Dear ladies and gentlemen, thank you for standing by, and welcome to Alnylam Pharmaceuticals' 2022 RNAi Roundtable conference call. I would now like to turn the call over to the company.
Good morning, everyone, and thank you for joining us for this RNAi roundtable where we'll be discussing our cemdisiran program. Cemdisiran is an investigational RNAi therapeutic in development for the treatment of IgA nephropathy and other complement-mediated diseases. My name is Chris Brickley, and I am Associate Director of Investor Relations and Corporate Communications at Alnylam. With me today, I'm pleased to have Eric Green, Senior Vice President, Head of Development Programs at Alnylam; Sonalee Agarwal, Vice President and Program Leader for cemdisiran; Ishir Bhan, Senior Director of Clinical Research. And I'm pleased to be joined by Dr. Jonathan Barratt, the Mayer Professor of Renal Medicine, the Department of Cardiovascular Sciences at Leicester General Hospital. Today's RNAi roundtable is the first of three roundtable webinars that we're hosting over the next several weeks to review progress across a selection of our programs.
Today's event is expected to run approximately 60 minutes. Eric will moderate the Q&A session at the conclusion of the presentations. And as always, if you'd like to submit a question, you can do so at any time during the event by clicking the Ask a Question button, which is located to the upper right of the slide window. Finally, as a reminder, we will be making forward-looking statements during this webinar, and we encourage you to read our most recent SEC filings for a more complete discussion of risk factors. And with that, I'd like to turn the call over to Eric.
Thank you, Chris. Hello, everyone, and welcome to the first RNAi roundtable of the session here in 2022. As Chris said, I'm Eric Green, SVP and Head of Development Programs here at Alnylam, and today, I will provide just a brief overview of Alnylam, our overall pipeline, before Sonalee and the team dive into the cemdisiran program specifically. Alnylam was founded just over 20 years ago to turn a new discovery in biology, RNA interference, into medicines to treat human disease and help patients hopefully live longer, healthier, and fuller lives.
In the past two decades, Alnylam has pioneered a new class of innovative medicines, leading to five approved products in less than four years, with ONPATTRO as the first-ever RNAi therapeutic approved in August of 2018, and AMVUTTRA as our most recent, with approvals in June of this year in the U.S. and more recently in Europe and the U.K. We are commercializing four of these medicines directly ourselves to the global commercial footprint that we have established. And importantly, we feel our organic product engine is capable of delivering sustained innovation that will drive our future growth. Here is our current clinical stage pipeline. While our initial programs were focused on rare genetic diseases, you can see that our earlier pipeline is more diverse, including several cardiometabolic programs, as well as our first CNS-targeted program, ALN-APP.
That's the green dot near the bottom of the slide, for the potential treatment of Alzheimer's disease and cerebral amyloid angiopathy. Today, as highlighted on this slide, you will see we'll be focusing on cemdisiran, our program in development for the treatment of IgA nephropathy and other complement-mediated diseases. So, as Chris mentioned, please remember to submit any questions you may have during the presentation. We'll keep track of those throughout the session and try to answer them during the Q&A at the very end. With that, I will now hand it over to Sonalee for an overview of the cemdisiran program. Sonalee?
Thank you, Eric. Hello, everyone. I'm Sonalee Agarwal, VP and Program Leader for cemdisiran at Alnylam. Today, I will provide a brief overview of the cemdisiran program in complement-mediated diseases with specific focus on IgA nephropathy or IgAN. Next slide, please. Complement C5 is a genetically and pharmacologically validated target. Cemdisiran is a potent C5 inhibitor that targets C5 in the liver, a predominant site of C5 production. C5 lowering reduces the activity of the terminal pathway of complement, which reduces circulating C5 by up to 99%. This may, in turn, reduce or halt inflammation and tissue damage. Next slide, please. Cemdisiran has the potential to address several complement-mediated diseases alone or in combination with monoclonal antibody. Currently, cemdisiran is being studied as a monotherapy in IgAN, where some maximum levels of complement inhibition may be effective, which we'll talk about in detail today.
In addition, cemdisiran is being studied in combination with pozelimab, an anti-C5 monoclonal antibody, by our partners at Regeneron for myasthenia gravis and PNH, where potent inhibition of C5 may be required. Next slide, please. Briefly, Regeneron is conducting multiple phase III trials in PNH and MG. In PNH, the combination is being studied in PNH-naive patients as well as in patients who switch from eculizumab. In addition, this combination is being studied in adult patients with MG. Next slide, please. We will now focus the rest of the presentation on IgAN. IgAN is the most common primary chronic glomerular disease in the world. We estimate about 350,000-450,000 IgAN cases in the U.S., EU, and Japan. Clinical features include proteinuria, hematuria, and kidney injury. An estimated up to 40% of patients progress to end-stage renal disease.
