IVERIC bio Inc (ISEE) 2021 Q4 法說會逐字稿

Good morning, and welcome to IVERIC bio's conference call. Representing IVERIC bio today are Mr. Glenn Sblendorio, Chief Executive Officer; Dr. Pravin Dugel, President; Mr. Keith Westby, Chief Operating Officer; Mr. Dave Carroll, Chief Financial Officer; Dr. Dhaval Desai, Chief Development Officer; Mr. Chris Simms, Chief Commercial Officer, and we are pleased to welcome Mr. Tony Gibney, our 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 IVERIC bio's 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 statements. 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.

Thanks, Kathy. 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 GATHER2, our second Phase III clinical trial for Zimura 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 1 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 U.S. FDA as well as the European Medicines Agency for marketing approval of Zimura in GA.

As we get closer to reporting the GATHER2 data, we continued our efforts internally to prepare for a potential filing of a new drug application for Zimura for the treatment of GA. We continue to gain momentum in building out our medical affairs team led by Dhaval Desai, our Chief Development Officer; and the commercial infrastructure led by Chris Simms, our Chief Commercial Officer. These are 2 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 Zimura. Earlier this month, the U.S. Patent and Trademark Office allowed claims for patent covered, covering methods of use of Zimura 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 fovea in a subset analysis of patients from GATHER1, which is our Phase III clinical trial for the treatment of Zimura in GA. These data were recently presented at this year's e Angiogenesis, Exudation and Degeneration Conference, and Pravin will provide more details on the analysis in a few moments, and you'll 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 GATHER2. The agreement further solidifies our plans to file an NDA with the FDA for marketing approval of Zimura for GA if the ongoing GATHER2 clinical trial meets its primary endpoint at 12 months. As you know, Zimura met its primary efficacy endpoint at 12 months with statistical significance in a previously completed GATHER1 pivotal trial.

In July, we announced the completion of patient enrollment in GATHER2. This was 4 months ahead of our original schedule. We also started the planning to initiate a Phase III clinical trial, studying Zimura 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 IIb screening trial of Zimura for treatment of autosomal recessive Stargardt disease.

We also initiated a number of preclinical tolerability and pharmacokinetic studies for IC-500, our 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 and 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 IC-500 during the mid-2023.

We also strengthened our balance sheet by raising approximately $108 million and $163 million in net proceeds from public offerings in July and October 2021, respectively. Dave will cover our cash and cash runway later in the call. We believe that these capital raises enabled us to accelerate preparations for a potential commercial launch of Zimura, and allow us to continue to invest in manufacturing capacity. In addition, we continue to invest additional money and additional life cycle initiatives for Zimura 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 Melinta Therapeutics, to our Board of Directors. We're thrilled to have somebody of Christine's caliber join our Board. Christine's extensive background of 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 is 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.

Thanks, Glenn, and good morning, everyone. As Glenn mentioned, we completed patient enrollment in GATHER2 in July 2021, with 448 patients enrolled, 4 months ahead of our original schedule. Based on this time line, we expect top line GATHER2 data to be available in the second half of 2022, approximately 1 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 therefore -- and thereby further derisk the GATHER2 clinical trial. As Glenn mentioned, we are targeting patient retention for the GATHER2 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 GATHER1 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 observe -- potentially observe the early and increasing treatment effect we previously observed in GATHER1.

Patient retention is clearly an integral part of the GATHER2 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 GATHER2, we are encouraged to see that our efforts to maximize patient retention in GATHER2 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 U.S. 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 Pravin.

Thank you, Keith. 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 analysis whether Zimura has the potential to slow the progression of GA into the fovea, 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 GATHER1 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 Machemer, Professor of Ophthalmology.

Consistent with the overall results of GATHER1, in the new analysis, a reduction in lesion growth in 5 standardized regions surrounding and including the central foveal area was observed for patients receiving Zimura 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 circumstantial growth pattern typical for GA patients.

GA has a major impact on functional vision, which could alter the quality of life and independence of effective individuals. We believe that the results from this exploratory analysis are another step in studying the potential of Zimura 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 fovea, the patient may have the opportunity to continue to drive, lead -- live independently, et cetera, for a longer period of time as compared to the natural history of the disease. Additionally, by preserving the central fovea, 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 iRORA to complete retinal pigment epithelial and outer retinal atrophy, or cRORA, and the progression of drusen to iRORA and cRORA in the Zimura 2-milligram and sham control groups, we plan to initiate a Phase III clinical trial, studying Zimura 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, sham-controlled, multicenter 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 on the intermediate AMD trial is a subset of the prevalent drusen population. We have been exploring several life cycle management initiatives for Zimura with efforts focused on potential sustained release delivery technologies.

Our goal is to derive a formulation of Zimura with a sustained release delivery technology that reduces the frequency of intravitreal 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 Zimura 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 are well positioned to expand Zimura's indications, build an AMD franchise and, subject to regulatory approval, commercialize Zimura for GA as the market leader. Thank you for your time. I will now turn the call over to Tony.

