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

Good morning, everyone, and welcome to the Apellis Pharmaceuticals, PEGASUS Top line Phase III Results Conference Call. Today's call is being recorded. At this time, I would like to turn the call over to Tracy Vineis, Vice President of Corporate Affairs at Apellis.

Good morning, everyone, and thank you for joining us today to discuss the top line results from the PEGASUS pivotal Phase III study, evaluating Pegcetacoplan or APL-2 in adults with Paroxysmal Nocturnal Hemoglobinuria or PNH. 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 after 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, Cedric Francois, who will discuss the Phase III PEGASUS results. Our Chief Medical Officer, Federico Grossi; Chief Financial Officer, Tim Sullivan; and Chief Commercial Officer; Adam Townsend will join for the Q&A section at the end of the call. Now I'm pleased to turn the call over to Cedric.

Thank you, Tracy. And good morning to everyone on the call and joining via webcast. We are very excited to share with you the positive top line data from PEGASUS, our Phase III head-to-head study of Pegcetacoplan compared to eculizumab in patients with PNH. As we announced earlier today in our press release, Pegcetacoplan is the first and only investigational therapy to demonstrate superiority compared to eculizumab on improving hemoglobin levels in patients with PNH. In the PEGASUS Phase III study, Pegcetacoplan met its primary endpoint demonstrating superiority to eculizumab with a difference in adjusted means of 3.8 grams per deciliter of hemoglobin at week 16, with promising results on the secondaries that we believe will translate into a clinically meaningful benefit to patients. Our most optimistic expectation was to see a 2 grams per deciliter or more change in hemoglobin and the trend on the secondaries. Needless to say, we are thrilled with these results, which show that pegcetacoplan has the potential to elevate the standard of care for people with PNH. I will first briefly discuss the significant need that exists for new treatments that can more completely control PNH and address the serious symptoms that patients with PNH continue to endure. PNH is a rare, chronic, life-threatening blood disorder associated with abnormally low hemoglobin levels, which is the consequence of hemolysis. A term used to describe the destruction of oxygen-carrying red blood cells. It is estimated that there are approximately 15,000 patients with PNH worldwide. Treatments available today inhibit C5 in the complement cascade, a part of the body's immune system. And while that approach has been life-saving for people with PNH, it does not stop all disease activity. Retrospective studies show that even on treatment with eculizumab, approximately 70% of patients have low hemoglobin levels, and recent studies indicate that this number may even be higher. Additionally, 36% of patients require at least one transfusion per year. Hemolysis can result in a range of debilitating symptoms commonly seen in the PNH population, such as severe fatigue, chest pain and transfusion dependence, all of which contributes to the heavy disease burden these patients experience. Two types of hemolysis, intravascular and extravascular destroy red blood cells in patients with PNH. Intravascular hemolysis directly destroys red blood cells within the blood vessel compartments. In untreated patients with PNH, this happens very quickly and can be effectively controlled by C5 inhibition with drugs like eculizumab. Now once intravascular hemolysis is under control, extravascular hemolysis starts destroying red blood cells by removing them from the bloodstream in the liver and the spleen. The scientific literature shows this process cannot be controlled with C5 inhibition and contributes to the anemia and transfusion dependency observed in patients with PNH on treatment with C5 inhibitors. By going upstream in the complement cascade and targeting complement C3 with pegcetacoplan, we aim to effectively control both intra and extravascular hemolysis with the hope of significantly improving the lives of these patients. On Slide 8, you will find an outline of the trial design of our Phase III PEGASUS study. PEGASUS is a multi-center, randomized, open-label, active-comparator controlled study in 80 adults with PNH who had been on eculizumab treatment for at least 1 year prior to enrollment, but had a hemoglobin level of less than 10.5 grams per deciliter, which affects approximately half of the PNH patient population. The primary objectives of this study were to establish the efficacy and safety of pegcetacoplan compared to eculizumab, the current standard of care. The study consisted of 3 phases. In the first month, which we call the run- in, 80 patients were dosed with 1,080 milligrams of pegcetacoplan twice weekly in addition to their eculizumab treatments. Of note, patients were not allowed to change their historical dose of eculizumab. During the 1-month run-in period, we expected all patients in the study to benefit from pegcetacoplan. And after the run-in, the patients were then randomized into 2 groups for a 16-week monotherapy evaluation period. 41 patients were randomized to continue with pegcetacoplan as a monotherapy, and we expected these patients to maintain the benefits that they gained during the 1-month run-in. The other 39 patients reverted back to eculizumab monotherapy. And after 2 to 4 weeks, were expected to return to their baseline hematological profile. At the end of the 16-week randomization period, we then evaluated the efficacy of pegcetacoplan against that of eculizumab by measuring the change in hemoglobin. When reviewing the primary endpoint data, it is important to understand that we wanted to evaluate hemoglobin levels without interference from transfusions. And to do so, in patients receiving even a single transfusion during the randomized period, we used the hemoglobin value before the first transfusion as the last value counted towards the final prespecified analysis of the data using the mixed effect model of repeated measures or MMRM. Any values after first transfusions were then censored from the data. This censoring method was applied to both the primary and the secondary endpoints. The study was 90% powered to detect a 1 gram per deciliter hemoglobin difference as the primary endpoint. Top line data show that pegcetacoplan met the study's primary endpoint, demonstrating superiority to eculizumab with a statistically significant improvement in adjusted means of 3.8 grams per deciliter of hemoglobin at week 16 with a p-value of less than 0.0001. At week 16, pegcetacoplan-treated patients had an adjusted mean hemoglobin increase of 2.4 grams per deciliter from a baseline of 8.7, compared to eculizumab treated patients who had a decrease of 1.5 grams per deciliter from a baseline of also 8.7 grams per deciliter. To contextualize the 1.5 gram per deciliter hemoglobin decrease in the eculizumab arm, it is important to keep in mind that many of the patients