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

Welcome, everyone. I'm Yigal Nochomovitz. I'm one of the biotech analysts at Citi. I cover Apellis since the IPO many years ago. So it's my pleasure to have with me Cedric Francois, the Co-Founder, President and CEO; David Acheson, who is SVP of North America Commercial; and the CFO of Apellis, Tim Sullivan. So welcome, gentlemen. Thank you so much. It's great to have you here. It's amazing. It's been a year since we did this last fall.

So let's start with some of the obvious debates. Maybe just as a first step, could you just give us an update on what you're seeing with the vasculitis events? How is that evolving? Is the rate the same? Is there anything new to say there relative to the last update you had a press release a few weeks ago, I think the end of August with some more data and the cadence of how often you'll continue to update the market on that important issue?

Yes, thank you, Yigal. No foreplay? I think, look, obviously, it was a tough summer for us going through these events and taking the actions that we did over the summer. But there are also a lot of positives that I think are worth highlighting, right? I mean we showed the greatest reduction in the growth of GA that has ever been shown in that disease, 45% slowdown on the growth of lesions between months 24 and 30 on patients with extrafoveal lesions. I mean that's something that really makes an enormous difference in lives of patients, right? So I want to start with that because the risk benefit here is very good, right? That's -- and what happens this summer needs to be seen in the context of what happened a couple of years ago when [indiscernible] came on the market. And not only had cases of vasculitis associated with it, but this phenomenon where there was a sensitization against the drug and you had more and more cases. So that sensitivity that you may have a drug that kind of nobody knows what it's going to do. Is it going to amplify, that uncertainty and that fear was kind of what took the sentiment that was there in July. And understandably so, right, for the physicians. But the key thing here is that what we see is something that occurs an extremely low rates, so approximately 1 in 10,000 injections. And with every month that goes by, we see that number consolidating more and more, right? And that is something that, as a base case, forget about whether we ever find a root cause because that is something that we'll work hard on, maybe the needle is there, et cetera. But as a base case, a risk of 1 in 10,000 is that the vast majority of physicians and patients considered to be acceptable in the treatment of this disease. So that is something that if I look back at how the summer kind of came together at the ASRS meeting in July, it was very important for us to start bringing [indiscernible] to the world of the retina. Again, because there is this PTSD from a couple of years ago. We wanted to come out of ASRS saying, here is the rates cases that we have. We have turned the world upside down. We worked with ASRS on doing that. ASRS and us may not have agreed on everything. But we just had a couple of more cases after 2 to 3 weeks of thorough, thorough investigation where normally, when you do pharmacovigilance, and there's a whole bunch of things that you didn't know. That was not the case. So that was a huge positive. And then importantly, of course, physicians continue to prescribe SYFOVRE in important numbers to patients, and that allows us to evaluate over time what the evolution is going to be of this phenomenon. First of all, and again, as a base case, the rate that we have is a rate that is viewed as acceptable by physicians and patients, especially when placed against the benefit that you have, right? I mean, if I tell you that over the course of less than 3 years, you can slow your disease in almost half, I mean that is something really exciting for people that are irreversibly losing vision. So in the meantime, we did an enormous amount of work looking into the root cause in August. And we identified something that we cannot possibly establish causality for, but something that at least allows us to evaluate one of the potential root causes. What does that mean? You remove it from circulation, and you find out if that brings the rate further down. That will take a long time to really evaluate in terms of its impact, et cetera. In the meantime, we feel very good with the stable situation that we are in right now.

How was that this -- what you're referring to is the 19-g filter needle and some of the structural variations? How is that identified or discovered? That -- was that through a very detailed diligencing of the manufacturing of those needles or how did that work?

