Apellis Pharmaceuticals Inc (APLS) 2023 Q2 法說會逐字稿

Good day, and thank you for standing by. Welcome to Apellis Pharmaceuticals Second Quarter 2023 Earnings Conference Call. (Operator Instructions) Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Meredith Kaya. Please go ahead.

Good morning, and thank you for joining us today. Earlier this morning, we reported our second quarter 2023 financial results. We will be happy to take questions from you on these results in the Q&A session. However, we will be focusing our prepared remarks today on SYFOVRE, including feedback from the recent ASRS Annual Meeting and an update on our comprehensive review of the rare safety events. With me on the call are Co-Founder and Chief Executive Officer, Dr. Cedric Francois; Chief Commercial Officer, Adam Townsend; Chief Medical Officer, Dr. Caroline Baumal; and Chief Financial Officer, Tim Sullivan.

Before we begin, let me 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 that actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. Now I'll turn the call over to Cedric.

Thank you, Meredith, and thank you all for joining us today. As Meredith said, we are going to take a different approach on today's call and focus the discussion on the rare events of escalators we have seen with SYFOVRE. We know you have questions, and we will do our best to answer as many of them as we can. But before we do, let me provide some overarching comments.

First, I have never been prouder to be part of the Apellis team. The past few weeks have been challenging and once again, the team has shown incredible dedication and resilience. Second, we had a strong second quarter. We reported approximately $90 million in total product sales, including $67 million for SYFOVRE, demonstrating the early strength of this launch. With more than 68,000 vials of SYFOVRE now distributed to physicians, SYFOVRE is having a positive impact on the lives of tens of thousands of patients across the United States.

And third, SYFOVRE continues to demonstrate increasing effects over time. Data from our GALE long-term extension study showed a reduction in non-subfoveal GA lesion growth of up to 45% between months 24 and 30 as compared to projected sham. These are incredible findings further strengthening our understanding of SYFOVRE as an important treatment for patients with GA.

With that, let's get into the discussion. Patient safety is our top priority, and we care deeply for the physicians who rely on us. We are conducting a comprehensive investigation into the potential causes of the events of vasculitis working closely within the retina community. We do not know the cause yet. And realistically, we may never identify a singular cause. What we do know, however, is that these events have been very rare and sporadic and that 0 events were reported in our clinical studies. SYFOVRE is a newly launched drug in a new disease with a new mechanism of action. It is not unexpected that events may emerge when bringing a drug into the real world, but it is expected that we take them very seriously.

Now let's get into some of your questions. First, what do we know so far about these events? And what are the visual outcomes for these patients? I will hand it over to Caroline to speak about this. Caroline?

Thank you, Cedric. As we get into the details, I want to recognize the patients and physicians who have been impacted by these rare but serious events. I will reiterate what Cedric said, patient safety is and has always been our top priority, along with providing physicians with the information they need to make the best decisions for their patients. Let me share what we know today. Overall, these events have been rare. We have confirmed 7 events since our launch in March and 1 additional reported event is being evaluated by Apellis. More than 68,000 vials of SYFOVRE have been distributed to physician practices. And based on our research, we estimate over 60,000 of those have been administered to patients.

These events occurred sporadically. There were 2 events following injections in April, 2 in May and 3 in June. This is important because as the number of injections increased each month, there was not a corresponding increase in the number of vasculitis events. Each event happened between 7 and 13 days following drug administration and all cases reported to Apellis occurred after the first injection.

We recognize that the numbers we reported on Saturday are slightly different than the numbers presented by ASRS. This is because we make determinations based on the information that we received directly from the treating physician and following review by external retina and uveitis specialists. Given physician confidentiality, we must be careful in what we share regarding detailed patient information. Additionally, these are highly complex cases and are sometimes difficult to interpret. However, we are working closely with ASRS to make sure we are better aligned in how we evaluate each of these events going forward.

It is still too early to know the outcomes for each of these patients. Retina vasculitis by definition is a severe inflammatory event that can potentially lead to significant vision loss. With standard of care treatment, we hope patients will recover, but this can take up to a few months. Of the 7 confirmed patients reported to us to date, 2 have recovered vision nearly back to baseline, 2 have severe vision impairment and are unlikely to be resolved and 3 are still evolving. For the 1 suspected case, the patient's vision has already returned to baseline. Working with the physicians, we are monitoring each of these patients very closely.

Thank you, Caroline. The next question is why these events are happening. What are we doing to find the cause? And what do we know so far?