coming into PEGASUS were transfusion dependent, which means that average hemoglobin levels at screening may have been elevated by recent transfusions. During the randomized period, we aimed to minimize the influence of any transfusions in the study by censoring all hemoglobin levels after a first transfusion. This accounts for the 1.5 gram per deciliter hemoglobin decrease in the modeled data for the eculizumab arm. Moving from the model data to the observed data, turn to Slide 10. In the observed data, all hemoglobin levels are represented as measured regardless of influence by transfusions. And as you can see on the graph, the change from baseline in the eculizumab arm was negligible and stable throughout most of the randomized period. The difference in the observed data between the pegcetacoplan and eculizumab arms at week 16 was 2.9 grams per deciliter. Moving on to the secondary -- the key secondary endpoints. Slide 11 summarizes our findings. On this slide, the blue dots represent the difference between the 2 arms. The horizontal lines centered on the blue dots represent the confidence intervals and the orange triangles represent the non-inferiority margins. As you can see, the data trended in favor of pegcetacoplan for every one of these endpoints. Because we met statistical significance on the primary endpoint, we were able to test key secondary endpoints in a hierarchical manner. Key secondary endpoints were to be tested for non-inferiority first. And if all were met, for superiority next on transfusion avoidance, absolute reticulocyte count and FACIT-fatigue score. By applying this method, we met non-inferiority for transfusion avoidance and absolute reticulocyte counts. However, we did not meet non-inferiority on LDH, which appears to be the result of variability in the eculizumab arm as represented by the wide confidence interval. As a result, we were not able to test subsequent endpoints in the hierarchy. As we now take you through the detailed data, we will show you both these modeled data as well as the observed data. With respect to transfusion avoidance, 85% of pegcetacoplan treated patients were transfusions-free compared with 15% of eculizumab treated patients during the 16-week randomized, controlled period. To put this in context, only 6 out of 41 patients in the pegcetacoplan arm required one or more transfusions post randomization compared to 33 patients out of 39 in the eculizumab arm. When we speak to PNH patients, they consider transfusions and low hemoglobin to be a heavy burden. And more than anything, we look forward to making a difference for them. Regarding change from baseline to week 16 in absolute reticulocyte count, pegcetacoplan treated patients had an adjusted mean decrease in absolute reticulocyte count of 135 billion cells per liter from a baseline of 217 billion cells per liter compared to the eculizumab treated patients who had a mean increase of 28 billion cells per liter from a baseline of 216 billion cells per liter. We believe that the decrease in the pegcetacoplan arm is the result of more complete control of hemolysis, which may reduce the burden on the bone marrow. On Slide 14, you can again see that the observed data were consistent with the modeled data as presented. On the key secondary endpoint of change from baseline to week 16 in mean lactate dehydrogenase or LDH. Pegcetacoplan treated patients had an adjusted mean change of minus 15 units per liter from a baseline of 258 units per liter compared to the eculizumab treated patients who had a change of minus 10 units per liter from a baseline of 309 units per liter. Note the large standard [ arrow ] Bars, indicative of the variability of the modeled data. On Slide 16, the observed data show low and stable LDH levels in the pegcetacoplan arm throughout the randomized period. And here too, please note the standard [ arrow ] bars. Next, we turn to Slide 17. On the key secondary endpoint of change from baseline to week 16 in FACIT-fatigue score, pegcetacoplan treated patients had an improvement of 9.2 points compared to eculizumab treated patients who had a decrease of 2.7 points. To contextualize those numbers, a 3-point change in FACIT score is generally considered clinically meaningful. On Slide 18, as with the other endpoints, here too, the observed data are consistent with the modeled data. Finally, and importantly, the safety profile of pegcetacoplan was comparable to eculizumab in this study. The incidence of serious adverse events between the 2 groups was similar. No cases of meningitis and no deaths were reported in either treatment group. The most common adverse events reported during the 16-week randomized, controlled treatment period in the pegcetacoplan and eculizumab groups where injection site reactions, diarrhea, headache and fatigue. Another common adverse event was hemolysis, which was reported in 4 patients in the pegcetacoplan group and 9 patients in the eculizumab group. This led to 3 discontinuations in the pegcetacoplan group. All patients who completed the randomization period in both arms entered the 32-week open-label pegcetacoplan treatment period. To put this in perspective, 77 of the 80 patients that entered the study decided to continue or switch to pegcetacoplan treatment in monotherapy after the randomized period was complete. We are thrilled with the Phase III results, which show that pegcetacoplan has the potential to elevate the standard of care for PNH patients in need. Following today's announcement, we expect to meet with regulators in the first half of 2020 to discuss next steps. In tandem, we will continue our commercial and medical readiness activities to prepare to bring this important treatment to PNH patients, if approved. Additionally, we expect the full results from PEGASUS to be presented at a scientific meeting and published, and we also look forward to providing an update on our Phase III PRINCE trial evaluating pegcetacoplan in treatment-naive patients later this year. These data represents the first Phase III results for a C3 inhibitor, which gives us strong confidence in the further development of pegcetacoplan as a platform approach to treating a wide variety of serious complement-driven diseases, including geographic atrophy and others. We expect that both Phase III trials in geographic atrophy will be fully enrolled in the first half of 2020 and expect to announce data in mid-2021. We intend to disclose our plans and timing for further clinical development of pegcetacoplan for patients with cold agglutinin disease and C3 glomerulopathy in the first half of 2020. And before we move on to Q&A, I would like to thank the patients, their caregivers, the investigators and other health care providers who participated in our PEGASUS study. And I would also like to especially thank the employees at Apellis for their dedication and passion. We are grateful to all of you for your efforts in helping to advance care for people living with PNH and other complement-mediated diseases. And with that, operator, please open the call for questions.

