Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Apellis Pharmaceuticals VALIANT Top Line Phase 3 Results conference call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session. To queue up to ask a question, please press star one on your phone. Please be advised, today's call is being recorded. I will now turn the call over to Meredith Kaya, Senior Vice President, Investor Relations, and Strategic Finance. Please go ahead.
Good morning, and thank you for joining us to discuss the results from the phase 3 VALIANT study, evaluating pegcetacoplan in C3G and primary ICMPGN. On today's call, I am joined by our co-founder and Chief Executive Officer, Dr. Cedric Francois; Chief Medical Officer, Dr. Caroline Baumal; Dr. Andrew Bomback, Director of Clinical Research in the Division of Nephrology at Columbia University. Tim Sullivan, Chief Financial Officer, and David Acheson, Senior Vice President of North American Commercial, will also join us for the Q&A session. 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. Now, I'll turn the call over to Cedric.
Thank you, Meredith, and thank you all for joining us this morning. We are thrilled to share the positive top-line results from VALIANT, our phase 3 study of pegcetacoplan in patients with C3G and primary ICMPGN. Study met the primary endpoint, achieving a statistically significant and clinically meaningful reduction in proteinuria compared to placebo. These results are the grand slam scenario for pegcetacoplan, positioning pegcetacoplan as a best-in-class treatment option for these patients. Caroline will review the data in more detail, and we are fortunate to have Dr. Andrew Bomback here today to share his perspectives. But first, let me provide a few introductory comments. C3G and ICMPGN are rare and debilitating kidney diseases affecting 5,000 people in the U.S. and 8,000 people ex-U.S.
These diseases are both characterized by excessive complement activation and breakdown of C3, leading to significant kidney inflammation, damage, and in many cases, eventual kidney failure. Treatment options are generally a kidney transplant or lifelong dialysis, neither of which is curative. Nearly 90% of transplant patients experience disease recurrence, and literature suggests that at least half of them end up losing their transplanted organ. VALIANT is the largest single trial conducted in these populations, and the only phase 3 study to enroll a broad population, inclusive of adolescents and adult patients with native and post-transplant forms of disease. Notably, the positive effects observed in the primary endpoints were consistent across all of these subgroups. pegcetacoplan also demonstrated statistical significance on key secondary endpoints, as well as nominal significance on additional secondaries. Importantly, pegcetacoplan was well tolerated in the study, and the safety profile was consistent with previously reported data.
We are ecstatic about what these results mean for the patients, physicians, caregivers, and everyone within the C3G and ICMPGN communities. With the VALIANT results in hand, we and our partner, Sobi, will be working closely with regulatory authorities. The goal of bringing these treatments to patients suffering from C3G and ICMPGN as quickly as possible. We plan to file a supplemental NDA for pegcetacoplan in early 2025, with an EU filing by Sobi also expected next year. If approved, and given the urgent needs for effective treatments for these diseases, we believe pegcetacoplan is positioned to become the leading treatment choice by nephrologists for these indications. These data also underscore the incredible power of C3. We believe the significant therapeutic benefit of targeting C3, as compared to other targets within complements, is due to its central role in controlling the complement cascade.
Apellis' C3-targeted therapies have repeatedly shown to be the most effective complement inhibitors across multiple therapeutic areas, including PNH, geographic atrophy, and now C3G and ICMPGN. With Syfovre and an expanding pipeline for Empaveli, we now believe we have two products with blockbuster potential. And as we look ahead to the future, we are excited about building this next phase of growth that we believe will deliver meaningful value to patients, shareholders, and employees. With that, I will now hand it over to Caroline.
Thank you, Cedric, and good morning, everyone. I am delighted to share these exciting top-line results with you today. Before we go through the data itself, let me first remind you of the study design. The phase 3 VALIANT study enrolled 124 patients with either C3G or primary ICMPGN.... The primary endpoint of the VALIANT trial is a log transformed ratio of urine protein to creatinine ratio, or UPCR, a key marker of disease progression in all patients at week 26 compared to baseline. Patient demographics were similar between the pegcetacoplan and placebo arms. The average age of patients enrolled was 26, so a young population. Patients on pegcetacoplan had mildly worse disease characteristics at baseline, including slightly higher proteinuria and lower eGFR as compared to the placebo group. Let me now review the data.
The study met the primary endpoint, showing a 68% reduction in proteinuria as compared to placebo at week 26, resulting in a p-value of <0.0001. As you can see on this chart, this was driven by a 67% reduction from baseline in the pegcetacoplan-treated arm, as compared to a 3.2% increase from baseline for the placebo arm. The effects following pegcetacoplan were observed within the first four weeks of treatment and then sustained throughout the 26-week treatment period. As shown on the next three slides, these positive results were highly consistent across the following three subgroups: C3G and ICMPGN, adolescent and adult patients, and native and post-transplant kidneys. First, pegcetacoplan showed a 66% reduction in proteinuria as compared to placebo in patients with C3G and a 74% reduction in proteinuria in patients with ICMPGN.
The p-values were less than 0.0001 and 0.0015, respectively. Looking at patients by age, pegcetacoplan treatment showed a 75% reduction in proteinuria as compared to placebo in adolescent patients and a 63% reduction in adult patients.
Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Apellis Pharmaceuticals VALIANT Top Line Phase 3 Results Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. To queue up to ask a question, please press star one on your phone. Please be advised, today's call is being recorded. I will now turn the call over to Meredith Kaya, Senior Vice President, Investor Relations and Strategic Finance. Please go ahead.
Good morning, and thank you for joining us to discuss the results from the phase 3 VALIANT study, evaluating pegcetacoplan in C3G and primary ICMPGN. On today's call, I am joined by our Co-founder and Chief Executive Officer, Dr. Cedric Francois; Chief Medical Officer, Dr. Caroline Bommel; Dr. Andrew Bomback, Director of Clinical Research in the Division of Nephrology at Columbia University. Tim Sullivan, Chief Financial Officer, and David Acheson, Senior Vice President of North American Commercial, will also join us for the Q&A session. 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. Now, I'll turn the call over to Cedric.
