Apellis Pharmaceuticals, Inc. (APLS) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the Apellis Pharmaceuticals DERBY and OAKS 18-month Data Conference Call. Today's call is being recorded. At this time, I'd like to turn the call over to Meredith Kaya, Senior Vice President of Investor Relations and Strategic Finance at Apellis.

Good morning, everyone, and thank you for joining us today to discuss longer-term data from the DERBY and OAKS Phase III studies evaluating pegcetacoplan in patients with geographic atrophy, or GA. For those participating via conference call, we have made the slides available via webcast. A replay of this call will also be available on our website following the call. Before we begin, I would like to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. On today's call, I am joined by our Chief Executive Officer, Dr. Cedric Francois; our Chief Medical Officer, Dr. Federico Grossi; and Dr. Jeffrey Heier, principal investigator of the DERBY study and Director of Retina Service and Retinal Research at the Ophthalmic Consultants of Boston. Tim Sullivan, our Chief Financial Officer; and Adam Townsend, our Chief Commercial Officer, will also join us for the Q&A session. Now I'm going to turn the call over to Cedric.

Thank you, Meredith, and good morning, everyone. We are excited to share with you this morning 18-month data from our Phase III DERBY and OAKS studies evaluating intravitreal pegcetacoplan, our targeted C3 therapy in a dose with geographic atrophy, or GA, secondary to age-related macular degeneration, or AMD. The results we are sharing today build on the 12-month data we reported last fall, further reinforcing our confidence in the potential for pegcetacoplan to become the first ever treatment for the millions of patients living with GA. The 18-month data demonstrate that continuous treatment with pegcetacoplan results in an increasing benefits to patients with greater amounts of retinal tissue saved over time. Specifically, data from DERBY and OAKS showed continued reductions in lesion growth beyond year 1, with both monthly and every other month dosing at month 18, meaning that there was a larger absolute difference between pegcetacoplan and sham NGA lesion area. Nominal p-values across both studies and both dosing regimens were all below 0.05. We also saw that starting at month 6, DERBY showed improving effects that were comparable with OAKS. And importantly, results from the combined studies show the potential for continued improvements over time. As you know, GA is a devastating disease that leads to the destruction of the retina and irreversible blindness. These data further demonstrate that pegcetacoplan can slow this process. And if extended out over time, treatment with pegcetacoplan could mean that patients save more and more of their retina each year and potentially preserve their vision for longer. We look forward to submitting our NDA next quarter, which will include these 18-month results. Collectively, we have a robust data sets across 1,500 patients and 3 similarly designed adequate and well-controlled studies, which show consistent and clear reductions in lesion growth as well as a favorable safety profile. We plan to seek a broad label for pegcetacoplan supported by the effects seen across both monthly and every other month dosing. We know that dosing flexibility is critically important given the variability of disease in this population, providing physicians with the ability to better treat this diverse patient population. And if approved, pegcetacoplan will be the first and only treatment available for patients, providing Apellis with the opportunity to establish the markets where nothing has existed previously, build awareness amongst physicians on the potential benefits of pegcetacoplan for their patients and then partner with physicians as they gain experience with the drug. We are preparing additional analyses, including the extrafoveal subgroup and the fellow eye comparison, and expect the results to be generally consistent with what we saw at the top line. We look forward to sharing these at upcoming medical meetings as we continue to educate physicians and patient communities about the potential of this novel therapy. We are also fortunate to have Dr. Jeff Heier here today to share his perspective on the data. More than ever, we believe pegcetacoplan represents a breakthrough for patients globally who are living with GA. And let me now turn the call over to Fede to walk through the data.