[Operator Instructions] Our first question comes from Anupam Rama of JPMorgan.

Congratulations on the data. A couple of questions that we've gotten this morning. I guess, first, can you help us characterize the nature and severity of the injection site reactions and diarrhea observed with APL-2? And then one question that we've repeatedly gotten this morning, how do you think about APL-2 here in a potentially transitional ULTOMIRIS world? And what's your ideal product label here? Is it specific to Soliris or C5 overall?

Thank you so much, Anupam. Well, let's first talk about the observations that we had related to injection site reactions and diarrhea. Well, I'll start with the latter. So all the cases of diarrhea reported here were mild cases of diarrhea, all of them, and none of them led to discontinuation. As it relates to the injection site reactions, the product was very well tolerated, and these are the typical things that you will see when you do a subcutaneous injection or an infusion. So because the volume is large, it's 20 CCs. You can have some bunching of the skin. You can have a little bit of pain, it may be a little bit red, and patients have to get used to that. And something that we see very clearly as well is that most of these injection site reactions are reported early on when patients are getting used to it, and then it becomes well tolerated. So we are not at all concerned about those observations from a safety or a tolerability perspective. Then as it relates to Soliris versus ULTOMIRIS. This trial was, of course, conducted against eculizumab. So we cannot draw any conclusions as it relates to how APL-2 or pegcetacoplan would perform against ULTOMIRIS. It is worth noting here that the mechanism of action of ULTOMIRIS is identical to the mechanism of action of Soliris. And that's the reason why we believe that pegcetacoplan shows the effectiveness that it did is related to the mechanism where we go upstream and by targeting C3 are able to address the problem of extravascular hemolysis. This study, in my opinion, maybe more than anything, I think, finally established that there is an important unmet medical need in this disease. I mean, these patients when they are being treated with C5 inhibitors, don't -- generally don't do very well. They are taking a life-saving drug, which is incredibly important, and we should all be really grateful for Soliris having been on the market for longer than a decade. But there is room for a lot of improvement in the quality of life of these patients, and that is what we attempted to do.

