So let's keep those two a little bit separate at this point, although I realize that they're interrelated. As far as the regulatory pathway is concerned, it couldn't be clearer. We have a SPA agreement with the FDA So all we have to do is to hit the primary endpoint for purposes of submission. So the regulatory pathway via the SPA agreement, I think, is absolutely clear. The second question, which is also quite important and germane, which is what about the functional benefit for patients? How do payers react to this? What is it that physicians are going to say? Having practiced retina for over 26 years, I'll tell you, patients are not necessarily going to understand or care about the percentages relating to function or the square root transformation or anything else. What they are going to understand is they're going to understand preservation of central vision and time. And what I mean by that is that we know from extensive studies that once you start getting geographic atrophy, within a matter of two years, over 60% of patients lose driving vision. Now, we know that in four or five years, most of these patients will have completely obliterated central vision. So the currency of language that everybody understands is that of time. So what we'll be able to show data for, because of the patients who we've selected who are non-central point involving, what we can say is if you take this treatment, you'll be able to drive for X years longer. You'll be able to read for X years longer or work for X years longer and And I think that's the currency of language that patients will understand, payers will appreciate, and certainly physicians will use as a currency of communication.
spk17: Got it. That's helpful. And then one other. How much of the filing has been completed at this point and can be completed ahead of having the final Gather 2 data? And how would the timing here compare with a typical timeline after a phase three.
spk08: Yeah, Greg, hi. It's Glenn. So, as we mentioned in the past, the regulatory team has been working on the data that they have available, which is gather one. Having that, I think, gives us a real good head start on completing the following once we see the data from gather two. So, we haven't specified timing. It really will be dependent on what the gather two data looks like. you know, which will, you know, kind of round out our strategy on the regulatory path forward. So, when we have that data, we'll consider giving guidance on the filing strategy. It's very important. It is a competitive situation, so we know timing for investors is important. But right now, to answer that question, we really need to see the Gather 2 data. Male Speaker 1 Great.
spk12: Thanks for taking the question.
spk16: The next question comes from Ken Cacciatore from Cowan & Company. Please go ahead. Hey, guys.
spk15: Real exciting time. Excited to see the data in September. Just wanted to ask about the extended release formulation. Real potential commercial advantage that you might have if you're able to move this forward to obviously be real beneficial for patients. Praveen, I know you talked about some of the unique characteristics of Zamora. Maybe you could flush it out just a little bit more. that you think make it real amenable for an extended release. If you would like, it would be interesting if you could compare to Apellis. We've not heard of them moving forward with an extended release. So if you were willing to maybe compare and contrast why they may be behind, that would be interesting. And also maybe you could bring Delsa Tech to life a little bit, how long you all have been working with them. Clearly going to be a very important partner to you all. can you talk about them and maybe a little bit of their history and success in developing extended release formulations and then maybe timing to get into clinic would be interesting. Thanks so much.
spk26: Praveen, you want to start?
spk18: Sure. Ken, good morning and thank you for the questions. So first of all, regarding our molecule, it's an RNA aptamer and there's a really big advantage to an RNA aptamer. Not only is it a small molecule, so the capacity for loading is going to be greater, But being an RNA aptamer as opposed to a protein, it can be completely denatured and renatured and be fully functional. So that's a huge advantage for a sustained delivery type strategy. We believe that this has advantages over our competitors. Again, I'd rather not speculate about the competitors. You can certainly ask them, but I do believe that we have a significant advantage here because of our molecule. In regards to Delsitec and other strategies that we're looking at, there are certain characteristics that were important for us. First of all, it had to be loadable to a capacity that allowed for a sustained release, and it certainly checked that box. It had to be tunable, and what I mean by that is that in the natural history of macular degeneration, depending on where we target the disease, the release characteristics may need to be different. In other words, the way that the release characteristics would be optimal for drusen, for instance, may be a little different than for more advanced geographic atrophy. So the release characteristics have to be tunable. Obviously, it had to be safe, and then it had to be scalable. So with Delsatech, with the preliminary studies that we did, we were quite confident that this fit all the boxes and that this would be a very, very good strategy. Having said that, I must also say that it's not going to be the only strategy. Obviously, we're looking at other strategies as well. Our intention, as I've stated many times and as Glenn has as well, is to be the retina company for all of macular degeneration and other retinal diseases. So not just geographic atrophy, but for earlier stages of macular degeneration. And what this sustained delivery strategy allows us to do is it opens up a new target of patients with earlier stages of macular degeneration and certainly allows for us to make the geographic atrophy patients be treated in a way that's much more sustainable as well. Thank you for the question, Ken.
spk16: The next question comes from Eddie Hickman from Guggenheim Securities. Please go ahead.
spk05: Good morning, and congrats on all the progress, and looking forward to seeing the data soon. Just two from me. Can you confirm what the SPA agreement says specifically about GATHER-1? Does it confirm that it sees it as a supportive study, or have they agreed to analyze them together as co-registrational studies? Does the SPA say anything about that? And then secondly, based on your physician feedback and experience with monthly anti-VEGF, is there sort of an expected rate of inflammation or endo-optimitis that might be expected just for monthly intravitreal injections, and has the FDA ever commented on what those acceptable levels may be from a safety perspective? Thank you.