These are really important question and we have been collaborating with the retina community to better understand the potential factors contributing to these events. One of the first questions we asked ourselves was why we did not see this in the clinical trials. There is a robust process for evaluating safety in a clinical study. Patients are assessed by the trial investigator and all imaging from the study is reviewed by a mass independent reading center. Following more than 23,000 SYFOVRE injections administered in our studies to date, 0 events of vasculitis have been reported. To confirm these findings, one of the first things we did upon receiving these case reports is go back to our Phase III data to make sure that nothing was missed.

We rereviewed all cases of intraocular inflammation and retina vascular occlusion and confirmed no vasculitis event. Additionally, we asked the panel of retina and uveitis specialists to rereview all severe intraocular inflammation events as well as 2 leading neuro-ophthalmologists to rereview our ischemic optic neuropathy event, both of whom further confirmed that there were no vasculitis events. We also know from our clinical trials that there was no indication of drug-related immunogenicity. Data showed no correlation between IOI events and any antidrug antibodies, providing evidence that these events were unlikely to be caused by an immune response to either the peptide or to polyethylene glycol. These findings are important to our investigation as there were no changes in the formulation of the product between clinical and commercial supply.

Thank you, Caroline. So if we did not see anything in the clinical trials, then what else are we looking into as a potential cause?

The next important area we look into was manufacturing processes and drug quality and there is no indication that these contributed to the vasculitis events. No single manufacturing lot was implicated. No manufacturing issues were identified related to intraocular inflammation and no quality issues or contamination such as endotoxins were found. There has been some confusion around SYFOVRE being a biologic and that these events may have been due to endotoxin. To clarify, SYFOVRE is not a biologic. It is a synthetic peptide that binds specifically to C3 and C3b. Levels of drug products endotoxin in all clinical and commercial batches of SYFOVRE are significantly lower than the reporting threshold and the FDA's expectation for ophthalmic dosage forms for injection. As for what else, we are continuing to investigate potential contributing factors. This includes looking into patient characteristics as well as evaluating any variations from the clinical trials to real world. We don't have any answers on these today.

Thanks again, Caroline. Okay. Now that we've talked about the investigation, let's turn to how the conversations have been with physicians over the past few weeks, and of course, specifically here at SRS. Caroline, why don't you start and then turn it over to Adam to share what you're both hearing from the retina community, and what this might mean for treatment going forward?

Sure. Thanks, Cedric. Over the past 2 weeks, we have been deeply engaged with the physician community. And as Adam will share also conducted some early market research to better understand perception and impact. Upon hearing of these events, the first thing I did was reach out to multiple physician practices to better understand their experiences with SYFOVRE so far. These are physicians who in total have administered thousands of SYFOVRE injections to date, and they have not seen any cases of vasculitis. Since then, we have continued to talk with dozens of leading experts in our field and just spent the past 4 days with hundreds of retina specialists at the ASRS meeting in Seattle.

Overall, physicians are eager for more information, and this will take time and more data. These are serious safety events and physicians need to understand how to think about treatment. As a retina physician, I can attest that my colleagues are experts when it comes to treating their patients, especially with intravitreal injections. They are thoughtful in the decisions that they make, understand the risks associated with these therapies and can effectively communicate the benefit risk profile to their patients.

I'll turn it over to Adam to share a bit of what he and his team are also hearing.

Thanks, Caroline, and good morning, everyone. The commercial team has also spent an enormous amount of time engaging with retina doctors over the past few weeks. And then in person this weekend at ASRS. Our #1 priority is to make sure that physicians know that we are sharing information with them as quickly as we can and that we are available to answer any questions they have. Following the member communication from ASRS, we have sent 2 communications to physicians sharing additional color and context about these events and held numerous calls with our physicians and our speakers.

The feedback we are getting from the field is very consistent with what Caroline spoke to earlier. Additionally, and prior to the ASRS meeting, we conducted some early market research with U.S. retina specialists, most of whom had previous experience treating patients with SYFOVRE. The key takeaways of this survey were that 1/3 of the survey doctors said they plan to continue using SYFOVRE as they had been prior to the vasculitis events in both new and existing patients. The next 1/3 said they plan to continue using SYFOVRE in their existing patients but may pause use in new patients. And the remaining 1/3 of doctors said they plan to pause treatment until they have more information or until their patients request treatment. Based on this, we do anticipate some sale bumpiness in the near term as many seek to gain more information.

Our job is to be a thoughtful, transparent partner over these next few months. We believe it is important to continue to bring this treatment to the millions of people suffering from GA in the U.S. and to be ready to bring this to patients worldwide very soon. A quick update on the latter. Our marketing applications are under review in multiple territories worldwide, including the EU, and we expect approval decisions starting in early 2024. With that, Cedric, I'll hand it back to you.