So the base kind of, I'd say, the running hypothesis for our investigation is that we did 24,000 injections in our clinical trial work, 24,000 and never saw something like this. So what was different between the clinical trials in the real world that may explain these cases of vasculitis. And one of the most important ones there was that in the clinical trial work to use something called a vial adapter, which is where you take the vial with SYFOVRE, you put an adaptor on it, and you suck the liquids through a filter that sits inside that vial, which is kind of a 3D construct in that filter. When we came on the market, we decided to provide ancillary kits with 2 types of filter needles. So filter needle is not a vial adapter, but something that you actually stick through the rubber and then pull it the liquids through the filter in that needle. We chose 2 needles to make sure that we could meet the incredible demand that there was. I mean, this was an amazingly rapid launch. And one of the important differences between these needles is beyond the size, of course, with 19-gauge being smaller compared to the 18-gauge and therefore, harder to pull the liquid up is that the filter material and the 19-gauge needle is made out of a monomeric nylon mesh, whereas the 18-gauge needle has a filter material that is identical to the one that sits in the vial adaptor. So again, not talking about causality, but when we looked at the structural variations that exist within that nylon filter, we decided that it would be prudent out of an abundance of caution to remove these needles from circulation and also evaluate that way, if there is maybe a potential cost of relationship.

So of the 8 cases though, I don't think you've been able to identify which needles, they -- those patients had, right? Is that correct? Or were they known to be 19 or not?

So there's not an absolute answer to your question. So the 19-gauge needle was the predominant needle that was on the market in the spring. Then you have many practices that have both needles sitting in their trees, right? And typically, the technicians or nurses or even the doctors that take these ancillary kits, they don't go checking for what needle is in there. They take it and it could be one or the other. So we have cases that were definitively linked to that 19-gauge needle, and then we had sites where both were available. And when we did a probabilistic analysis, that is where it became quite striking that there was an association that was quite profound with a 19-gauge needle. So again, that's not causality, we will only find out in the months to come. But combined with what we found on the structural variations, we thought that was a prudent step to take.

Okay. So there's some correlation statistically, but it's not -- you can't link it in terms of a cause. And the nylon -- that nylon mesh, is there anything in the understanding of that material that could be -- could precipitate this type of vasculitis or that's -- is that a known contributor independently or no? Do we know?

So small fragments of nylon, but I'm not saying that it's the nylon, right? It could be other particles -- could be -- we don't have any presence to draw any conclusions from that. So it goes back to the point of establishing causality is impossible here, but there is kind of the circumstantial evidence on which we build to be able to reduce the case load, because, again, the clinical trial experience tells us how clean this product was during our experience there.

Are there other leading hypotheses outside of this material question?

So there are several things that we look into. But I'd say this is an important one, especially, because we had an immediate step to take with it as well, right, that we could look into. There are others that are more complex. But I think it will take time to evaluate. And we'll have to see where it leads.

Because when we've talked to a lot of the retina KOLs and quite a few of them have said that it's an underlying MOA issue and that it would happen with the Iveric molecule as well. Do you -- what is your response to that? I mean is that still a fair postulation that it could be underlying related to the C3 inhibition or that's not a likely cause of this?

That would be very unlikely, because if there was an MOA issue with something that is a prevalence as the complement system in our bodies, you would expect to see it more often and you probably would have seen it in the clinical trial experience. So I'd say the only -- I mean, talking about if you want the one alternative hypothesis to the needle that is one that we also need to look into is the polyethylene glycol, right? There may be a very unique type of hapten on polyethylene glycol that causes a very rare event to occur, I mean, against 1 in 10,000. It's very hard to determine. But again, then when you dive into that, you have to also think about the presentation. These cases happened between 7 and 14 days, meaning it's delayed type hypersensitivity or a foreign body reaction. So again, not diving into it, but there's many, many things that we need to take into consideration.

What are the plans in terms of updating the market. And I've also gotten a lot of questions from investors about when is ASRS going to say something, would it be retina society? Would it be AAO? And then I think a lot of people have continued to ask me about why there's some small discrepancy between the way ASRS reports and the way you report? But I know that gets kind of technical, but...