Thank you, Meredith, and thank you all for joining us this morning. We are thrilled to share the positive top-line results from VALIANT, our phase 3 study of pegcetacoplan in patients with C3G and primary ICMPGN. The study met the primary endpoint, achieving a statistically significant and clinically meaningful reduction in proteinuria compared to placebo. These results are the grand slam scenario for pegcetacoplan, positioning pegcetacoplan as a best-in-class treatment option for these patients. Caroline will review the data in more detail, and we are fortunate to have Dr. Andrew Bomback here today to share his perspectives. But first, let me provide a few introductory comments. C3G and ICMPGN are rare and debilitating kidney diseases affecting 5,000 people in the U.S. and 8,000 people ex-US.
These diseases are both characterized by excessive complement activation and breakdown of C3, leading to significant kidney inflammation, damage, and in many cases, eventual kidney failure. Treatment options are generally a kidney transplant or lifelong dialysis, neither of which is curative. Nearly 90% of transplant patients experience disease recurrence, and literature suggests that at least half of them end up losing their transplanted organ. VALIANT is the largest single trial conducted in these populations and the only phase 3 study to enroll a broad population, inclusive of adolescents and adult patients with native and post-transplant forms of disease. Notably, the positive effects observed in the primary endpoints were consistent across all of these subgroups.... Pegcetacoplan also demonstrated statistical significance on key secondary endpoints, as well as nominal significance on additional secondaries. Importantly, pegcetacoplan was well-tolerated in the study, and the safety profile was consistent with previously reported data.
We are ecstatic about what these results mean for the patients, physicians, caregivers, and everyone within the C3G and ICMPGN communities. With the VALIANT results in hand, we and our partner, Sobi, will be working closely with regulatory authorities. The goal of bringing these treatments to patients suffering from C3G and ICMPGN as quickly as possible. We plan to file a supplemental NDA for pegcetacoplan in early 2025, with an EU filing by Sobi also expected next year. If approved, and given the urgent need for effective treatments for these diseases, we believe pegcetacoplan is positioned to become the leading treatment choice by nephrologists for these indications. These data also underscore the incredible power of C3. We believe the significant therapeutic benefit of targeting C3, as compared to other targets within complement, is due to its central role in controlling the complement cascade.
Apellis' C3-targeted therapies have repeatedly shown to be the most effective complement inhibitors across multiple therapeutic areas, including PNH, geographic atrophy, and now C3G and ICMPGN. With SYFOVRE and an expanding pipeline for EMPAVELI, we now believe we have two products with blockbuster potential. As we look ahead to the future, we are excited about building this next phase of growth that we believe will deliver meaningful value to patients, shareholders, and employees. With that, I will now hand it over to Caroline.
Thank you, Cedric, and good morning, everyone. I am delighted to share these exciting top-line results with you today. Before we go through the data itself, let me first remind you of the study design. The phase 3 VALIANT study enrolled 124 patients with either C3G or primary ICMPGN. The primary endpoint of the VALIANT trial is a log transformed ratio of urine protein to creatinine ratio, or UPCR, a key marker of disease progression in all patients at week 26 compared to baseline. Patient demographics were similar between the pegcetacoplan and placebo arms. The average age of patients enrolled was 26, so a young population. Patients on pegcetacoplan had mildly worse disease characteristics at baseline, including slightly higher proteinuria and lower eGFR as compared to the placebo group. Let me now review the data.
The study met the primary endpoint, showing a 68% reduction in proteinuria as compared to placebo at week 26, resulting in a P value of less than 0.0001. As you can see on this chart, this was driven by a 67% reduction from baseline in the pegcetacoplan-treated arm, as compared to a 3.2% increase from baseline for the placebo arm. The effects following pegcetacoplan were observed within the first four weeks of treatment and then sustained throughout the 26-week treatment period. As shown on the next 3 slides, these positive results were highly consistent across the following three subgroups: C3G and ICMPGN, adolescent and adult patients, and native and post-transplant kidneys. First, pegcetacoplan showed a 66% reduction in proteinuria as compared to placebo in patients with C3G, and a 74% reduction in proteinuria in patients with ICMPGN.
The P values were less than 0.0001 and 0.0015, respectively. Looking at patients by age, pegcetacoplan treatment showed a 75% reduction in proteinuria as compared to placebo in adolescent patients and a 63% reduction in adult patients. The P values were less than 0.0001 in both subpopulations. And finally, pegcetacoplan treatment showed a 68% reduction in proteinuria in patients with native kidneys and a 65% reduction in transplant patients. P values were less than 0.0001 and 0.0228, respectively. You can see that the transplant patients in the placebo arm worsened by approximately 45%, which is unusual relative to the placebo groups in the other analysis. We believe this is due to complications with the transplanted kidney.
There are preexisting issues with the transplanted kidney related to medications such as immunosuppressants or possible rejection episodes. C3G recurrence can exacerbate kidney damage, and therefore disease may progress faster. As part of this analysis, we also assessed the key secondary endpoints. Pegcetacoplan achieved statistically significant improvements on the composite renal endpoint, which is defined as achieving stable or improved eGFR compared to baseline and a greater than or equal to 50% reduction in uPCR compared to baseline. Pegcetacoplan also achieved statistical significance in patients with a proteinuria reduction of at least 50%. Both P values were less than 0.001. Regarding the histologic index score, while pegcetacoplan did not meet this endpoint, it did show a numerical improvement.
The remaining two secondary endpoints, C3c staining and improvement in kidney function as measured by eGFR, achieved P values of less than 0.0001 and 0.0322, respectively. Overall, the secondary endpoints all favor pegcetacoplan treatment relative to placebo. The totality of the efficacy data shows that pegcetacoplan rapidly, significantly, and consistently improved key outcomes for patients with C3G and ICMPGN. Turning to safety, pegcetacoplan demonstrated favorable safety and tolerability consistent with its established profile. Rates of adverse events, serious adverse events, and adverse events leading to study drug discontinuation were very low and similar between the pegcetacoplan and placebo groups. There were no cases of meningitis or serious infections attributed to encapsulated bacteria. In summary, the VALIANT data showed that treatment with pegcetacoplan resulted in improvements across multiple measures of disease activity and was consistent across a broad population.
