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spk02: Good morning and welcome to Ivericbio's conference call. Representing Ivericbio today are Mr. Glenn Splendorio, Chief Executive Officer, Dr. Praveen Dougal, President, Mr. Keith Westby, Chief Operating Officer, Mr. Dave Carroll, Chief Financial Officer, Dr. Double Desai, Chief Development Officer, Mr. Chris Sims, Chief Commercial Officer, and we are pleased to welcome Mr. Tony Gibney as Chief Business and Strategy Officer. Tony joined the company in mid-December. It's a pleasure to have you with us, Tony. I would like to remind you that today we will be making statements relating to Iverick Bios' future expectations regarding operational, financial, and research and development matters. These statements constitute forward-looking statements for the 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 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 November 9, 2021, 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 except as required by law. I would now like to turn the call over to Glenn.
spk05: Thanks, Cathy. Good morning, everybody, and thank you for joining our fourth quarter and year-end conference call. As we think about 2022, we continue to focus on execution, as evidenced by Gather 2, our second phase 3 clinical trial for Zamora for the treatment of geographic atrophy, or GA, which continues to exceed our expectation with an injection fidelity rate well above our stated goal of greater than 90% at month 12. We look forward to sharing top-line data in the second half of the year, This will be approximately one year after the enrollment of the last patient in, plus, as you know, the needed time to do the database lock and analysis, which Keith will speak to in a few moments. If the 12-month results are positive, we plan to file applications with the US FDA, as well as the European Medicines Agency, for marketing approval of Zmora in GA. As we get closer to reporting the GAT2 data, We continued our efforts internally to prepare for a potential filing of a new drug application for Zamora for the treatment of GA. We continue to gain momentum in building out our medical affairs team led by Double Desai, our chief development officer, and the commercial infrastructure led by Chris Sims, our chief commercial officer. These are two experienced and well-seasoned leaders with experience in working and launching retina drugs with blockbuster potential. We continue to execute on our IP strategy for Zamora. Earlier this month, the U.S. Patent and Trademark Office allowed claims for patent coverage covering methods of use of Zamora to treat GA. The patent, once issued, is expected to expire in 2034. We're also excited to have announced the results of a post-hoc analysis that evaluated various GA growth parameters to explore the rate of disease progression within the regions in the phobia in a subset analysis of patients from GATHER-1, which is our phase three clinical trial for the treatment of Zamora NGA. These data were recently presented at this year's angiogenesis, exudation, and degeneration conference, and Praveen will provide more details on the analysis in a few moments, and you will see why we are quite excited by this new data. As we think back over the past year, we successfully achieved a number of major milestones that we believe have laid the groundwork for 2022 to be a banner year for us. Let me briefly recap some of the significant highlights. First, we received a written agreement from the U.S. FDA under a special protocol assessment, or SPA, for the overall design of Gather 2. The agreement further solidifies our plans to file an NDA with the FDA for marketing approval of Zamora for GA if the ongoing Gather 2 clinical trial meets its primary endpoint at 12 months. As you know, Zamora met its primary efficacy endpoint at 12 months with statistical significance in a previously completed Gather 1 pivotal trial. In July, we announced the completion of patient enrollment in Gather 2. This was four months ahead of our original schedule. We also started the planning to initiate a phase three clinical trial studying Zamora in patients with intermediate AMD in the second half of this year. We continue to enroll patients in our STAR clinical trial. This is our phase two B screening trial of Zamora for treatment of autosomal recessive Stargardt disease. We also initiated a number of preclinical tolerability and pharmacokinetic studies for IC500 or HTRA1 inhibitor. However, we anticipate that the start of the IND-enabled tox studies will be later than originally planned. This is primarily due to the availability or lack of availability of study slots at contract research organizations in the wake of COVID-19 pandemic. We expect to submit an investigational new drug application or an IND to the FDA for IC500 during the mid-2023. We also strengthened our balance sheet by raising approximately $108 and $163 million in net proceeds from public offerings in July and October 2021, respectively. Dave will cover our cash and Cash One later in the call. We believe that these capital raises enable us to accelerate preparations for a potential commercial launch of Zamora and allow us to continue to invest in manufacturing capacity. In addition, we continue to invest money in additional lifecycle initiatives for Zamora in order to expand the patient population with additional indications, such as the initiation of an intermediate AMD trial and investing in multiple sustained release delivery technologies. On the corporate front, we're excited to welcome Christine Miller, who is the President and Chief Executive Officer of Malenta Therapeutics, to our Board of Directors. We're thrilled to have somebody of Christine's caliber join our board. Christine's extensive background in commercialization and supply chain management will be a valuable addition to our board of directors. We're also, as Kathy just mentioned, excited to welcome Tony Gibney to our company. He joined as Chief Business and Strategy Officer this past December. Tony's an experienced biotech executive and former investment banker, and as you know, is well-known throughout our industry. We look forward to Tony's leadership and extensive experience in contributing to our future success. I will ask Tony to say a few words about our business development strategy later on in this call. I'd like to now turn the call over to Keith.