Yes, but it's an important question, right? I mean, because we all want things to be exact and precise and this is anything but, right? I mean when we talk about -- maybe very briefly going back to that, what is vasculitis? I mean vasculitis is inflammation of the blood vessels. And vasculitis on a systemic level that's typically associated with a pure autoimmune event against vessels. In the eye, what we're talking about is essentially a complication of inflammation. So severe inflammation then complicates into vasculitis, meaning when you put in fluorescein dye, it will leak from the blood vessels, right? That means the vessels are inflamed, probably as part of para-phenomenon of the overall inflammation. And then in very rare cases, that can be occlusive. That, whether you call it IOI, vasculitis occlusive that if you showed any retina doc, you will get differing opinions. We have a very good education process in which we have 4 independent reviewers that look at these cases and tell us, this is what we believe it is, right? And then we classified as such, that's how it gets communicated to the FDA, that's how we communicated to the community. ASRS may use different criteria, and that's why you may have small discrepancies. But these are not big discrepancies, right? I mean the key thing when you look at these cases is what are the visual outcomes in these patients, right? Many of these patients with vasculitis have complete recovery of their vision, right? So there is -- and there are some that don't. I mean, absolutely. I mean there are some very bad cases there as well. But you can't -- there's no way of uniformly looking at this, right? So at the end of the day, you look at the outcomes, you look at what is the phenomenon that occurs there. But what's key is that's extremely rare, and it is sporadic in nature. It's not something that's increasing over time.

And now those -- the 19-g needles are out of the circulation, that's right, so they're getting weaned out?

Yes, as you know, that is a very complex process right? And many of these practices have boxes with -- I mean even the practices where we did a thorough effort to get rid of all the needles, once in a while, there's still one that pops up. So it's -- and to be clear, I mean thousands of injections, tens of thousands of injections were done with the 19-gauge needle without an issue as well, right? So it is not that 19-gauge needle is evil. It's probably a combination between there can be structural variations depending on who handles it and then maybe patient predisposition in the wrong combination at a wrong time.

One more vasculitis question, then we'll move to other things. Okay. So because you -- we know all summer, we've been talking about root cause and at one point, I think you said you may never find a root cause. It sounds like you have some hypotheses at this point, do you feel you're closer to getting to that or not? Or are you just going to monitor the situation, collect the data as you're doing and as long as the rate stays the 0.01%, that's steady and it's understood, the risk is understood?

That is the baseline. I mean finding the root cause for these events considering their rarity is, in most cases, impossible. So that should be our running assumption that we never find out. We've done amazing work in the past months to look into what could be contributing to do this. And again, it stands out in the clinical trials, we didn't have any cases, right? So hopefully, that will help us. But the main fact is 1 in 10,000 is something that physicians and patients feel very comfortable with [indiscernible] speaking.

So I mean you put out some numbers with the vials. And actually, according to our model, things had started to actually tick up again, and we've raised the numbers a little bit, I think, for the third and the fourth quarters. So speaking about the commercial trajectory, what type -- David, what type of impact are you seeing in terms of new patient starts and those on therapy. What is the risk stratification protocol look like now post what's happened over the summer? How is the education effort? How is it getting everyone back on track? Is there an understanding that like we just talked about with Cedric that the risk is well defined in a very narrow corridor and it's not going to get higher -- may not get lower, but it's not going to get higher? Yes. So.

A lot of questions there. So thank you. Let me take off on the first one on the impact on the launch. So first of all, we feel really good about the continued use of the product week-over-week. And we do have accounts that continue to order. We have accounts that come on new that haven't used the product, and that's consistent week-over-week, which is good. We did some market research, which I'm sure you probably remember before ASRS to get a kind of a stratification of what accounts we're doing or thinking about with vasculitis cases that we had. And it would kind of breaks down in the 1/3 and 1/3 and 1/3. So 1/3 of the accounts we're super solid on moving forward. They haven't changed practice. They haven't had any issues, continue to order and put more patients on product. About 1/3 of the account said, look, I've got patients on product, we'll continue to treat them. And we'll -- we won't move them to anything other than SYFOVRE, but we're not going to put new patients on product. And about 1/3 of the accounts -- remember, we have a lot of accounts that hadn't written yet still. So a lot of those in the bottom third said, I'm just going to wait, we'll hold off, won't put any patients on product at least for a while. But I think we'll end up finding and what we're starting to see now is that the rate of vasculitis continues to be very rare and low like what Cedric was talking about. You'll start to see, I think, these physicians come around and treat patients, which we're definitely seeing. As far as the stratification or how they have the conversation with their patients, it's all about the patient conversation that the physician is having around the risk. And it's all in the upfront discussions with the patients. Here's the risk. If you don't do it [indiscernible] if you do, and they make a conversation between them and the patient, they make a decision together. And that's fairly consistent with any product that you're going to have, right? So I think they've gotten very specific on those discussions with their patients seems to work well in accounts that are used product. and there's a lot of confidence I think in regards to those discussions with the patients. And I can't remember the other 4 questions that you asked.