Thank you, Pravin, and good morning, everyone. It is truly a pleasure to be here with you this morning. I'm excited to join IVERIC bio and to work with Glenn and others and the leadership team who I've known for many years as well as Pravin, 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 Zimura, 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 Pravin just mentioned, with a near-term focus on sustained-release delivery technologies for Zimura. 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.

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 Zimura clinical programs, increased manufacturing activities for Zimura 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 Zimura in GA and Stargardt, and the initiation of an intermediate AMD clinical trial, preparation and potential filing of an NDA and MAA for Zimura, continuing preparations for potential commercial launch of Zimura, investing in sustained-release delivery technologies for Zimura and the advancement of our IC-500 development program.

Excluded from these estimates or any potential approval or sales milestones payable to the Archemix Corporation, or any potential expenses for the actual commercial launch of Zimura, including sales force expenses, and any additional expenditures related to potentially studying Zimura in indications outside of GA, Stargardt and intermediate AMD, resulting from the potential in-licensing or acquisition of additional product candidates or technologies or any other associated development we may pursue.

I'll now turn the call back over to Glenn. Thank you for your time.

Thanks, Dave. As we look ahead to 2022, we'll continue to focus on the execution of GATHER2, with the retention of patients and preparing for potential commercialization of Zimura in the U.S. as our top priority. We will continue our internal efforts to prepare for a potential filing of an NDA for Zimura for the treatment of GA if the GATHER2 results are positive. We also look forward to initiating a Phase III for Zimura intermediate AMD trial and investing in additional life cycle initiatives such as sustained-release technologies for Zimura.

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.

(Operator Instructions) And the first question comes from Kenneth Cacciatore with Cowen and Company.

Congratulations on all the progress. Your competitors' results really helped nicely confirm the impact on complement inhibition study extrafoveal lesions. And obviously, a 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 extrafoveal lesions. Talk about how easy it is to diagnose. I know once a product is approved, I would imagine you can implement a strategy to really help educate clinicians on an earlier diagnosis, but I'd like to hear about that.

And then maybe talk about how the FDA would handle a label here in terms of extrafoveal versus foveal? So that's question #1 with a couple of parts. And then just question #2, you talked about the progress on looking for extended release formulation. Just like to hear a little bit more about the ease or maybe lack thereof of Zimura in formulating into extended release, kind of what are you seeing in your early work here and then maybe talk about would a implant be something that you look at? There seems to be some success right now moving forward with the TKIs on an implant strategy. Just a little bit more around the sustained-release formulation work.

Well, thanks, Ken, and we'll work on question 1, which I think has 3 parts, and we'll break it up amongst the team. The first part is the amount of extrafoveal patients in the total population of GA, which we estimate to be about 1.5 million in the U.S. And of that, about 2/3 have extrafoveal. So I hope that helps with that. The second question on really diagnosis and finding these patients. Pravin, 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, Pravin, on the diagnosis question.

Thank you, Glenn. And Ken, thank you for your question. The diagnosis part, Ken, is really with fundus examination essentially. 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's really will be made not just by specialists, but by general ophthalmologists as well as optometrists. And that's where most of the extrafoveal 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 extrafoveal is really the vast majority of the patients and these currently reside with general ophthalmologists and optometrists. And our expectation is that once there is 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 maybe 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.

Thank you, Pravin. Let's go -- we'll come back to your NDA question, Ken, I just want to get a clarification on exactly what you're looking for. But, Tony, a couple of words about extended release and the early work that we're doing there and the type of technologies that may be applicable here.

Sure. Happy to, Glenn. So we're looking at a number of technologies. And they're really across the spectrum of available technologies for back-of-the-eye diseases, some of which are quite late stage in valid and some that are really more emerging technologies. I have to say, I think that at Zimura, 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 implant technologies, we're looking at microparticles, we're 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 Zimura 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 Zimura in its current formulation. So stay tuned.

Great. And my question was on the label. Obviously, there seems to be impact on all areas of the foveal and extrafoveal. But just wondering how do you think the agency will handle label given the patient enrichment for GATHER1 and 2?

Yes. So Ken, firstly, I think we need to obviously see the data from GATHER2 before we talk about label strategy. But I'll let Pravin answer that because I think we have some thoughts on how we position our data with the agency. Pravin?

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 fovea-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 competitors' studies as well. So the one thing that I would take home from this is that we certainly derisk GATHER2 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 borrower scrutiny. I think the FDA completely understands how important it is for patients with fovea-affecting geographic atrophy to have some area in the parafoveal areas survive.

There are patients that I remember I used to treat that had lesions in the parafoveal area with eccentric fixation, and they would use that area to stop from bumping into furniture or stop their hands from getting burned 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.

And the next question comes from Mike Ulz with Morgan Stanley.

Just quickly on GATHER2 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?

Yes, 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, managed through that. So that's why we wanted to give the numbers both on injection fidelity running well ahead of our projected guidance. 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 health care 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 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.

Got it. That's helpful. And then maybe just a 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?

Yes. Great question, Mike. Pravin, do you want to take that one in terms of the design?

Sure. Thank you for the questions. First of all, I want to say, if you just look at the biology of this disease, if complement inhibition works in extrafoveal 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 all together.