I will now hand over to Professor Jonathan Barratt, who is the Mayer Professor of Renal Medicine at the University of Leicester. Professor Barratt's research is focused on a bench-to-bedside approach to improving our understanding of pathogenesis of IgAN. He was a member of the FDA, an American Society of Nephrology Kidney Health Initiative, Identifying Surrogate Endpoints for Clinical Trials in IgAN Working Group. He's also a member of the steering committee for the International IgA Nephropathy Network. Professor Barratt, I will hand it off to you.
Thank you very much, Sonalee, so what I'm going to cover in the next 15-20 minutes are the current developments and treatment options for IgA nephropathy. If we can go to the first slide, what you see in front of you is a diagrammatic representation of the kidney, and each kidney is made up of approximately a million nephrons or filtration units, and we are unable to regenerate nephrons, and therefore the number of nephrons you're born with is the number of nephrons you're going to have to use for the rest of your life to avoid kidney failure, and if you lose a nephron, we just cannot replace it, which is really important when we start thinking about how we treat diseases that cause loss of nephrons in significant quantities.
Now, IgA nephropathy is a disease of the glomerulus or the filter that you can see in this diagram, and in terms of diagnosing IgA nephropathy, the only way we can do this is with a kidney biopsy. If we could go to the next slide. You can see a kidney biopsy here being performed. We get a core of tissue, which is examined under the microscope, and as you'll see in the next slide, you'll see an H&E-stained kidney biopsy, and you can see the glomeruli beautifully marked out here as balls of cells with the tubulointerstitium and the tubules surrounding those glomeruli, and we are able to look at the structure of those glomeruli under the microscope, but in IgA nephropathy, the key feature that we see is in the next slide, which you'll see here.
These glomeruli, every single one in both kidneys, light up with the IgA protein, which is deposited within those glomeruli and triggers inflammation and scarring. And the importance to this presentation is if I was to stain for complement, the C3, it would look almost identical. So wherever we are seeing those IgA deposits within those filters, we will also see evidence of complement activation. And that's why targeting the complement system, I think, is going to be critical to our future management of IgA nephropathy because we always see complement activation in this condition, and it's associated with the inflammation and scarring of those filters. If we go to the next slide, just some basic features. As Sonalee has already said, IgA nephropathy is the commonest pattern of primary glomerulonephritis across the globe.
It's responsible for the development of kidney failure in up to 50% of patients over a 20-25 year period. But as most patients with IgA nephropathy are diagnosed in their 30s, we need to really start thinking about lifetime risk of kidney failure. And we've done some work in the U.K. using the Rare Disease Registry. And it's likely that most patients with IgA nephropathy will be at risk of developing kidney failure in their lifetime because they're diagnosed in their 30s, and they have another 40-50 years' worth of life they need to get out of their kidneys. And as I said at the beginning, when you lose nephrons, you can't replace them. So this is a significant problem for these people. We know that globally, one in 10 patients is on dialysis because of IgA nephropathy.
That's heavily skewed towards East and Southeast Asia, but globally, it is a significant problem, and we know that if patients are fortunate enough to get a kidney transplant, this disease recurs in the kidney transplant, and it is a significant source of loss of kidney transplants and having to return to dialysis for our patients, and you've already had the disease burden mentioned by Sonalee, but here you can see figures for the U.S., estimated prevalences for the EU, and you can see far more commonly seen in East and Southeast Asia, with over 800,000 people estimated to have IgA nephropathy in China alone. If we go to the next slide, this disease has been known about for over 50 years now, but in 2022, we still have severely limited treatment options for our patients, and hopefully, that's going to change over the next five years.
As I've said, I strongly believe that complement therapies are going to play a critical role in how we go about treating IgA nephropathy for the foreseeable future. If we go to the next slide, what I want to do here is just briefly talk you through what we understand at a high level about the pathogenesis. We think the main feature is the formation in the circulation of IgA-containing immune complexes listed as five in this diagram. And we think the main substrate for those immune complexes forming is this abnormal form of IgA. A lot of people call it Gd-IgA1, but it's poorly galactosylated, so it has changes to the sugars at the hinge region, and it's a polymeric form of IgA.
