Good day, and thank you for standing by. Welcome to the Phase III VALIANT Study Results Webinar conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session over the webcast. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Meredith Kaya. Please go ahead.
Good afternoon, and thank you for joining us to discuss the detailed results from our Phase III VALIANT study with pegcetacoplan in patients with C3G and IC-MPGN, which was just presented at the American Society of Nephrology Kidney Week. Before we begin, let me point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. Lastly, to submit questions, there is an Ask a Question button. If you're on your mobile, there is a button on the top left of the screen, and if you're on your desktop, it should be on the top right of the screen. Now I'll turn the call over to Cedric.
Thank you, Meredith, and thank you everyone for joining us, especially on this Saturday, of course. We are here in beautiful San Diego, and it is my pleasure today to be joined by Dr. Carla Nester, a distinguished nephrologist at the University of Iowa Stead Family Children's Hospital and lead principal investigator for our VALIANT study. She's also one of the best-known specialists in these indications and has been an incredible collaborator to us throughout this process. Dr. Nester, just about an hour ago, shared the full results from our VALIANT study at ASN earlier this morning, and she will be walking through these remarkable results with all of you in a few minutes. We are absolutely thrilled by what these results mean for patients, physicians, caregivers, and everyone within the C3G and IC-MPGN communities.
And, we were also very privileged here to have our partner, Sobi, along by our side. We are working closely with regulatory authorities with the goal of bringing these treatments to patients suffering from C3G and IC-MPGN as quickly as possible. Currently, we are on track for a supplemental NDA for pegcetacoplan in early 2025, with an EU filing by Sobi also expected for next year. And with that, I will now turn over to Dr. Carla Nester.
Thank you, very much for the introduction, and I also want to reiterate that I'm actually quite excited about this. I'm a glomerular disease physician who has waited many, many, many years to have a therapy that I could actually use in this group of patients. And, not only is this amazing data, but it looks finally like we'll have the treatment approach we need for this group of patients. In order to begin our discussion, what I would like to do is go to the pathway that's involved in this. And really what I want to share with you is that this set of diseases, C3 glomerulopathy and immune complex MPGN, are driven by dysregulation of the alternative pathway of complement. And I recognize that this is a little bit of a confusing slide.
Even our physicians generally don't appreciate slides about the complement system, but really what I want to share with you here is that unlike anything else that's tried in this field, pegcetacoplan will bind C3 and C3b, essentially shutting off the alternative pathway, and what that really means is that the C3 convertase doesn't work, the C5 convertase doesn't work. Eventually, with both of those being blocked, we have much or if not complete reduced renal inflammation and also significant stoppage, if you will, of direct structural renal damage that results from the membrane attack complex, so again, this agent is sublimely targeting, if you will, the underlying disease mechanism in this set of diseases. Now, we can talk very briefly about the trial, and the trial design is very similar to a number of other trials in this space, if you will.
But specifically, what we're talking about is a placebo-controlled randomized study that compares pegcetacoplan to placebo at twenty-six weeks. These patients are brought in, they're screened. We ensure that they actually are on standard of care, which is often mycophenolate mofetil and steroids. They also must be on maximum dose of whatever their supportive measure is, ACE inhibitors, ARBs, SGLT2 inhibitors, et cetera. They have to be on all of those agents for ninety days prior to being randomized. They're randomized one to one, either to the pegcetacoplan one thousand eighty milligrams, subcutaneous infusion twice weekly, or to placebo. The results you're going to be seeing today are the primary and secondary endpoints at twenty-six weeks for that group of patients.
But it's also probably important to note here that the patients that have actually passed through the twenty-six weeks are, many of them are continuing to be followed out in VALE, is the name of the study for open-label extension. So we will be continuing to get additional data on this group of patients. But for now, let's proceed forward with the twenty-six weeks. First, let's talk about what are the patient populations. First, this is the first study that is actually completed in both adolescents and adults, so these are patients down to the age of twelve. Also, the first study to complete in primary C3 glomerulopathy and immune complex MPGN, and also the first placebo-controlled study, I'm going to say, in patients that are either native kidney or transplant. So this is a placebo-controlled transplant group of patients also.