spk09: Thanks, Glenn, and good morning, everyone. As Glenn mentioned, we completed patient enrollment in Gather 2 in July 2021 with 448 patients enrolled, four months ahead of our original schedule. Based on this timeline, we expect top line Gather2 data to be available in the second half of 2022, 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. A major priority for us is to continue to aggressively drive patient retention and thereby further de-risk the Gather2 clinical trial. As Glenn mentioned, we are targeting patient retention for the GATHER-2 trial as measured by injection fidelity rate through month 12 of greater than 90%. Injection fidelity is calculated by dividing the total number of actual injections by the total number of expected injections. We consider injection fidelity to be the most important and stringent measure of patient retention because it reflects the timely administration of the drug or sham into the patient's eye. As of today, we continue to maintain an injection fidelity rate of well above our 12-month target of greater than 90%. As a comparison, the 12-month injection fidelity rate for our GATHER-1 trial, which showed a statistically significant reduction in GA progression at 12 months, was 87%. We continue to focus on injection fidelity, not only to protect the integrity of the data, but also to potentially observe the early and increasing treatment effect we previously observed in Gather 1. Patient retention is clearly an integral part of the Gather 2 outcome. To date, we are excited to have reached a trial completion rate of 84% for Year 1, the time point for the primary efficacy endpoint of the trial. Therefore, with only approximately 16% of Year 1 visits remaining in Gather 2, we are encouraged to see that our efforts to maximize patient retention in Gather 2 have resulted in even greater patient retention than was observed in GATHER1 through the same time period. To summarize, GATHER2 has exceeded our expectations for patient recruitment, patient retention, and injection fidelity. We continue to work with our investigators to provide a safe environment for patients, which we believe increases the patient's comfort and confidence to continue to participate in the GATHER2 clinical trial. As we discussed in the past, we implemented a number of initiatives to reduce the risk and exposure to COVID-19 for our patients and the staff treating them. We have found that many principal investigators are enthusiastic and committed to participating in GATHER2 clinical trial. We believe the positive GATHER1 12-month data further supported by the positive 18-month efficacy results and the safety profile that was maintained throughout the trial, along with the early and increasing treatment effect observed in GATHER1, are key motivators for retention in GATHER2. In addition, there are currently no therapies approved for GA in either the US or the European Union. Turning to Stargardt disease, patient enrollment in the STAR trial is ongoing with the goal of enrolling approximately 25 additional patients for a total of approximately 120 patients. The results of this trial are expected after the top line results of GATHER2. Thanks for your time, and I will now turn the call over to Praveen. Thank you, Keith.