Thanks, Cedric, and good morning, everyone. Before we review the data, let me first quickly remind you of the study design. DERBY and OAKS are double-masked randomized controlled global Phase III studies comparing the efficacy and safety of monthly and every other month intravitreal pegcetacoplan with sham treatment in 1,250 GA patients across more than 200 sites worldwide. The primary efficacy endpoint of both studies was the reduction in growth of GA lesions from baseline to month 12 as assessed by fundus autofluorescence. The studies are continuing for a total of 24 months, while patients remain in the randomized masked treatment groups. In addition to our current 18-month analysis, lesion growth will be assessed again, and secondary functional endpoints will be formally tested at month 24. Let me now review the data. As you can see on this slide, treatment with pegcetacoplan in both DERBY and OAKS shows continued and clinically meaningful reductions in lesion growth from baseline out to month 18. As you can see on the right, OAKS shows a linear and consistent treatment effect through month 18 with p-values of less than 0.0001 and 0.0018 in the monthly and every other month treatment arms, respectively. And on the left, DERBY shows a slight improvement effect from baseline to month 18 with p-values of 0.0254 and 0.0332, respectively. The analysis at 18 months was performed in exactly the same way as the 12-month analysis, supporting the robustness of the results in this analysis. What this means in terms of absolute GA lesion size is that at 18 months, there is an increasing separation between pegcetacoplan and sham, resulting in a larger absolute difference over time. For example, at 12 months, we saved an average of 0.41 square millimeters in retinal tissue in the OAKS monthly arm as compared to sham. At 18 months, this increased to 0.66 square millimeters. To put this into context, the fovea, which is the area of the retina responsible for the highest visual acuity, is less than 2 square millimeters in area. Therefore, if these effects continue over longer period of time, we expect that the difference in absolute lesion size for the amount of retina saved will have an increasingly substantial impact. We then look at the effects with pegcetacoplan at 6 months intervals. The reason for doing this is that we aim to understand how the treatment benefit evolves over time. There are 2 key takeaways from this slide: first, the effects seen in DERBY are comparable with OAKS starting at 6 months and continue through month 18; and second, in both studies, pegcetacoplan show continuous reductions in GA lesion growth over time. As you can see, in DERBY, there are marked improvements in months 6 to 12 as compared to months 0 to 6. Reductions in lesion growth in the monthly arm increased from 6% during 0 to 6 months to 17% during 6 to 12 months, with a similar increase seen in every other month dosing. Effects were sustained through 18 months. We know that there were faster progressing patients in the treatment arms in DERBY as previously shown in the fellow eye analysis at 12 months, which created a higher hurdle to overcome when compared to sham. There is natural variability in the data based on the [ heterogeneity ] of this population, but the trends indicate that treatment with pegcetacoplan results in improvement effects over time. These improvement effects become clear when looking at the combined data from DERBY and OAKS, as shown on this slide. From month 12 to 18, pegcetacoplan showed a 21% and a 17% reduction in lesion growth as compared to sham in both monthly and every other month treatment, respectively. This is compared to 13% and 12%, respectively, in months 0 to 6. Moving now to safety. At 18 months, pegcetacoplan continued to demonstrate a favorable safety profile, consistent with safety at 12 months and with longer-term exposure. The pull rate of new onset exudations at month 18 was 9.3%, 6.2% and 2.9% in the pegcetacoplan monthly, every other month and sham groups, respectively. Over 18 months, the rate of infectious endophthalmitis was 0.044% per injection, and the rate of intraocular inflammation was 0.23% per injection out of a total 9,145 injections. There were no events of retinal vasculitis or retinal vein occlusion. We are planning to include this data in our NDA submission, which is on track for the second quarter of this year. We also continue to plan for our MAA submission in Europe in the second half of 2022. I will now turn the call over to Dr. Jeff Heier.

Thanks, Fede, and good morning, everyone. Geographic atrophy is an advanced form of AMD, which leads to the destruction of the retina and blindness. And unfortunately, there are no treatments currently available. Importantly, GA is not a 1-year disease or even a 5-year disease. Patients can live with the devastating effects of GA for 10 to 20 years or even longer, losing more and more of their vision every year. My patients have lost their ability to do many of the simple things in their lives, like driving, grocery shopping or even just taking a walk around the block. In essence, they've lost their independence. Therefore, for me, having longer-term data to show how pegcetacoplan treatment will benefit patients over time is incredibly important. The DERBY and OAKS data shared today show effects that are continuing and even improving well into year 2. This means that there is an increasing amount of retinal tissue being preserved, and it is the loss of retinal tissue that is robbing patients of their vision. Additionally, I was really pleased to see the data across both studies act more consistently over time. Combined with its favorable safety profile, these data reinforce the potential for pegcetacoplan to become the first ever treatment for patients living with this debilitating disease.