Again, I already mentioned that they, these are patients, the vast majority of them already on expert-guided, i.e., the best we can do medical management with their mycophenolate mofetil, their corticosteroids, and their stable, optimized anti-proteinuric drugs like ACE inhibition, et cetera. Fairly standard for this group of patients or glomerular disease trials is they were not included if they had too much global or glomerular sclerosis, and that's really just functionally because that is perceived to be non-retrievable disease or disease that we can't necessarily impact. So of course, those patients were excluded. Also included in the inclusion study is they had to have at least one gram a day of proteinuria, and that was both for native disease or transplant patients.
Again, that's the group of patients that we believe the greater than one gram a day of proteinuria patients are the ones that we believe that have the worst slope to kidney failure. That's why they were included in this study. They had to have a GFR or an estimated glomerular filtration rate, their measure of kidney function of at least thirty milliliters per minute. Then finally, because this is a complement inhibitor, they needed to be vaccinated against those agents or those organisms, if you will, that we have thought that they may be susceptible to. This includes Strep pneumoniae and the Neisseria meningitidis subtypes. Importantly, they could not have transplant rejection if they were a transplant patient.
They could not have chronic infection, primarily, of course, because this would not be a patient population that you would want to trial them, if you will, on a complement inhibitor. Otherwise, you can see clearly that the any other exclusions were fairly standard for a trial of this type. In this slide, you can see the comparison of the pegcetacoplan group compared to the placebo, and essentially, they're the same population. This is obviously important for our statistics to understand that we're looking at the same group of patients. Roughly, the age was the same. Roughly, we have the same amount of adolescents versus adults. The vast majority of these patients were C3G. That's consistent with what we know about the general population, if you will.
But of course, in this group is a group of primary immune complex MPGN patients, and they are spread out across both the pegcetacoplan and the placebo group. And then finally, you'll see that, of course, that there were some post-transplant recurrence patients in this. The only thing I really want to highlight here for you is that it does look like the placebo group with an 87 milliliter per minute GFR had slightly better kidney function coming into this study. So here's our primary and key secondary endpoints.
The primary endpoint is log transformed ratio of urine protein to creatinine ratio at that 26 weeks, but a number of other key secondary endpoints, which include achieving a composite renal endpoint, and that includes greater than or equal to a 50% reduction in urine protein and stabilization of the glomerular filtration, so a less than or equal to 15% change reduction in that GFR, that's our composite renal endpoint. We also studied the reduction of the number of patients or proportion of patients that actually reduced their urine protein by at least 50%. This is clinically very important for a nephrologist, so that's one of the reasons why this endpoint is here. We studied the change in the activity score.
So what that really means is how active was the kidney biopsy, that what does the change in that score look like, and very importantly for me, who studies a lot of the complement-mediated kidney diseases, is this idea, the idea of studying the amount of C3 that is actually deposited on the kidney, and for a non-nephrologist, what this really means is, again, I mentioned to you that this disease stems from the alternative pathway, dysregulation of the alternative pathway. On the biopsy, what you see is C3c deposition as a result of dysregulation of the alternative pathway, so that particular endpoint is critical as far as I'm concerned. And then finally, the other key secondary endpoint is change in GFR at twenty-six weeks. So let's jump into the data, and it's absolutely fantastic data.
It is actually, frankly, more than the average glomerular disease physician expects out of an agent but let's, let's just start. Highly, statistically and clinically significant proteinuria reduction of 68.1% in the pegcetacoplan group as compared to the placebo. As importantly, this proteinuria reduction was observed as early as week four after the start of the agent. It's also important to note, because we shared with you in the inclusion criteria were a number of subgroups, so it's important to note that there was a consistent, clinically meaningful proteinuria reduction across each of these subgroups, so you can see along the right-hand side, you can see the changes in the urine protein.
But, on the left-hand side, you will see that you had excellent change or improvement in the urine protein, whether you're an adult or a pediatric, or excuse me, an adult or a pediatric patient, which again has not been shown in any of our data up to this point. You had an excellent improvement in your change in urine protein, whether you're C3G or immune complex GN, and very importantly, you also had these changes, whether you were native kidney disease or whether you were post-transplant, so again these findings were clinically meaningful changes in the urine protein, regardless of the subgroup that was involved. Important for the clinician, because this often translates also to what the patient sees. Significantly more patients achieved greater than a 50% proteinuria reduction if they were in the pegcetacoplan group compared to the placebo.