I can't either. But anyway, but you said the 1/3, 1/3, 1/3. So if I remember correctly, you presented that on the 2Q call, but you actually had done the analysis before the ASRS -- [ time ] of the ASRS. So I guess the question is, is there an updated partitioning of those 1/3, 1/3, 1/3 now or not?

We did some additional market research in the middle of August [indiscernible] the ASRS and information came back almost identical. So only a couple of weeks span of time in there and I'm confident that we'll do research again in -- here in September to get another test, but that's where we're at currently.

Okay. Are you noticing any patterns or commonalities in terms of based on geography, academic versus private practice, size of the practice, location in the United States where there's trends that are better or worse?

Not really. What you'll see in a lot of cases is academic centers are always a little slower to take on a new product. So that's not abnormal. But generally speaking, it's personal preference at the physician level and comfort and making sure they have all the right answers for the questions that their patients are going to have as soon as they're comfortable with the FDA, they move forward based on personal preference. So I can't tell you if it's a large account [indiscernible]. It's a little bit [indiscernible] decisions are made.

Okay. And I know this is a sort of specific question, but for those very rare docs that did have an ROV patient, are they -- are some -- have you talked to them in terms of potentially bringing them back into the fold and using the drug again? And how is that working?

Yes. So those physicians are well known by us. And we know and had conversations, both on the medical side and on the commercial side. some of them continue to treat. And they realize it's very, very bad, and they manage it patient to patient with specific discussions. And I think they know that it's one of those things they'll manage long term with the product. But feel comfortable that they can continue to treat others will take time, but we are close to the and we know them all well.

Okay. how you -- Cedric, with the FDA in this ROV signal -- has that been a discussion? I mean, I know you've, of course, updated them, but do you need to do anything more specific? Is that something that could end up changing the label or it's just going to be known in the medical community that it's a risk to be aware of and that won't change the packaging -- package insert?

Yes. I mean we're in continuous discussions with FDA, of course. The -- I think it will depend on how things evolve. I think once -- when we understand it well and we -- there may be an inclusion in the label but at I think with the rate here is very important making sure that it stays where it is, and it looks like it does. So where it ends up, we'll see, but it has been a very friendly process so far.

Okay. any early thoughts, David, in terms of the impact of [indiscernible] on how things are going for you guys? Is there -- are you seeing an impact? Or you're just seeing more interest in the GA drugs class overall or?

Good question. It's early. We just launched product out in the marketplace last week actually was the first [indiscernible] that we're aware of. So it's early. When we really don't have -- I haven't heard a lot of details on the specifics around the use of the product, at least up at this point in time. And we continue to stay focused on our efforts and I'm sure you'll see -- we'll see more as the weeks come along, but it's very early for them.

But the expectation would be that like the private equity retina practice, they're going to stock both drugs? Is that -- or is it not going to work like that they're going to pick?

Look, it's a big marketplace. There's room in the market for both products I think it's going to come down to some of these accounts that are highly penetrated with us, we'll have to make a decision on what they're going to do if they're going to try another product. But the market is big and it's yet to be seen exactly what's going to happen with them.

Okay. And Tim, how are things looking in terms of the inventory and the channel? Like how is that -- has that been building despite what's happened over the summer in terms of the channel inventory?

I mean the inventory has been relatively consistent, right, at the distributor level. So there are 2 levels of inventory we kind of monitor. One is the distributor level. The other one is at the physician level. The distributor manages that inventory based on the demand from the physicians that they're forecasting and they're seeing. And so there was some work down as the demand took it dip post ASRS. But it's obviously -- it's pretty much where it needs to be in terms of -- we said that it ranges between 2 and 3 weeks of demand out the door for the distributor. And so it hovers in that zone, and it's corrected and so it's where it needs to be.

Okay. Prefilled syringe is still a ways away. Is that right? Or how far are you from getting that launched?

It takes a few years, right? But of course, incredibly important for us and something that's a high priority.

Are you accelerating that even more now given the recent events? Or has it just always been a high priority?

It's always been a high priority. There's no really a way to accelerate these things. So...

And just for people a little less familiar, the reason that, that's better or if I can say better is because you don't have to do the multiple steps. You don't need to have withdrawing from the vial. So there's less room for error.