Thank you, Dr. Heier. In summary, pegcetacoplan's transformative potential in GA is further reinforced by the 18-month data, demonstrating the increased benefit for the millions of people with GA who are at risk for blindness with no treatment options. We continue to believe we have a drug that is increasingly effective, with a favorable safety profile and a flexible treatment regime. All of us at Apellis remain committed to bringing pegcetacoplan to GA patients, filing an NDA in the second quarter of this year and advancing our ambition to be #1 in the retina. I would like to close by expressing my sincere gratitude to patients, physicians and site staffs participating in the DERBY and OAKS studies. This program remains close to our hearts, and it is thanks to all of you that this milestone was made possible. And to our amazing team at Apellis, we are so grateful for your unwavering commitment to advancing care for people living with GA and other complement driven diseases. With that, operator, please open the call for questions.

[Operator Instructions] Our first question comes from Madhu Kumar with Goldman Sachs.

Yes. So I think our first one goes to Dr. Heier. I guess, very practically, how should we think about new onset exudations, the kind of rates that have been seen so far in the context of the disease? And also, to the company, can we get a little more detail about those events? Like how well managed were they by anti-VEGFs? Were there any kind of broader vision sequelae associated with them? Like how should we think about these kind of events that are emerging between 12 and 18 months?

So a very important question. As you pointed out, we know that the rate of choroidal neovascularization is increased in these patients. The way I look at this and the way I have discussed this with patients when we talk about involvement in the studies is we -- if you develop choroidal neovascularization in this study, we have a treatment for choroidal neovascularization. It's a treatment that works extremely well, obviously, anti-VEGF injections. A rate that is in this order, and we see, it's essentially 6% per year, right? So we see 9% at 18 months, which still falls in line with the 6% per year. That -- we can treat that, and we typically catch these cases early because these patients are being followed carefully and at least through 12 months, and I haven't seen the 18-month data, how these patients are doing. But at 12 months, these patients were typically doing well and had been treated on label with therapies. When I tell patients the rate of CNV, we know how to treat this, and the rate is relatively low. Again, if we're talking 10% -- less than 10% at 18 months, the flip side is development of geographic atrophy is virtually 100%. So we know that's going to progress. So I would much rather be able to manage choroidal neovascularization in the less than 10% that it occurs and find a treatment for the geographic atrophy that is absolutely going to occur and for which, currently, we have no therapy.

Cool. I guess, do the [ weight ] in case speaks to in the 12- to 18-month kind of treatment on anti-VEGF, this is for the company, the 12- to 18-month anti-VEGF management of CNV events.

Say that -- so I'm not sure I understand the question.

My question is for the company. To your point about you haven't seen the 18-month data, what could the 18-month data [ contributes ] in terms of how well CNV is managed so far?

Fede, I'll defer that to you.

Thank you, Jeff. Yes, Madhu, so it's basically the same at 18 months as it is at 12 months. So these are well managed with anti-VEGF and show consistent favorable safety profile.

Our next question comes from Umer Raffat with Evercore.

It's Jon Miller on for Umer. Two, if I may. The biggest disparities between the 2 trials, obviously, are in those first 6 months. And I know that over -- since the 12-month data came out, we've been doing a lot of talking about baseline imbalances as explaining some of the differences between these 2 trials. But then, of course, the disparity seem to go away from 6 months onwards. So how do we explain the disparity in the first 6 months between the 2 trials that then seems to go away with more follow-up? And then secondly, what would it take to be maybe a little more quantitative about your confidence that the effects really is increasing over time? Obviously, we've seen -- we've all seen the chart now, and it looked pretty interesting. But can we expect a more formal analyses of that increase in effect size at a medical meeting or perhaps in a later release?

Yes. Thank you so much on 2 very important questions. So as it relates to the first 6-month period, really, what you see there is a reflection of the fact that in the DERBY trial, in the monthly arm, we enrolled patients that are very fast progressing. And so we also see that through the analysis with the covariate, and we can see that by looking at the fellow eye. So every patient has one study eye, most patients have bilateral GA. So you can use the fellow eye to get a sense of how aggressive the disease is progressing in these patients. And it turns out that in DERBY, in the monthly arm, these patients were "very bad." So in the first 6 months, we feel that there is a kind of a catch-up moment that needs to happen in DERBY. And as you mentioned correctly, between month 12 and months -- between month 6 and month 18, you see that catch-up to OAKS gradually take place. Then as it relates to the increased effects, so for me, it is quite remarkable to see, when you have the joint studies together, how every 6-month segment shows essentially a slope that seems to be increasing. We'll see how that's going to go from month 18 to 24. We're very excited to look forward to whether that trend continues to be the case. But it's quite remarkable that both for the monthly as well as for the every other month group, which remember, are different patients, right, you see that same trend line over 0 to 6, 6 to 12 and 12 to 18. And it is worth mentioning, as the last point here, is you would say, well, why exactly do you look at it that way? Because if I have geographic atrophy today, right, it doesn't really matter how aggressive the disease was 2 years ago. I want to know how aggressive the disease is today because most of these patients are going to be on treatment for not 2, but 5, 10, 20 years or longer. So slowing down the progression of that disease is something very important.