For instance, the subjects were 31 times more likely to achieve that greater than 50% proteinuria reduction if they were being treated with agent. And again, this often translates to patients being moved from nephrotic syndrome, so these are patients with high-grade urine protein, lipids that are very much out of control, lots of edema. These are all things that actually will bother your patient. A number of these patients by getting that 50% reduction in urine protein, were moving out of that nephrotic range, picture. And in fact, the next slide will give you even more detail on that. And we recognize that this next slide is a little bit confusing, but really what I want to do is start with the dark blue boxes, if you will.
Actually, we're going to talk about the dark blue and the dark gray boxes, but so let's start with the dark blue. Patients in the pegcetacoplan group who started this study, there were eight of those, 8% of those patients actually had a urine protein that was less than one gram. And the significance of the less than one gram, frankly, is that if I have a patient that comes to my clinic and they have less than one gram, I now stop thinking about or start worrying about whether they need to be treated further. So that's a cut point for me with respect to escalation of cares, et cetera. Anyway, 8% of patients had less than one gram at baseline that were exposed to pegcetacoplan. By the time of 26 weeks, there was 51% of patients.
But also, if we go back to this concept of whether they had nephrotic range proteinuria, so that's greater than or equal to three grams of urine protein. We had 38% of patients that had nephrotic range proteinuria at baseline, but after treatment with the agent, we only have 14% of patients. So again, clinically meaningful, not only for the clinician, but also for your patient. And that simply just was not seen in your placebo group, and I can let you, you know, sort of work through that a little bit more yourself. But for instance, the 1 gram of urine protein group was 10% in the placebo group at baseline, and it got worse. So it was 20% after 26 weeks.
A very important, I already gave you a highlight about this or perhaps telegraphed this just a bit, but this is going to be incredibly important to your clinicians and this concept of can you reduce the patient's transit to renal failure? In fact, this is the first time we've seen a trial that actually gives us a statistically significant stabilization of the estimated glomerular filtration. If you don't know this disease, you don't know that these patients progressed end-stage within ten years. The vast majority of them progressed end-stage within ten years of diagnosis. This agent suggests that it stops that transit. In fact, these patients not only have the same downward slope, they actually have an improvement in the pegcetacoplan group as compared to the placebo.
Also, very importantly, I indicated to you that part of the diagnosis is that this concept of dysregulation of the alternative pathway and then deposition of C3 on the biopsy. Pegcetacoplan treatment resulted in a clinically significant clearance of C3c. That happens to be how we know that in the laboratory, that there is C3 being deposited on the biopsy. Clinically significant clearance of C3 deposition on the renal biopsy. Let's take that one step further, and 71% of the patients in the pegcetacoplan group actually achieved a zero intensity staining. Now, as a clinician, I obviously am not going to use the term cure, but if you presented a patient to me at 26 weeks, I would have to say, if I looked at their biopsy and didn't know anything else about them, they no longer meet the diagnostic criteria for C3G.
So again, that would be considered an impressive result for me. Then let's think about what happens with the proportion of patients who actually achieve that composite renal endpoint. A proportion of patients who did achieve this, again, it's a greater than or equal to 50% reduction in the urine protein and a less than or equal to 15% reduction in the GFR at 26 weeks. You were 27 times more likely to achieve that composite renal endpoint if you were in the pegcetacoplan group. This is actually just a reproduction of some of the histologic parameters. And again, at the time that this study was being created, as nephrologists, we felt like the activity score was a reasonable score to actually be able to monitor these patients.
We've progressed to an understanding where it's not completely clear, based on how that activity score is built, that it's the perfect measure. Nonetheless, this group of patients had an adjusted mean difference in the pegcetacoplan versus placebo arm, meaning the pegcetacoplan group did get an improved activity score. It did not happen to be clinically or, excuse me, statistically significant. But again, I will say, based on how we've transitioned to our understanding of the activity score, I'm, I am not bothered by this at all as a clinician. Finally, I think it's important to actually fairly share the safety. We've shown some really amazing changes in things that matter to C3G and immune complex MPGN patients. So not only this improvement in urine protein, but stabilization of GFR, loss of staining on the biopsy, etc.