We think this IgA is derived from the immune system of the mucosal tissues, so those immune cells that line our respiratory tract, our gastrointestinal tract, our genitourinary tract. We think that these immune complexes form both by these IgA molecules, these Gd-IgA1s, sticking to one another, but also potentially triggering an autoimmune response where we have antibodies that react against these IgA molecules, and these amplify the size of those immune complexes. Of course, all of this occurs against a genetic background. That genetic background not only determines whether you're likely to develop IgA nephropathy, but if you develop IgA nephropathy, it also determines whether you're likely to develop rapid kidney failure or not. That's what we think is happening systemically in this disease. What happens when we get into the kidney itself?
So if we go to the next slide, these immune complexes deposit in those fine filters, and I showed you that kidney biopsy lighting up in green. The presence of those immune complexes triggers the resident mesangial cells to proliferate. They release pro-inflammatory and pro-fibrotic cytokines and mediators. This, in turn, recruits into the glomeruli inflammatory cells, which can get to the point of severe inflammation or so-called crescent formation. We see these soluble mediators crossing the filtration barrier and interacting with podocytes in the glomeruli and the tubular epithelial cells, activating those cells, damaging those cells. And actually, these immune complexes can cross a damaged filtration barrier and come into direct contact with podocytes and tubular epithelial cells. And all of these features drive the changes that I see when I look at a kidney biopsy in IgA nephropathy.
And you'll see in brackets M, E, C, S, and T. Those are the features of the Oxford classification by which we score all kidney biopsies in IgA nephropathy. Each of those features independently predicts outcome. And so the kind of features we're seeing in the laboratories, for instance, podocyte injury, is a key precursor to glomerulosclerosis, which is the S score segmental sclerosis. And we can recapitulate those features in the kidney biopsy with what we see when we culture kidney cells and we run animal models. And what is absolutely clear is that all of these features are amplified significantly if we also have complement activation. And that, again, is underpinning why I think inhibiting the complement system is going to be critical in how we manage this disease going forwards.
If we just go to the next slide, if you want to find out about the current treatment and the unmet need in any of the glomerular diseases, this is the best article you're likely to read. This was produced at the end of last year and really sums up the world literature in all glomerular diseases in terms of what we understand about best ways to treat, best ways to monitor, best ways to diagnose. And I'm just going to run you through what we wrote for the IgA nephropathy chapter. And what you see here is if you make a diagnosis of idiopathic IgA, which is the type of IgA I'm talking about here, and it's the type of IgA that we are including in all the clinical trials, we need to score the kidney biopsy with that Oxford score.
We need to risk stratify our patients with the risk prediction tool, ideally enroll patients in a registry, but most importantly of all, commence optimized supportive care. And that involves blood pressure management, maximal RAS inhibition, lifestyle modification, and addressing cardiovascular risk. But even if we do this to the best that we can, patients will still develop progressive kidney failure. They will develop it more slowly, but they will still develop progressive kidney failure. And we are in desperate need for additional therapies. So if we look at the next slide, what you will see here is that if you still have significant proteinuria, after you've had three months of optimized care, that has identified you as being at high risk of progressive kidney damage.
Our first point of call, reviewing all the world literature on all treatments that have been assessed up to 2021, was the best option we felt was to enroll a patient in a clinical trial because there were no safe and reliably effective therapies, we believed, out there to treat IgA nephropathy. If, however, there were no clinical trials available or the patient did not want to or was unsuitable, you could consider systemic corticosteroids. Because we know of their toxicity and their poor tolerability by patients, there needed to be a thorough toxicity risk stratification before you considered them. For the commonest glomerular disease in the world, we have so little evidence of how best to treat it above supportive care, our major recommendation in 2021 was to put patients into clinical trials of new therapies because we desperately need them.
How does this fit with what patients think? Again, if you are interested in IgA nephropathy, this is a free report that you can easily access from the NKF website. It was led by the FDA and the IgA Nephropathy Foundation. It talked to patients about current treatments and what their aspirations were for the future. What you can see here in the next slide is the key themes from those patients. They talk about their symptoms. They talk about the impact on their mental health. In particular, they talk a lot about the symptoms that the treatments actually cause rather than the disease itself. By treatments here, we're talking about systemic glucocorticoids. If we go to the next slide, you'll remember that the KDIGO guidelines were to put patients into clinical studies. Is that acceptable to patients?