Our next question comes from Tazeen Ahmad with Bank of America.

Maybe two from me. Thanks for putting together that deck, and it was helpful to look at the details. But I was just curious if you could give us any color on the breakout between the results for foveal and nonfoveal and, if not today, if you plan on presenting that at any kind of medical conference. And then maybe a question for Dr. Heier. I'm just curious as to your view about whether you think that the rate of nonexudative CNV could be predictive of exudations for patients in general.

Thank you so much, Tazeen. Well, I'll quickly address the first one. So we will present the extrafoveal data and as well as the fellow eye analysis at a later point in time. But I can generally tell you that the trends are very similar to what we saw at the 12 months. So no surprises should be expected there. And Jeff, I will turn it over to you to speak about nonexudative CNV.

Sure. So as we think about the differences in exudative and nonexudative CNV, and this is a topic that clinicians and clinical trialists and imaging experts talk about all the time, the exudative CNVs are the ones that we always treat. They're the ones that certainly impact visual acuity. And so there's no question that we always treat these. As we think about the nonexudative CNVs, looking at those can be helpful in predicting down the road whether patients will become exudative or not, but it's certainly not absolute. And so treating the exudative patients is what's critical. I hope that answers it.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the update. Just two quick ones. For the company, maybe a logistical question, which is with the 18-month data on hand, what are the final sort of gating factors to submitting the NDA in 2Q? And logistically, I just wanted to confirm that the 24-month data, safety or otherwise, won't be submitted to regulators here in the U.S. And then for the KOL on the line, based on the known data, the totality of the data, particularly the 12-month data in extrafoveal lesions, how do you think about subgroups of patients or your patients overall and incorporating this into your treatment practice?

Thank you so much, Anupam. So our NDA is on track for the second quarter submission. The full data set from the 18-month will be included in that. And the 24-month data is not scheduled as a major amendment. So all of that remains unchanged from the way we planned in the last couple of months. So Jeff, over to you.

Yes. So I certainly, and many of my colleagues, have spent a lot of time thinking about how will we incorporate this treatment if it gets approved into our clinic. And certainly, with the data I've seen, I have patients that I will absolutely want to treat. And I would envision, without a doubt, patients who have extrafoveal lesions will be important to treat as trying to prevent them from affecting central vision. But there are other patients who are not just extrafoveal that I think early on will be important to treat. There are patients who have foveal lesions, but still have good vision because part of the fovea is still intact or areas close to that are intact. There are patients who have subfoveal small lesions. So even though their vision may be significantly hampered, even the 20/100 or 20/200, the lesion is small. And keeping it small is important to maintaining some level of quality vision. And then I think as we go on and we understand this better and we understand the cumulative impact of these patients, we've all seen the time lapse images from imaging experts like Frank Holz and Glenn Jaffe and others that have shown how these lesions grow over time. And so even lesions that look significant now over a 5- and 10-year time lapse get larger and grow from arcade to arcade. So in my mind, I've seen patients who have large lesions in one eye and moderate lesions in their good eye. And if we can prevent that from growing from the moderate lesion to the large lesion, we are still helping patients maintain some level of independence. So I think I know where I'll start, but I also can envision the need for other patients.

Our next question comes from Lyla Youssef with Cowen.

Congrats on the update. Maybe just quickly from us, could you maybe comment on the discontinued -- the number of patients that discontinued the trial before month 18 on each arm? And then as a quick follow-up, for any of the cases of intraocular inflammation, were any of them associated with meaningful vision loss?

Yes. Lyla, I had a hard time hearing you, but I think what you were saying is whether there was -- whether a lot of patients were lost to follow up at 18 months. Is that -- was that the question?