Thank you, Adam. Okay. Another question on everyone's mind is how we think these rare events will impact SYFOVRE sales and ultimately, of course, our cash runway. And how are we thinking about financing at this point? Tim, can you comment on this?

Of course. Thanks, Cedric. As of the second quarter, we had $1,616 million (sic) [$616 million] in cash. based on our current assumptions, this provides us with a runway into the first quarter of 2025. However, these safety events may impact the sales trajectory in the near term, but because it is all very new, we don't know the magnitude. We are monitoring demand very closely and in parallel, looking at our overall spend to ensure we are being disciplined and thoughtful going forward. We will be transparent with you, but we don't have all of the details for you today. As for financing, we are not under any immediate pressure to raise money. As we always do, we will evaluate multiple ways in which to finance the company at the right time and with our shareholders in mind.

Thank you, Tim. On to the last question then because the ASRS was not just about safety for us this weekend. We also presented some exciting new data from our GALE long-term extension study. Caroline, can you please give us an overview about some of the new data that was shared.

Yes. Absolutely. Thanks, Cedric. We had a strong presence at ASRS this weekend with 7 podium presentations. Notably, we shared for the first time data from our GALE extension study, reinforcing the long-term efficacy and safety of SYFOVRE. These data demonstrated that SYFOVRE reduced GA lesion growth by up to 39% in the monthly arm between months 24 and 30 as compared to the projected sham arm. What we were most excited about were the effects seen in nonsubfoveal GA patients, as Cedric mentioned earlier. Between months 24 and 30, SYFOVRE reduced nonsubfoveal GA lesion growth by 45% in the monthly arm. This means that within 3 years, patients with nonsubfoveal lesions are seeing the rate of GA progression slow by nearly half.

This is the first time we have seen slowing of GA lesion growth at this level in a large, well-controlled study. The safety profile in GALE was consistent with previously reported Phase III data. In addition to the GALE data, we also shared data using AI technology, demonstrating the effect of SYFOVRE in protecting photoreceptor cell degeneration. Photoreceptor cells are responsible for visual acuity and the degradation of these photoreceptor cells are significantly reduced upon initiation of SYFOVRE treatment. Both the GALE and the photoreceptor data along with additional analysis presented over these past few days contribute to the most robust data set against GA and reinforce the importance of treatment with SYFOVRE to help to protect against this irreversible disease. I'll turn it back over to Cedric for closing remarks.

Thank you, Caroline. We are very excited about the data presented at ASRS. Although it has been a turbulent few weeks, we believe that we have a strong future ahead of us. We are closely monitoring the safety of SYFOVRE in the real world and will formally update on the rate of events on our quarterly calls. We will not be commenting on future individual cases. We intend to handle the situation with the utmost integrity and transparency and do what is right for our patients, physicians and investors.

Blazing a new trail in geographic atrophy is not easy, but I am confident in the Apellis team, and we look forward to bringing SYFOVRE with good patients in need worldwide. We are also proud of the impact that EMPAVELI is having on patients with PNH. Additionally, we continue to advance a robust clinical and preclinical pipeline to achieve our goal of improving the lives of people living with debilitating diseases by bringing new and innovative complement therapies to market.

Let us now open the call for questions. Operator?

(Operator Instructions) Our first question comes from the line of Umer Raffat with Evercore.

It's John on for Umar. I would love a little bit more clarity on the inventory in that 68,000 vials shipped as of this past weekend. Can you confirm how much inventory and average stock keeps on stock and how much inventory would be in the channel at any given time. Then furthermore, one bit of feedback that we were hearing out of ASRS is that there may have been a change from trial to commercial in the device. Was there a supplier for the trials that had automatic draw up of the SYFOVRE solution? Commercial docs have been complaining that drop from the vial obviously, is challenging, and that's a little bit different for this product. So is that something that could be driving this or something you've looked into?

Thank you, John. I will hand the first question over to Adam and then take the second one.

John, it's Adam. So yes, of the 68,000 vials, those have been distributed to physician practices. And we contacted our top prescribers. And on average, we -- after those discussions, our top prescribers tell us they held approximately a week's worth of inventory within their fridges. So the vast majority of those 68,000 vials are likely not sitting in fridges, they're probably being used with patients. So on average, about a week held in a refrigerator. Hopefully, that answers the first part, and then I'll hand back to Cedric.