These data underscore the potential for pegcetacoplan to prolong kidney function by directly targeting C3, the underlying cause of the diseases. We are excited to share the full VALIANT data, including the detailed secondary endpoint analysis and upcoming medical meeting. I will now turn it over to Dr. Bomback.
Thank you, Caroline. Good morning, everyone. This is one of those moments as a physician that we look forward to for our patients. Thousands of patients in the U.S. are currently living with either C3G or immune complex MPGN, many of whom will progress to kidney failure within the next 5-10 years. As a nephrologist, you want to do everything that you can to prolong your patient's kidney function, but right now, all we have to treat these diseases are medicines that address their symptoms, nothing to address the underlying cause of the diseases. If faced with kidney failure, patients with C3G and MPGN have 2 options: dialysis for the rest of their life, which is a complex and demanding treatment that requires ongoing medical support and significantly reduces their quality of life and life expectancy.
The other option is to get a kidney transplant, and while this is a much better option, the benefit is relatively short-lived due to a high risk of recurrence. In fact, we recently published a paper in which we looked at disease recurrence in C3G patients with native kidney failure who had received a kidney transplant, and our results showed that recurrence of the C3G in the transplant occurred in 89% of the patients at a median of approximately one month after transplantation. We've previously shown that recurrent disease leads to early loss of the transplants. This speaks to how urgently treatments are needed and the importance of early treatments in these diseases. The VALIANT data with pegcetacoplan set a high bar for efficacy in these populations.
I was heavily involved in the study as one of the principal investigators, and the data surpassed even my own expectations. As a nephrologist who takes care of many patients with these diseases, I consider a 30% or more reduction in proteinuria as clinically meaningful for these diseases. So to see a reduction that is more than twice that amount in the largest randomized trial in these diseases is astounding. These effects, combined with the stabilization of eGFR, are truly impressive. I believe that pegcetacoplan will become a transformative treatment for patients, and if approved, look forward to the day when I can offer it to my patients with C3G and immune complex MPGN.
Thank you so much, Dr. Bomback. I would like to close by expressing my sincere gratitude to patients, physicians, and site staffs participating in the VALIANT study. It's thanks to all of you that this milestone was made possible. And to our amazing team at Apellis, we are so grateful for your unwavering commitment to advancing the care for people living with these diseases. And with that, we will now open the call for questions.
At this time, we will conduct a question and answer session. If you would like to ask a question, please press star one on your phone now, and you will be placed into the queue in the order received. Once again, to ask a question, please press star one on your phone now. Our first question comes from Jonathan Miller of Evercore ISI. Your line is open.
Thank you so much, guys, for taking our question, and congrats on really amazing data here. Can you just walk us through your expectations for commercialization here. Obviously, you have Sobi partnership ex-US. But when we think about market sizing and your ability to penetrate compared to the competitors, can you walk us through your expectations for your ability to take share and for doctor enthusiasm to treat with pegcetacoplan, as opposed to iptacopan?
Thank you so much, John. I'm going to hand over that question to Dr. Bomback, because I think really what stands out here is what Empaveli seems to be doing for patients with this disease, and that is really the primary consideration here. The markets will follow, but I think your question as it relates to the competitive dynamic and how this drug could find a seminal place as a standard of care in this disease is what is key. Dr. Bomback, would you mind commenting, please?
Sure. With the caveat that we're obviously responding to, you know, preliminarily released data and not what's formally published in the literature and not what's, you know, been presented in all the granular details. So the iptacopan data that I would be commenting on is what was shown at the ERA meetings in May. So if you compare the proteinuria reductions with iptacopan versus what we just saw with pegcetacoplan, they both have statistically significant proteinuria reduction, but clearly the pegcetacoplan reduction is much greater than was seen with iptacopan. You're comparing about 68% reduction with pegcetacoplan to about 35% reduction with iptacopan.
Again, both are very, very clinically meaningful, both are statistically significant, but obviously, if you had a choice between 68% and 35%, if those numbers hold out in the final data that's released, it's clear what one is doing a stronger job of getting disease control. We think proteinuria reduction is crucial to slowing the outcomes of this disease and changing the natural disease course. So obviously, the more proteinuria reduction you get, the better you would be inclined to halt disease progression.
So I think if both products are available and both products are equally priced and equally, you know, given to patients, that they could have either one, with the one difference being a subQ versus an oral, I still think patients would probably opt for the one that has the better proteinuria reduction, and I think probably the typical nephrologist would push for that as well. Again, these are preliminary data that we've seen, so I'm just commenting on the data that I've seen for both of these drugs. But if those numbers hold out, it would favor one over the other. I'm not sure if I completely answered your question.
I think you hit most of the highlights there. I guess then one more for the team then. Given where we're sitting today, are there any expectations of bottlenecks or trip-ups that can happen that would lead to delays in getting the drug on the market and into patients?
Thank you, John. So well, the beauty here, of course, is that we have a lot of real-world experience with EMPAVELI. We know how to manufacture this drug very well and at scale. What is key here for us as well is that we have so many patient populations included in this study, right? So adolescents, adults, pre-transplant, post-transplant. Specifically for the adolescent population as well, we want to be able to make the enabled device available, which is the subcutaneous administration of the EMPAVELI. So that, you know, causes a little bit of extra time, maybe a month or so, in terms of being able to file, but we are, of course, going to work as diligently as we can towards the SME.
Great. Thank you very much.
Thank you, John.
Our next question comes from Tazeen Ahmad of Bank of America. Please ask your question.
Okay, good morning. Thank you for taking my questions. First one is also maybe directed to Dr. Bomback. Can you frame for us, just based on the comments you just made about the preference for PEG versus iptacopan, what % of your patients do you think would be on PEG, over time at peak? And is there a subset of the population at all that you think would not be as well served from taking PEG, just based on the data that we've seen? And then, a question for the Apellis team. In terms of pricing, this is a rare, rare disease. Without telling us what you think you're going to price it at, can you give us a range of what similar drugs like these are priced annually? Thanks.