But we did it in a safe fashion, which, of course, is gonna be critically important to your clinicians, and your patients. You can see, both the comparison between your pegcetacoplan and placebo groups, that essentially the treatment emergent adverse events were very similar across both groups. And very important in this scenario is that, again, I mentioned at the very beginning that, in the old days, we used to worry about blocking the complement system might cause, meningitis infections, if you will, in these patient populations. But again, that's not been borne out frankly, as much as we thought it would be, but for sure, it wasn't obvious, or it did not happen in this study. So again, very safe approach to these patients despite the the very important clinically significant results.
This frankly is consistent with the 2000 patient years of pegcetacoplan exposure in other medical settings. So in summary, pegcetacoplan is both safe and effective in this phase III VALIANT trial. Proteinuria reduction of 68.1% was noticed, and in fact, this was across all subgroups, and particularly, there was a 50.8% of patients achieved a urine protein that was less than one gram. So again, that's a you know clinical remission as far as a clinician is concerned. Statistically significant stabilization of eGFR, so they gained 6.3 milliliters per minute in the pegcetacoplan group in a patient population that historically has lost GFR points regularly. And then finally, we now know that this is well tolerated with no encapsulated organisms, no encapsulated meningitis infections rather.
And this is consistent with what we know about this agent in particular over about 2,000 patient years of exposure. Of course, there's lots of investigators involved in this study, so I'll have to thank all of them, but also all of the patients who have braved taking on a placebo-controlled study in this ultra-rare disease. Thank you.
Thank you, Dr. Nester and Cedric. That concludes our prepared remarks for today. We'll now open the call for questions. As a reminder, to submit questions, there will be an Ask a Question button on your screen. If you're on the mobile, it's on the top left. If you're on your desktop, it should be on the top right. So with that, I will get started with questions. We have a number in here for you, specifically, Dr. Nester. The first one is: You referenced the stabilization of disease based on the eGFR data. Can you go into a bit more detail on how the prognosis of the patients would change with pegcetacoplan treatment, and what % would be expected to go on to renal failure at 10 years on pegcetacoplan versus placebo?
Yeah. So historically, what we know about this disease is that more than 50% of the patients would traverse to kidney failure within 10 years of diagnosis. And that is, you know, you can sort of count back. That means they would be losing anywhere from 6 milliliters to 10 milliliters per minute of GFR points over that intervening 10 years, if you will. So that's a pretty steep slope towards kidney failure. We would love it if we had an agent that just flattened that out, you know, so that there wasn't a loss of 6 or, you know, 5 to 6 a year, if you will. But it's even more impressive for us, actually, if we get gain of GFR points from an agent, for instance. So and I think it's also worth mentioning at this point, because this disease...
I don't think I said this early on, this disease affects young people. So these are people who are in school or early in their careers, etc. If they go to end stage within that ten years of diagnosis, if you're an eight-year-old or a twelve-year-old or a twenty-year-old, you're talking about dialysis and then multiple kidney transplants, frankly. So if you can prevent the transit to kidney failure, you've made an amazing change in that group of patients.
Thank you. Next question is, Can you talk a little bit about why the secondary endpoint, the change from baseline in the activity score of the C3G histologic index score, did not meet statistical significance, considering the positive treatment effect? What could be driving this mechanism?
...To be completely fair, I don't know. It's possible it could change with longer follow-up, but if you were to ask me to guess, I would say no. I think the problem is actually, this is my opinion, that the problem is not actually the agent. The problem is actually the scoring system, in that over time, we've discovered that the scoring system probably double counts some things and forgets to count other things. And then frankly, it probably is also not clear about how quickly the changes will happen and whether they're durable changes, if you will. And again, it goes back to it's probably a problem with the activity score. It was never meant to be used in the setting of therapeutics. That's really the bottom line.
But we've also learned a lot more about that activity score since actually it was starting to be used in these trials.
Thank you. There are a number of questions that I'm gonna try to get to on how you think about pegcetacoplan and iptacopan and how you treat your patients. So I'll go through a few of them, and hopefully, for those submitting questions, I get to all of them. First one is, just based on what you know today, would you use pegcetacoplan or iptacopan if they were both available? And how do you think about it in the context of adolescents and adults or pre and post-transplant?
Yeah, so the truth is that I may well use both agents, but at the end of the day, the push, if you will, will be to use the most effective agent, and so you know, today, if you ask me which one I'm gonna use, I'm gonna use pegcetacoplan, right? Because that's the one with the best data. There may be some patient preferences based on method of delivery, but at the end of the day, these patients are going to listen to their providers, and this data is going to speak very loudly to the providers. So I think that it's going to be the pegcetacoplan that's going to filter to the top, frankly, actually, for this group of patients.