spk11: Thank you all for joining the call this morning. I hope that you are all well. On our previous earnings call, we discussed that part of the GATHER program, in addition to evaluating the overall rate of GA growth, we're going to be investigating through supportive analyses whether Zamora has the potential to slow the progression of GA into the phobia, thereby preserving central vision. which would otherwise be lost in this relentlessly progressive blinding disease. Two weeks ago, data from a post hoc analysis that evaluated various growth parameters to explore the rate of disease progression within various regions in the fovea in a subset of patients from the GATHER-1 clinical trial were presented at the Angiogenesis Exudation and Degeneration Conference by Dr. Glenn Jaffe, Director of the Duke Reading Center and Chief of the Retina Division of the Duke Eye Center, and Robert Mockerman, Professor of Ophthalmology. Consistent with the overall results of GATHER1, in the new analysis, a reduction in lesion growth in five standardized regions surrounding and including the central foveal area was observed for patients receiving Zimora 2 milligrams as compared to patients receiving sham over a period of 18 months. We believe the observed pattern of reduction in GA growth in the different regions is consistent with the natural history of the disease and recent clinical trial results in which complement inhibition has been observed to be associated with a greater reduction in GA growth in patients with non-foveal GA, which is known from the natural history to be faster progressing than fovea involving GA. This analysis supports our expectation that we would see a greater reduction in growth away from the foveal center, reflecting the circumferential growth pattern typical for GA patients. GA has a major impact on functional vision which could alter the quality of life and independence of affected individuals. We believe that the results from this exploratory analysis are another step in studying the potential of Zumura to preserve central vision by slowing the progression of GA. The significance of this data is that it has the potential to bridge anatomical results to functional outcomes, in other words, By preserving the central phobia, the patient may have the opportunity to continue to drive, read, live independently, et cetera, for a longer period of time as compared to the natural history of the disease. Additionally, by preserving the central phobia, we believe we have the potential to show a visual acuity benefit over time. It must be stressed, however, that this is an exploratory post hoc analysis that requires confirmatory prospective trials. Over time, we anticipate performing a similar analysis for GATHER2 to further build upon these insights. Turning to earlier stages of AMD, based on our hypothesis regarding complement inhibition as a mechanism of action to treat AMD, In the previously announced results from a post-hoc analysis from GATHER1 evaluating the progression of incomplete retinal pigment epithelial and outer retinal atrophy, or IORA, to complete retinal pigment epithelial and outer retinal atrophy, or C-ORA, and the progression of drusen to IORA and C-ORA in the ZUMURA 2 milligram and sham control groups, We plan to initiate a phase three clinical trial, studying Zamora in patients with intermediate AMD, a stage prior to the occurrence of GA, in the second half of 2022. We expect this intermediate AMD trial to be an international, randomized, double-masked, SAM-controlled, multi-center trial with approximately 200 patients per treatment group. We expect to treat and follow all patients for 24 months. We plan to obtain feedback from regulatory authorities that will influence the ultimate design of this clinical trial and our development strategy in this indication before initiating this trial. Drusen is a hallmark of the onset and progression of AMD. We estimate that by 2039, there will be approximately 6 million individuals with Drusen in the United States and 8 million individuals with Drusen in the EU countries. The population we look to enroll from the intermediate AMD trial is a subset of the prevalent Drusen population. We have been exploring several lifecycle management initiatives for Zamora with efforts focused on potential sustained release delivery technologies. Our goal is to derive a formulation of Zamora with a sustained release delivery technology that reduces the frequency of intradictoral injections while maintaining comparable efficacy and safety to monthly injections. We have been exploring and evaluating a number of potential sustained release delivery technologies, including conducting feasibility studies with various technology providers and analyzing the resulting formulations containing Zumora and the sustained release delivery technology. If any of these technologies meet the performance thresholds that we have established, we may pursue longer-term development collaborations. We are fully committed to delivering treatments for AMD, including earlier stages of the disease, such as intermediate AMD. We believe we're well-positioned to expand Zumora's indications, build an AMD franchise, and subject to regulatory approval, commercialize Zumora for GA as the market leader. Thank you for your time. I will now turn the call over to Tony.
spk04: Thank you, Praveen, and good morning, everyone. It is truly a pleasure to be here with you this morning. I'm excited to join Averick Nile and to work with Glenn and others in the leadership team who I've known for many years, as well as Praveen, Dave, and all my new colleagues. I appreciate the opportunity to say a few words about our business development priorities and broader strategy. We are continuing to explore all options for the future development and potential commercialization of Zamora, including potential collaborations outside of the U.S. I want to reiterate our plan to develop and commercialize Zimura in the U.S. where we can leverage our retinal expertise particularly well. As we continue the development of our product candidates and programs and prepare for the potential commercialization of Zimura, we will continue to pursue selective business development opportunities that advance us toward our long-term strategic goal of becoming a dominant and sustainable leader in retinal diseases. We plan to continue to evaluate on a selective and targeted basis opportunities to obtain rights to additional product candidates and technologies for retinal diseases, as Praveen just mentioned, with a near-term focus on sustained release delivery technologies for Ximera. Thank you for your time this morning. I look forward to connecting with all of you soon. I will now turn the call over to Dave.