And this workshop absolutely endorsed that approach because patients were more than willing to be approached and to be involved in clinical trials. And that was an overwhelming response when asked, both by the IgA Nephropathy Foundation but also by the FDA members who attended the meeting. And if you look at that very last bullet point, you can see here the real problem we have with corticosteroids, which are the only treatment that some clinicians use at the moment. And that is that they have a significant negative impact on patients. And if you ask any IgA nephropathy patient if they've had systemic steroids, they will tell you they never want them again. No matter what they do to their kidneys, the side effects are so intolerable that they just do not want to be exposed to these medications.
And so if we go to this final slide, again, this reinforces our approach from KDIGO. We want our patients in clinical studies. Patients are happy and want to be in clinical studies, and they understand our rationale for looking at reductions in proteinuria and protection of kidney function. And they are willing to think about taking new treatment options based on this kind of data that is being generated. So if we go to the next slide, so these are the research recommendations in the KDIGO guidelines. And actually, this is very similar to all of the CNS in that what we want to have are therapeutic strategies that minimize or avoid completely systemic corticosteroid exposure. And so in IgA nephropathy, we have a number of studies ongoing at the moment. Some are looking at non-immunosuppressive supportive care.
And here we have the endothelin receptor antagonists, sparsentan and atrasentan. We have data coming out from SGLT2 inhibitors such as dapagliflozin. If we go to the next slide, we also have therapies that are targeting specific aspects of the pathogenesis. And so we have targeted release formulation of budesonide. We have inhibition of B-cell activation, and we have inhibition of complement system. And that's what I'm going to really focus the remainder of my talk on. If we go to the next slide, here you'll see the current phase III clinical studies that are either in follow-up or recruiting at the moment. And you can see here NEFECON, which is the NEFECON, which has now been approved.
The importance of that, above anything else, is it shows the regulators will approve a therapy on a surrogate marker, a nine-month change in proteinuria, which I think is fantastic for drugs like cemdisiran, where you can have a very clear regulatory pathway in terms of what it's going to take for a phase III study. We've got the PROTECT study in follow-up, and then we've got these other four studies, ALIGN, APPLAUSE, ARTEMIS, and VISIONARY, that are in recruitment at the moment. You will see, looking at the primary interim endpoint, all are looking at early changes in proteinuria. If we go to the next slide, so complement activation, I hopefully have convinced you it's important in IgA nephropathy. If we go to the next slide, it was identified very early on in the 1970s as being absolutely critical to the development of inflammation in IgA nephropathy.
If we go to the next slide, I'm not going to summarize the literature for you other than to say if we look at all the studies that have been measured, blood biomarkers of complement activation, if we measure the degree of complement activation in the kidney, or we measure complement markers in the urine, unequivocally, the more complement activation you have in IgA nephropathy, the worse your outcome. Now, that's observational. The proof of the pudding, of course, is if we can block complement activation, can we improve outcome? And so if we go to the next slide, this was able to be tested for the very first time with the introduction of eculizumab, monoclonal humanized antibody to C5.
If we go to the next slide, we can see that there were early case studies, single studies of patients who were given eculizumab, and this showed that actually you could alter the natural history of IgA nephropathy, giving us information to tell us that this approach could be valuable. If we go to the next slide, so what we have now is we have a number of studies that are looking at complement inhibition in IgA nephropathy, targeting different aspects of the cascade. We have cemdisiran, which you're going to hear a lot more about from Ishir. We've got a phase II study of ravulizumab, currently recruiting. If we go to the next slide, we've had a very small open-label study published of avacopan of seven patients showing some efficacy, showing that actually blocking C5a can be advantageous in IgA nephropathy.
If we go to the next slide, we've got a small basket trial of pegcetacoplan. I haven't seen any of the IgA nephropathy data from this study yet. It may well be presented at the ASN meeting coming up. But we've got a C3 approach as well, which has been tested. The next slide, we can focus in here on the lectin pathway with narsoplimab, which targets the MASP-2 protease. And what you've seen from the early data here is that blocking the lectin pathway can reduce proteinuria, again reinforcing the importance of blocking complement in IgA nephropathy and impacting on outcome. If we go to the next slide, we then have drugs targeting the alternative pathway, and the one most advanced and in phase III is iptacopan, which has early phase II data, again supporting an antiproteinuric effect of blocking complement activation.