spk08: Eddie, thank you. Maybe we'll work backwards. We have some logistics we're trying to manage today, so Doug will take the second question first, and then Praveen will take your initial question.
spk10: Yeah, Eddie, thanks for the question. So in terms of physician feedback on rates of endophthalmitis and inflammation, you know, the easy answer to that is they want it to be zero. But if you look at, you know, kind of commonly prescribed retina therapeutics that are out there, you know, roughly in that one to less than 1% range is kind of where we see inflammation and less than 1% certainly for endophthalmitis is where we typically look. for safe drugs. And so that's kind of the number that we have in our mind. And at the end of the day, the number is going to be the number, whatever it's going to be. But that's what we're generally understanding in terms of the physician feedback on inflammation and ophthalmitis. I will give it back to Glenn for the SPA agreement.
spk08: Praveen, you want to take that? I mean, you had firsthand conversations with the regulators.
spk18: Sure, Glenn. I'll be happy to do that. And Eddie, good morning, and thank you for the question. So what I would say regarding a spa agreement is there are a couple of take-home messages that are really important here. First of all, the FDA advised us to apply for a spa agreement. And this was done when the GATHER2 study was half-recruited. So what that should tell us is the level of alignment and the level of confidence the FDA had in the earlier discussions we had with them, albeit all informal. So that's the first take-home message. The second one is after Having gone through the entire spa process, which, as you know, involves an army of statisticians and clinical trialists and so forth, they agreed on everything that was there. The only thing that they wanted slightly changed was they wanted a slope analysis. In other words, they wanted us to assume a constant rate of growth. We hadn't assumed anything at all. Nothing else was commented upon. They agreed with the endpoint. They agreed with the mixed random effects model, as well as the sample size, all of those things. And as you know, we're happy to do that. That really didn't change anything as for GATHER-1. However, the SPA agreement really is for one study only, and that was GATHER-2. The FDA had really no obligation to comment on GATHER-1. However, they went out of their way to comment on GATHER-1, and what they said was that they were in agreement that our pre-specified analysis was absolutely valid. They also thought that their preferred analysis was absolutely valid. And when the application is made, they will look at GATHER-1 and GATHER-1 both ways with the pre-specified analysis as well as the preferred analysis. So we are very confident because the FDA has commented on gather one and given us a sparking for gather two, that they're very well aware of the entirety of the program. Um, and both the programs together, uh, will be certainly valid for submission.
spk08: And Eddie, what I'll add to that is, um, you can go back to our prior press release where we did both calculations for gather one, the pre-specified plus the FDA preferred analysis. And what you will see is consistency in the rates of efficacy there. And happy to provide that if you don't have access to it.
spk05: Joshua, thanks. And actually, one final one. When it comes to the CNV versus sort of exudations, do you plan to have at the top line release any data from the Cole Eye Institute, or are you expecting the primary readers in the study to be evaluating CNV in the way that it was done in a post-hoc manner by the Cleveland Clinic, or will it be done by Duke?
spk08: Great question, Eddie. Praveen, do you want to cover that?
spk18: Sure, I'll be happy to. So, Eddie, the fact of it is that I don't know if there'll be much difference at all because our definition is very, very clear, but our plan at this point is to continue to use the Duke Reading Center as the primary point of analysis for a coroneovascular membrane formation as per the definition that is traditional and as they defined it in Gather 1. Now, we also had the Gather 1 analysis done by the Core Reading Institute, and the reason for that is because the Duke was no longer masked to that data. And we wanted to make sure that the reading center that defined and will look at the exudation rates remains completely masked. Therefore, I don't think that analysis plan is going to change at all for Gather 2.
spk23: Great. Thank you so much.
spk16: The next question comes from Kambi Yazdi from Jefferies. Please go ahead.
spk14: Hi, team. Good morning. Kambi's on for Chris. A few questions for me. Do you plan to do an EMA filing as well as an FDA filing? What are kind of the differences in those two agencies' stances on GA therapies? Second question, what was the relative performance of Deltatech sustained release technology versus some of the other options you considered? Third question, what IMD endpoints are you going to propose to the FDA for intermediate AMD? And I'll pause there.
spk08: Thank you. Okay, great question. So I'll ask, we'll go backwards. Keith, do you want to talk a little bit about the Deltatech technology first, and then we'll to address the other questions.
spk19: Sure. Happy to do that. Thanks, Camby, for the question. So in terms of Deltatech, I know Praveen talked a little bit about it, but we, you know, there were a number of factors that we looked at to, in terms of feasibility. But really, the silica-based gel is really important for us because the Aptimer, again, is very compatible with that. So the number of things that we looked at in terms of loading, In terms of tunability, you know, and we've also done a number of other feasibility studies with a number of other companies. So as we continue to move on, I'm sure we'll put out additional data here. But this, again, won't be our only, this is not our only plan here. We're looking to do additional drug delivery efforts around Zamora.