Thank you, Adam. So I think, John, we had an important objective this week and coming to ASRS. And that was first of all, to work closely with ASRS and get a very good sense of what is happening nationwide, i.e., how large is this problem? Is there something that we have missed. And secondly, is this rate changing over time, right? And so what's very important here and the key objective of this weekend and the research that we did in the past couple of weeks is that we can conclude that these events are very rare. And as Caroline mentioned earlier, that they don't increase over time, right? They're sporadic in nature. I think that is really, really important. Then, of course, comes the question, what is the potential etiology behind this.

And as you can imagine, of course, and as you mentioned, the best starting point is what was different in the clinical trials versus the real world. We are going to be very methodical and we are not going to engage in hypothesizing until we have data. And I think that is really important. That is something that we owe to physicians and to patients. In that investigation, the first step was to find out is the direct product that we are delivering to physicians today, the same as the drug product that we used in the clinical trials. And the answer is, yes. We are now going to take next steps to evaluate other factors that could have [stayed] role, but we will indicate on those when we have more clarity.

So when you see the product is the same, you're specifically not talking necessarily about any of the additional materials that may have come along with the vial of drug like syringes, drop, existing devices, things like that.

All of this will be part of our investigation.

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

Also, I wanted to clarify upon some of your prepared remarks. So Cedric, how are you thinking about on a go-forward basis, the risk mitigation plan? Maybe this is appropriate for Adam, because Adam, you've talked about what you've done so far, but I think docs probably would benefit from guidance from the company going forward. And so where are you in trying to plan that out. Secondly, I wanted to clarify, were all of the cases of escalators that were reported to ASRS, were they injected by retina specialists or were any of them done by general ophthalmologists. And then I have a follow-up.

Thank you so much, Tazeen. So first of all, briefly on the risk mitigation and docs guidance. I think it is really important here that we have a label that we have a way of -- that we have thoroughly evaluated in clinical trials of distributing this products and using this product, and that is something that we, of course, want to stick to as closely as possible. We have communicated with physicians through letters to update them, and we will continue to do so to make sure that the route of communication are thorough. We will continue to work with the ASRS. As far as it relates to practice mitigation steps, et cetera.

We are going to be working with the retina community, but the retina community is better positioned than anyone, right, to talk about how this should be handle. I think, again, the most important fact that we wanted to get our hands on this weekend was to understand the rate and the sporadic nature and to communicate that with ASRS to the community. So I think that is really important. The vasculitis cases that were all reported, I will look to Caroline, but I believe we're all done by retina doctors. That is correct, yes.

Okay. And then lastly, I think ASRS said that there's been a suspected case that maybe hasn't been confirmed that occurred after the second SYFOVRE injection. I think this was not reported to you. But over the past weekend, have you had the opportunity to learn a little bit more about that particular patient's characteristics.

Yes. I think it's important to point out here that suspected cases are suspected for a reason, right, in the sense that we -- there are many [confirming] factors that come into this. This is not an exact science, right? But the key thing is that after kind of a really thorough search nationwide, right, that we ended up realizing that we are very close to where we were a few weeks ago, right? There was not like a hidden Tsunami that all of a sudden came our way. So there will, in all likelihood, be new cases. We will take those and evaluate those. We will continue to work with ASRS, but with the knowledge that the rates and the sporadic nature of these events create a risk-benefit profile that physicians can then openly communicate about with their patients.

Our next question comes from the line of Anupam Rama with JPMorgan.

Maybe a question on how you segmented the physicians. So the -- maybe the 1/3 of physicians who you've talked to that are remaining -- going to continue to prescribe -- can you give us a sense of where these physicians fall into sort of what you've seen amongst your top prescribers to date?

Adam?

Yes, absolutely. So yes, the 1/3 of our market research, so they tend to be actually a mix. So they're a mix of our top prescribers, large accounts, but they're also slightly smaller accounts. So the SYFOVRE users within our market research had between 1 and 250 patients. So you can tell there that there's a broad bolus of SYFOVRE use within that snapshot market research we did prior to ASRS. So we tend to get usage across the large PE-backed accounts and smaller accounts as well. So in our market research, that was consistent within that 1/3.

Our next question comes from the line of Colleen Kusy with Baird.

So we've heard similar feedback on the needle in the commercial kit. Are there any progress -- is there any progress made on potentially developing a prefilled syringe for SYFOVRE and how long would that take to bring to market?

So again, as mentioned earlier, our investigation around the ancillaries as part of the overall investigation. And of course, a prefilled syringe is an important objective for us. It was before these events occurred as well. That is unfortunately something that takes several years of development as was the case for Lucentis and Eylea as well. We are working very hard towards that, but that is not something that you should expect in the near future.