spk10: Thank you, Tony, 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 expected year-end cash balance and our expected cash runway. For the quarter, our net loss totaled $33 million, or $0.29 per share, compared to a net loss of $25.4 million, or $0.27 per share, for Q4 2020. This increase in net loss was driven primarily by an increase in R&D expenses associated with our Zamora clinical programs, increased manufacturing activities for Zamora, and increases in personnel costs, including stock compensation associated with additional R&D staffing. For the full year, our net loss totaled $114.5 million, or $1.12 per share, compared to a net loss of $84.5 million, or $1.14 per share, for 2020, again primarily due to an increase in R&D expenses. Turning to our expected year-end cash balance and cash runway, we now expect our year-end cash balance to range between $215 million and $225 million, We estimate that our cash, cash equivalents, and marketable securities will be sufficient to fund our planned capital expenditures and operating expenses through at least mid-2024. These estimates are based on our current business plan, which includes the continuation of our ongoing clinical development programs for Zamora, NGA, and Stargardt's, and the initiation of an intermediate AMD clinical trial, preparation and potential filing of an NDA and MAA for Zamora, continuing preparations for potential commercial launch of Zamora, investing in sustained release delivery technologies for Zamora, and the advancement of our IC500 development program. Excluded from these estimates are any potential approval or sales milestones payable to the Archimex Corporation, or any potential expenses for the actual commercial launch of Zamora, including Salesforce expenses, and any additional expenditures related to potentially studying Zamora and indications outside of GA, Stargardt, and intermediate AMD, resulting from the potential in-licensing or acquisition of of additional product candidates or technologies for any other associated development we may pursue. And I'll turn the call back over to Glenn. Thank you for your time.
spk05: Thanks, Dave. As we look ahead to 2022, we'll continue to focus on the execution of Gather 2 with the retention of patients and preparing for a potential commercialization of Zamora in the U.S. as our top priority. We will continue our internal efforts to prepare for a potential filing of an NDA for Zamora for the treatment of GA if the Gather 2 results are positive. We also look forward to initiating a Phase 3 Zamora Intermediate AMD trial and investing in additional lifecycle initiatives such as sustained release technologies for Zamora. I want to thank you all today for listening in and your continued support. and we look forward to providing you with updates on our progress as we move along. We will now turn the call over to the operator so we can open up the lines for questions. Keith, I'll turn it to you.
spk01: Yes, thank you. At this time, we will begin the question and answer session. To ask a question, you may press star, then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then 2. At this time, we will pause momentarily to assemble the roster. And the first question comes from Ken Cacciatore with Cowan and Company.
spk08: Hey, good morning, team. Congratulations on all the progress. You know, your competitor's results really helped nicely confirm the impact on complement inhibition studying extra fovea lesions. And obviously, your post hoc analysis also focusing on your enrichment strategy really validates it. So just wondering, could you talk about the percentage of GA patients that have extra fovea lesions Talk about how easy it is to diagnose. I know once a product is approved, I would imagine you're going to implement a strategy to really help educate clinicians on earlier diagnosis, but like to hear about that. And then maybe talk about how the FDA would handle a label here in terms of extra foveal versus foveal. So that's question number one with a couple parts. And then just question number two. You talk about the progress on looking for extended release formulations. I'd just like to hear a little bit more about the ease or maybe lack thereof of Zamora in formulating into extended release. What are you seeing in the early work here? And then maybe talk about Would an implant be something that you'd look at? There seems to be some success right now moving forward with the TKIs on an implant strategy. It's just a little bit more around the sustained release formulation work. Thanks so much.
spk05: Well, thanks, Ken, and we'll work on question one, which I think has three parts, and we'll break it up amongst the team. The first part is the amount of extra foveal patients in the total population of GA, which we estimate to be about 1.5 million in the U.S. And of that, about two-thirds have extra fovea. So I hope that helps with that. The second question on really diagnosis and finding these patients. Praveen, let me turn it over to you, and maybe we'll tag team on the NDA. And for the extended release, we'll maybe ask Tony to comment. So, Praveen, on the diagnosis question.