That is correct.

That's the essential reason.

That's the simple answer, yes. And the thing is you have to understand the eye is incredibly sensitive, right? So when you -- even when you go up and down with the plunger, the oil that sits around the plunger to make it glide against the plastic and end up in the material that then ends up in the eye. I mean, things may come through the filter that are not the drug that like, I mean, all of these things could play a potential role in causing inflammation in the eye and with the prefilled syringe. We know from the history of anti-VEGFs that is a very effective way of dealing with that.

Would that be priced the same, the $21.91, I mean, at current pricing? Or would it be kind of a premium or that's TBD?

That's TBD.

Okay. All right. So you're a little bit -- let's talk about Europe. So I think you've said a decision in early 2024, how have those discussions been going? How have they been in terms of receptivity to the understanding the ROV risk as well as, of course, the very good data you mentioned, which I don't want to -- really want to requote the 45% reduction in GA lesion growth between what do you say month 24 to 30, right?

Yes. Correct.

So just how those discussions going overall?

Discussions have been going great. I mean the -- look, the European process rates, you have 2 reports or countries that get you to the approval. And then after that, the importance is to also get reimbursement in most important geographies, Germany always typically being the first one where you want to go. And key in that whole approval process, frankly, is education and something that we started on many, many years ago, 4 or 5 years ago, we started working towards the European approval, not just at a regulatory level, but also at the payer level. So that work has gone very well. The recent cases of vasculitis are part of the story, part of the package, but not something that we think will derail that process. And yes, that has been going exactly according to our plan.

Okay. So when would we get the CHMP opinion that's coming towards the end of the year?

That is correct and the approval early next year.

Okay. And you would expect the same substantially similar marketing label language? Or are there any notable differences in Europe that you would want to point out?

We cannot comment on it yet. So...

Okay. And then for the launch in Europe, that's going to be a partner? Or you're going to do that? What's the plan? Are you going to do that yourself? Or?

No. We've -- business has always been our intention, and this is what we worked hard on with our European group rent to launch this product ourselves in Europe. We're prepared to do that. We're excited to do that. It's something that makes a lot of sense in terms of the medical interactions, the retina community also makes sense financially. I mean, the investments that we make there, we believe are going to pay off very well for us. And again, it's part of a long-term strategy that we've built on since 2018, '19.

All right. Do you want to make any other comments that I didn't ask about GA or we can talk about EMPAVELI and the pipeline?

No. We're -- this is -- I think it's important when you kind of dive into the details on the picture of the fact that this is the leading cause of blindness in the elderly in the western world. Patients need treatment to slow these lesions down. There are so many physicians that I've spoken with in the last couple of months that tell me, I mean, I love this drug, and I would take it in our beta if I had the disease. So would I -- so would all of us. I mean it's like -- it's a great privilege to be able to do this. And I think that will be reflected in the market.

Are you hearing anecdotes as far as physicians that are monitoring the lesions that can -- I mean, anecdotally, you can see that there's a deceleration is on a patient by patient that's very, very hard to do. But I'm just curious if there's some anecdotal little evidence of that?

Well, so there's 2 aspects here that are intriguing read. I mean when you have bilateral geographic atrophy and you treat one eye compared to the fellow eye, you can often see a difference. Also, when you look at OCT and really segment the photoreceptor cell there from the RPE cell there, the effect and impact on saving photoreceptor cells is immediate and complete, right? So that is something that also, on OCT with people that have the proper equipment, can be seen.

Okay. What are physicians saying about time on therapy? I mean, it's obviously, it's a chronic therapy, but what is the sentiment right now -- treat without cessation essentially? Or is there some view that you need to treat for a certain amount of time? Or I mean nothing in clinical data would suggest that. I would suggest that the more you treat, the more you diverge.

That is correct. So we've had patients on treatment for 5 years. So yes, It's a chronic treatment and again, with that great benefit of increasing effects over time. So...

I should also ask about the other one, the GALE. What's the plan to show us that additional data? Are we going to get an update?

Yes. So that will be done in publication. So I think with the GALE study, you start losing a lot of -- it's a 3-year extension. So it's really 5 years of treatment. At some point, you start to see a lot of attrition, because patients also want to go to the commercial product, which is not associated with all of the hassles of being in the trial. So I think we're right now around that time point where we're probably towards the end of having quality data from GALE to show. But really looking forward to compounding all of that in the publication and I'm presenting it.