I'm happy to go first. So if you look at C3G natural history data, only about 5%-10% of patients have a mild course of the disease where you might be able to get by with only treating them conservatively with blood pressure medication or SGLT2 inhibitors, for example. But about 90% of patients are expected to progress. So of the C3G population, I would say 90% should be offered targeted therapy, such as pegcetacoplan or iptacopan. Whether you're going to go one versus the other, if both drugs are available, there might be some very small subgroups of patients who have genetic variants that you would sort of lean towards one over the other, but the majority of patients don't have those kind of genetic variants.
So, you're still sort of looking at 85%-86% of the patients should have options between both.
...As I said, if these data hold out, most people will be inclined to choose the one that has the greater proteinuria reduction, all things being equal. But all things aren't always equal. Sometimes insurances will only cover one versus the other. Sometimes insurances will say you have to do one versus the other. So, there's always the payer part of the equation. But in terms of the population with C3G, that would be expected to wanna be on-- that their nephrologist would want to put them on therapy, that's about 85%-90% of all C3G patients, I think should be, should be offered therapy.
I'm back. I'm gonna hand the question on pricing over to, David Acheson, who is on the call as well.
Hey, Tazeen, this is David. Thanks for the question. And it's a great question, by the way. So we're still doing a lot of work. Obviously, these data bring in a number of things for us to look at in the marketplace. But I'll just remind you that EMPAVELI is out already for PNH, and there's a price attached to that. So we've got some work to do to make sure we're, we're in the correct range, but you know, currently this will be a franchise, not just a single indication product moving forward.
Okay. So are you gonna keep the price for PNH the same as you think about indications that you might wanna pursue on a go-forward basis across all of your products?
Unless the market tells something different, Tazeen, that would be the plan moving forward. But again, we've got some work to do to make sure we're correct about that.
Okay, thanks.
Our next question comes from Anupam Rama of J.P. Morgan. Please ask your question.
Hey, guys. Thanks so much for taking the question, and congrats on the update. Maybe a quick question for Dr. Bomback. Like, how do you think about uptake of the product in the pre- versus post-transplant setting? And then for the company, how do you think about the sales force infrastructure now that you have these VALIANT data in hand? Thanks so much.
Okay, this is Dr. Bomback again. So I think everybody post-transplant should be offered this kind of therapy, complement targeted therapy, at the time of transplant. Now, whether or not that's gonna be an option, I'm not sure. But, in theory, everybody should be offered this therapy at the time of transplant because we have shown that the disease comes back typically within the first six months. So to use this drug as a prophylactic rather than a treatment would be ideal. I think if patients are progressing towards kidney failure, I would still start them on the drug because I would want it to be continued through the transplant process.
So I, I think this and any other directed target- targeted complement therapy that modifies the disease course is an ideal way to help those patients who are diagnosed late in the disease, who progress to kidney failure, to protect their transplant from, from recurrent disease that would make them lose the transplant.
Thank you, Dr. Bomback. I will hand over the Salesforce question again to David.
Thanks, Cedric. Great question. As you guys know, for our PNH team, we have a fully loaded commercial organization that promotes that product in the field as well as in-house. And our anticipation is to help move forward and leverage that team to help launch this product, with, of course, a review, especially with this kind of data, of the impact in the marketplace and how quickly we will see uptake with physicians and patients. We're gonna take a deep look into that. And you know, with this kind of data, also, if there's investment needed with the size of the market, we'll certainly look at that too.
We'll leverage what we have, and then, hopefully we'll have a chance to take a deeper look in the next few months on what that looks like moving forward.
Thanks so much for taking the questions.
Our next question comes from Salveen Richter of Goldman Sachs. Please ask your question.
Good morning. Congratulations on the data. Two questions from me. One is, could you help size this opportunity and, you know, the proportion of patients right now that take treatment and how you expect that to expand over time? And then just, speak to considerations where you might use an oral agent, you know, instead of the non-oral here, as you treat the population. Thank you.
Thank you, Salveen. Dr. Bomback, would you care to comment, please?
Sure. So, this first part of the question, if you could just repeat it.
Sure. Could you just help us understand the size of the opportunity here, the number of patients?
Okay, yeah. Oh, yeah. So it's 1-2 per million incidents, and the point prevalence is about 1 in 10,000. I'm sure the Apellis folks have a much better size estimate of the patient population because pharma companies do a better job than academics at estimating the market size. But that's typically what our literature says, 1 per million incidents, 1 in 10,000 point prevalence. As I said, about 85%-90% of those patients should be offered therapy. To the second part of the question about whether to use an oral versus a subQ, look, patients obviously would prefer an oral agent over a subcutaneous agent. But if a subcutaneous agent is what's available to them-...
And if a subcutaneous agent is being recommended to them as a more powerful therapy, they're gonna go with efficacy over just, you know, convenience. I can tell you that, you know, patients of mine who are receiving this drug as part of clinical trials or compassionate use, I've really not had any issues with doing the twice-weekly injections. You know, it's not something like insulin, where you have to do it four times a day. You're just talking about two injections a week, so it's pretty manageable.
Thank you, Dr. Bomback. And Salveen, so we estimate that in the United States there are approximately 5,000 subjects, of which we believe 1,000- 1,500 are transplanted, and ex-US, so Europe and other geographies, another 8,000 subjects. Did that answer your question?
Yes. Thank you.
Thank you.
Our next question comes from Yigal Nochomovitz of Citigroup. Please ask your question.
Hi, great. Thank you so much, and congratulations on the really, really strong data. I had a few for Dr. Bomback, if I may. I'd like to get a better understanding of how these proteinuria results would translate into kidney function in terms of eGFR. You mentioned that the improvement was a stabilization at 6 months. What would you have expected for a decline in kidney function for this population over that time? We know from IgAN that a 50% proteinuria reduction we believe translates to 3-4 ml/min improvement. Is it similar in C3G and ICMPGN, or is it different? And if you could comment on that, please. Thank you.
I mean, we tend to think of C3G and ICMPGN as sort of along a spectrum, so what applies to one would typically apply to the other. So there's data from the RaDaR study that shows that once you get to above a 25%-30% reduction in proteinuria, you start to see significant changes in proteinuria. Sorry, in eGFR slopes. So you know, for me, as I said earlier, anything over a 30% reduction in proteinuria should have a significant impact on the eGFR decline.
What you're seeing in this study, and what you've seen also in the data that's been shown with the iptacopan, is that when these drugs work, they don't just slow the decline of GFR, they actually just flatten out the slope, which is a really remarkable result, for a disease that's so progressive. You know, the average patient with this disease loses their kidney within somewhere between 8- 9 years on average. So that typically translates out to about a 6- 7 mL per minute GFR loss per year. And that's sort of what you see in the placebo arms of these trials. And so to get a flattening of the slope, a remarkable, just a remarkable change in the natural disease course. And so I hope that answered your question.
Yeah, no, thank you. And then I had a few questions with regard to the post-transplant population. I know this may be a bit detailed, but did you see any differences in activity depending on the time from which they were transplanted? Were the ones that were transplanted closer, treated closer to transplant, doing better? And were some of these patients already in transplant failure at the time they received pegcetacoplan?
Yeah, I mean, I will speak briefly on this, and then I will refer to the folks from Apellis. The transplant patients in this study have more than 1 gram a day of proteinuria. That's a more advanced stage of recurrent disease than we typically see. So in order to be eligible for this study, you need to have more than 1 gram a day of proteinuria. So if you're a transplant patient with that degree of proteinuria, despite all the immunosuppression you're getting to protect your transplant, it's a very, very aggressive and advanced form of C3G recurrence, and it's typically later in the disease course of recurrence than we see in our patients.
There's another study that Apellis has sponsored called the NOBLE Study, and some of that data has been presented at meetings such as ERA and ASN, which is focused solely on recurrent disease in transplanted populations. It's the earlier recurrent patients that are in those studies who don't really have much proteinuria. We saw really nice results in terms of how the drug works in those patients, in terms of stopping the C3 deposition that is the pathogenic mechanism of the disease. When I look at how this drug is gonna work in the typical recurrent patient who gets followed at a good transplant center where they can diagnose recurrence early, the NOBLE data to me will be more meaningful. The transplant patients in the VALIANT study really are patients who are getting the drug late in their disease course.
It's great that it's helping them, but they're not the typical ones that I would expect to be following. 'Cause at our center and at most good transplant centers, we try to diagnose recurrence very early, and if we had a drug that could work, we would give it to them very early. We wouldn't wait till they had more than a gram a day of proteinuria.
Got it. Thank you.
As a reminder, if you would like to ask a question, please press star one on your phone now. Our next question comes from Steve Seedhouse of Raymond James. Please ask your question.
... Good morning. Thank you, and congratulations on the result. First question for Dr. Bomback and for the company is, you all no doubt know complement is implicated in a whole bunch of different kidney disorders. Iptacopan, for example, was approved for IgAN just yesterday. So what does this result and just how profound the proteinuria reduction is forecast maybe about the opportunity for EMPAVELI across IgAN and lupus and perhaps some others? And specifically for the company, what plans are you maybe already thinking about or discussing in terms of development in other kidney diseases?
I'm happy to answer first. I think if it works in C3G, which is a pure alternative complement-mediated disease, it should work in diseases that have alternative complement contributions. That would include, you know, complement TMA, which obviously it's already been shown, but it would also include a disease like IgA nephropathy. But in terms of what the company is planning, obviously I don't have that insight, so I'll toss it to them.
Thank you, Dr. Bomback. So I think one of the remarkable things here that, which was even a surprise to us, is the magnitude of the effect and the very strong control that must be associated with inside the glomerulus. That means that pegcetacoplan has exquisite target engagement in the glomerulus, and that, obviously, to your point, Steve, opens up a window in a whole range of new indications. You know, we were very happy to see the approval for iptacopan in IgAN. For us, that is, of course... And remember, iptacopan is an alternative pathway inhibitor, whereas pegcetacoplan blocks both the alternative as well as the classical pathway. And of course, in IgA nephropathy, there is an important classical pathway contribution that works.
So these are important indications that we will, of course, take under consideration, and we are already working on a strategy to go there. But further details to follow.
Okay, and on C3G specifically, when you frame the market opportunity, so the 5,000 patients of whom 1,000- 1,500 are transplanted, the untransplanted patients, are they all already diagnosed by biopsy? My understanding is that biopsy is essentially the only way for a definitive diagnosis here. Or is there some work to do to identify and formally diagnose some of the prevalent population here, just given there's been no approved drug to date?
Yeah. Thank you, Steve. So, the majority of these patients are diagnosed and identified, and to your point, specifically with the biopsy. So yeah, this is a population that is well known with the community, that is, you know, very well informed and communicative. So, you know, we look forward to hopefully being able to offer this new therapy to the nephrology communities.
Okay, and just quick on eGFR, do you have pretreatment assessments to do a slope analysis of how patients in either cohort were trending in terms of their eGFR slope pre and post-treatment? Or is the analysis just going to be restricted to change in eGFR post-treatment?
So it is change in eGFR post-treatment. So we had a screening period of 10 weeks, which is not enough really to create a pre and post slope. But we do have, of course, the control group, which after the 24 months of the initial phase, after six months, then switches over to active. So there we do have an opportunity to actually look at the initial decline that then hopefully will stabilize when these patients go over onto active and reflect what we see in the first six months in the active group. So but, but really exciting here, and Dr. Bomback alluded to it earlier, right? I mean, is to see that stabilization of eGFR. And when you see a separation of the eGFR, it is driven in this disease by the decline that you see in the placebo group.
So again, you know, the full picture really to get your data included in the analysis, we would have to wait until 12 months, but we already know that, that it reflects clearly what we see with you this year.
Nice. Okay, thank you. Congratulations.
Thank you.
Our next question comes from Colleen Kusy of Baird. Please ask your question.
Great. Thanks. Good morning, and thanks for taking our questions, and congrats on the data. First question for Dr. Bomback. Does a patient feel a difference in a 30% reduction versus a 65%+ reduction in proteinuria, or are there other factors that you think will be impacted by achieving higher reductions in proteinuria?
So like most kidney diseases, C3G, especially in the early stages, are asymptomatic, so they're not going to really feel something other than elation at looking at their labs. I mean, these patients are young. They're very savvy. They know how to evaluate their disease based on their blood work. So they'll ask, you know, "What's my creatinine? What's my proteinuria? What's my serum albumin? What's my C3 level?" So they shouldn't actually have a physically different sensation in terms of a 30 versus a 40 versus a 50% reduction. But obviously, they'll be able to see their labs and see what shows the improvement. But we typically don't see really bad symptoms from the disease until the GFR is well below 30.
... That's helpful. Thank you. And then, for the company, if you could provide a little bit more background on the histologic score, the secondary endpoint that was not that sig, and how important that endpoint will be in your regulatory conversations, and then your confidence in the overall package supporting approval?
Thank you, Colleen. Well, we have the perfect person on our call to discuss this because Dr. Bomback actually came up with this score and can comment on it.
That's right. We developed a score at Columbia. It's a scoring system for a kidney biopsy that is meant to give prognostic information on how a patient will do. So the score was actually developed to be at the time of diagnosis and to be a predictive for outcomes like remission or progression to end-stage kidney disease. So it's never really... It's been validated in Spain, and it's been validated in Turkey for that reason. It's never really been validated for response to therapy, and partially that's because there are elements of the score that are really difficult to see any changes in. There are some elements of the score in terms of activity that you would expect to change over time as disease is successful, which are some of the inflammatory markers. But, in general, it's more of a prognostic tool than a evaluate.
So to me, when I look at histologic data, from these kinds of studies that are doing serial biopsies, what I'm really trying to see, because we don't have good biomarkers of complement activity. I mean, I'm sure, you know, the company is going to show you data on the Wieslab assay and C3 levels and, maybe even better biomarkers like GD levels. But to be honest, the field of complement biomarkers is very immature at this time. And the best biomarker of complement activity is still the kidney biopsy and the immunofluorescence staining on the kidney biopsy. It's how we diagnose the disease, and for me, it's how we would know we got control of complement. So when I look at their histologic data, I'm really most impressed by the staining intensity of C3.
I'm similarly, you know, enthused and, you know, excited to see that the majority of these patients, I don't have the number off the top of my head. I'm not sure if they're sharing that number with you. I don't want to say it, but the vast majority of these patients are losing two orders of magnitude of their C3 staining, which is a real sign that the disease is being controlled, it's being stopped by C3 inhibition. And so that's, that's the histologic parameter that I look at first for these kinds of studies, is what's happening to the intensity of C3 staining, because that's, to me, where the disease begins.
Great. That's helpful. Thanks for taking our questions.
Thank you, Colleen.
Our next question comes from Phil Nadeau of TD Cowen. Please ask your question.
Good morning. Let us add our congratulations on the strong data. One question for the company, then a couple for Dr. Bomback. First, to Apellis, can you give us some sense of when the data will be presented? Is that likely to be later this year, or will you wait till after the FDA filing? And then for Dr. Bomback, a couple on kidney function. So comparing the Apellis data to the Novartis data, here, the preservation of kidney function was nominally statistically significant, whereas there was just a trend in the Novartis data with a p-value of approximately 0.2. Is that a meaningful difference in your mind that suggests pegcetacoplan is better at preserving kidney function?
Then second, also on kidney function, you mentioned that most patients will lose their kidney in 8-9 years. Looking at the data that we have here, can you give us some sense of how that natural history of the disease will be changed by treatment? Thanks.
Thank you so much, Phil. So we are hoping to present this data at the American Society of Nephrology at the end of October. I will hand it over to Dr. Bomback for the second part.
I don't feel equipped to answer that question because I think you're asking about data that Apellis isn't sharing with you, in terms of eGFR data. I can just tell you that as a nephrologist, what will be most enthusiastic to me is the flattening of the GFR slope. You know, whether that's gonna meet statistical significance is, it's a lot of it's numbers. You know, these. It's hard to show GFR changes in a six-month period. It's hard to show GFR changes in a 12-month period. If you look at most of the data in glomerular diseases that actually show GFR changes, it's over two years. So sometimes you have to be a little bit creative.
I know that's how Novartis is, you know, showing their data with comparing the slope on drug to the, you know, the year before being on the trial. But you know, in terms of going through the GFR trial, I don't think we've been today, we've been told anything other than just the p-value. So a lot of this just depends on what, you know, numbers to me. What I'm most again looking at is, I and what nephrologists do in clinical practice is they chart out the progression of GFR, and then they see what happens when you put the therapy on, and then they can say, "Look, it's stabilized.
Great. That's very helpful. Thanks for taking our questions.
Thank you, Phil.
Our next question comes from Akash Tewari of Jefferies. Please ask your question.
Hi, this is Kathy on for Akash. I have two quick questions. So first of all, for EMPAVELI, what does the time to effect look like? So for example, if Fabhalta shows an immediate reduction in the first few weeks, but doesn't get as deep of a response as to what you're showing with EMPAVELI. So, is there a steep drop or is it more linear? And then additionally, what other indications do you think EMPAVELI can break into, and how should we think about adjacent disease indications given today's data, such as certain diseases that you believe that EMPAVELI could show a superior benefit to versus Fabhalta? Thank you.
Thank you so much, and I had a hard time hearing the second part of your question, but the first one is, it is we see a very, relatively speaking, right, a relative, a very fast onset, of activity. So within a month, you kind of see these corrections really penetrate. And also, I think importantly, reflected in the histopathology, right? So you may recall from the NOBLE trial that after three months, you already see the clearing of the kidney. And then for your second question was for other indications. Could you repeat that, please?
Yeah. So what other indications do you think EMPAVELI can break into, and how should we think about adjacent disease indications given today's data? For example, are there certain diseases that you think EMPAVELI could show a superior benefit to versus Aspaveli?
Thank you so much. So again, kind of going back to IgA nephropathy, that is, of course, the indication that is going to be very interesting to us. In IgA nephropathy, there are probably north of 5,000 patients that are transplant. And then again, in that post-transplant segment, you know, you have a very important unmet need, and that is where our data really shines as well with that histopathology data available. So again, the wonderful news here, beyond of course, what this means for patients with C3G and ICMPGN, is the target engagement that we see in the glomerulus for pegcetacoplan, combined, of course, with the safety profile that we have now very clearly established in PNH and other indications in the real world as well.
Great. Thank you so much, and congrats on the data.
Thank you.
Our next question comes from Ellie Merle of UBS. Please ask your question.
Hey, guys, congrats on the data. Just how are you thinking about the size of the target prescriber base and how centralized or not is the treatment of these conditions? And then in terms of the mix between the academic setting or transplant centers versus patients in the community, I guess, what proportion are managed in the academic setting versus the community? Thanks.
Thank you so much, Ellie. Dr. Bomback, would you like to comment on that, please?
Currently, if you are a community nephrologist and you have a patient diagnosed with these diseases, you are encouraged to send your patient to an academic center that has expertise. I don't think that will change. Probably the best model for this is going to be what happened with atypical HUS and Soliris. In the first couple of years, it was almost entirely done by academic nephrologists, and maybe just after like 5-7 years, did community nephrologists start taking, you know, charge of the patients themselves and using the drug. I think it would be a similar pattern. That in the beginning, only academic centers would be using these agents, and all the patients would still be filtered towards those academic centers, given their expertise in the disease.
Got it. Then I guess just for Adam, just the size of the target prescriber base.
Yeah, this is David. Oh, go ahead. Go ahead, Cedric.
I was going to hand it over to you, Dave. Go ahead.
Yeah. This is David. I'm standing in for Adam today. We're looking at that now. It's a little bit varied, and especially with, you know, the fact that we've got the academic centers. We don't have that as solidified, and one of the things we were waiting for was this data to really push forward. More to come, and we'll be able to give you some more details, I would say probably in Q3.
All right, great. And then just in terms of the filing strategy, is the plan to file on the 6-month data or will you need the 12-month data to file?
So that is a great question, Ellie. So as you know, for iptacopan, there was a request from the FDA to include the 12-month data. We believe that the data at six months is sufficiently meaningful, but of course, that is going to be a discussion with you.
Great, thanks, and congrats.
Thank you.
Our next question comes from Jack Padovano of Stifel. Please ask your question.
Hi, this is Jack on for Annabel. Thanks for taking our question. So I know it was mentioned that the recurrence rate of disease in this population, post-transplant, is pretty high, but what does the transplant rejection rate look like in terms of timing? These are some pretty advanced patients, but is it still too early to have seen any transplant failures in the trial? And will that be something that you'll be measuring in the extension? Kind of basically asking when we might see the impact of that functional outcome, if at all.
... Will you require any rejection statistics to get a prophylaxis in a potential label?
Yeah, thank you, Jack. So for that, too, we actually have the best expert on the call, Dr. Bomback, if you would, maybe comment on that.
Yeah. So, I mean, it's a multi-part question. So the first part is, you know, these patients don't lose their transplant from rejection. They lose their transplant from the disease recurrence itself. So keep in mind, the typical patient with C3 glomerulopathy who ends up getting transplanted is an adolescent or a young adult who has no other comorbidities. They should have the ideal transplant outcomes. Their allografts, their kidney transplants, should be expected to last 20-30 years. And in our data that we've published previously, they're all losing their kidneys from allograft recurrence. The dense deposit disease patients are losing it much faster than the C3GN and the ICMPGN patients, but they're all losing their kidneys, typically in the range of 5-12 years. That was published in AJKD.
So these are really early allograft losses, really early transplant failures from recurrent disease, but not from rejection, from the disease itself. To your second question, I don't know what the plans are in terms of their analysis, but I can tell you what I would hope would be the case. Remember, everybody in this study got crossed over to open-label extension at six months. So given what we've seen of how this drug potentially works, I would expect that none of the patients who are transplanted in this study, if they remain on open-label extension, should lose their kidney from the disease recurrence unless they enrolled very, very late in their disease course, and basically, they got the drug too late. But otherwise, it should stabilize their, their allograft, and they shouldn't necessarily lose their, their allografts from disease recurrence if they remain on peg.
Great. Very helpful. Thank you.
Our next question comes from Frank Brisebois of Oppenheimer. Your line is open.
Hi, this is Jacqueline for Frank. Thank you for sharing these impressive results. My question is, with your plans to submit sNDA in early 2025, what are your expectations for the review timeline? And are there any aspects of the data package that you believe might expedite the progress, the process? Thank you.
Thank you, Jacqueline. So we will file, as you mentioned, early next year. The typical timeline, this is a supplemental NDA, so there is a precedent for it. A conventional timeline there would be 10 months. Should we get priority review, it would be six.
Thank you.
Thank you.
Our next question comes from Douglas Tsao of HC Wainwright. Please ask your question.
Hi, good morning. Thanks for taking the questions. I'm just curious to hear from Dr. Bomback. Can you hear me? Can you hear me?
Okay.
Yeah, I just curious to hear from Dr. Bomback, his perspective in terms of this data showing benefit in both patients with C3G as well as the ICMPGN population versus, you know, obviously, the Iptacopan only did the C3G patients. Thank you.
Well, you know, as I said, most of us view these diseases along a spectrum, that they're not necessarily two distinct diseases, that they're along a disease spectrum. Obviously, this study includes both C3G and ICMPGN patients. In my experience, ICMPGN patients are less common than C3G patients overall. And I think that's reflected in this study, which is more represented by C3G patients. And then, of course, you, as you've mentioned, the iptacopan studies are separate. So, you know, again, I view them as one large group because I've seen patients with one biopsy called ICMPGN and then a repeat biopsy called C3G. So my... You know, the way I approach these data is, you know, what's good for one should be good for the other.
I'm not sure if I got all of your question answered, but.