Yes. It was how many patients discontinued the trial before month 18 in each arm. And then as a follow-up, were any of the cases of intraocular inflammation associated with meaningful vision loss?

Okay. Thank you so much. So for the 18-month data and kind of the follow-up throughout the trial, that will come later, but we have been very pleased with the retention rate in the study and for that matter also with the number of patients that go into the extension study, GALE, which is the 3-year follow-up study beyond DERBY and OAKS. So with the intraocular inflammation, again, more details will follow there. But at this point in time, we haven't seen anything that gives us a cause for concern from a safety perspective.

Got it. And then maybe I have one quick follow-up question. For the -- you noted that you're preparing the analysis of the extrafoveal lesions and the subset and how the efficacy compared there. Will that be included in the filing that you'll submit in Q2?

Yes. So we will -- look, we will, of course, compile all of the data. But I want to remind people that the way we will submit the application is for all patients with geographic atrophy, which is how we ran FILLY, DERBY and OAKS, all 3 studies. And there will be 4 components to our NDA submission. There will, of course, be the safety package. Then there will be the biological activity, which we will establish with 2 positive studies between FILLY and OAKS. And then the fellow eye analysis in patients with bilateral GA for the treated eyes and a dose response slowdown compared to the untreated fellow eyes. Third chapter will then be the effect size because between the 3 studies, we have effects between 12% and 29%. And with covariate analysis, we can harmonize those data and kind of compensate for having good patients in the active or the sham. And for example, in FILLY, at 29%, that is probably an overestimation of how good the effect is, whereas in DERBY, clearly, as we now see as well, with this 18-month data, we had bad patients in the active arm. With the covariate analysis, clearly, effect size is around 20%. And then the last piece, chapter #4, of course, what we are talking about here today, which is the data at 18 months -- beyond 12 months up to 18 months, which kind of establishes the durability and the continued benefits that you can get from treatment with pegcetacoplan in a disease that's again not a disease of 1 or 2 years, but 5 to 10 or 20 years or more.

Our next question comes from Steven J. Seedhouse with Raymond James.

The effect on the lesion growth post month 18, I guess, I was expecting whatever data you had already available by now. So I'm hoping you could comment maybe on if you have that data analyzed and if the absolute delta continues increasing post month 18 as well.

Yes. So the -- we decided to release that when we have the full complete data set, just as a matter of due course, but we are very excited about what we've seen. I will be masked, we will all be masked, of course, between now and the 24-month standpoint. But what we have seen so far looks very promising in terms of continued trends.

Great. Okay. And then on [ missed ] injections post month 12, was that also consistent with what you had observed and reported prior to month 12?

That is correct.

Okay. And then lastly, I guess, it's unclear if you're concluding that you have a dose response here or not based on the longitudinal analysis maybe, maybe not, but based on the 6-month segment analysis you're reporting, maybe. So I guess, I'm asking, do you think there's a dose response? And will you pursue approval of both doses when you file?

Yes. So there is a very slight dose response, right? But certainly, it's far less than the 50% that you would expect from every other month compared to monthly, right? So this is something that I'm personally very excited about. Possibility to treat every other month, especially in patients that are early on in the disease, right, and that want to make a long-term investment in retaining as much vision as possible is something that I find particularly attractive. And we will file both for monthly as well as for every other month in our NDA. And it is worth noting that the nominal p-value in DERBY not just slipped below 0.05 in the monthly arm, but also in the every other month arm. And maybe, Jeff, if you don't mind kind of throwing the question to you, how your view is on the possibility of treating every other month, I think that would be interesting to people on the call as well.

Yes. Certainly, one of our concerns over treatment for GA is that there's no biomarker data that you would be able to use that would enable you to modify the treatment regimen. So unlike wet AMD, where the OCT and presence or absence of fluid helps us to manage these patients and extend therapy, that's really not possible here. And so if you have data for every other month that looks close to the monthly, and we believe that we can preserve vision with a less frequent regimen, that certainly will make compliance and treatment burden much more manageable.

Could I just -- one more for Dr. Heier since we have you on. I was hoping you could maybe comment on basically the 0.5 millimeter square difference in lesion size that manifests in a pooled analysis at month 18. In your experience, how meaningful is that absolute difference?