Thank you. Is there any other variables that you'll be considering beyond patient demographics when you're making treatment decisions?
Well, right now, for instance, this is the only trial that actually has data in the down to 12-year-old. So if I needed to treat a 12-year-old today, of course, it's going to be pegcetacoplan. It isn't going to be another agent, and we don't even know when other trials finish their 12-year-old and up group, whether it will be this good of data. So again, I have to go back to if I needed to treat today, in that patient population, for instance, the adolescent patient population, it will have to be with this agent. I will also say that there is some. You know, because obviously I was in the clinical trial, and my adolescents actually appreciated the twice-weekly dosing instead of having to take more regular, more scheduled dosing of other things.
We'll need time to sort some of that out, but up to this point, I haven't seen a downside to this type of dosing.
Okay, thank you. Another question. If you can put into context for us, the 71% of patients who had zero C3c staining deposits, does this effectively mean the disease progression is being reversed?
I would even take that, of course, this is my opinion, but I would even take that one step further, and say that in that biopsy, it looks like their disease is no longer there, right? So if we are no longer depositing C3 on the biopsy, and that depositing of C3 is actually what's causing damage to the kidney, causing damage to the basement membrane, which of course causes increased urine protein, et cetera. So eliminating the deposition of C3 means the disease has stopped. Now, I struggle just a little bit, you used the terminology reversed. You know, if there is already scar on a given biopsy or in a given patient, that's gonna stay there.
But this agent would suggest that you're not going to develop any more problems after you reach that zero, in the deposition.
Thank you. I'm gonna give you a little bit of a break and ask Cedric a couple of questions now. First question for you, Cedric. I know this is in the weeds, but just curious as to why the 68.3% proteinuria reduction reported in the top line is now 68.1% today. How should we rationalize the difference?
Thank you, so sometimes you see the top line in the final QC, you know, there are certain data that are corrected, so this was a small adjustment that had to be made. But, the results that are presented today are the final results that will be part of the complete study report that goes into the supplemental NDA.
Thank you. Another question for you, Cedric. Any recent interactions with the FDA on the six-month data and whether that will be acceptable for approval? And should we take the FDA being accepted as de-risking that?
I think, look, again, we had a meeting with the FDA before we ran this trial, our end of phase two meeting. At that meeting, we agreed on what the design of the trial would be and that the primary endpoint would be at six months. We believe that we have accomplished what was asked of us, and that is the discussion we will have in our pre-filing meeting with the FDA.
Do you think there's enough patient exposure and data in the post-transplant patients for that to be part of the label?
I think that, because by design, we've, from the beginning, been very keen on including patients in the post-transplant setting. We have a couple of patients in the trial evaluations. We also, of course, have the thirteen subjects that were studied in NOVEL. These patients, particularly the histopathology findings of the C3c deposition, we think speaks loudly for itself. Again, it's hard to anticipate what will end up in the label, and we're not gonna, you know, be speculating about that, but we believe that we have data that certainly support it.
Great. For you, Dr. Nester, which patients would be most eligible for pegcetacoplan?
... I think it would be safe to say that all C3G patients would be eligible, basically, because what we're doing right now, even with the immune suppressants that we use, they're very nonspecific. They have not gone through randomized controlled trial. And even, you can see in the cohorts there, the range of response to these medications is anywhere from, well, at best, we're getting 30% response, and even those are not getting actually slowing of their slope to kidney failure. They're actually getting an improvement in the urine protein. So I think that once there is a randomized controlled trial available to us with this degree of, what we believe are kidney-centric results, it will be the top line therapy, I presume.
Thank you. We've received this question from a few people, and thinking about choosing which treatment to provide your patients, assuming they're both approved, what % of your C3G and IC-MPGN patients would you imagine being on pegcetacoplan versus iptacopan?
Again, it's hard to second-guess what a patient might choose, but from a clinician standpoint and we saw this actually when we were talking to the general ASN population today. The clinicians there were incredibly impressed with this data, and there is no doubt that they will drive the care here. With this degree of response, I can't say 100%, but I would say that the majority of patients should end up on pegcetacoplan, frankly.
Thank you, and kind of, going with that, does oral versus SQ matter for your C3G patients, or is it only efficacy for them?