That's helpful. And a follow-up. So at least one of the patient's vision did recover encouragingly. Anything notable about that case that you think can be applied if future cases come up? Any guidance on how you think the best treatment for these cases would be in the future?

Caroline?

As I presented earlier in this talk that 2 of the patients have recovered vision nearly back to baseline and 3 cases are still in evolution. What I would say is that these cases are so rare and complex, it's difficult to make any interpretation about treatment guidelines at the present, but we will continue to communicate with the retina community and update them when we have some guidance.

And last one from us. Just in Europe, have you submitted these vasculitis cases to European regulators? And do you expect that to be part of the review?

Of course, we communicate all safety events to all the regulatory authorities.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

On the survey you conducted, you mentioned that the market research was conducted before ASRS. So just when you presented the survey to the physicians, was that just based on the content of the ASRS letter from mid-July? Or were there any further details that they were given with respect to either the retinal images or detailed aspects of the case studies presented on Saturday?

Adam?

Yes. So what we did was with the survey, we only used the letter from ASRS as the basis for that.

Okay. And then just being very specific with respect to the statement around drug product or manufacturing. I mean, are you saying that, that excludes the potential of the underlying mechanism of action of SYFOVRE on C3 inhibition? Or does the drug product in manufacturing just apply to the way the excipients were produced or any other aspects of the manufacturing process, but not necessarily the motive action itself.

Yes. So the mode of action is going to be part of the broader investigation. But again, the mode of action was the same in the clinical trials, of course, as it was in the real world. So again, no answers there yet. All we can say is that the product that was manufactured and used in the clinical trials, is the same product as the product that we are distributing to physicians to date, all within the same specs and the same manufacturing process.

Okay. And then I know, Caroline mentioned a few times these are highly complex cases. And I don't think I saw in the ASRS slide any demographics on the -- other than [GA] -- is there anything you can say, any potential commonality in terms of comorbidities or other conditions or disease conditions that may be at least a hypothesis that you're going to pursue? Or are these all just highly divergent, highly complex and no clear way to pursue hypothesis other than, obviously, the commonality of all having GA.

These cases are so rare that, as you can imagine, kind of trying to find commonalities between patients require something that would require a much larger denominator or numerator. So -- and we continue to track it and continue to investigate. But right now, all we have done is be able to exclude manufacturing. The rest will be subject to further research.

Our next question comes from the line of Steven Seedhouse with Raymond James.

I have a commercial one and then a follow-up for Caroline, if I could. Some of the numbers that we now have in hand of 42,000 vials distributed to offices in the second quarter. 60,000 per the ASRS letter as of July 15. That implies, if we back out 1Q as well, it implies like 8,000 or 9,000, let's say, in the first 2 weeks of July that were distributed, and then we have the 65,000 number on July 21 and 68,000 on July 29 that you're updating today as well, which would imply like 8,000 vials distributed in the second half of July. So can you just collaborate that math? I mean, I appreciate you said that you expect some sales impact, and certainly, the survey work suggests that. But it really does look like the first half and the second half of July had about the same number of vials distributed.

Thank you, Steve. Adam?

Steve, yes, I think your math is right. But one thing to think about is this week and -- sorry, the week just gone. And this current week is obviously the ASRS weekend. So a lot of physicians are actually here or were here in Seattle. So we always calendarize some bumpiness for this week as physicians tend to attend these conferences. But the orders for vials are continuing and have continued throughout the last couple of weeks as your math explained.

Okay. And for Caroline, just there seem to be some discussion during the ASRS panel presentation on Saturday that Tapan and Jack, for instance, especially vancomycin is not necessarily an optimal approach for management of retinal vasculitis if that is suspected, which it wasn't because it hadn't been observed in the clinical study. And based on the Beovu experience, I think something like intraocular steroids, especially early on, might be a better approach and could maybe mitigate some of the worst outcomes now that this is a known possibility. So is that characterization accurate? And do you think visual outcomes could be improved just on that basis alone going forward if this happens in the future.

Well, as I said before, and thank you for that question. These cases are complex, and they're not all bound by commonality. I think we have more to learn with our retina colleagues on management of these cases.

Our next question comes from the line of Phil Nadeau with TD Cowen.

A couple from us. First, on the conclusion that manufacturing was involved, can you discuss a bit more of the basis for that conclusion, what assays were performed and generally, what analysis did you do to conclude manufacturing is that an issue?