spk11: Thank you, Glenn. And, Ken, thank you for your question. The diagnosis part, you know, Ken, is really with a fundus examination, essentially. You know, one can see these patients and see the geographic atrophy with a routine fundus evaluation. Now, you can also see it very clearly with an autofluorescence. And this is a diagnosis that really will be made not just by retina specialists but by general ophthalmologists as well as optometrists. And that's where most of the extra foveal patients currently reside. There's a referral bias, as you can imagine, for retina specialists because they're usually referred the most severe patients. That means fovea involving. However, the ones that you're referring to, the extra foveal, is really the vast majority of the patients. And these currently reside with general ophthalmologists and optometrists. And our expectation is that once there's a therapy for these patients, These patients will be referred to retina specialists, as was the case for wet macular degeneration. Now, it's important to state that these patients really do suffer from a loss of visual function. Although their visual acuity may be 20-20, they may not be able to see a straight line. They may not be able to finish reading a sentence or finish reading an Excel table because of a blind spot. So these patients, we would imagine, would be younger in the workforce, and therefore much more desperate and much more compliant as well. In regards to the other questions, Glenn, I'll turn them back to you. I'm happy to answer as you direct.
spk05: Okay, thank you, Pravin. Let's go, we'll come back to your NDA question, Ken. I just want to get clarification on exactly what you're looking for. But Tony, a couple words about extended release and the early work that we're doing there and the type of technologies that may be applicable here.
spk04: Sure, happy to, Glenn. So we're looking at a number of technologies, and they really cross the spectrum of available technologies for back-of-the-eye diseases, some of which are quite late-stage and validated and some that are really more emerging technologies. And I have to say, I think that Xamarin, given that it's an aptamer, rather stable, seems to be rather conducive to a number of the technologies, but not every technology. And so as we look at the feasibility, we are looking – at implant technologies or looking at microparticles or looking at others. And as we continue to gauge the feasibility, really our targeted goal is to really move forward those that are most amenable to Zimora and meet our targeted goals for sustained delivery in a way that really doesn't compromise patient care, but it really continues the benefits that we're seeing with Zimora in its current formulation. So stay tuned.
spk08: Great, and my question was on the label. Obviously, there seems to be impact on all areas of the fovea and extra fovea, but just wondering how do you think the agency will handle the label given the patient enrichment for GATHER 1 and 2?
spk05: Yeah, so again, first thing, I think we need to obviously see the data from GATHER 2 before we talk about label strategy. But I'll let Praveen answer that because I think we have some thoughts on how we would position our data with the agency. Praveen?
spk11: Thank you, Glenn, and Ken, thanks again. So I must say from the very start that we haven't had any formal labeling discussions with the FDA. Obviously, it would be premature to do so. What I will tell you is that our expectation is that the label will be broad. Now, it doesn't mean that complement inhibition doesn't work in patients with phobia affecting lesions. It's just that the delta, given the natural history, would be less. And that's exactly what we see in our studies and in our competitor studies as well. So the one thing that I would take home from this is that we certainly do risk gather, too, by picking the proper patient population. Now, again, our expectation is that if we're able to slow down a faster-growing geographic atrophy safely, there's no reason that we wouldn't be allowed to treat patients with a slower-growing geographic atrophy, having met a much higher bar of scrutiny. I think the FDA completely understands how important it is for patients with phobia-affecting geographic atrophy to have some area in the paraphobial area survive. There are patients that I remember I used to treat that had lesions in the paraphobial area with eccentric fixation, and they would use that area to stop from bumping into furniture or, you know, stop their hands from getting burnt in a hot stove. That's terribly important. It's difficult to measure, but it's terribly important, and we feel that the FDA will recognize that and allow a broad label.
spk08: Great. Thanks, team. Real exciting time for the company. Congratulations on the progress. I'll go back in the queue.
spk01: Thanks, Ken. Thank you. And the next question comes from Mike Alls with Morgan Stanley.
spk06: Hey, guys. Thanks for taking the questions. Just quickly on Gather 2 in terms of the injection fidelity rate. You're obviously tracking above your goal of 90%, and that's exceeding your expectations. But I'm just curious, more recently, if you've seen a break in the trend there at all due to Omicron?