Okay. So I think when you did the restructuring, you mentioned plans to streamline EMPAVELI commercial organization. So can you kind of flesh that out in a little bit more detail? What does that actually mean? And how you plan to grow the brand going forward with a smaller footprint?

Yes. No problem. And Cedric can comment or Tim internally as well. But the -- so one of the things that we did when we -- across all of our organization is anybody, all of the teams that we're customer-facing, we did the best we could to keep them fully intact. So if they're focused on EMPAVELI or on GA, we kept all of those teams, customer-facing in place. Most of the work that we did commercially came from in the corporate office or other budget cuts that we went through. So the EMPAVELI team, for example, hasn't changed [indiscernible] at all on any of the field teams outside of a few tweaks that we made and that includes on the medical side as well as on the commercial side. And the focus there has been the same. I mean we are in the key centers. We continue to see growth month-over-month. New patients going on products, a high level of consistency of patients staying on product. And I don't anticipate that will change. It really in the life cycle of that product now, it's about the focus on the customer and the patients, and that's where we kept our resources.

Okay. What about the on-body delivery system. That's something that you had a PDUFA that was missed. But now it's -- what's the latest thinking on the approval timing for that? And then how does that make things easier for patients to have the OBD system?

We are very close, right? And it's unfortunate when you get these [indiscernible] because it's something that really will benefit patients, makes it much easier to self-administer at home and with the orals coming onwards having that competitive profile is something really important. So I think we'll have it just in time in that sense. But of course, there will be a little bit of a lag in actually bringing it to all of our patients. I think the key here that we have with EMPAVELI and that always stands out when we talk about it, is the compliance rates. So 98% compliant is something that you very rarely see with any drugs, right? And that is what we have.

Anti-VEGFs not even that high.

So that's right. So it's a testament to -- and the notion of you use twice 30 minutes per week doing that. Patients that are taking and are used to it is absolutely not a big deal. So I think the patients that are on EMPAVELI that are used to it, I think, are going to be very faithful to the product as they have been before. Once the orals are on the market, of course, newly diagnosed patients will be harder to convince with our products than with the orals.

Have you done clinical work in combo with factor D, factor H inhibitors? Or is that something you wouldn't do?

No, I don't think there's really a point to doing that. I mean with EMPAVELI, you really cover both extra and intravascular hemolysis.

Okay. All right. What about the other expansion opportunities? You've kind of narrowed the funnel a little bit. Maybe just, first of all, go through what you decided to keep with the pipeline prioritization, what you decided to I guess, pause or just stop? I don't know what the right word is, but just can you go through the pipeline just which are the ones -- I know your IC-MPGN and C3G, but I think CAD, I'm not sure, I think you stopped that one or...?

Well, cold agglutinin disease and hematopoietic stem cell associated with thrombotic microangiopathy, HSCT-TMA are 2 indications that are being run by Sobi, right? So those trials -- those are less revenue-generating opportunities. It's a really important one from a revenue perspective and also an opportunity, of course, is C3G and IC-MPGN. So those 2 indications, we had a wonderful Phase II clinical trial experience with that. We've also had a lot of patients that have requested to use that on a compassionate basis. So we know that this drug shows a very interesting and important profile that we think will translate into being a really important drug for these patients. So those studies are ongoing. Next year, we will have the data from that, and we think it will make a big difference. The NOBLE data, which was a small Phase II clinical trial that we ran to look at histopath is something that we will be presenting at ASN. I think it's in November. And kind of as an opportunity, you're talking about approximately 18,000 patients, right, between C3G and IC-MPGN where about half of the patients over 10 years will go to end-stage renal failure. And we're talking typically about younger individuals, right? I mean teenagers in their 20s. So 10 years is not a long time. And importantly, after you get transplanted, there's a 50% to 70% chance of a relapse, right? So terrible disease, enormous unmet needs and one that we think we'll be able to address beautifully.

So what is the endpoint? What are you trying to show protection against ESRD or slowing of the -- degradation of the EGFR? What are the end points? And what do you want to show to go into the pivotal?