Okay. So I was just curious just how you were gonna interpret, you know, that the data, you know, with this study with both patients. So obviously, it sounds like you don't necessarily see this as significantly distinguishing between the other dataset.
I don't. I don't.
Great. Thank you so much.
Thank you, too.
Our next question comes from Biren Amin of Piper Sandler. Please ask your question.
Yeah. Hi, guys.
Hello.
Thanks for taking my questions, and congrats on the data. Maybe for the company, would you expect broad approval regardless of baseline proteinuria levels, or would the label be restricted to patients with more than 1 g of proteinuria baseline?
Thank you, Biren. It is early to talk about that, of course, but, you know, this is, you know, the data is very homogeneous, right? Across populations and across various baseline proteinuria levels. So, I think it would be rather a surprise if there's a limitation on the baseline of proteinuria, you know, in, in the treatment of these patients.
Maybe a question for Dr. Bomback. What percentage of your patients are uncontrolled on the current stable therapies like ACEI, mycophenolate, steroids? And specifically, if you could talk about transplant versus non-transplant in terms of those that are uncontrolled on their current regimen.
In the native patients or the non-transplant patients, I would say, as I said, only about 5%-10% do we feel comfortable that their disease is mild enough that we can control them with an ACE inhibitor or an angiotensin receptor blocker. So of the remaining 90%, maybe 15%-20% have been stabilized on mycophenolate mofetil, which is CellCept, a drug that's primarily used for lupus, but it's been co-opted for this disease. So, you know, that gives you the remainder, about 70%, we need, we need drugs like this that actually target the disease course. So, you know, the overwhelming majority. Now, for the transplant patients, remember, they're on mycophenolate and a calcineurin inhibitor, which suppresses proteinuria.
So if you just look at their labs, usually over the first three or four 4 years, they're not really showing any real clinical evidence of the disease. But as we've shown in our recent publication in the Clinical Journal of the American Society of Nephrology, where we did protocol biopsies, where we're biopsying patients regardless of their clinical labs, the disease comes back right away, and it actually progresses over the first two years histologically. Meaning that we see more activity, more chronicity, and still intense C3 staining. The disease remains unchecked, and gets worse over the first two years histologically. So those patients are gonna start to show clinical manifestations at around years four and five, which aligns with the data we've previously shown about losing the allograft at around the 8- to 12-year range. So, I would say they're uncontrolled. I mean, they...
Their labs don't scream being uncontrolled, but I would say they're uncontrolled.
Thank you.
If there are any final questions, please press star one now. We have a question from Gregg Suvannavejh from Mizuho. Please ask your question.
Hi, this is Sam Lee for Gregg. Congrats so much on the data. Maybe one for the company and a couple for Dr. Bomback. I guess in terms of the population size and, you know, what percentage of C3G and ICMPGN patients do you expect to respond to a C3 inhibitor, approximately? And then for Dr. Bomback, you know, what do you, in your, for your patients, expect, what is the split, I should say, between pre-transplant and post-transplant patients? And, among the post-transplant patients, would there be a reason to give iptacopan over pegcetacoplan, in terms of, I guess, efficacy, all things being equal in this harder-to-treat population? Thank you.
Thank you very much. So, with respect to the first question, I mean, I will just refer to the fact that out of 124 subjects, we had six patients drop out of the study. So that is a reflection, I think, of and by the way, that was not just, you know, for lack of efficacy. So, it was a remarkable study in every respect, and we believe something that, hopefully be available to all patients with C3G and ICMPGN. Dr. Bomback, I will hand it to you for the second part.
Yeah, there's a lot, a lot in those questions. So I wanna make sure... I, I may not get every part of your question. Let me go to the first part, which was the, I think you were asking, like, the breakdown between native disease and post-transplant. I mean, there's much more native disease out there than post-transplant. So I can't give you percentages, though, 'cause I've never really seen that breakdown, but I can just tell you, in my own practice, I, you know, our, our Glomerulus Center follows about 150 native patients and about 15-20 post-transplant patients. So that's probably representative, I would hope, of, of the general, you know, experience elsewhere. To your question about using iptacopan versus pegcetacoplan in the post-transplant setting. So based on what I've seen of the iptacopan data, they have phase...
Their phase 2 study had recurrent disease. In their phase 2 study, there's a bunch of post-transplant patients, and that data is very, promising in terms of proteinuria reduction, GFR stabilization, and, histologic changes. And I've, I've obviously heavily involved in the NOBLE study with pegcetacoplan, and I think it's a great option there, and you've seen some nice data here in the VALIANT study for post-transplant. But to be honest, if the drugs are used the way I want them to be used, which is prophylactically, rather than waiting for the disease recurrence to be diagnosed, I don't think there really will be a difference in terms of how these drugs would be helpful because I think they'll both help patients because the disease won't be that severe, and won't even hopefully be present when they're started.
Even if you wait for disease recurrence, if you just do it by histologic recurrence, let's say you do a protocol biopsy at six months, you see the disease is back, but the patients have no proteinuria. Again, I would think that either drug would be a good option for patients. I don't think there's a big difference in terms of safety profiles in the data that I've seen from both of these drugs. They both have good safety profiles. As we said earlier, you know, some patients might prefer an oral versus a subQ. But again, it's gonna—these patients are incredibly savvy. You saw both with the iptacopan study and now with the pegcetacoplan study, they were enrolled very fast. They actually exceeded enrollment goals, in terms of both numbers and time to enroll the last patient.
These are patients who are very eager to be treated because they know that the disease course without treatment is awful. So they're gonna take whatever they can get, and they're gonna take it as soon as they can get it, and they're gonna do everything they can to get these drugs.
Sounds helpful. Thank you.
Thank you so much.
That was our final question. I will now turn the call to Cedric Francois for closing remarks.
Well, thank you so much, everyone. Thank you, Dr. Bomback, for joining us. Thank you for the people on the line and our analysts. We'll be available the rest of the day to answer any questions should you have any. You can contact Meredith, of course, as always, and thank you for your time. Have a great day.
This concludes today's conference call. Thank you for attending.