Yes. Thank you, Phil. So as you know, the way these investigations start by looking into manufacturing are actually quite well standardized, right? So our CMC group has a process to go through where a lot specifically -- a lot specifically get investigated to find out that all of these cases were not related to one specific lot. We then look whether all the drug product that was shipped was within the specs that are predefined in our registrational batches and through the NDA. And then much more work around testing and evaluating whether the possibility of the introduction of a manufacturing problem was involved in these cases. And the answer to that was no.

You may recall the EPREX situation about 20 years ago where EPREX was associated with red cell aplasia and I think it turned out to be the change like the supplier, the rubber stoppers something that seemed totally inoculus. If that same situation had been the case here, would the analysis you did to look at manufacturing and supply have picked up that as a potential cause. Are they that detail?

If there was a change between what we did in the clinical trials in terms of how we manufacture the product and what we do now in the real world, we would have told you. So this is all within the same specs and the same use and the same manufacturing process that we used in our clinical trials as well.

Perfect. And then second question, ASRS, there were some questions from physicians on the per patient incidents. Since it seems to happen after the first dose physicians were wondering what would be the risk of a naive patient of going on therapy. Do you have any estimates as to how many patients are on therapy. And so what is the per patient incidence of a naive patient getting the vasculitis.

Yes. Thank you so much for that question, Phil. It's very early, of course, to look into something like that. Of course, the majority of these estimated 60,000 injections in the real world are probably going to -- will probably have been first-time injections in first-time patients. So that, of course, provides a huge denominator from which to work. And now we're going to find out, right? I mean, whether this is the first injection phenomenon, subsequent injections. We just don't know a lot yet other than the fact that it's an extremely rare event and that it is an event that is sporadic in nature, right?

And I think that's really important to bear in mind is that the retina community ran through kind of a very traumatizing event a couple of years ago, where a product was introduced, where an increased incidence over time was taking place where this product was sensitizing patients and more patients came on the wood works and physicians, that is absolutely not what is happening here. So I think it's important to state that categorically.

Then last question for us. In terms of the path going forward, do you have any information on when ASRS could provide an update on its analysis of cases? Or does Apellis have any time lines to providing an ex disclosure on either your root cause analysis or the incidence of vasculitis?

Yes. So as we mentioned, we will provide a quarterly update as it relates to the rates and we are going to provide updates on the investigation when we have things to tell, right? So we're not going to make an update unless we have real clarity around understanding this. And we are going to continue to work with ASRS. We're very grateful for the partnership that we have with them.

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

Maybe shifting gears a little bit towards GALE. Just in the context of the safety events and given that GALE is really delivering on [doing] those increasing effects over time, just wondering how you've heard the feedback in terms of patient participation in the U.S. for the clinical study and whether sort of those subgroups are continuing on, especially given that these events aren't being observed in clinical study.

Yes. Thank you so much for that question, Justin. So first of all, as you may recall, the number of patients that went from DERBY and OAKS to GALE was very high, right approximately 80% of the patients in the trial decided to go into this 3-year extension study. We are actually I think, months away from having the first patient who has been on treatment for 5 years with SYFOVRE already in the GALE study. So an incredibly rich and important data base for us to understand not just the safety but also, as you mentioned, the efficacy.

As Caroline mentioned earlier, if you have a patient with extra foveal lesions and as a reminder for those that are not familiar with this, these are patients who have GA in the periphery of their vision. So still with typically a good ability to read and recognize objects with their central vision. In other words, patients that can really benefit, being able to slow down the progression of the disease by something that looks like it's close to 50% is, of course, incredibly important. And with all of these things, of course, we have these safety events which we take very seriously, which we will investigate on the flip side the efficacy profile is also evolving and something very exciting, I think, for patients to look forward to.

Our next question comes from the line of Derek Archila with Wells Fargo.

Just 2 from us. I guess first off, can you just remind us how many patients present with bilateral disease. And I just -- do you think the ASRS notification may deter docs from doing injections in both eyes and then also, I know you haven't said you're still working on the investigation, but no similarities or commonalities between these patients experiencing retinal vasculitis has been determined, but if there is, would you expect future label language that could direct patients or -- sorry direct docs to the patients who are best suited for therapy? Is that something that would ultimately end up happening?

Let me start with the second question. It is way too early to talk about that. We are obviously in very close communication with the FDA on all of these things. That is something that we will evaluate and potentially do when more information is available. As it relates to bilateral patients, Caroline, maybe you could speak to that.

Thank you, Cedric. As the ASRS did present -- they did present that one bilateral case. And I think that -- that is -- retina physicians who are very thoughtful in what they do. And we typically do include bilateral injections in our treatment paradigm. And however, that case does highlight that when we have a new product, it may be prudent to consider unilateral injection first time with use.