If we go to the next slide, so where do I see the next 10 years? The next slide, I think it's going to be exciting. I think in the next slide, you'll see we're going to have new therapies for our patients. In my final slide, what you'll see is we're going to have therapies that are able to treat in a non-immunosuppressive way, such as endothelin receptor antagonists, SGLT2 inhibitors. We're going to be able to switch off the production of pathogenic IgA with mucosal steroids or B-cell-directed therapies. Critically, we're going to be able to also turn off the complement system because from the data, you'll see that Ishir is going to present, and that will be presented at scientific meetings coming up. If we can target the complement system, we can get inflammation under control very, very quickly in the kidneys.
And that means we can start saving nephrons very, very early on in the disease process. And that, I think, is going to be critical if we're going to keep our patients' dialysis for the duration of their life. So I'm going to finish there, and I'm going to hand over to Ishir now, who's going to give the data on the phase II studies. So over to you, Ishir.
Thank you, Professor Barratt. I'm Ishir Bhan, a Senior Director in clinical research and the clinical lead for the cemdisiran program, and I will be presenting the cemdisiran phase II data. Next slide, please. The cemdisiran phase II trial is a randomized double-blind study in patients with IgA nephropathy or IgAN. The patient population included 31 patients with biopsy-proven primary IgAN. All patients had persistent proteinuria of at least 1 g/ day and an estimated glomerular filtration rate or eGFR of at least 30 mL/ min/ 1.73 m² . All patients were on stable optimal treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for at least three months, unless they were unable to tolerate this therapy. Including patients must have been free of steroid or other immunosuppressive treatment for at least six months prior to enrollment.
Following a 14-week run-in period, patients were randomized in a 2:1 fashion to either cemdisiran or placebo for a 36-week treatment period. All patients continued on their baseline standard of care therapy with ACE inhibitors or ARBs throughout the study period. Week 32 assessments included the primary endpoint of % change from baseline in the 24-hour urine protein- to- creatinine ratio or UPCR. Selected secondary endpoints included % change from baseline in the 24-hour urine protein, change from baseline in UPCR as measured by spot urine, and incidence of adverse events. Exploratory endpoints included change from baseline in eGFR, markers of renal damage and inflammation, and measures of complement activity. Patients optionally continued into an open-label extension period. Next slide, please. Baseline demographic and disease characteristics were largely similar between the groups. Mean age in the placebo and cemdisiran groups were 37.6 and 40.5 years, respectively.
The population had a slight Asian predominance, consistent with the expected demographics of the disease. BMI was 26.8 and 30.4 kg/m² in the placebo and cemdisiran arms. The time since diagnosis was 2.5 and 1.8 years, respectively. Blood pressure was well controlled in both groups. The mean baseline 24-hour urine protein was 2.9 and 2.5 in the placebo and cemdisiran groups, respectively, with corresponding UPCRs of 2 and 1.6 and eGFRs of 61 and 72. All but one patient in each group was on background therapy with an ACE inhibitor or ARB. Next slide, please. The primary endpoint of change from baseline in 24-hour UPCR at week 32 demonstrated a placebo-adjusted reduction of 37.4% in the cemdisiran arm. The secondary endpoint of change from baseline in 24-hour urine protein unadjusted for creatinine demonstrated a similar placebo-adjusted reduction of 36.2%.
A similar magnitude of effect was observed at an earlier week 16 assessment. The magnitude of these results is believed to be clinically meaningful. Next slide, please. A higher proportion of patients demonstrated reductions in 24-hour UPCR with cemdisiran at clinically relevant thresholds compared with placebo at week 32. 31.8% of patients treated with cemdisiran achieved at least 50% reduction in 24-hour UPCR at week 32, compared with 12.5% of placebo-treated patients. A greater percentage of cemdisiran-treated patients also demonstrated efficacy when measured as either a 30% or greater reduction or when measured as any reduction of UPCR from baseline. Secondary endpoints also included change from baseline in UPCR as measured in spot urines, which were measured from a single voided urine sample instead of a 24-hour collection.
This assessment demonstrated a placebo-adjusted reduction in proteinuria of 45.8% at week 32, consistent with a clinically meaningful reduction and providing similar evidence of efficacy to the 24-hour urine data. Spot urine assessments were conducted every four weeks and demonstrated an onset of effect by week eight that remained stable over time. With respect to safety, no adverse events or AEs led to treatment or study discontinuation. One death, which was also considered both a serious and severe AE, occurred in the cemdisiran treatment arm. This was a consequence of postoperative complications following coronary artery bypass surgery and was not considered related to study drug. Two treatment interruptions occurred in the cemdisiran arm, both considered related to study drug. One patient had urticaria, and one patient had an atopic dermatitis flare-up.