I think that there may be some patients that the oral route will be... You know, this is the way it is in all of our medications. The oral route may be important to some of them, but again, I will go back to these are a rare group of patients who heavily depend on their clinicians, giving them advice and telling them which agent is going to be the best for them. And again, hands down, this agent is going to be the best as far as anything that we've seen up to this point, anyway.
I think I might also add to that is that, when we think about that transition to renal failure, we were talking about it even after the ASN, that, the RaDaR data, which is some of the registry data out of the UK, suggests that for every 10% that you drop the urine protein, you substantially change the hazard ratio towards kidney failure. So it may be incredibly important for the average patient that you see a 68% reduction versus a 35% reduction, for instance. That's going to come up again and again as you're collaborating with your patient, about, you know, which one is going to be recommended for their use.
Okay, thank you. Another question: How would different baseline eGFR affect the results of these endpoints? For example, would you expect patients with higher baseline eGFR to show greater reductions in proteinuria or vice versa? In a range of estimates for the relationship between proteinuria reductions and improvement in eGFR outcomes in patients with C3G, do you have a robust estimate for that?
I maybe don't. Maybe I'll have you say it again. I'm sorry.
No, no problem. How would different baseline eGFR affect the results of these endpoints? For example, would you expect patients with higher baseline eGFR to show greater reductions in proteinuria or vice versa?
Oh, now I understand. Actually, it's more difficult to relate the baseline GFR to the proteinuria, frankly, than it is to the eGFR endpoint that was here. We might have expected, because earlier patients don't tend to lose their GFR as quickly. So we might have actually expected there to be less differential between the treatment group and the placebo group, because the placebo group appeared to have a slightly better GFR starting out. That should have benefited the placebo group, is where I'm going with that, and it didn't.
This is a question for both of you, actually. One of the questions is, based on these data, do you, Dr. Nester, see the potential utilization of Empaveli in other nephrology indications? And then the follow-up question for Cedric would be: What other indications? We've talked about explaining other indications in nephrology. Can you expand more on what specifically we're looking at?
I'll start by just saying quite generically, excuse me. Targeting the alternative pathway has become incredibly popular in the glomerular disease setting in terms of, and I don't say that lightly. I say that more in that we're beginning to understand more and more that these glomerular diseases, for instance, do in fact have an alternative pathway based in part on their disease. There's lots of details to be worked out, but it wouldn't surprise me at all if alternative pathway becomes a target in many more of the diseases in the coming months, even years, frankly.
Yeah. Thank you, Dr. Nester. So from our perspective, we are doing the work, and we are, of course, only a couple of months after the top-line data, but we are really excited about what we can do for patients in several other potential indications, and in the near future, we'll provide an update on what we intend to do.
Thank you. Dr. Nester, can you discuss if efficacy was consistent across adults versus adolescent C3G versus IC-MPGN and native versus post-transplant?
Yes. The proteinuria reductions were. You can refer back to one of the slides on that right-hand side, and you can see that the proteinuria reductions were actually excellent across all of those subcategories of disease.
Can you also comment on what might be driving the numerical differences between adolescent and adult patients? Is there a clinical argument that younger patients have accumulated less kidney-
Yeah, absolutely. That would be our best guess as a nephrologist standpoint, again, that possibly treating the patient sooner, regardless of whether it's an adult or a pediatric patient, treating the patient sooner is likely to be, to have some benefit.
Question for you, Cedric. Are you seeking a disease-modifying label? What would you need to present to FDA and eGFR stabilization to achieve this? Would they need some type of proof of treatment durability to help characterize disease-modifying?
It's too early for us to comment on that. So, again, our regulatory strategy and what we intend to do on that end is gonna be subject to the next couple of months.
Question for you, Dr. Nester. How variable or heterogeneous are the patients, and how does that impact your treatment decisions? How comfortable are you with the results given the activity score issue?
Yeah. So this is a very heterogeneous group of patients, if you will. But importantly, there's no way to reduce that heterogeneity. I mean, me, as a clinician or as a scientist, I can't reduce. I can't better bin the patients, if that makes sense. I can't separate them out better. So this type of study where you looked at everybody as a collection is perfect because you're getting everybody, you know, the heterogeneous nature of the disease. You're actually getting to all of them, actually, with this. And again, I will go back to the activity score. It is my firm belief that it is not meant to. We have got a better understanding that it's not meant to necessarily be used in a clinical trial setting.