Yes. That's a good question. It's -- they're -- having seen these patients day in and day out, and their approach is any benefit is important. And you have to keep in mind that the benefit that you see right now at 1 year and then a slightly greater benefit at 18 months, these changes are cumulative over time. And so over time, if you're making a 0.4 millimeter difference every year, when you're out 5 years and you're out 10 years, those differences are actually huge. And so while these are not extremely large differences, they are meaningful differences. And depending on the patient and the lesion location and the underlying vision, these can be very, very important changes. And cumulatively, the difference becomes huge when you look at it over time.

Our next question comes from Chris Howerton with Jefferies.

Congratulations on the update. For me, the -- maybe for Cedric, I would love to talk about what you're seeing in terms of rates of nonexudative CNV and if you can comment at all on whether or not those were predictive of conversions to exudations. And then secondarily, I guess, also to Cedric, curious how you would respond to the idea that, to me, it looks like the OAKS data is relatively consistent in its effect size, whereas DERBY is changing over time. So rather than the overall effect size improving over time, it's more reversing to a mean. So curious how you would respond to that comment.

Thank you so much, Chris, for that question. So nonexudative CNV, to get to the first question, is not something that we measure in our clinical trials. It's not, as far as I know, something that anyone measures in their clinical trials because the techniques and the technologies that you need to measure that are called OCT angiography and indocyanine green imaging, ICG. You could theoretically include that in a protocol, but then the question becomes how clinically relevant is that because it is something that physicians, retina docs would typically not treat with anti-VEGF either. And Jeff, since we are fortunate to have you on the call, maybe you can quickly elaborate on that as well.

Sure. So I do think there are some studies that are looking at OCT angiography to look at nonexudative CNV. And there's still a lot we're learning about it, and we continue to evaluate that. But at this time, certainly, what we treat is exudative CNV, and that's what we were focused on in these programs.

Thank you so much, Jeff. And then as it relates to the changes over time, so in DERBY, I think, again, the fact that we have a much more aggressive or more rapidly progressive population in the monthly arm of DERBY is something that, I think, is also reflected in the variability that we see. But as you correctly mentioned, Chris, between month 6 and 18 to see the reversion to the mean and kind of get OAKS and DERBY to look like they behave much more similarly in the reduction of growth rate is very encouraging to us.

Our next question comes from Colleen Kusy with Baird.

So in your conversations with the FDA, have they expressed you any interest in other analyses of the primary endpoint such as slope? And how do you think this 18-month data could play into that?

Thank you so much, Colleen. So the slope is actually very important, right, and that is what we are looking into here with the 18 months by breaking it out into these 6 months segment. So the slopes look very good. This was not our primary endpoint analysis, and we had agreed on our primary endpoint analysis with the FDA. But the FDA will, of course, look at all the data available. I think the slope personally is very important, again, going back to the point that this is not a disease of 1 year or 2 years, but 5, 10, 20 years or longer.

Our next question comes from Justin Kim with Oppenheimer & Company.

Congratulations on the results. Look forward to talking about them later today as well. Just a couple from us. With these encouraging findings and continued benefits and potentially the expanded benefit, just wondering if this suggests greater confidence in some of the secondary endpoints of interest expected at the 24-month follow-up.

Thank you so much, Justin. So of course, the 24-month data, we'll have to see what happens with the functional endpoints. But it's important to point out, of course, that measuring visual function is something very difficult, right? Visual acuity is a reflection of only the foveal vision. Microperimetry also has a limited number of points, and even reading speed. There's a lot of variability. We'll see where we end up at 24 months, but the important message here today is that saving for the receptor cells in the long run should translate into a functional benefit. The question is at what point that starts manifesting itself. And maybe, Jeff, you would like to add some points to that.

Yes. There's -- for -- we've recognized for years that vision alone would really be a difficult endpoint for geographic atrophy, both for central involvement, where it's obvious that the vision is already impacted, but also for the impact of lesions that are surrounding the center and impact reading and navigation and -- meaning walking and other such functions. So there's clearly importance to limiting the growth of these lesions. And you would expect at some point that, that would have an impact on vision, especially the earlier you treat lesions. Many of the patients involved in these studies, though, already have foveal involvement, already have visual decrease. So you're not going to see it in those patients.