So we're extraordinarily fortunate to have a very, very collaborative and consistent FDA. And the purpose of our meetings is that really nobody has 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 as we have with the groups like 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.

And the next question comes from Tiago Fauth with Credit Suisse.

Congrats on the progress so far. So just to go back to a point you've mentioned on GATHER2 being relatively the risk based on patient selection. So again, we haven't seen (inaudible) fully replicating their filings in FILLY 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 GATHER2 will actually replicate GATHER1 finding? And why you can expect a potentially different outcome than what you saw from a 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 (inaudible) based on potential approval and launch? Sorry, multipart question there, but that's it.

Yes. No problem, Tiago. I think we have 3 questions. First on GATHER2, and how we're feeling about the derisking. I think there's a few things to cover, and I'll let Pravin add to my commentary. One, we have an unusual situation that we have 1 of 2 Phase III trials done. So we have the benefit of the GATHER1 data. And we also have the benefit of the -- which -- and the 12-month data was the primary end point, but also in GATHER1, we had the benefit of the 18-month data to see what happened in the 6 months after. And as you know, we continue to see a separation of the curves.

As to another factor, did you pick the right patients? We always believe that we did. And then with our competitors' data, with their subset analysis of extrafoveal lesion showing quite similar numbers in terms of efficacy, we felt that, that's a further derisking.

On the recruitment and the reason we put the concept of injection fidelity, and obviously, to keep the integrity of the study you want 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 we're well into the 80% range, demonstrates that these patients are coming back. And also going back to GATHER1, we had a terrific trial and data to show those patients that finished a Phase III 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 Pravin 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 GATHER2. Pravin?

Thank you, Glenn, and, Tiago, thank you for the question. Let me just divide my answer into 2 different parts. The first part would be the consistency and validity of GATHER1, and the second part would be how we derisk GATHER2. And both are really important questions. So if you go back and look at GATHER1 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. So with everything in GATHER1, 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 do we derisk GATHER2? The most important answer is really by having GATHER1, 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 III study with the first Phase III study already being so overwhelmingly positive. But the other ways that we derisked GATHER2 is by taking the proper patient population. And we did this for several reasons, but the important one here is the biologic one, which is that is one complement is the most active and 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 Dhaval Desai, 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 derisk GATHER2 in the face of an overwhelmingly positive and consistent result for GATHER1.

Thanks, Pravin. And Tiago, to your second question around the patent, I think it's one of a multipronged strategy that we laid out in -- for life cycle of this product. So this is a patent that covers methods of using Zimura. And once issued, it is expected to expire in 2034. I think it's under the umbrella of life cycle. Tony spoke a little bit about the initiatives for extended delivery. Obviously, strengthening the IP portfolio is a 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 1 step in the 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.

Sure. 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 Zimura whatsoever, first off. And then the total payments related just to the first indication is in the $20 million to $25 million range, I think it's $23.5 million, something like that. This will all be in our 10-K, and it's actually in last year's 10-K also. And then no royalties and those milestones just relate to clinical and regulatory milestones, that's it.

And the next question comes from Annabel Samimy from Stifel.

I had a couple here. So I guess there's been some question about patient motivation to -- or physician motivation to treat is high. Patient motivation to continue to treat chronically, I would say, at the late stages of disease like where they're starting to see functional issues 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?

Okay. Thanks, Annabel. So 2 questions there. And I'll have Pravin answer the first question because as he, in a prior life, is 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 what happens to these patients at the end of their 12 months, what happens in year 2. So Keith will lay that out for you. So Pravin, let me turn it over to you first.

Great. And thank you for your question. Let me just divide the answer into 2 different parts, the GA part as well as the intermediate AMD part. And 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 the disease that occurs as early as the patients in their 50s and 60s and always starts extrafoveal, 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 4 to 6 months or so. Another way of looking at this is that there was a recent article that looked at the entire U.K. database that was authored -- the senior author was (inaudible) that showed that patients with geographic atrophy end up losing driving vision, 60% or so lose driving vision in 1.6 years, which is just really stunning. And in about 3 years, 40% or so have their central fovea 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 50s 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 read -- 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 is a treatment available, we believe those patients will be referred rapidly to the retina specialists, 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 and the same kind of reasoning that I mentioned where they may be able to have visual dysfunction because of not seeing straight line with the metamorphopsia, or scotomas or blind spots.

And currently, with the version 1 of Zimura, 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 Zimura 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 specialists maybe once every 6 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.

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 1. GATHER2 is designed as a 2-year study. So as these patients complete year 1, they're rolled into year 2 of the study. Just important to note the design. So as patients receive monthly injections that are on the 2 milligrams Zimura arm in year 1, at the 12-month time point, they're re-randomized to either continue to receive monthly injections of Zimura 2-milligram or every other month. The sham patients continue on sham. I hope that helps to answer your question?

Yes. And all of them have been rerandomized, all the 84% that have completed have been randomized?

That's correct. That's correct. Those patients come off, they go into year 2.

And this concludes the question-and-answer session. I would like to turn the call for the management for your closing comments.

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.

Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines.