Good morning, everyone, and welcome to the Apellis Pharmaceuticals Pega Results Conference Call. Today's call is being recorded. At this time, I would like to turn the call over to Tracy Veniz, Vice President of Communications at Apellis.
Good morning, and thank you for joining us today to discuss the detailed results from the PEGASIS pivotal study evaluating pegcetacoplin or APL2 in adults with paroxysmal nocturnal hemoglobinuria or PNH, which were presented virtually today in an oral session at the 25th Congress of the European Hematology Association. For those participating via conference call, we have made the slides available via webcast. 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 Doctor. Cedric Francois, Co Founder and Chief Executive Officer of Apellis and Chief Medical Officer, Doctor. Federico Grossi. Joining us for the Q and A section will be our Chief Financial Officer, Timothy Sullivan Chief Commercial Officer, Adam Townsend and Doctor. Peter Hillman, Professor of Experimental Hematology at the University of Leeds and investigator in the PASIS study.
With that, I'm pleased to turn the call over to Cedric.
Thank you, Tracey, and good morning to everyone on the call and joining via webcast. We are excited to welcome you to this morning's call to discuss the detailed results presented today at EHA from our positive PEGASYS Phase 3 study evaluating pexetacopan compared to ekulizumab in adults with PNH. In January, we were proud to announce that pexitacoplan 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 and promising results on key secondary endpoints that we believe will translate into a clinically meaningful benefit to patients. Pexepacopalan is the 1st and only investigational therapy to demonstrate superiority compared to ekuleizumab on improving hemoglobin levels in patients with PNH. Today, new data presented at EHA reinforced the findings from January, demonstrating PAXIvant Copeland's potential to elevate the standard of care for patients.
Texitacopan, a targeted C3 therapy, demonstrated substantial improvements over C5 inhibition in the following important ways. 1st, hemoglobin levels improved by 3.8 grams per deciliter, 53% higher than the eculizumab arm. 2nd, LDH was normalized in 71% of patients on pixitacoplan versus 15% on eculizumab. 3rd, 85% of patients on pexidacoplan were transfusion free versus 15% on eculizumab. And 4th, patients on pexidacoplan achieved an 11 point difference in facet fatigue score over patients on eculizumab.
These improvements were achieved while showing a comparable safety profile and with patients receiving optimized eclizumab dosing, including 30% on higher than label dose in the study. Importantly, these findings were observed independent of prior transfusion status. Before we review the data set in more detail, I'd like to discuss the significant unmet need that exists for people living with PNH. It is estimated that there are approximately 15,000 people with PNH worldwide. PNH is a rare, chronic, life threatening blood disorder that when left untreated has historically resulted in death in about 35% of patients over the course of 5 years.
VNH is characterized by the destruction of oxygen carrying red blood cells through processes called intravascular and extravascular hemolysis. Intravascular hemolysis refers to the direct destruction of red blood cells inside the blood vessels. Extravascular hemolysis refers to the removal of red blood cells from circulation in the liver and the skin. Intravascular and intravascular hemolysis work in tandem to cause the debilitating loss of red blood cells in PNH. Currently available treatments inhibit the complement cascade, a part of the body's immune system, downstream at a point called C5, which controls intravascular, but not extravascular hemolysis.
Consequently, people living with PNH continue to suffer from debilitating symptoms, including severe fatigue and transfusion dependence. Pexitacoplan targets C3, which is upstream in the complement cascade. By being upstream, pexifacopalan can control both intra and extravascular hemolysis, thus better controlling the disease and providing relief to patients. I'd now like to turn the call over to our Chief Medical Officer, Doctor. Federico Brosi, who will review the results presented at EHA today.
Well, thank you, Cedric. First, I would like to express my excitement about the data presented today at on our pivotal study. The results presented today show that pexeta copland, by targeting C3, may have the potential to control both extra and intravascular analysis and thus redefine the treatment for people living with PNH. Before reviewing the results, I wanted to provide a brief summary of the trial design for Pegasus. A detailed schematic of the trial design can be found on Slide 7, so I will only give a high level overview.
PEGASUS is a multicenter, randomized, open label, Arctic comparator study in 80 adults with PNH who had been on eculizumab treatment that had hemoglobin levels of less than 10.5 grams per deciliter. The primary objectives of the study were to establish the efficacy and safety of pegzetacopalan compared to eculizumab. The secondary endpoints included transfusion avoidance, change from baseline in reticulocytes, change from baseline in LDH and change from baseline in facetratic scores. Now we can turn to the results. To help you follow the charts and graphs, exetacopalan is represented in orange and eclizumab in gray.
As Cedric mentioned before, pexetacoplim met the study's primary endpoint for efficacy, demonstrating superiority to eclizumab 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. Importantly, the data presented today show that this benefit in hemoglobin level was consistent across patients, independent of bio transfusions. As shown on the Slide 9, in patients with low or non transfusion requirements, meaning patients who received fewer than 4 transfusions in the prior year, the mean baseline hemoglobin was 8.9 grams per deciliter. In this group, pegcetacofen treated patients had an adjusted mean hemoglobin increase of 2.97 grams per deciliter compared to equilishimab treated patients had a change of minus 0.01 grams per deciliter from baseline. Similarly, in patients with high transfusion requirement, meaning patients who received 4 or more transfusions in the prior year, the mean baseline hemoglobin was 8.5 grams per deciliter.
In this group, exetacoplin treated patients had an adjusted mean hemoglobin increase of 2.11 grams per deciliter compared to eclizumab treated patients who had a change of minus 4.02 grams per deciliter from baseline. Based on the prespecified analysis, hemoglobin levels following transfusions were excluded. This is done to isolate the impact of treatment from that of transfusions, which can otherwise artificially increase hemoglobin levels. This explains why a drop in hemoglobin levels can be observed in patients with high transfusion requirements in the eclizumab group. Turning now to the secondary endpoints.
As shown on Slide 10, exotecoplan effects on transfusion avoidance was consistent across patients independent of prior transfusions. As you can see in the subgroups on the right, in patients with low or no transfusion requirements, 85% of petrocapelin treated patients were transfusion free over 16 weeks compared to 31% of epiluzumab treated patients. In patients with high transfusion requirement, 86% of texetacopan treated patients were transfusion free compared to only 4% on eclizumab treated patients. Turning now to Slide 11. In addition to transfusion avoidant and a share in January, all key secondary endpoints trended in favor of texetacotland at week 16.
Today, we presented data on normalization rates of the primary and key secondary measures. The most striking results are on LDH. 75% of pexepacoplin treated patients achieved LDH normalization compared to only 15% of eculizumab treated patients. This demonstrates that pexetacoplin's control of intravascular hemolysis. On reticulocytes, 78% of pexetacopalan treated patients achieved reticle site normalization compared to 3% of ekizumab treated patients.
This reflects the relief of the 1 model of patients with PNH when both intra- and extravascular hemolysis are under control. Even on hemoglobin, in these severely ill patients, 34% of patients on pexetacopalan achieved normalization compared to no patients on eculizumab. Another critical issue for patients living with PNH is fatigue. 73% of pegzilcoflin treated patients achieved at least a 3 point improvement in facetratic score compared to no patients on eculizumab. Just to bring context to this, a 3 point improvement in phasipathic score is considered to be clinically meaningful.
As Cedric said earlier, patients in pegcetacopan achieved an 11 point difference in facet fatigue over patients on eculizumab. Slide 13 illustrates the important finding, which we had hoped to accomplish in the design of the study, that the full benefit of pegzetagoplan was achieved in 1 month of combined therapy and then maintained when people switch to pegcetecoplan monotherapy. Equally important, and again as anticipated, patients who discontinued pegcetecoplan and return to eculizumab monotherapy should their baseline numbers over the course of 1 to 2 months without safety concerns. 2 other points I was noting here. 1st, indirect bilirubin and absolute reticulous accounts are markers of extravascular hemolysis, and both improved with pegzetacoplin.
Together with the LDH data, these results speak to pexeta coupling's ability to control both intravascular and extravascular hemolysis and differentiates Perceta Copplant's targeted C3 approach from C5 inhibition. Finally, Slide 14 shows how C3 loading on red dot cells, which is known to be the driver of extravascular hemolysis, disappears almost completely with pegzetagoplan treatment, again, reflecting what happens clinically. Turning now to the safety data presented today. The safety profile of texetacopalan was comparable to eclizumab in this study as shown in Slide 15. No cases of meningitis and no death were reported in either treatment group.
The most common adverse events reported during the 16 week randomized controlled treatment period were injection site reactions and diarrhea in the pex tachytoplank arm and headache and fatigue in the eclizumab group. Injection site reactions were mostly mild and were more frequent at study initiation when patients were getting used to subcutaneous infusions. Non lead to trial discontinuations or dose modification. Diarrhea cases were also almost exclusively mild, not associated with treatment initiation and mostly single event occurrence. Here as well now resulted in trial discontinuation or dose modification.
Another common adverse event observed was hemolysis reported in 4 patients in the pexetacopan group and 9 patients in the eculizumab group. Patients in the eculizumab group entered the study on an optimized dose, and no change was made in response to the hemolysis events. By protocol, patients in the pegzilobelcoplane group could not be efficiently adjust for dose, and therefore, 3 of the 4 emoligies event led to discontinuations. We believe that dose optimization will allow us to further reduce the occurrence of hemolysis on pexepacoplim. In conclusion, these results demonstrate that pexetacoplin control both intra- and extravascular hemolysis in PNH.
The robustness of pexetacopalan's efficacy results, together with its safety results, suggest that pexetacopalan has the potential to elevate the standard of care in PNH by addressing the totality of the disease. We are thrilled to be one step closer to making a difference in the lives of patients and families impacted by PNH. Now to you, Sever.
Thank you very much, Federico. In conclusion, I want to reiterate the substantial improvements demonstrated by pexitagoplan, the targeted C3 therapy over C5 inhibition in the PEGASYS study. 53% higher hemoglobin levels versus the aqulizumab arm, 71% LDH normalization versus 15% on aqulizumab, 85% of patients transfusion free versus 15% on eculizumab and an 11 point difference in facet fatigue, all while showing a comparable safety profile and independence of prior transfusion status. We are thrilled with these results, which reconfirm plexitacoplan's potential to elevate the standard of care for all PNH patients. Last month, we announced our plans to submit a new drug application or NDA for pexitacoplan for PNH to the U.
S. FDA in the second half of this year. And today, we announced our plans to submit a marketing authorization application to the European Medicines Agency in that same time frame. Based on feedback from discussions with regulators, these positive PEGASIS data will serve as the basis of our marketing applications. We also expect 48 week top line PEGASYS data in the second half of this year.
The PEGASYS results underscored the importance of targeting C3 in PNH, and we are working to bring pexetacoplan to the PNH community as quickly as possible. Finally, it is worth noting that the PEGASIST study data also validates the further development of texitacopalan as a platform approach for serious complements driven diseases. We remain the only company with a targeted C3 therapy in late stage clinical trials, and we are on track to complete enrollment in 3 Phase III studies this month. Our 2 Phase 3 DERBY and OAKES trials for pexitagopalan in patients with geographic atrophy will be fully enrolled in the coming weeks, and we expect top line results from these trials in the Q3 of 2021. We also expect that enrollments will complete shortly for our Phase III PRINCE trial in treatment naive patients with PMH with top line data in early 2021.
And finally, we plan to share soon the strategy and timing for further clinical development of pexida co plan for patients with full like glutenin disease, C3 glomerulopathy and other indications. We look forward to sharing our continued progress with you. In closing, I'd like to thank the patients who volunteered, their caregivers, investigators, health care providers, our employees and investors, all of whom were so important in bringing this potential treatment closer to patients. And with that, operator, please open the call for questions.
Thank you, I show our first question comes from the line of Jonathan Miller from Evercore ISI. Please go ahead.
Great. Thanks guys for taking the question and congrats again on the data. I guess 2 for me. First on discontinuations. So I understand that the SOLIRIS arm has more optimized dose and leftover hemolysis in the APELIS arm maybe is being driven by that lack of optimization or inability to do optimization on the trial.
Would your expectation be that discontinuation of therapy would be near 0 on the APELIS arm as well if you could do that dose optimization? And in future trials, would we expect to see much lower discontinuation rates or more even, I should say, discontinuation rates between this and the comparator arm? Secondly, on the OVH endpoint, I'm struck by the fact that when you include the transfusion data, the post transfusion data, obviously that endpoint looks a lot better. But the while the endpoint itself is very highly variable, it also has the largest change on the Epellis arm when you compare without post transfusion data and with post transfusion data. So what's given the relatively small number of patients that got transfusions on the APELUS arm, what is driving that enormous difference in that enormous variability in LDH, the small number of patients?
Thank you so much, John, for those questions. So first of all, to talk about the discontinuations that happened. So near 0 is a tall order. And as scientists, we don't like to go there. Do we believe that we can improve?
Absolutely. So it is important to bear in mind that in the PEGASIST study, we had a small dosing adjustment that was possible, that was incorporated in the protocol, but it was not aggressive enough. And when somebody has a hemolysis event, physicians want to take immediate and quick action. So that was something that maybe with the benefit of hindsight, we could have been more aggressive on in the Phase III, but we will now further evaluate whether that can be changed. I think we can absolutely reduce it to near 0.
It's obviously a tall order, but we will see where we can get. I think it is also important to note that these hemolysis events happens after the 1 month of combined dosing, right, where pexetechoplan was added to ekulizumab and when ekulizumab was withdrawn. So it is right in that phase. Once patients are stable on the texida co plan dose, we have seen with now a lot of patient years behind us, a very robust and steady course on these patients. So I think in the end, it will become a matter of when the patients are weaned off of their C5 till now, in approximately 10%, that may be needed.
Now going to the LDH. So with the LDH, what's interesting is that the depending on the lab that you use, the levels are approximately 2 50 units per liter as the upper limit of normal. When a patient has an episode of hemolysis and when that LDH is released from the red blood cells, the spike that you get is not an increase of 10% or 20% in LVH. It is a multiple of that, easily 10 times, sometimes 20 times that value. So you can imagine in a study with 80 subjects, where you even have one patient where all of a sudden you have a hemolysis event, right?
If you put that against the background of an overall LDH measurement, that creates a lot of variability. And that is really what accounted for the difficulty in using this as non inferiority statistical analysis. But what is key is that LDH is an important safety marker for intravascular hemolysis by extension for your control on thrombosis, and we are very happy with the data that we had in this study.
Thank you. Our next question comes from Madhu Kumar from Baird. Please go ahead.
Hey, everyone. Thanks for taking our questions. I really have 2 for Peter Hillman and then one for the company. So Doctor. Hillman, first, in your practice, what is the fraction of patients that do you think would really be actionable to use APL-two on in terms of their PNH having anemia associated with extravascular hemolysis?
And then secondly, if you were to get a patient on to APL2 and they were to show good induction of hemoglobin, good reduction in red blood cell transfusions, how likely would you be to want to consider switching them to a new agent if a new agent were come along that showed similar properties to what APL2 has shown so far
to date? And I'll follow-up with the question for the company.
Okay. Thanks for the question. So in terms of the proportion of patients who we would consider for pegcetagoplan type therapy. I mean, Cedric, I think mentioned it early on, all of our patients on eclizumab have some degree of extravascular hemolysis, which is unveiled by the C5 inhibition. And the mean sort of reduction in hemoglobin is about 4 grams per deciliter, which is obviously a significant amount.
The patients going into the PEGSYS trial were the patients who had the most extreme hemolysis extravascular hemolysis on eculizumab and were clearly asymptomatic and often transfused. So I tend to think about it in thirds. About a third of our patients, I would say, would be eligible for PEGASYS with severe extravascular malaroscis causing symptoms. And then probably about another third of patients have significant anemia. And many patients have symptoms because of the anemia, fatigue, lethargy, and would benefit from therapy.
And so going back to the first question, I think these patients going to PEGSIST because they have the most severe hemolysis are probably going to be the ones that we'll see we shouldn't see we'll probably see a higher rate of breakthrough. And so 3 out of 41 is sort of manageable, I think. And as Cedric said, we haven't really explored how to control that. I would hope that with the less severely affected, we wouldn't see as much. So that's a proportion that we would certainly consider.
And the results in this trial are very impressive compared to what we've seen. And obviously, a lot of work with eclizumab and other C5 inhibitors. We just don't see a normalization of reticulocyte count on hematology as we're seeing in with pegcatic implants. That really is different to any of the trials we've had. In terms of the switch, well, if a patient is well controlled on this therapy and the patient seems tolerated well, we would be other therapy.
So in our practice, we wouldn't generally switch patients unless there was a specific reason. I mean, obviously, route to administration and patient preference comes into that. But I think if a patient was stable, we would be cautious about switching, particularly to a therapy that might have a different target. So switching C5 inhibitors is sort of fine because it's probably not the same as eclizumab effectively. But switching to a different target would be a concern.
Okay, great. And then for the company, when you think about the second half filings in the U. S. And Europe, is the expectation to file for PNH in the context of a C5 inhibitor generally or PNH in the context of aculizumab specifically? How are you thinking about the clinical data?
And what kind of line of therapy and what kind of prior therapies, APL2 therapy would support?
Yes. Thank you so much, Madeline. And so good to hear your voice. So I think that the look, the Pegasus trial was designed to accomplish a number of things, right? The first one was to expose or just kind of elucidate, I should say, how important extravascular hemolysis is in this disease and how much better this disease can be controlled if you target C3 versus C5 and address the problem of extravascular hemolysis.
So obviously, that will be reflected in our label discussions with the regulators, where the second element of this study was the fact that even on those transfusion or less transfusion dependent or transfusion independent patients, we saw similar benefits as we saw in the transfusion dependent patients, again going back to the point of the broad hematological control. And at the end of the day, I think in a couple of years, we will probably look back on C5 inhibition as kind of a limited control of PNH and where, hopefully, with this therapy and maybe with other therapies that come along, we can find a way to control extravascular hematics properly and really make these patients or get them as close as possible to a normal state with minimal hemolysis. So that is kind of a long winded answer to your question. The bottom line is we'll seek for a broad label. We have a 4 month monotherapy phase in this study.
Should there be any limitations on the label, we always have the PRINT study for a potential supplemental NDA. But right now, we don't believe that, that will be needed.
Okay. And now, Ashish, I'll squeeze one last question. Among the 9 eculizumab patients who had breakthrough hemolysis, how have they performed once they switched on to APL2 as part of the long term of the label extension?
Well, that's the news for the next release, Madhu. So what's important here is 77 of 77 patients that were still in the study at the end of the 4 months randomized period, all 77 entered into the expansion. And again, that stresses how much better these patients feel. I mean, for me, what was most striking and quite frankly, a little bit painful because of the design that we had is that we had 39 subjects who came into the study, who for 1 month were able to experience the benefit of extravascular hematics control with dexivechoplan And then we're told by the physicians, look, we're sorry, but you're in the control group, right? You're going to go back to being just on SOLIRIS.
But if you stay in the study after 4 months, you will have the opportunity to go back into the extension on fixedotecoplan. And 39 of 39 patients went through that and made sure that they could go back. And I think that, more than anything, tells you how important it is in the context of making these patients feel better.
Cedric, if I could just add to that last statement you made. I mean, and I take some responsibility as being involved in the design of this trial from the beginning. So the switch back and that was quite difficult for patients because they had been chronically anemic and symptomatic and transfused for often years. And then within 4 weeks have a normal hemoglobin and we're back functioning normally. And so of all the trials we've done where we randomized against one drug against another, it's been very difficult because the patient then has to go back for 4 months onto their old treatment.
Even with the trial study correctly, it's about where we had randomization against placebo, they didn't know the benefits they would gain from the eclizumab in 2,004 when we did that trial. And so this is really a unique experience.
Thank you, Pete. And maybe just one little thing to add there because I think important. One of the important reasons why we did this was also from a safety point of view because when we designed this study, we asked ourselves the question, in the real world, what is a patient going to be anxious about if they are proposed with the option of switching from C5 to C3? And one of the things was, well, what if I try this and it doesn't work? So the first step was, you can try it on top of your drug.
You don't have to stop taking your C5 inhibitor. And then should you not like what you your improvement after 1 month, well, you can discontinue the C3 inhibitor while staying on your C5 inhibitor and go back to where you were before in 1 to 2 months and do that safely. That piece because extravascular hemolysis is, we believe, not dangerous for patients. And this study showed that. So there is reversibility in everything.
And that was something important that we needed to show in this
step. Thank you. I'll show our next question comes from the line of Anubhav Rama from JPMorgan. Please go ahead.
Hey guys, congrats on the update and thanks so much for taking the Maybe just a follow on question to the prior question, but what are the final gating factors here to the second half filing here in the U. S. And EU? Just what are the gating factors there? And then can you remind us of the dosing protocol in the PRINCE study?
And if there you guys made some comments about dose optimization and maybe walk us through if that's part of the protocol for PRINCE as well? Thanks so much.
Thank you so much, Anupam. Great hearing you. So the answer to your first question is writing, making sure that as a first filer of an NDA, do that with top quality. We have hired extraordinary people to do that, and we look forward to our first NDA and MAA submission. For the second question, I'm going to give the words to Federico to talk a little bit more about the dosing in print.
Thank you, Cedric. The dosing schedule in PRINCE is the same, with the same small increase in doses if the patients have emaglobin. Now you need to think of PRINCE of a very different population because PRINCE studies have not been treated with eclizumab before. So it's very likely that they don't have as much emolises ongoing. And from a study perspective, it's important to have a stable dose and the same dose on basis to be able to determine what are the phenotypes of the patients that do not respond.
So we have not because of PEGAS include any major those modifications in PRINCE because we need to establish that baseline, and that's what we're doing. So we're going to study those modifications separately.
I show our next question comes from Yigal Nochomovitz from Citigroup. Please go ahead.
Hi, guys. Thanks very much for taking the questions and congrats on a nice data set. I have one for Doctor. Hillman and one for the company. Doctor.
Hillman, given this set of data in the treatment experience population for pegzetacopalan, I'd love to hear your thoughts on how you would view using pegzetacopalan versus eculizumab in the treatment naive population?
I mean, I think as I said earlier, I think So in terms of and also the fact that it's subcutaneous and the patients can self administer the drug makes it more attractive than our current C5 inhibitors. So I don't have any great concern for the majority of patients going on to treatment. I think we have to collect more safety data. I mean, any drug that's licensed, we obviously get more experience as we get through the next 1 or 2 years of treatment. And I guess the only patients I would have an anxiety about treating with another agency is that this will be someone who would treat for active thrombosis.
I mean because we know that what is on those in that situation. That's a very small proportion of our patients now who start treatment for that reason. But they were the only ones I would probably favor C5 inhibitors. We have some more data on thrombosis, which obviously will be slow because it's quite a rare event in PNH.
Okay. Thanks. And then Cedric or Federico, just on the infections, obviously, you didn't have any sepsis or meningitis. Could you just comment in a little bit more detail on the types of infections that you did observe for both treatment arms, please?
Yes,
Thank you, Guido. Most of the infections were typical infections that you see, upper respiratory tract infections, unit tract infections, and they all result in the normal course with a single course of antibiotics. So no major surprises there and equally distributed across their arms.
Thank you. Our next question comes from Ellie Merrell from Cantor Fitzgerald. Please go ahead.
Hey, guys. Thanks so much for taking the question. Just on your interactions, I guess, both with the FDA and EMA, any differences in sort of how they're thinking about labeling discussions and endpoints in patient populations and any trends that you've noted there? And then I guess another question for Doctor. Hillman.
You mentioned that you think a lot of your patients, I guess, are stable and doing well on therapy and therefore you wouldn't sort of consider switching. Can you sort of maybe give us more color on, I guess, how you're considering maybe like you found that stable on C5 and sort of how you're thinking about some of these endpoints like hemoglobin levels and what you would consider, I guess, stable or target levels?
Thank you, Eli. Great to hear you, and I will pass the words to Pete in a second. But the answer to your first question is quite simple. So as far as it goes for the label, we believe that this was a switchover study, but with that 4 month monotherapy phase in that and the control that we had with it. So we will go for a label that is as broad as possible.
So for now, we will not comment beyond that, But more to follow in the months to come. Pete, I will hand it to you for the second question, please.
Okay. Thanks for the question. I think there are 2 The first question was whether the patient was established on pegcitinib and whether we would switch them to an alternative proximal inhibitor. So in terms of C5 patients, so we have a large number of patients obviously who are on C5 inhibitors. And I think the patients who certainly would fulfill the PagSeg's criteria, if we had availability of the drug, we would consider those as ideal patients as we have the data.
I think a significant proportion of the other patients who run a low hemoglobin may well benefit from a drug like pegzilosecagliflozinab and the route of administration is also quite attractive for those patients because the we currently have eclizumab every 2 weeks, which obviously is an undertaking. So I would think that probably half of our patients you sort of have a discussion with now if we're able to use it. And then as we get more confidence, I think that would probably increase. In terms of switching later on, I mean, to a different targeted therapy, we probably wouldn't change to from a very effective agent to one that we didn't have data about sort of factor Ds or factor Bs and things. But they're way we're quite a long way behind really.
Does that answer your question?
Yes, very helpful. Thank you so much.
Okay.
Thank you so much, Eileen.
Thank you. Our next question comes from Steve Seedhouse from Raymond James. Please go ahead.
Good morning. Thank you. One of the questions FDA evidently had about your primary endpoint was whether hemoglobin increase would translate into clinical benefit in the patients that already have high hemoglobin. So I was hoping you could comment first on whether hemoglobin further increase in patients that had sort of the highest level of baseline in the study. I understand obviously there's a cutoff at the screening measurement, but just in whatever subgroup you want to comment on those that were the highest, did hemoglobin further increase and also facet fatigue and transfusion dependence and all those things that you reported, were they better or similar in the pegzetacoplan arm in the patients with highest hemoglobin at baseline?
And then I guess just what would be the read through for patients with hemoglobin greater than 10.5 grams per deciliter at baseline?
Thank you so much, Steve. So that is a really, really great question. I think, obviously, it was our primary endpoint. We're, of course, very happy with the data on hemoglobin. But as I mentioned in the beginning of the call, it really comes down to the broad hematological correction and the associated benefit to the quality of life of the patient.
It's not just about hemoglobin, right? Now we'll give you an example of patients or of patients that may have normal hemoglobin levels. Those were not included in the study, of course. But patients with normal hemoglobin levels almost always only get there because they have very good bone marrow. And you can have patients that are producing 3 to 4 times the normal output from their bone marrow in order to get there.
Now bear in mind, these are patients who have sick bone marrow to start with. And I cannot cite you a paper that would tell you that having a high radiculocytosis for decades is a problem, right? But if you can avoid it, and why would you not do that? And I think that kind of speaks a little bit to what Pete mentioned, and I would love to hear his feedback on that, is that at the end of the day, if you can control hemolysis properly and do it with a drug that is equally safe, why would you not do that? And we're obviously early still, but with now between the studies that we have close to 150 patient years of dosing, we start to feel very good about what we've seen.
Maybe Pete, you would like to add something to that?
Thanks, Cedric. A couple of things. First of all, I mean, obviously, we took the worst patients in Tobegasus and the mean hemoglobin has obviously was way below 10.5% is 11.5% on week 16 and consistent. And the difference between that and the occlusal arm is despite the fact that the majority of patients in the occlusal arm are being transfused. So obviously that will affect the hemoglobin to some extent and there's still a very big difference between the two arms.
So I think that would suggest that especially with the normalization of RITIKX, which happens actually very quickly, which is very impressive, shows that you were switching off the process of extravascular malts. And I would anticipate in the majority of patients who are anemic on C5 and it was that they would respond into the normal range. That's why I having treated quite a number of patients in this trial, I would predict would happen. I think the other sort of important point is the fatigue score. So the fatigue score, even in trial where we randomized between placebo and nacolizumab, there was an 11 point difference.
In this occasion, there's over 11 point difference between pegzidiguana and eclizumab and rivipity in the worst affected patients. But that's a very meaningful difference. And if you look at the curves, I mean 52 is the maximum you can get on a fatigue score and we're getting quite close to it on the prosthetic plan arm of these most of the affected patients. So I think it is that's the normalization of hemoglobin and the normalization of hematopramases is what immediately makes the data stand out to me.
Thank you, Steve.
I appreciate it. Okay. I had just a follow-up mechanistically, actually maybe 2 quick follow ups. The mild diarrhea signal in the treatment arm, what do you think is going on there? Does it have to do with the volume of injection or excipients formulation, something not necessarily related to C3 inhibition per se?
Yes. No, thank you, Steve. I mean, it's a mystery to me to us why that happens because it doesn't happen after the start of treatment. So it's spread out over the 4 months. They are mild.
And most importantly, and I want to stress this again, these were almost exclusively single events. Now if you look at the percentage difference, 20% on pexadacopalan, 0% on ipizumab, you would think that it's drug related. We don't know by which mechanism that would be. But yes, we don't know the answer to that. What's important here is they were almost exclusively single event and MELD in nature.
So we'll have to figure that out.
Yes. I mean, 8 out of 9 were single events, grade 1. So it really hasn't been a clinical issue in my experience with treating the patients.
Okay. That's helpful. And then I just had a point of clarification for myself on the hemoglobin data. So the high transfusion requirements subgroup, the SOLIRIS patients obviously dropped about 4 grams per deciliter. You mentioned this excludes measurements post transfusion, hence the drop.
I just wanted to clarify, so the exclusion of those measurements seems to only apply to the post treatment measurements, but not the baseline. So the baseline are in fact impacted by recent transfusions given that decline. Is that correct?
Yes, that's correct. So the best way to think about it is that many of these patients, the severely affected patients need and there's a patient who used that term, top up transfusions. So not only do they need transfusions, they need them on a regular basis and they're often going to be on a schedule every 4 weeks, every 6 weeks. If now they come into the study and that interval becomes longer, right, then obviously, they're going to go and go lower than where they were before, right? So that is the end.
And what was important in this study is that once you get a transfusion, obviously, you will disproportionately favor the transfusion dependent population on the hemoglobin values. So that is why the analysis had to be done the way it was.
Thank you. I see our next question comes from Matthew Luchini from BMO. Please go ahead.
Hi, good morning and thanks for taking the questions and congrats on the data and the progress. So, 2 for me. First, I guess, the answer to this was alluded to in the one of the prior question answers. But I just wanted to be clear that the 48 week extension data, the long term PEGASUS data is not a gating factor to file. So that's just point of clarification 1.
And then secondly, as we think about the potential label expansion opportunities that you're thinking about whether it's C3G or CAD, Maybe if you could just give us a sense given where we are right now and the data that you have in hand and other data that's being read out from potential competitors, How you're sort of what gating factors are on your mind or how you're weighing the different pros and cons of pursuing some of those other opportunities for PASX filgot? Thank you.
Yes. No. Thank you so much, Matt. So on the C3G and the colegglutinin disease and the other indications, we'll talk about that more in the future. And I have to apologize, my line was breaking up a little bit when you asked the first portion of your question.
Could you quickly repeat that, please?
I just wanted to confirm that the next Pegasus update, the 48 week is not a gating factor to your ability to file.
Okay. No, it is not. So we will give you 120 day safety update. That's the purpose. But from an efficacy perspective, we have what we need.
Perfect. Thank you.
Thank you.
Thank you. Our next question comes from Justin Kim from Oppenheimer. Please go ahead.
Hi, good morning. Congratulations on the presentation and thanks for taking my question. I had two questions left for Doctor. Hillman. Doctor.
Hillman, as you think about
the potential availability of texiticofilin for your
patients, given the randomized withdrawal design of the study, how informative have those experiences been for adoption of the product for your patients switching from eculizumab and potentially rabiolizumab? And then a second question on facet fatigue scores. The sensitivity of these findings over even hemoglobin were encouraging. Do you anticipate that fatigue could be the important sign of extravascular hemolysis and a rationale for the drug's use in milder patient subset?
Okay. So in terms of the I'll follow the first question, I was kind of touching on the second one. So the first question was, just to remind what was her first question?
Sure. How informed it has the randomized withdrawal design?
Okay. Yes. Okay. Yes. So I think I mean, it's hard to answer.
Actually, it's correct. I mean, we've had issues with 1 or 2 other C5 inhibitors about stopping and twitching was a problem. And so it's been really encouraging that, first of all, every patient responds to the combination in PEGASIS. And we know we can safely withdraw it. So I think it's reassuring really.
I mean the only problem we run into really with withdrawal was stopping the pegcetica plant, which obviously we won't do in the real world. So I'm still comfortable with that. And I think that, as Cedric said, I think it gives you more assurance that our patient is doing well. Although I suspect that we won't need a month overlap. I mean, we see the change and you see it.
You see it on the curves that we're showing very quickly with the combination. So I suspect in the real world, we probably won't need this longer rollover. It doesn't concern me that we have all the data as well with the combination. So obviously, with ravaluzumab, there'll be more C5 drug around for longer because of the half life. But that obviously isn't a concern in this situation.
So I'm sort of happy about that. In terms of fatigue, yes, I mean, if you I mean, I recently did a patient group meeting here and we're probably 50 patients in the room and fatigue is many on treatment. And fatigue is an ongoing issue for patients on ecalizumab. I mean, it's better because they're not getting complications and not the hemoglobin is not being transfused as much, but there is ongoing fatigue. So I think as we get more comfortable with the therapy, that will be an important criteria for switching for patients who are significantly perceived, yes.
Thank you. Our next question comes from Brian Chang from Bank of America. Please go ahead.
Hi, guys. Congrats on the progress and thanks for taking my call. My first question is for Doctor. Hillman. One quick question on your presentation at EHA.
Can you provide more color on the 2 discontinued patients who had lower serum concentration of pachytacopan before their hemolysis event? The question on that is, is there is the lower serum driven by more by compliance or are there other confounding factors? Thank you.
Okay. So certainly, I mean, 2 of the patients were mine. So we didn't see there's been really no compliance issues within this study. Patients have taken the doses as and when they should have done. So I'm sure there's no compliance issue.
There's an anxiety about patients with uncontrolled intravascular hemolysis. So when the LDH goes up, we tend to switch the patients. And I don't think we had and Federico mentioned, I don't think we have we didn't have the dosing we would have needed to try to stop the breakthroughs really. And so I think in subsequent studies, we're going to have to do that. So does that answer your question?
Yes. Thank you. And maybe for Cedric and the team. Based on your discussions of the FDA and EMA, can you talk about what your base case assumption is for the labeling? And more importantly, how does that differ from what eclizumab, Ecellaris has currently in the label for PNH?
Yes. Thank you so much, Brian. So as I mentioned earlier, we are not ready to talk about label yet. I just want to mention that we do have kind of a long monotherapy phase in the PEGASA study. So we'll talk more about that in the future.
But we hope we're hopeful that we will get a broad label, but that's subject to further discussions.
Okay.
Thank you.
Thank you very much.
Our next question comes from Phil Nadeau from Cowen and Company. Please go ahead.
Good morning. Thanks for taking my question. I guess, two clarification questions on the data. First on the adverse event profile, there's 2 different categories of severe adverse events that have different numbers. And I'm kind of curious what's the difference between those categories and what drives the difference?
So you cite severe treatment versus treatment emergent adverse events as 19.5 percent for pexetagoplan versus 12.8% for eculizumab. But then serious are 17% for apixitupine versus 15% for eclizumab. So what's the difference between those two categories? And what kind of events drove those percentages? And then second is on transfusions.
What was the baseline requirement for transfusions in the 16 weeks leading into the study for both arms?
Did it occur?
Yes. Well, the difference is on the criteria, what is severe and serious adverse events. So serious adverse events has a clear definition, and there is a regulatory definition, extension of hospitalization, death and such. And those are serious. And a serious adverse event can be mild, moderate or severe.
And then on any of the AEs, again, you have the same criteria, mild, moderate and severe for any type of AIDS. I don't have top of my head what were those severe adverse events, but they were equally distributed on both arms. Did that answer your question on that, on the difference between the 2?
I think so. So the severe adverse events is more your own characterization, whereas the serious is something that's a regulatory defined criteria.
Is that
what you're saying?
So NAA can be you have a grade mild, moderate and severe. And then serious is just a definition for seriousness that is a regulatory definition, yes.
Got it. Okay. And then on the transfusions, what was the transfusion requirements for the 2 arms?
The transfusion requirements or the criteria for transfusions? What proportion
of patients needed a transfusion before beginning the study over the prior 16 weeks or 32 weeks?
So the on the patients that require 36% of patients require less than 4 transfusions before the so it was a fifty-fifty split. Is that you're asking how many patients? Sorry, I'm not getting the question right. What was the proportion of patients that require less than 4 and more than 4 before the study?
I'm just curious whether so for most data for SOLIRIS, you don't see 85% of patients needing a transfusion. So I guess I'm kind of curious, did more patients on SOLIRIS need a transfusion in the trial than needed one prior to entering study?
Yes. So we started approximately with a fifty-fifty split because we require that a minimum of 50% of patients were heavy transfusion dependent, those with what we call the heavy burden of transfusions. The rest of the patients, some of them had one requirement in the past year, but most of the patients had 2 or 3. And that trigger that was the trigger that 80%. So don't forget that the patients go into this co treatment for a month, and then they lose C3 inhibition.
So they get extravascular monocyt and that trigger a transfusion, and that's what led to that 80%. But we started with 50% of patients with a requirement of 4 or more transfusions.
Got it. Okay. That is helpful. Yes. Thank you.
Thank you, Sean.
Our last question comes from Thiago Fauch from Credit Suisse. Please go ahead.
Hey, guys. Thanks for taking the question.
So I'm just curious when you're talking about dose optimization, did you actually have any dose modifications in the ATL2 arm during the study? And how did that perhaps influence the responses for those patients? And perhaps one for Adam as you have the filing slated for the 2nd year, if you could just briefly talk about your go to market strategy. Any plans for potential partnerships or any color you can provide at this moment? Thank you.
Diego, can you take the first question?
Yes, I'll take the first question. So as Cedric said before, the protocol didn't allow for a lot of room on dose optimization. So we had a single step dose increase that was based on LDH levels, but it was about a 10%, 15% dose increase, and that was not sufficient on some of the patients that had hemolysis. So what we're doing now as the future steps is trying to phenotypes the patients that have hemolysis. And it was answered before by Pete, trying to determine what it is that makes these patients have low, paxetacopan levels in the serum.
So two efforts, one is find the right dose, but also try to phenotype the patients if we can determine a priority what are the patients that will require more dosing before they start pexertagal?
Yes. Thanks for your question. It's Adam. So we've been preparing for the last year building out lean commercial and medical affairs organizations in the U. S.
And ex U. S. We are interacting compliantly with physicians through medical affairs and we're also building great relationships with PNH communities all over the world. It's a great opportunity for us to elevate the standard of care in PNH. We also are very thorough in our homework.
So we're looking at models where if there is a strategic partner that can have meet patients all over the world, we look at discussing those type of opportunities. But we have the capability to meet those needs ourselves. And if we can do it better with a strategic partner, that is something that we should obviously look at. So we're ready for a world and we're ready to really, really meet those needs of the PNH patients around the world. And this data is just a great opportunity to do so.
This concludes our Q and A session. At this time, I'd like to turn the call back over to Doctor. Cedric Francois, CEO, for closing remarks.
Thank you so much, and thank you, everyone, who joined us this morning. In closing, today's news further demonstrated the potential of the exetacoplan to elevate the standard of care for people with PNH. It also validated our targeted C3 approach to developing treatments for serious complement driven diseases. I want to give a special thank you to Pete for joining us. It really means a lot.
We've been working together for such a long time with him and the rest of the P and H community, which is unbelievably patient dedicated. I think that's worth mentioning. Now we look forward to continuing our progress and keeping you updated along the way. Thank you very much, Irina.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.