Got it. Maybe just for the commercial setting then. I mean, as you think about an available agent potentially, just curious, given some of the observations on the commercial activity, how applicable are the average results compared to sort of the patient by patient results? The question I'm trying to ask is, is it possible to use these on a patient level and sort of identify patients who have a blunting of their progression and sort of say that this is a patient who's responding? Just wondering how you think about that. And maybe even from a dosing perspective, if you have sort of like a monthly and then try to explore every other month that's in your toolkit, what are the sort of options available and doable at a patient level?

Yes. Thank you, Justin. Look, that would be a dream come true, right? And we are doing a lot of work on that with AI instruments and analyzing the data, et cetera. Currently, it is not possible to make that prediction, right? It is also, without a doubt, not going to be part of the label. So I think, unfortunately, it will take some time to kind of bridge how we can bring these instruments in, but I think it's something very exciting for the future. And I do believe that it's possible to get closer to that holy grail.

Our next question comes from Yigal Nochomovitz with Citigroup.

I have one for Dr. Heier. So for the patients with the foveal lesions that already have the central vision disruption, I'm curious how you make the argument to patients that they should still receive pegcetacoplan given that their central vision is already depleted. And then secondly, just a related question, would you envision scenarios where patients could get the monthly regimen in one eye and every other month in the other eye? Or will the frequency of the regimen always be consistent across the eyes?

Yes. Those are two great questions. Let me answer the first one about patients with foveal lesions. There are -- it is very common in my clinic to have patients who are count fingers vision in one eye with a large, almost arcade to arcade geographic atrophy scar, and they're 20/200 or 20/400 in their fellow eye with, let's say, a 3-disc diameter geographic atrophy scar, which would take up a much smaller part of the posterior pool. That patient fully understands that the eye that is 20/400 with a foveal scar is still much better off than the patient at count fingers with an arcade to arcade scar. It's very easy for those patients to appreciate the difference. And if you can prevent that patient from that 3-disc area scar from being a 5-disc area or an 8-disc area scar, there's clearly advantage there. There are also patients who have CNV in their fellow eye. And so the -- even though their vision is such that they're legally blind, they still have a certain level of functionality that preserving that size of scar and minimizing loss of retinal tissue is very important. For the second question, that's really a challenging one to answer right now. And I think, over time, we need to have more of an understanding of the data. Personally, I'd want to understand the differences between the monthly and every other month more in depth with some of the subanalyses. And one of the other things that I would imagine we'll have is an understanding if the average lesion size that of patients that entered the study is 3-disc areas, somewhere in that range, a little bigger, it's -- you could model out what the changes over time would look like with the different rates of progression, whether a 12% rate or a 15% rate or a 20% or a 25% rate, what does that look like over time and get an idea of modeling what that would look like for patients and get an idea of what a difference of, say, 3% or 5%, the difference between the monthly and every other month arms will look like. And that may be something that some patients would say, "My lesions are far out. This is -- I just want to stop them. And every other month works for me versus monthly." But I think those questions are really going to require a lot more understanding and more analysis. So it's not one that I would certainly want to make to patients right now.

Our next question comes from Ellie Merle with UBS.

Maybe just on the regulatory front and kind of the history of sort of the trial design and picking like 12 months as the primary endpoint versus, say, a longer time point. Maybe can you give context for why 12 months have been selected and maybe just if you plan to, I guess, share the data with the FDA -- the 18-month data with the FDA before filing. And I guess, any like conversations that you've had around how they're thinking about sort of the appropriate time point to measure GA lesion growth just given the nature of the disease?

Yes. Thank you, Ellie. So that's a very good question, right? I mean, the balance that you have here again is the point that you have a disease in which many patients have that for decades, and they're not going to require treatment for a decade, but not having to run trials for that period of time. So you need to choose a cut-off and the arbitrary "cut-off" of one year was chosen. I mean, to put it plainly, to know that you could have realistic -- or financially realistic trials, right, that you could do. So -- but within that framework, again, we talked earlier about the slope, about understanding the longer-term progression of the disease becomes very important. It's important to note that the analysis that we run here at 18 months is the exact same analysis as we did at 12 months, right? So this is an analysis that really allows us to understand how the disease evolves over time, and we're very excited by what we are seeing. The 18-month data, to your point, will be completely included for safety as well as for efficacy in our NDA.

Our next question comes from Joseph Stringer with Needham & Company.