spk05: Yeah, Mike, thanks for the question. And I think one of the reasons we wanted to – reinforce our progress today is that Omicron does present complications, but I think we were able to knock on wood, manage through that. So that's why we wanted to give the numbers both on injection fidelity running well ahead of our And also a key point that Keith raised today is where we are in the injection progress, which was 84%. So I think the protections we put in early on for both patients and healthcare workers as it related to the pandemic, I think have continued to pay off. And in fact, Keith's team put a little bit extra diligence as Omicron started to hit its peak to be sure that, you know, patients were managed, patients got to the visit, a lot of prep work and then a lot of follow-up work. So that was the reason we talked about injection fidelity today because we feel we're in real good shape.
spk06: Got it. That's helpful. And then maybe just to follow up on the intermediate AMD study that you're going to start in the second half, You gave us some sense at a high level of how you're thinking about the design, but you're also planning to meet with the FDA prior to starting the study. So just curious, what are the areas you're looking for feedback from the FDA? Is it endpoints? Is it enrollment criteria or any color you can provide there? Thanks.
spk05: Yeah, great question, Mike. Praveen, do you want to take that one in terms of the design?
spk11: Sure. And good morning, Mike, and thank you for the questions. you know, first of all, you know, I want to say if you just look at the biology of this disease, if complement inhibition works in extra foveal geographic atrophy, you can be quite confident that it will work in earlier stages because that's where complement is even more active, which is intermediate AMD. What the FDA has stated publicly is to say, look, this is a major problem, and there is a major advantage to not only slowing down the death of photoreceptor cells but preventing it altogether. We're extraordinarily fortunate to have a very, very collaborative and consistent FDA. And the purpose of our meetings is that really nobody's done this study before. So the answer to your question, Mike, yes, all of the above. We intend to sit with them and say, look, here are the parameters that we know from working with the community as we are and we have with the groups like the CAM group and the Macustar group. and say, look, here are the parameters that we know are predictive of geographic atrophy, and this is what we would like to study, and these are the patients that we'd like to enroll, and that's the discussion we intend to have. Again, the FDA is extraordinarily collaborative, and we believe that whatever feedback they give us will greatly influence the design and the development of this trial.
spk06: Got it. Thank you.
spk01: Thank you. And the next question comes from Tiago Faust with Credit Suisse.
spk07: Hey, thanks for bringing the question. Congrats on the progress so far. So just to go back to a point you've mentioned on GADDR2 being relative with the risk based on patient selection. So again, you haven't seen Derby and Oaks fully replicating their findings in Philly, and maybe baseline characteristics could have played a role there. So can you just kind of recap kind of the factors that make you confident that GADDR2 will actually replicate GADDR1 findings and why you can expect a potentially different outcome than what you saw for your competitor. And a quick follow-up, and you guys alluded to some new IP that you have. Can you just recap the current portfolio of intellectual property and also any outstanding financial obligations to our Chemex based on potential approval and launch? Sorry, multi-part question there, but that's it.
spk05: Yeah, no problem, Tiago. I think we have three questions. First on the GATHER-2 and, you know, how we're feeling about the de-risking. I think there's a few things to cover, and I'll let Praveen add to my commentary. You know, one, we have an unusual situation that we have one of two Phase III trials done, so we have the benefit of the GATHER-1 data. And we also have the benefit of the, which in the 12-month data was the primary endpoint, but also in gathered one, we had the benefit of the 18-month data to see what happened in the six months after. And as you know, we continue to see separation of the curves. As to another factor, you know, did you pick the right patients? We always believed that we did. And then with our competitors' data, with their subset analysis of extra fovea lesion showing quite similar numbers in terms of efficacy, we felt that that's a further de-risking. On the recruitment and the reason we put the concept of injection fidelity in, obviously to keep the integrity of the study you want, you know, high retention rates, and we felt the best way to measure that was through injection fidelity. That's why we created that concept and we continue to update that. And the fact that we're running well ahead of our guidance and, you know, well into the 80% range, you know, demonstrates that these patients are coming back. And also going back to gather one, we had a terrific trial and data to show those patients that, you know, we finished a phase three trial. So I hope that created some momentum. And I think our investigators did talk to their patients about that. So for all the above, and I'll let Praveen add some additional commentary on that, we feel that we've seen a number of signs that are encouraging as we get to the end of Gather 2. Praveen?
spk11: Thank you, Glenn, and Tiago, good morning, and thank you for the question. Let me just divide my answer into two different parts. The first part would be the consistency and validity of Gather 1, and the second part would be how we do risk Gather 2, and both are really important questions So if you go back and look at gather one and now that there's more data coming from our competitors and others, what you will see is this remarkable consistency in terms of the efficacy profile and in terms of the safety profile. So in terms of the efficacy profile, what you'll see is, as you know, is an immediate separation with the delta getting bigger and bigger with every visit. And that's true in the 2 milligram dose. That's true in the 4 milligram dose. That's true whether it's a square root transformation analysis or a non-square root transformation analysis. And that's actually even true in all the retrospective studies we've done. So that kind of consistency should give us a great deal of confidence in the robustness of the data. And it's the same thing that you see on the safety side as well. I mean, you see a superior safety profile, and you see a dose-dependent response. With everything in Gather One, what I would tell you is that the confidence that we get is from the absolutely remarkable consistency of the data, which is in line with the science. Now, the second part is how have we de-risked Gather Two? The most important answer is really by having Gather One, as Glenn said. It's really unusual. In fact, I don't recall a time in my 30-year career doing clinical trials where I've ever recruited for the second part of a phase three study with the first phase three study already being so overwhelmingly positive. But the other ways that we've de-risk gathered too is by picking the proper patient population. And we did this for several reasons, but the important one here is the biological one, which is that is when complement is most active in geographic atrophy in the earlier stages. And clearly that was confirmed by our competitors' results. The second is that we have a mixed random effects model that is particularly stringent and validated by the FDA. As you recall, we've got a SPA agreement where all of the trial has been looked at, including our mixed random effects model. And thirdly, and what we are doing right now, and Keith and Evelyn Harrison and Davil Desai and their group are doing so well, is to have that injection fidelity at a number that's just unheard of, which is above 90%. And that's despite having no vaccine, having Delta, having Omicron, our guidance hasn't changed. So we believe we're doing everything that can possibly be done to de-risk GATHER2 in the face of an overwhelmingly positive and consistent result for GATHER1. Thanks, Parveen.
spk05: And Tiago, to your second question around the patent, I think it's one of a multi-pronged strategy that we laid out. for lifecycle of this product. This is a patent that covers methods of using Zamora. Once issued, it is expected to expire in 2034. It's under the umbrella of lifecycle. Tony spoke a little bit about the initiatives for extended delivery, obviously strengthening the IP portfolios part of that, and we'll look to continue to find ways to extend this franchise. So we were happy to report today on that patent, which is just one step in a number of things that we're working on. The third question, Tiago, was related to financial obligations, and I'm going to ask Dave to cover that.
spk10: Sure, thanks. Tiago, thanks for the question. And let me just open up with, it's a really great deal for us. There's no royalties on Zamora whatsoever, first off. And then the total payments related just to the first indication is, you know, in the 20 to $25 million range, I think it's 23.5, something like that. This will all be in our 10K, and actually in last year's 10K also. And then no royalties. And those milestones just related to clinical and regulatory milestones. That's it. Thanks, Tiago.
spk07: Appreciate all the questions. That's it.
spk01: Thank you. And the next question comes from Annabelle Samamey from MOTS Default.
spk03: Hi. Thanks for taking my questions. I had a couple here. So I guess there's been some question about patient motivation to to um or physician motivation to treat is high um patient motivation um to continue to treat uh chronically i would say at the late stages of disease like you know where they're starting to see functional issues is is likely high but i'm just a little bit curious in the intermediate stages of disease to what extent are these patients compromised functionally and I know you're motivated to try to treat these patients as early as possible in disease, but I guess I'm trying to understand the patient motivation to treat earlier in disease. And maybe you can just talk about that in terms of where you think the most likely treatment will be, even if you have meaningful data on the intermediate population. And I guess the second question I have, is on the 84% completion that you've talked about. Are all these patients expected to move into the 18-month portion of the trial? And if so, or if it's an option, and to what extent have these patients, have those 84% also moved into the 18-month portion of the trial? Thanks.