AEs occurring in at least 10% of patients in the cemdisiran arm included injection site reactions or ISRs in 40.9% and peripheral edema in 13.6%. The majority of ISRs were mild and transient. Events of peripheral edema were reported as mild and not related to cemdisiran. There were no safety signals regarding liver function tests, hematology, or renal function related to cemdisiran. In summary, multiple subcutaneous doses of cemdisiran led to a clinically meaningful reduction in 24-hour UPCR observed at week 32 relative to placebo. There was a 37.4% reduction in 24-hour UPCR at week 32 relative to placebo, and 31.8% of patients treated with cemdisiran achieved at least a 50% reduction in 24-hour UPCR at week 32, compared with 12.5% of placebo-treated patients.
Spot urine data are consistent with 24-hour urine data and remain stable over time with an initial treatment effect emerging at weeks. Cemdisiran was generally well tolerated in patients with IgAN. The most frequent adverse events were injection site reactions and peripheral edema, and no AE led to treatment or study discontinuation. These data support further evaluation of cemdisiran as a potential therapy in IgAN. We thank the patients, their families, investigators, study staff, and collaborators for their continued participation in the cemdisiran phase II IgAN study. I will now turn it back over to Sonalee.
Thank you, Ishir. To briefly summarize, we are quite excited about the potential of developing cemdisiran in IgAN and complement-mediated diseases. IgAN affects approximately 350,000-450,000 patients in the U.S., EU, and Japan and has limited treatment options. As discussed today, the phase II data shows clinically meaningful results across multiple endpoints with no safety concern. We continue to conduct additional phase II analysis, and phase III study planning and discussions are ongoing. Finally, our partners at Regeneron continue development of cemdisiran in combination with pozelimab in PNH and MG. I will now turn it over to Eric to moderate the Q&A session.
Great. Thank you, Sonalee. And thank you to Professor Barratt and Ishir for walking through the data. It's great seeing some questions come into the webcast, but please continue to put more in clicking on that Ask a Question button on the upper right. So maybe I'll start off going to you, Ishir, on the data you just mentioned and the 37% reduction relative to placebo in UPCR. You mentioned that's clinically meaningful. Can you expand a little bit more about why we think that is?
Sure. We're very pleased with the top-line results here showing 37% mean UPCR reduction relative to placebo. Proteinuria is a well-established predictor of progression to renal failure, so we believe these results are clinically meaningful. Furthermore, we believe the favorable results seen in the secondary endpoints are quite encouraging as well.
That's great. Earlier in the presentation, Professor Barratt said today there are rather limited options available for treatment. Maybe lots in development. We can get to that in a minute. But with all the caveats, no head-to-head study has been done. But how do you think about putting these results from our phase II study in context with what's currently available?
Sure. Given only one FDA-approved product, which is TARPEYA, which is a steroid, there are limited options for patients. Importantly, proteinuria is a well-established predictor of progression to renal failure in IgAN, so we believe a reduction in proteinuria is clinically important. In addition, we saw encouraging results on a number of secondary endpoints. We cannot compare directly to other drugs in development since, as you mentioned, there are no head-to-head trials. However, based on the available data and KOL feedback, we believe the safety and efficacy of cemdisiran observed to date has the potential to provide a meaningful treatment option for patients within IgAN.
Great. Thanks, Ishir. Maybe going to Professor Barratt. There's lots of different ways that are being explored to try to treat this disease. But maybe you could talk a little bit more, and you went through quite a bit. But why do you believe complement inhibition, and maybe even specifically C5 inhibition, could be a promising strategy for the treatment of IgAN?
Thanks. Yeah. So I think one of the things I was trying to allude to is we diagnose our patients late because it's an asymptomatic disease. And because we can't regenerate nephrons, we have to fight really hard to keep the nephrons the patient has at the time of diagnosis surviving for the remainder of that person's life. And so when I make a diagnosis on kidney biopsy, I can see the inflammation. I can see the complement activation. And what I want from a therapy is I want to be able to turn that inflammation off as quickly as I can to preserve those nephrons that are still going to be able to survive. And that's where a complement therapy really offers a great opportunity to be able to switch that inflammation off, to be able to switch down infiltration of inflammatory cells, and to preserve nephron function.
I have to say I think we will be using these agents with other agents at the same time to try and switch off the production of pathogenic IgA. But I think those will take time. What we need is an urgent, quick treatment that will reduce inflammation quickly. That's where complement inhibition is going to be key. C5 clearly sits in an integral, important downstream part of the complement cascade. If you block C5, you're going to stop production of the anaphylatoxin C5a. We've seen with the avacopan data in that very small study I mentioned that that can have very positive effects. We're also going to stop the production of the membrane attack complex, which we know is present in the glomeruli and IgA nephropathy.