Our next question comes from the line of Eliana Merle with UBS.

What's your understanding in the cases if all of those were given using the provided administration materials? Or did any of the physicians choose to use, say, a different syringe for the injection or maybe deviate in any way from the proper administration procedures. And then just also, you alluded to -- you submitted the safety findings to the EMEA. Just any color on that so far from those interactions.

So again, I think it's important to note here that we are very fortunate that the retina community is so professional and experienced with intravitreal injections, right? I mean this is the heart and the bread and butter of these practices for the last 15 years or so. So that is something that needs to be remembered here. Syringes, ancillaries, as mentioned before, will be part of our broader investigation, and we will comment on that when we have more information. As it relates to the EMEA, we communicate, as I mentioned, everything, of course, to these agencies it becomes part of the evaluation that evaluation with EMEA so far has been going well. So for now, we don't see any changes.

Great. And just a quick follow-up. In the patients that had IOI, who didn't have retinal vasculitis. I guess, did they have any vision impact? And any color on if those cases fully recovered?

Yes. I think that is a very important question, Eli, because there is a bit of a misconception with the way the slide was presented that IOI cases and vasculitis are confusable with each other. Intraocular inflammation is very normal with intravitreal injections and the rates of intraocular inflammation that we have seen in our trials and in the real world are in line with what we saw in the clinical trials and with what we saw or what you would see with anti-VEGF injections in general. So on that end, we have no concerns. It's of course, these cases of vasculitis, which do look like they are kind of a severe complication of severe inflammation that draw our special attention. So I think that's an important difference there. IOI cases without vasculitis, typically having a much better recovery. I don't know, Caroline, if you would like to add something?

We looked into -- we're looking into every single case that is reported to us and the rates of IOI that we've seen in the real world are consistent with the clinical study.

Our next question comes from the line of Annabel Samimy with Stifel.

I just wanted to go back to the methods that were used in clinical trials versus the methods that are to be real world, is there anything that you can sense from the way physicians are assessing a patient right now in the real world for treatment versus what was done in clinical trials where you obviously didn't see any of these the cases of retinal vasculitis and anything that you can gather from that to, I guess, develop some kind of risk mitigation plan or some kind of protocols that they can even better assess the patients going forward?

Yes. Thank you, Annabel. So look, as mentioned before, we have as strong a desire as anyone, more probability than anyone to try to understand this, but it is very important to be methodical in that process, which is something that we are very much dedicated to. So we don't want to comment about what could be. We are going to look into everything. And when we have more information, we will share it. Of course, as a general comment, and that is how it works, right? Clinical trials are different from the real world where there is much more variability on every front and being able to understand these signals, which again, it's unfortunate, but it is not at all unique, right? Many drugs when they go into the real world will run into unexpected findings. At that point in time, it is on the company on us as a sponsor to be diligent to take these cases seriously and to evaluate them and communicate them properly.

Okay, great. And then as far as the differences between what was reported to Apellis versus what ASRS reported on. Are you going to be getting these cases and reviewing them? Or -- and -- to what extent is your independent panel overlapping at all with the ASRS panel? Is there any (inaudible) are they completely different sets of physicians?

Yes. Thank you so much for that question. So the wonderful news here from my vantage point is that this partnership that we had with the rest committee ASRS was a very thorough process and a collaborative process, where many of these cases were shared overlap, as you could see from that slide. And Importantly, we set in stone that the rate is extremely rare and that it is sporadic in nature, right? Being up or down 1 case, we ended up remarkably close to each other, right? So now about the exact nature of these cases, exclusive, nonexclusive, depending on which experts you show this to, you're going to get different answers, right? But the most important thing here is you cannot count these cases as to 1 up or 1 down or even to their nature, but we are very much in the same ballpark, right? So this is a very rare event, unfortunately, and one, again that is sporadic in its distribution over time.

Okay. Great. And if I could just follow up with one more. I know that a lot of people have been making a Beovu comparison. And maybe just to repeat in context for us one more time why this is not going the way of Beovu maybe in terms of onset in the rarity. Can you maybe just speak to that again so we can sort of put that in context.

Yes. Thank you, Annabel. So we're very fortunate because Caroline was actually the lead author on the lead paper on the Beovu investigation and the work that was done there. So she is uniquely positioned to comment on this.

Thank you, Cedric. I think that what we have seen with SYFOVRE is very rare. In contrast, the rate of vasculitis with brolucizumab was 3.3% in patients who are in the HAWK and HARRIER studies, and we did not see this at all in our clinical studies. Also, as you alluded to, the onset and the clinical features differ from what was seen with brolucizumab.