So this is based on proteinuria reductions, which is something that we have been discussing with the FDA at length before we got into this. And where, again, kind of the correlation to end-stage renal disease and supporting publication around that was important as well.

Okay. And are the IC-MPGN and the C3G, how similar are they in terms of etiology? Are they easily confused or not?

Yes. So histopathologically, they look very, very similar, almost identical. Difference -- the only difference between the 2 is that in IC-MPGN, you have, as the name indicates, immune complexes, which means that you have immunoglobulins sitting in these glomeruli. And that is something that will activate the classical pathway of complement in addition to the alternative pathway. So there is an important or belief to be an important classical pathway component of complement to the etiology of IC-MPGN, whereas in C3G, there are no immune complexes sitting in the glomerulus and it's viewed to be entirely alternative derivative.

Okay. And then what about the -- you have a collaboration with Beam Therapeutics. I don't think most people aren't -- don't know much about that. Can you review what the goals there are?

We've kept it very secret. Beam has a lot of programs, but this is something we're particularly excited about. In the next year, you will start hearing much more about those programs. But they are very important to what we do. They're kind of the ultimate once and done solutions in the context of complement, which has never been done before. And it's been a collaboration that's been incredibly productive and rewarding.

And you also had, if I'm not mistaken, an siRNA program at one point, were that one got paused or no?

No. So we are actually in the clinic right now with the dose escalation phase with our siRNA products. So that brings the levels of C3 down. And that allows you when using combination with, for example, EMPAVELI, we believe that allows you to lengthen the interval between the doses. We don't know by how much yet, that remains to be evaluated and then there may be interesting opportunities to explore for siRNA on its own as well.

So that -- so you're not thinking intravitreal for that one?

No.

Because it's -- that's just too complicated or that wouldn't make sense?

Well, I think that's not something that we view as a kind of interesting alternatives. We think that in the eye, it's very important to control the convertase activity. When you bring the C3 levels down, we don't know yet how far you need to go to control the convertase activity, but it could be quite profound. Definitely would see 5 siRNA that was shown in the past. So I think, to take the risk on pharmacology with siRNA product that we don't think is going to make a difference. It's not something we're interested in right now.

So were there any programs that were halted in this restructuring in terms of research phase or early clinical or not really? Can you just review which ones were?

So we had an additional indication for EMPAVELI, well 2 actually that we were exploring. Those have been halted. We then also had a lot of work related to the molecules that combine anti-VEGF with anti-C3 for the treatment of wet AMD that has been halted. Then we had a molecule 1030 that was meant to control C3 inside the brain with an intrathecal injection that was halted as well.

So these other indications for EMPAVELI were never disclosed or what were they?

I don't think we ever disclosed that.

All right. I guess then to finish off. So . I mean, Cedric or Tim, I mean, in terms of the restructuring, just kind of go through the thinking there, you had the runway guidance to 1Q '25 before. I'm assuming it's extended by a certain amount by now. What was the thought process in terms of doing restructuring? Obviously, at these levels, you probably didn't want to do an equity raise, obviously, but just what was the thinking in terms of that decision?

Sure. So for the first half of the year, we've been guiding to having a cash runway into the first quarter of 2025. Obviously, with the uncertainty that came around the revenue that starting in the middle of July with the vasculitis cases, that when we got called into question a little bit in terms of just knowing where the top line would be. And so that's something we'll have a little bit of a better sense of. And I think we'll guide on runway a little more probably in October when we do our earnings. But in the meantime, it was incumbent on us to really manage our expenses as efficiently as possible. So we took the necessary step to do the restructuring, and we did it decisively really for that reason to maximize our ability to kind of manage the cash through until we really understand the revenue a little bit better.

That was -- I mean, operationally, this summer has been really remarkable for us, but having to say goodbye to colleagues was incredibly hard last week and incredible employees that we had to let go, unfortunately. So that's always difficult. But it was important and the right thing to do.

What about -- do you have plans to bring in other assets into the company or you're satisfied with the portfolio as it is currently?

We are very happy with how the focus has been established now. And in the near future, we look forward to seeing SYFOVRE regain its rightful place in the world. And [indiscernible] continue to do what it does for patients and for our pipeline to continue to grow.

All right. Well, we can end 2 minutes early then. All right Thanks, Cedric. Thanks, everyone. David thank you.