We know at sublytic concentrations it is causing mesangial cell activation and driving the production of those inflammatory factors I talked about in my presentation. So I think inhibiting complement is going to be a mainstay for treatment of IgA nephropathy in the future, and C5 represents an obvious target to me to try and hit those anaphylatoxin and C5b-9 productions that we know are driving glomerular inflammation.
Excellent. You mentioned this is an asymptomatic disease. So kind of maybe walk us through a little bit of a patient shows up in your clinic. How do you consider or think about IgAN as a potential diagnosis? And what are some of those key clinical features of a patient that walks in with this disease?
Yeah. So unfortunately, most of the time, the patient hasn't got a clue they're ill. And they've been picked up by chance because I've had their urine dipsticked, or they've had their blood pressure measured, or they've had their kidney function measured. So most of the time, patients come in thinking, "What's all the trouble about? Why am I seeing a kidney doctor?" But the presence of blood and protein in the urine, once you've done some basic tests, is synonymous with inflammation in the glomeruli, and it needs a diagnosis. We don't have any blood tests that help us make that diagnosis in IgA nephropathy, and so we move straight to kidney biopsy. So the identification of significant levels of blood and protein is the key factor.
And as I say, it's often a bolt out of the blue and very upsetting for the patient when you tell them they've got a diagnosis of a chronic kidney disease with a significant risk of developing kidney failure when they thought everything was fine and they had no symptoms. So I think what's great about where we are at the moment is I can tell my patients now that actually we are going to have some treatments, and we may well be able to keep this disease under control and stop you developing kidney failure in the future. I couldn't have done that five years ago. But with data like you've just seen and the other studies that are going on, I think we've got a realistic possibility of being able to manage this disease over the long term.
So there's kind of two ways I want to take from that last statement. But first, maybe then on the diagnosis, any sense of what the diagnosis rate is for these patients? We saw fairly large numbers of prevalence that is theoretically out there. But how many of those patients roughly do you think we're seeing in clinic?
In my practice in the U.K., we cover a population of 2 million. We will be diagnosing around 30 cases a year. But that's underdiagnosing. I think we've got to be really clear about this. These are the patients who fortunately have a urine dipstick test, or fortunately have their blood pressure checked, or fortunately have had a blood test. There is a lot of IgA out there that is just not diagnosed. We did a study of the U.K. Biobank, which has 500,000 U.K. people. They've all been genotyped. We took all the genetic risk alleles from the Genome-Wide Association Studies, generated a genetic risk score, and looked in that population and looked at the likelihood of patients who have any history of blood in the urine, any history of proteinuria, any history of high blood pressure.
We reckoned that one in five of those people had IgA nephropathy as the cause. It just wasn't diagnosed. We're talking about many thousands of patients here in terms of just from the U.K. Biobank alone. I think there is a massive underdiagnosis of IgA nephropathy out there.
Thank you. The other part of the previous last statement you mentioned was kind of chronic kidney disease presents potentially chronic treatment. So what would be your thoughts about long-term treatment of IgAN with a complement inhibitor such as cemdisiran?
My view is I think we're going to move very much towards induction remission and maintenance and remission maintenance therapy. I think complement therapies fit very nicely into induction remission. I think they fit very nicely into treatments of relapse. I think in terms of maintenance of remission, my guess is we will be using cyclical treatments to try and maintain remission and limit exposure to immunomodulatory drugs. It's really in uncharted territory. We will be using drugs in combination. I don't think we have anything that is going to be permanently curative, and therefore we are going to need long-term therapy. Of course, all the clinical studies at the moment finish at two years. That's the data we will have. In my view, we will have induction therapy. Then we will have maintenance of remission. They will look different for different patients.
And different patients will require different levels of medication to keep them in remission because we know how heterogeneous this disease is. And what we desperately need, therefore, are biomarkers to help us monitor response to therapy. And I know I've been chatting with Ishir and the team about looking at biomarkers to help monitor response to cemdisiran. And these are going to be things that are going to be incredibly useful to us clinicians when we need to work out how on earth we're going to use these drugs over 10 and 20 years or more in patients with IgA nephropathy. So at the moment, I can't give you a clear answer because we just don't have any data. But I think we're going to be leading complement inhibitors long term in our patients, probably used cyclically, definitely used for relapses.