But I don't believe that that's because of the agents that are being used, 'cause this is not the only study that it's been used in. It's not actually the agents that are being used, it's actually probably the score itself. And again, it did go in the right direction, so I wanna, I probably should put a plug in for that. But the point is that I frankly, based on what we now know about the activity score, I'm not bothered by the lack of statistical significance anyway.
Thank you. Apellis estimates the market to be approximately five thousand patients between C3G and IC-MPGN in the U.S. Based on your experience, does this sound accurate to you?
I think it does. I think that there is a little bit of heterogeneity, you know, if you're talking about a UK cohort versus a US cohort, et cetera, et cetera. But generally, we have thought that that the C3G cohort will be somewhere around two thousand, twenty-five hundred, more or less like what you've already mentioned. And then the IC-MPGN basically doubles that. You know, that's essentially what we know. The only thing I will offer is that we have gotten a lot better at diagnosing it, so it's possible that that number will go up, but I don't believe that it will go down because now we know how to diagnose the diseases.
Thank you. A question about the primary endpoint. In the VALIANT primary endpoint, proteinuria was measured using a first morning spot urine test, whereas in the iptacopan study, it was measured using a twenty-four hour urine test. Would you expect to see any difference in the outcome given these slight differences in the way proteinuria was measured between the two trials?
No, I actually don't think so. And in fact, in the nephrology community, we're quite undone about what is the absolute best test to do, frankly. I will tell you that in the pediatric nephrology community, we are much more satisfied with results that are generated off of a first-morning void. In part, that's because children's urine, the urine protein in children can be quite variable throughout the day. And unfortunately, it's a group of patients where twenty-four hour urines are more frequent, more likely to be inaccurate, if you will. So what I think you should be hearing, and I'm sure there's potential disadvantages to both, but I think that they should be equal in terms of giving you an outcome, frankly.
Great. Next question is, how important is the C3c staining result to physicians, and in particular, the fact that pegcetacoplan appears to decrease the staining intensity to zero in some of these patients?
My personal opinion is that's the absolute best endpoint in this study. But of course, you know, I, as I'm a nephrologist, I have to pay attention to the urine protein, too. So, I mean, it's important that we had this much reduction in the urine protein because that's clinically... Again, that will make a difference in the patient's phenotype, you know, whether they're swollen, whether they've, you know, got really lots of lipids, you know, et cetera. But for me, as a complement scientist, that absence of the C3 staining highly suggests that we're shutting the disease off. And that's what the animal model would tell us needs to happen in order to fix this disease.
Thank you. A follow-up to that question is that, you know, we've seen now the Apellis or the VALIANT data on C3c staining and the data from NOVEL. We haven't seen any data from Novartis yet with the iptacopan on C3c staining. Is that something that we should expect to see in the coming months?
I think that, yes, that is something that you should expect to be seeing. I think that I don't know where it would be on their endpoints, but I'm sure. And again, you know, we think that that drug should work in the right place. It's just that we haven't seen all of the data yet, if you will, in terms of, like you said, for the C3c staining and.
Great. There's just a couple of more questions. Understanding that you just presented the data, what's been the initial feedback that you've received so far?
It was amazing the number of thumbs up I got when I was leaving that huge conference hall. Just random people thinking that this was excellent, and it's generating a lot of excitement amongst the... You know, and these are all nephrologists, right? So these are people who know what our track record has been in the glomerular diseases, and so it's generated a lot of excitement today.
Last question, are there any other compounds in development in these diseases that you are watching right now?
Yeah, so I'm a big fan of the alternative pathway blockade, but there isn't anything far enough along in that that's really actually frankly close. There are other agents like siRNA agents, et cetera, but they're considerably down the road and enough of a mechanism difference, frankly, that I think there's a lot of work that needs to be done on those before we'll get it, you know, get to where we need to be on those.
Okay.
So the short answer to that is no. I can't think of anything other than those that's coming.
That's all the questions that I have for now. The people that are listening, if you have any further questions, feel free to reach out to me. Thank you everyone, in particular, Dr. Nester, for joining us today, and for all your time, and hope everyone has a great rest of your weekend.
Thank you.
This concludes today's conference call. Thank you for participating, and you may now disconnect.