And our next question comes from Umer Raffat of Evercore ISI.

My 3-part single question. So Cedric, I want to start with a disclosure you guys made, and then I'll get into a couple of questions on the trial. So the disclosure was that, I'm seeing this disclosure that the company will meet with the regulatory agencies, and will discuss the data, obviously. But it also says that FDA has advised you that hemoglobin stabilization, a rise in hemoglobin levels may not translate to a clinical benefit when entered the trial with high hemoglobin levels. So I just want to get clarity, is this an approvable endpoint? Or what exactly does FDA need to see? Point #1. Point #2 is -- so I understand that censoring on the primary endpoint led to the wide confidence intervals for LDH. But we did see that LDH levels were starting to rise on APL-2 therapy. Can you speak to that? And then finally, could you reconcile for us, I know about half the patients were not transfusion-dependent coming into the trial. But then the transfusion avoidance was as low as 15% in the Soliris arm, and I understand the transfusion nondependent doesn't mean 0 transfusion. Could you just reconcile those 2? And again, congratulations on the data.

Thank you so much, Umer. Would you do me a favor and repeat the third part of your question, please? Because that was the one that I got [indiscernible].

So half the patients that came into the trial were not transfusion-dependent. So let's say, half the patients on Soliris arm. But then during the trial, 15% of Soliris arm was patients that had transfusion avoidance, meaning it dipped from 50% to 15%. Now in reality, those are 2 different terms, transfusion dependency, the way it was defined versus transfusion avoidance. But if you could just reconcile those 2, that would be really helpful.

Okay. No problem. Thank you so much, Umer. Well, we'll start off with the regulatory question. So when we met with the regulators to discuss the PEGASUS trial, we were very keen on showing the superiority and the benefit that we could provide to patients on treatment with C5 inhibitors. The FDA's perspective was, well, we are interested first in you showing non-inferiority, kind of in line with the other studies that were going on with C5 inhibitors, and then we can discuss superiority. We believe that it was really important to focus on hemoglobin. But it is important to note here that the role of extravascular hemolysis and the impact of hemoglobin in these patients, et cetera, was very poorly understood several years ago. So as we discussed this, we really wanted to have hemoglobin as that primary endpoint. And the FDA basically gave us the feedback, look, fine, but we're going to have to evaluate the data when it comes in and gave us some soft guidance as it relates to what they wanted to see. Now we powered the study to be superior for 1 gram per deciliter. And the soft guidance that we did get from the FDA at the time was, should you only show that, we will not know what to do with that. Should you show a statistically significant improvement in the presence of a trend on the secondary endpoints, that means that you are having a real impact on patients, we'll evaluate it. But it was -- it was all soft, and it was basically the fact that in one trial we wanted to accomplish 2 things. One was, of course, to get approval, the second was to immediately show superiority for pegcetacoplan. So it all was going to depend on the data. With the data that we currently have, we feel very strongly that we have established a strong case, and we will meet with regulators in the first half of this year to hopefully get a path forward based on the PEGASUS study alone. That's the first part of your question. Then as it relates to lactate dehydrogenase. So there are -- we had cases of hemolysis in the pegcetacoplan arm, 4 to be precise, we had 9 cases in the eculizumab arm. And these hemolytic cases, as you know very well, are associated with LDH increases. So you will have variability. And that hemolysis, in our case, those 3 patients ended up leaving the study. So in the observed data, that leads to kind of the further correction that you see on the LDH levels. What I think is key to also appreciate here is that the patients that came into the study in the eculizumab arm, came into the study on already optimized doses of eculizumab and stayed there throughout the study. So we did not require -- we did ask physicians to not change the eculizumab dose throughout the whole period. With pegcetacoplan, we got a very satisfactory result as far as it relates to LDH and to hemolysis, 4 is still more than what we want. We believe that there is room for improvement, and we are going to be evaluating strategies to get there. We took it down from 9 to 4 here, and we are going to work on bringing it further down from 4. And then as it relates to your last question, as it relates to the patients coming into the study. You are correct that we stratified the study for half of the patients to be transfusion-dependent and half of the patients to be not transfusion-dependent. In retrospect, that was maybe a bit of an unfortunate term because it doesn't fully explain what we did there. So let me briefly elaborate on that. The transfusion-dependent patients that were brought into the study were patients that very clearly had unstable hemoglobin and therefore, were on a repetitive cycle of transfusions, which translated into typically more than 4 transfusions per year. And these patients were important for us because we could expect these patients to have at least one transfusion during the 4-month treatment period or the randomized period of the study. The other half of the patients we called transfusion independent, but what transfusion independent meant in the protocol was fewer than 4 transfusions. It didn't mean that they had 0. And many of these patients have occasional transfusions, just not more than 4 per year. And -- so these are patients that came into the study that were categorized as transfusion independent that really had, in many cases, had a history of transfusions. And obviously, that is what you see translated here in the eculizumab results as well.

And the next question comes from Madhu Kumar of Baird.

Congratulations on the readout. So really kind of one key question we have, how do you think about -- now that you have the PEGASUS data in hand, how you evaluate the PRINCE trial? And how you evaluate other systemic APL-2 indications like cold agglutinin disease like C3G, and kind of how do you look at the broader systemic APL-2 space?

Yes. So that is, quite frankly, beyond our excitement and our happiness around the data in PNH. What stands out here as well is, I don't want to call it remarkable, but a really satisfactory safety profile, right? I mean, that's the -- it is something that allows us to explore the full potential of C3 inhibition and control using pegcetacoplan in a wide range of indications. So this is something that we really look forward to. You know that we have our Phase III clinical trial in geographic atrophy, where we are close to fully enrolling 1,200 patients, and where there's an completely unmet need in probably about 1 million patients in the U.S. alone. We also have our data, as you mentioned, cold agglutinin disease and C3 glomerulopathy programs that we intend to move forward into confirmatory testing. So that is something that we are very much looking forward to. As it relates to the PRINCE study, the PRINCE study was designed and executed to give us a backstop for any potential label limitations that we may encounter from the PEGASUS study. So obviously, the PEGASUS study was very much designed as a switchover study, where you go to patients who are Soliris experienced. But at the end of the day, we would like to have a monotherapy treatment-naive label as well, and that's something that we believe PRINCE will be able to give us.

Okay. And then a follow-up question. What -- how does this result affect the interactions with SFJ? What are the kind of next steps with SFJ with regards to that collaboration?

I will give the word to Tim Sullivan, our Chief Financial Officer, to answer that question.

Madhu, so I missed the last piece of it, can you just repeat that?

What are the next steps with SFJ? [indiscernible]

So next steps with SFJ are -- we've obviously updated them on the data. As you probably know, the terms are favorable to us, and that we don't have any payback requirement until the drug is actually approved. But next steps are really just deciding on whether or not we want to take the additional capital that's offered to us in the SFJ agreement, and we'll make that decision in short order.

And our next question comes from Yigal Nochomovitz of Citigroup.

Congratulations on the outstanding results. I just was wondering, in terms of the read-through to the other C3 diseases, particularly GA, Cedric, is there any specific feature of the current PEGASUS data that you would point to as most relevant in terms of read-through to GA or just the general view that the complement-mediated activity is, obviously, therapeutically very beneficial in PNH.

Thank you, Yigal. That is an excellent question, of course. I think what the PEGASUS study shows beyond any doubts is that we hit -- the mechanisms that we have been studying now for probably 15 years is exactly the way we wanted to do it. It's maybe worth mentioning here briefly that the way in which pegcetacoplan targets C3 is yes, we call it a C3 inhibitor but more than anything, it is a convertase stabilizer. So we do not try to get rid of all C3. What we try to get rid of is uncontrolled and undesirable over activation of complement. And as a matter of fact, in patients with PNH, when we reach the efficacy that you see in PEGASUS, we still have probably about 10% of free-floating C3 in circulation. And that may account for the safety profile that we see as well. So all we know as it relates to geographic atrophy is that pegcetacoplan does exactly what we intended it to do. And hopefully, in geographic atrophy, that will translate into being able to repeat what we saw in the [ study ] clinical trial.

And our next question comes from Ellie Merle of Cantor Fitzgerald.

Congrats on the data. Just taking a step back, thinking about the commercial implications of this. Can you comment a little bit on how the baselines of the patients in the study might compare to say a typical patient that's on Soliris or ULTOMIRIS commercially? And any key, sort of, differences or things that you think are notable to point out in comparing those baselines?

Thank you so much, Ellie. So I will briefly answer the second part of your question, and then let the commercial interpretation be answered by our Chief Commercialization Officer, Adam Townsend who is here with us. So as it relates to -- because I think really what your question alludes to is, okay, how many patients with PNH on eculizumab are really going to benefit from this. Is this is a very small percentage or larger? And there, it is worth noting that extravascular hemolysis is not something that affects a small percentage or a medium percentage of patients with PNH. This is a mechanism of red blood cell removal that affects the vast majority, if not all patients with PNH as soon as they are treated with C5 inhibitors because controlling intravascular hemolysis allows extravascular hemolysis to take over. The question is, how as a patient are you affected by extravascular hemolysis. And in the PEGASUS study, we took the 50% or so of patients that are disproportionately affected by this. But at the end of the day, our objective is to better control this disease. And that is what pegcetacoplan aims to do. And I will let Adam report to you how we intend to use that from a commercialization perspective.

Ellie, it's Adam. Thanks for your question. I think one thing we should just say today, it's great news for the PNH community today to see this data. I mean, as I'm sure you know retrospective studies show that on eculizumab, about 70% of patients with PNH still have low hemoglobin levels. They suffer from fatigue, they have difficulty breathing. We also know from data that 36% of people who are treated with eculizumab will require one or more transfusions. There is a high unmet need within this market. We truly look forward to speaking to key opinion leaders and patients about this data. I mean, of the 15,000 people living with PNH worldwide, 8,000 to 10,000 of them in the U.S. and Europe. We think there's a large potential unmet need with those patients for us to go and elevate the standard of care with the data that we've shown within this PEGASUS study. So we've been planning commercially for the last 6 months to get ready to do that. We are ready to execute that plan, and we really, really look forward to serving those patients.

Got it. And just a quick follow-up. Was there any relationship seen between the baseline reticulocyte count? And I guess the response on hemoglobin or transfusion independence seen in this data?

So that -- thank you, Ellie. That is an interesting question. That was not part of our top line analysis. And at EHA, we look forward to presenting more data as it relates to PEGASUS.

And our next question comes from Justin Kim of Oppenheimer & Company.

A big congratulations on the data. Maybe just somewhat of a pre-commercial question or a clinical question. As we anticipate the next step for pegcetacoplan, are there any plans to broaden the clinical switch experience with ravulizumab? And I know you haven't had a lot of time with these data, but could you provide any, sort of, thoughts or additional color on the tolerability profile during the run-in period?

Thank you, Justin. So again, that's a very key and important question, ravulizumab is a drug that is rapidly being adopted in the PNH community. And again, pointing out what I mentioned earlier, targets the same mechanism. So when you look at the published data, as it relates to eculizumab versus ravulizumab. The clinical outcomes seem to be very similar. There may be a bit of a lower incidence on ULTOMIRIS as it relates to breakthrough hemolytic events. But in terms of average hemoglobin response and unmet need, we consider these 2 products to be very similar, if not the same, with the benefit, of course, of convenience for ULTOMIRIS. Our purpose in this study was to study eculizumab -- Soliris versus pegcetacoplan. And we wanted to, as I mentioned earlier, expose the unmet need. We also implemented a design in the clinical trial that makes it very easy for physicians who have patients on treatment with eculizumab. And in the future, ravulizumab as well and where patients are suffering from transfusions do not have satisfactory hematological profiles to be able to find out over a 1-month combined dosing period, whether pegcetacoplan can actually make these patients better. So the whole purpose of this study was to create for a minimally invasive and really easy way for physician and patients to know whether their condition can be improved. That's why we did the study the way we did it. And -- so we may do an additional small study with ULTOMIRIS, we don't know that yet. But the key thing here is we were focused on the patient need. And we believe that pegcetacoplan is addressing the problems that are remaining in PNH because of the fact that C5 does not control the disease as completely as it could or should.

Okay, great. And maybe just as a follow-up, talking a little bit about, sort of, that ease of experience. Can you comment as to what proportion of patients had a higher level of eculizumab dose stably, I guess, prior to entering the study. [indiscernible]

Thank you, Justin. So that is also an excellent question. We will discuss that in more detail at EHA as well. Worth mentioning here is that on the average population, approximately 20% of patients have a higher dose of eculizumab then by posology, so by label. It is obviously to be expected that in the PEGASUS study, a higher number than 20% is probably what was involved here. But at this point in time, we are not going to comment on that, and we look forward to discussing that at EHA.

And the next question comes from Brian Cheng of Bank of America.

Congrats on the data. I guess single back on the data. Can you give us a little more kind of granularities on the split of responses for patients who were previously transfusion-dependent versus independent? Did you see any increase in transfusion needs in those patients who were independent before? And I have a follow-up.

Okay. Thank you so much, Brian. So again, that level of detail will come later. But I think what's kind of an important place to look at here are the observed data on LDH as it relates to the eculizumab arm because I think that is what you seem to be referring to. Is there an increased transfusion rate or not? Where is that line? In the modeled data, we censor all the data after a first transfusion, right? So because it's very much focused on that primary endpoint readout where we don't want the transfusions to confuse the hemoglobin levels, right? Now as it relates to the LDH levels, which kind of give a good indication of where the population sits. When you look at the observed data in the eculizumab arm, what stands out here is that at screening, and after they kind of go back to their baseline following the run-in period, so about a month after going back on monotherapy, these levels are more or less the same. And -- so the take-home message here is that patients in the eculizumab arm benefited from pegcetacoplan for 1 month, and then seems to go back pretty much to the same state where they were before.

Okay. And then one more follow-up on continuation, any more color on that? And when do patients discontinue in the PEGASUS when they're on the peg arm?

So the timing of that is also going to be subject of further analysis, and we'll talk about that more at EHA. I think what is key to kind of bear in mind here is we brought the hemolysis rate already down from 9 in highly optimized eculizumab patients to 4 on pegcetacoplan without optimization, providing room for further improvement. And that is something that we look forward to working on, I think, with the mechanism and with everything that we understand, we think we can further improve on that.

And our next question comes from Phil Nadeau of Cowen and Company.

Congratulations on the data. Also a 3-part single question. First, were there any imbalances in the baseline characteristics between the arms? In particular, what was the baseline dose of Soliris in the 2 arms? Second, any difference in the severity or quality of the infections between the 2 arms? And then thirdly, just more of a theoretical question. Is there any reason to expect rebound hemolysis when APL-2 is withdrawn? I appreciate your comments as to why the Soliris levels of hemoglobin could decrease versus baseline, an alternative explanation would be if there's some brief rebound hemolysis, when APL-2 is withdrawn. Is that at all possible?

Thank you, Phil, for those 2 questions. So the first question as it relates to the baseline Soliris -- the baseline characteristics, including the Soliris dosing. So what's important here is that the baseline characteristics were well stabilized across the groups. The average LDH level in the eculizumab group was a little bit higher on baseline than it was in the pegcetacoplan group, but not something that stands out. But on all the other characteristics, it was well balanced between the 3 groups, and we'll go into detail when we present this at EHA. As it relates to the infections, there too, there was nothing notable in terms of different types of infections or the nature. The best way to think about this is that in the 2 groups, we saw an infection frequency, duration and course of infections that could be expected from an 80-patient population over a 4-month or 5-month time period. So again, there's nothing that stands out there that gives us a safety consideration. Then as it relates to the rebound when patients are withdrawn. So that is, of course, a very good question, and I think kind of refers to the same question that Brian had, which is, does the hemolysis occur immediately after you take away Soliris or is this something that actually goes on while you are on treatment with Pegcetacoplan? Those are very important questions that we look forward to answering, but we first want to have the opportunity to dive deeper into the data that we have right now.

And just in prior studies, have you seen rebound in hemolysis when APL-2 is withdrawn or is that not something that you've ever observed?

No, we actually did observe this, and this was something very important to us, of course, as we designed this study because in the PHAROAH [last ] study, which was the Phase Ib trial that we conducted with APL-2 in patients who were Soliris experienced, very similar population to what we had here. What we found is that after being on combined dosing between APL-2 and eculizumab, when you withdraw eculizumab, there is a risk for -- even though you saw an improvement with APL-2, there is the possibility of not having complete coverage, which is shielded by eculizumab. So that was something really important for us in the PK/PD analysis and in establishing the dosing of 1,080 milligrams twice per week. So it is certainly possible that the hemolytic events that we're talking about here happened in the waning periods. But again, that is something that requires further analysis, and we'll talk about more later.

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

Congrats on the data. So just 2 quick ones for me. Did you have any patients that actually move from a twice-weekly dosing regimen to every 3 days on the APL-2 arm during the study, since you had a few cases of hemolysis there? And the second question is just related to the regulatory process. I'm curious where you guys stand specifically for manufacturing and controls validation, kind of what's your capacity right now? And if there are any other [ gating ] steps of potential regulatory submission?

Thank you [Foreign Language] Tiago. Look, the -- I'll start with the second part of your question. We are ready with the CMC. This is not on the critical path as it relates to our NDA filings. So we made a heavy and expensive investment in making sure that we can handle the manufacturing, quite frankly, not just for PNH, but with the hope that pegcetacoplan will become that platform and a drug opportunity that allows us to go after multiple therapeutic areas. So that is something that has historically been really important to us. You correctly pointed out that we had a provision in the protocol that should there be hemolysis in the trial that physicians would be allowed to increase the dose to a 3-day, 3-day regimen. Which is an increase compared to a 3-day, 4-day regimen. Whether that happened and in how many patients, et cetera, is going to be the subject, again, of further analysis. But it's worth noting here that we had only 4 patients that experienced hemolysis. So we're not talking about 4 patients that went on a 3-day, 3-day regimen. We're talking about 4 patients that were reported to have had hemolysis.

And our next question comes from Laura Chico of Wedbush.

I guess, just one, I'm not sure if you'll be able to give much color here, but just going back to the earlier question around the disclosure FDA endpoint. Could you speak a little bit perhaps to the responses by the hemoglobin starting points? Any, I guess, just kind of general comments you can talk out there?

I'm not sure I understand the question, Laura.

Sure. For -- I guess, kind of how did response vary by patients that had lower baseline hemoglobin versus patients that might have been towards the higher end?

I see what you mean. So again, that is not part of the top line analysis. And maybe Dr. Grossi, would you like to -- our Chief Medical Officer is here with us, and will answer that question for you, Laura.

Yes, we have not. So all those are sub analysis that we'll be running in the future. So very likely we'll be looking at all subgroup analysis when relates to different levels, the baseline for the different parameters, not only for hemoglobin, we're looking forward to presenting that in the future.

Okay. Just one other follow-up, if I may then. I guess, related to the earlier question on the injection site reactions. Could you just remind us where you stand in terms of kind of characterizing APL-2 in terms of the peg tag? I guess, the earlier [ tax ] work you had done was with a once-daily subcu dose in animals. But if you transition more to the twice-weekly or even a 3x per week dose, would that require additional preclinical [ tax ] work to do? Or I guess, kind of what additional work needs to be done in terms of the pegylation characterization?

No more preclinical work is needed. All the proper characterizations have been done.

Okay. And maybe one last one, if I could squeeze in there. Were you monitoring for any antidrug antibodies in the study?

Yes, we were. We did not see any immunogenicity in this study either.

Ladies and gentlemen, this does conclude...

I also have one question here from an email. I just wanted to point out here. So there was a question as it relates to the LDH levels. So what we are extremely happy with here and what I would encourage everybody to take a look at are the observed data on the LDH levels. Because remember, the only patients that are not included in these observed data are the 3 subjects in the pegcetacoplan arm that throughout that period may have experienced hemolysis. And at that point in time, left the study, but to control that we saw on LDH with pegcetacoplan, I think, is indicative of the level of control that we have over hemolysis. And when you look at the data throughout the 16 weeks of the randomization period, I would say this is beyond what we had expected.

And this does conclude our question-and- answer session. I would now like to turn the call back over to Cedric Francois for any closing remarks.

Thank you so much, operator. Well, in closing, apparently, I don't have any notes for that. So I'll just wing it. I want to thank everyone for joining this call. The PEGASUS Phase III trial results are really an exciting validation of the potential of pegcetacoplan to elevate the standard of care for people with PNH. And it's also a study that I think really showed us what the unmet need is in this disease and how pegcetacoplan, hopefully, will be able to address that when, again, hopefully, it will be approved. We look forward to continuing our pipeline. We have our data now in PNH, but there are many other diseases where we believe C3 related mechanisms can provide important benefits to patients. And I want to, again, thank not just all the employees, the patients, the physicians, but also the investors that allowed us to do this research and move this product forward. And we look forward to hopefully sharing much more with you in the months and years ahead. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.