spk05: Okay, thanks, Annabel. So two questions there. And I'll have Praveen answer the first question, because in a prior life as a treating physician, I guess there's nobody better to talk about patients and patients' motivation on this disease. And on the completion rate, I'll have Keith answer that, including, you know, what happens to these patients at the end of their 12 months, what happens in year two. So, Keith, we'll lay that out for you. So, Praveen, let me turn it over to you first.
spk11: Great. Annabel, good morning, and thank you for your question. Let me just divide the answer into two different parts, the GA part as well as the intermediate AMD part. There's really a fallacy out there that with geographic atrophy, this is a disease that occurs in far older patients and the disease progresses extremely slowly. We simply know that that is not true. We know that this is a disease that occurs as early as the patients in their 50s and 60s. It always starts extra foveal always progresses circumferentially fairly rapidly. And I use that word rapidly, deliberately. If you look at great natural history studies that have been done by Genentech Roche, you'll see that that movement of geographic atrophy occurs in a matter of months, not years. We're talking about four to six months or so. Another way of looking at this is that there was a recent article that looked at the entire UK database that was authored. The senior author was Usha Chakravarti that showed that patients with geographic atrophy end up losing a driving vision. 60% or so lose driving vision in 1.6 years, which is just really stunning. And in about three years, 40% or so have their central phobia completely obliterated. So this is truly a relentlessly progressing blinding disease. And these patients, again, that we're targeting, are the whole gamut of patients with early disease as well as late disease. You can imagine that these are patients who may be in their 650s and 60s that may not be able to see a straight line and functioning as an architect or an engineer or may not be able to finish reading a sentence and are functioning as an attorney or an accountant. These are people that have 20-20 vision but are visually completely dysfunctional, and we believe that they'll be very motivated when there's a treatment available to slow down the progression of this disease. And again, those patients are not necessarily all with retina specialists at this point. They are with optometrists and general ophthalmologists. But once there's a treatment available, we believe those patients will be referred rapidly to the retina specialist. And we've seen this in wet macular degeneration as well. Now, switching to intermediate macular degeneration, phenotypically these patients can be identified as early as in their 30s and 40s, and you're exactly right. A lot of them in the very early stages are not symptomatic. In the later stages of intermediate AMD, they are symptomatic in the same kind of reasoning that I mentioned, where they may be able to have visual dysfunction because of not seeing straight line, what we call metamorphopsia or scotomas or blind spots. And currently with the version 1 of Zimora, We feel that there are enough patients with intermediate AMD where that impact will be made to prevent progression to a blinding disease, which is geographic atrophy, and that will be very important. For the earlier stages, our life cycle management of Zamora that Tony referred to is terribly important. We believe that if we can have a sustained delivery type strategy where patients have to come in to the retina specialist maybe once every six months or once every year, that will be quite acceptable to prevent them from having to suffer through geographic atrophy. I hope I've answered your question. Thanks for the question.
spk09: Yeah, thank you. Thanks, Annabel. This is Keith for your question on the 84% completion. Just a couple of things. So you're correct, 84% of completion of year one. Gather 2 is designed as a two-year study. So as these patients complete year one, they're rolled into year two of the study. Just important to note the design, so as patients receive monthly injections that are on the 2 mg Zamora arm in year one, at the 12-month time point, they're re-randomized to either continue to receive monthly injections of Zamora 2 mg or every other month. The sham patients continue on sham. Hope that helps to answer your question.
spk03: Yes, and all of them have been re-randomized. All the 84% that have completed have been randomized. That's correct.
spk09: That's correct. As those patients come off, they go into year two.
spk03: Okay. Okay. Great. Thank you.
spk05: Thanks, Annabelle.
spk01: Thank you. And this concludes the question and answer session. And I would like to turn the call for the management for any closing comments.
spk05: Well, thank you, Keith, for moderating today. And I want to thank everybody for joining. And we look forward to a continued dialogue about our progress through the rest of the year. Goodbye, everybody, and have a good day.
spk01: Thank you. The conference has now concluded. Thank you for attending today's presentation.
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