A question for the KOL, and this is kind of a follow-up to an earlier question on potential use of pegcetacoplan in patients with foveal versus extrafoveal lesions, just curious if you would see a difference or, at least based on your experience with these patients, a difference in sort of the patient willingness with -- patients with earlier stage disease, say, extrafoveal lesions versus foveal lesions, a difference in the willingness of the patients? Or is it -- would it be -- do you foresee that it's harder to convince the patients with the earlier stage disease to potentially take the drug and slow lesion growth? Just curious if you could comment on that from a patient perspective.

Sure. Absolutely. There are so many factors that go into that. And probably, the most important ones are fellow eye disease. If the patient has lost vision either from GI or from exudative disease in the fellow eye, they're highly motivated to maintain the vision in the good eye at all costs. Family history plays a role. Many of these patients will come in and say, "My parents, my older brother, my sister all have severe vision loss from AMD," and many of those are from dry AMD. And in fact, many of them will say, "I always thought wet AMD was the worst disease to have. But now, I'm learning dry AMD is worse because you don't have any treatment for it." So I think history goes into a lot. Also their history over time in terms of that patients come in and we look at the OCTs virtually every time, and patients have become imaging experts. The first thing they want to do is see their OCTs. And on the OCT, while historically, we've used them for wet disease, the unfazed image shows the dry disease, and it shows geographic atrophy. And so they can see that very well, and they can see the progression over time. And many patients will come in and say, "How does this look from last year and 2 years ago? And can you show me what that looks like?" So I never convince a patient that they need treatment. We simply talk about their disease. And the majority of them say, "What can I do? Is there anything available?" And they have extreme frustration that, right now, there isn't anything. But I'll tell you, the patients in the study are highly motivated. And many of the patients who were ineligible for the study for various reasons are highly motivated.

Our next question comes from Madhu Kumar with Goldman Sachs.

Yes. One more follow-up for Dr. Heier. I guess, kind of based on the conversation we've been having earlier, this notion of long-term assessment of these patients, so kind of very practically in the GALE open-label extension trial, what are you looking to see that would kind of enhance or affect your views about the use of peg in geographic atrophy?

So you hope to see that these changes that occurred in the earlier phase of the study are maintained. On a patient-by-patient basis, it's very challenging. You -- because you will certainly look and, as a masked examiner, will often look at their old scans and/or at their baseline scans and will look at eye-to-eye and just among ourselves say, "Oh, there's a difference here or there isn't." What you hope to see now that you know that they're getting study drug is you hope to see that you continue to show what seems to be a slower rate. But again, you can't tell from a patient-to-patient basis that the effect is strong or not, right? Their -- patients may think they're progressing, and yet they're progressing much slower than they would have been. When the fellow eye is -- has sort of bilateral symmetric disease, it's a little bit easier to say, "This eye seems to be growing at a greater rate than the other eye." But what we hope to see is just when you look at these over time that there is a continued slowing of the growth of the geographic atrophy. Patient-by-patient basis, though, it's tougher to make that assessment.

And as you follow in from that, like, is there any thought that the crossover data, how that would look relative to this kind of initial intervention data? Given to your point, it's 2 years later, so many of these patients might have progressed over 2 years on sham in a way that makes kind of interpretation difficult. How do we think about kind of crossover patient data in terms of its interpretability?

Well, it will be interesting to look at those patients and look at them on 6-month intervals, just like you saw in the 18-month data. And if you see that in the first 12 months they had a growth rate of X, and now in the 12 to 18 -- sorry, in the first 24 months, they had a growth rate of X, and now in 24 to 30, their growth rate is a little bit slower. And 30 to 36, it's now 15% slower, you can still appreciate that change. Now the patients, whether the patient appreciates because the lesion is bigger or not remains to be seen. It really depends on the individual patient's lesion, location and such.

And I'm not showing any more questions at this time. I'll turn the call back to Cedric for any closing remarks.

Thank you, operator, and thank you to everyone for joining our call today, especially you, Dr. Heier. It means the world that you joined us here. Today marks another important milestone for us here at Apellis as we continue to establish ourselves as the leaders in complement and work to bring pegcetacoplan, a first-in-class treatment, to the millions of patients living with GA. We look forward to updating you on our continued progress, and have a wonderful day. Thank you.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.