spk08: Thanks, Keith. And I'll take the next two questions. First, on the regulatory filing strategy, as mentioned this morning in our conversation, we do plan to submit a filing to the EMEA that will follow the NDA that we file. We have engaged experts and advisors in Europe to help us through that process and that planning for EMEA, but it is our expectation that we will have a filing We have not defined the timing just yet. The question related to endpoints for intermediate AMD, also a very good question. As you know, we had said we will engage with FDA prior to starting any trial with intermediate AMD. We believe the strategy may be a collection of different endpoints. And I think the best way to handle that is we need to have the discussion with the regulators first. and then get back to you on the results of those discussions. So a little bit hard to put bookends around that right now, but obviously the team has many ideas, and we're looking forward to our discussion with FDA.
spk14: Awesome. Thank you so much, Glenn. And then maybe as one final follow-up, from a functional perspective, going back to that kind of distance from phobia analysis, How does, can you help us understand how a patient with GA lesions about like, you know, 100 microns from the center is different than, you know, 500 microns from the center versus, of course, foveal and then kind of the time it would take to progress from 500 microns to 100 microns and then all the way to the central vision? Thank you. That's my final question.
spk08: Sure, thanks. Again, very good question. I'm going to ask both Dovel and Praveen to comment on that. Dovel will begin.
spk10: Yeah, thanks for the question. So if you think about distance from the foveal center and kind of how a patient perceives that, you just think about, you know, kind of looking into a kaleidoscope, right? And then the closer that lesion is to the foveal center, just imagine not seeing black spots right near the middle. And then if they're further away, you kind of see it more out in the periphery. So obviously, the closer it gets to that center point, the more of your functional vision gets impaired. In terms of the progression of those lesions, it's highly variable. And that's one of the things about this disease that really leads us to think we need to treat it early and we need to get after it as aggressively as possible. Because depending upon the size of your lesion at baseline, the distance, what kind of banding pattern, they can all grow at different rates. So it's hard to say on average, what will a lesion grow, how fast will it go from 500 to 100 microns away? Praveen?
spk18: Yeah, you know, what I would say is I think there's very good evidence now that what we traditionally think of as an endpoint, which is visual acuity, is not a good endpoint for visual function. What we have, what you can have, for instance, is excellent visual acuity, but still have terrible visual function. And If you think of how visual acuity works, you're in a dark room with a bright light at the end. And, you know, life is rarely like that. And if you think about your day today, you're really not going to have that situation at all or very little if at all. So the regulatory agencies and other agencies do recognize that. there are other functional parameters that are really important. And if you wonder how it affects a patient's day-to-day life, if you wear glasses, all you have to do is take a little scotch tape and put it a little bit off-center in the bottom or on the sides. And what you'll realize is that you simply can't function. So even if you're 500 microns away or further, what you'll find is that there are lots of patients out there who are visually dysfunctional with lesions even though it seems further away. It could, for instance, be an architect that may not be able to see a straight line in the upper corner. It could be a lawyer who may not be able to read a sentence because of a dark spot. So there are lots of patients out there that are visually dysfunctional. These patients are quite desperate to stop that lesion from progressing. And how fast is it progressing? Well, you know, we know from studies, as I mentioned earlier on, that in a matter of time, two years to lose driving vision, about five or six years to lose complete foveal vision. So what we can offer with Zomora version one in the GA patients is to be able to say, look, if you take this treatment, this is how much time you will have to continue to function and do your functional activity. And hopefully what we can do is go even earlier and not just slow down the rate of death, but to prevent death altogether. And that really would change the trajectory of the disease.
spk02: Awesome. Thank you so much.
spk16: We have time for one more question, and that's from Colleen Cussey from Baird. Please go ahead.
spk28: Great. Good morning. Thanks so much for taking our questions, and congrats on the progress. So in the 8K, it says the criteria for the next tranche of debt financing is meeting the primary endpoint and the data are supportive of filing. Can you talk about whether those are actually two different things? And anything else you can say on what will be considered sufficient clinical data package to support submission? And can you just confirm that the SPA says p-value of 0.05 would be the threshold for significance? Thank you.
spk08: Well, thanks, Colleen. I'll let Dave take the first question. So thanks for the question, Colleen.
spk21: Yes, it is. That's our position there.
spk08: That's an easy answer. Colleen, on the SPA agreement, double .05, can you confirm that? Yeah. Yeah, it is. And, Colleen, there was one other question mixed in there, I think. Did we hit it all?
spk28: So I think the question was if those are two different things, me and the primary endpoint, and the data are supportive of filing. And the response was yes, those are two different things. Okay.
spk07: Thanks, Colleen. Appreciate the question.
spk16: There are no more questions in the queue. This concludes our question and answer session. I would like to turn the conference back over to Glenn Splendorio for any closing remarks.
spk08: Well, thank you, Operator, and thank you, everybody, for listening to the call this morning. As I mentioned before, great progress in the last quarter, and we're quite excited that we have reached the one-year point with Gather 2. And we look forward to a conversation in September about that data. Have a great day, everybody. Bye bye.
spk16: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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