Different in terms of when was the onset.

Well, so with brolucizumab, the onset was typically after 3 to 4 weeks, and of note, having the events were more common with multiple injections with a shorter time interval between injections and this played a role in the discontinuation of some of the brolucizumab clinical studies. As well, brolucizumab caused an arteritis and different sorts of features on clinical exams.

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

Just curious, can you comment on the return to vials and what visibility you have into this? More specifically, how many vials have been returned and/or how many practices have returned SYFOVRE vials.

Adam?

So yes, we have seen some vial returns, but the number is actually very small.

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

Just first, I'm just curious, Adam, in terms of the market research for the physicians who said that they are either pausing altogether or the third who are stopping with new patient start, I'm just curious if you got a sense from -- and maybe this is more anecdotal, but just what would they sort of does it -- do they need to see to restart?

Yes. Thanks for the question. So within the [read section] with our conversations at ASRS this weekend, I think a lot of physicians are the ones that have said they would pause, they want to just see what happens over the next couple of weeks, right? This has all happened relatively quickly over the last few weeks, and they want to see that stability. They want to see if any more information comes out. They have found having conversations with their patients about a rate would be important, and they want to hear updates from Apellis in a very transparent way. That tends to be the theme for those physicians that are either pausing new starts or have decided to pause for enough time to get more information. That was a consistent theme at ASRS as also within our research. Caroline, I don't know if you want to add anything to that based on your positions. Caroline says the same thing. So that's where we are.

So just to be clear, so Adam, so it's not as if they're waiting for some definitive sort of conclusion on this issue. There just seems like they're waiting more to see some stability for lack of a better word, to sort of get a sense of now that it's come to life that more cases are coming out of the wood work, et cetera?

Correct.

Great. And then just as a follow-up, I think somebody asked and I'm not sure maybe I missed the answer, but just do you know of the 68,000, how many were first injections right now?

We don't know but our assumption is that the vast majority are first injections.

Okay. Great. And then just one final quick one. Are you continuing with DTC work or I know you had just started the Henry Winkler campaign? Or is that on pause right now?

Yes, it's a great question. So DTC has had a really good impact and has driven patients to have conversations about losing vision. I think we'll be very thoughtful moving forward how we use that. Now is the time for us to have really transparent open conversations with physicians. But the DTC impact and getting patients to go and check their vision, I think, is a good thing for all. All patients who are of a certain age. So I'm very proud of that work, but we'll be thoughtful in how we use that moving forward.

Our next question comes from the line of Laura Chico with Wedbush.

I had just one clarification question. I apologize if I missed this. But I think rest noted there was one incident that occurred after a second injection. So I just wanted to clarify if I have that correct, but also how Apellis came to kind of a different conclusion there? And then I have a follow-up.

So that was a suspected case. We need to look into that based on our findings also for our first injections.

Okay. And then just kind of going back, Adam, thank you for the market research color. I guess I realize it's premature, but what is your expectation around how the dosing interval frequency might evolve over time here now that we've kind of encountered these safety events. How do you think physicians are going to lean one way or another in terms of the dosing interval with SYFOVRE.

Yes, absolutely. So our assumption and my assumption was prior to these vasculitis -- rare vasculitis events, the vast majority of physicians were using every other month type dosing. And I think this just confirms that, again, every other month dosing will be used by the vast, vast majority moving forward. And I expect that to be consistent for the future. And I think as we progress through this and people look at the GALE data and the increasing effects over time and once the physician segment that needs to get comfortable with these safety events gets comfortable, I think you'll start to see a little bit of fluctuation as monthly dosing moves, but every other month will be the vast majority. Caroline, from your perspective, anything you want to add?

I think that physicians are very, very thoughtful and very experienced with this type of medication and the vast majority of physicians appreciate having a label that's so flexible. I've heard all different sorts of things, but I think between every 6 to 8 weeks with every other month dosing is the preferred paradigm.

Thank you. I would now like to hand the conference back over to Cedric Francois for closing remarks.

Thank you very much. Well, in closing, thank you all for joining us today. It's been, of course, an intense couple of weeks for us. But we are very happy with how we come out of ASRS because we believe that we have gained significant clarity. We are ready to take on the next couple of weeks. We will continue the investigation and promise to continue to be as transparent as we have been. We are around later today and tomorrow. If you have any additional questions, feel free to reach out to Meredith. Thank you.

This concludes today's conference call. Thank you for your participation. You may now disconnect.