I think it would vary from patient to patient.
Excellent. Another question. Question came in a little bit more on the disease itself. So once treatment's initiated in this disease, where do these IgA deposits go? So the question is, do they stay lodged in the kidney but without activation of complement? Or is there any other thoughts about kind of how the disease responds to treatments that we've used so far?
Yeah. So the best example there is if we have a treatment that turns off the production of pathogenic IgA, over time, those IgA deposits are likely to disappear from the kidney. And the reason I say that is there are reports of kidneys that have been removed for transplantation that actually had IgA nephropathy. And that was an error, but it happened. And these kidneys were transplanted into people who had kidney failure, but the kidney failure wasn't due to IgA nephropathy. So they had a normal circulating IgA system. And what happens is when those transplant kidneys were biopsied some three, six, nine, 12 months later, those IgA deposits that were there disappeared because the kidney wasn't being inundated with abnormal IgA immune complexes and therefore had an ability to clear what had been deposited. It just needed time to do it.
So for me, where I see treatment going is that we will give complement inhibitors to switch off all that inflammation, accepting there are IgA deposits there. And then with therapies to stop the production of the pathogenic IgA, over time, we will reduce the rate at which those immune complexes accumulate. We may not stop it completely. So there may well be a little bit of inflammation, which is why we might need a continued exposure to an anti-inflammatory such as a complement inhibitor. But we are going to be able to reduce down that amount that is accumulating significantly and therefore protect the kidney in the long run.
Helpful. Very helpful. Any other questions? Just starting to come in. I appreciate that. And these are really exciting. So please continue others on the line. If you have more questions, please feel free to enter them. There's a question about proteinuria improvement slightly waning. So I think this is Ishir looking at the phase II data. So maybe I'll go to you first. It looks like the results kind of flattened between week 16 and 32. Any insights on that? Is that kind of the maximal effect we should expect? Or how would you think about interpreting those data?
I think what we see is fairly consistent results from week 16 to week 32. It's important to remember this is a small study. There are expected to be fluctuations over time, but those are not necessarily statistically meaningful. What we've seen so far is that both from the spot urine data that you saw as well as the 24-hour urine data is that those measures are stable over time. We're continuing to follow patients in the open- label extension period, and we'll have more data to report in the future.
That's a great point. That always is an interesting point, right? So up to how many years do we continue to follow those patients?
Currently, three years.
Three years. Okay. So we'll see that long trend. We won't have the placebo arm, I presume, at that point, obviously, but we'll see how the cemdisiran arm continues.
That's right, and the placebo patients will transition onto cemdisiran in that open-label extension.
Okay. So you'd see that transition. That's great. Maybe related to that, Ishir, you'd mentioned some additional analyses. What else do we think we would plan to disclose at future medical conferences? If I share too much, unfortunately, but.
Sure. So future presentations could include initial data from the phase II on eGFR, for example, as well as data on other measures of complement level and activity. Dr. Barratt mentioned we're looking at a number of biomarkers.
Great. Thank you. So the question just came in. Dr. Barratt commented on how he thinks about long-term safety of complement inhibition in IgA patients. And maybe that's kind of related to the earlier question on long-term treatment, but maybe specifically on the safety of this question. Professor Barratt?
Yes, so obviously, we're worried because the complement system is there to help us fight pathogens. And therefore, we are worried that complement inhibition will increase the risk of infection. I think it's fair to say, and Ishir, correct me if I'm wrong, but there really was no signal for infection in the phase II study, and certainly, when you look at the data for other complement inhibitors in IgA nephropathy across the board, there has not been a safety signal with regard to significant infectious episodes that is worrying at all, which is good for the class of drug. I think in terms of cemdisiran, the safety profile, I think, is very reassuring. I think we clearly have to think about immunization for encapsulated organisms, and that is part and parcel of the protocol and routine and part of the course.
But to date, we haven't seen any significant cause for concern. Now, clearly, these are all short-term studies, and we are going to need more longer-term data. But of course, you have to remember that IgA nephropathy is a different disease to something such as atypical hemolytic uremic syndrome or other diseases where complement inhibitors are used. So I don't think we can necessarily extrapolate from one glomerular disease to another because background therapy, organ involvement is different, and therefore risk of infection is different. But certainly, the data I've seen in IgA nephropathy is very reassuring, but it's something that is clearly on the radar and will be looked at in all the phase III studies and in post-marketing phases.
Excellent. So you mentioned other complement diseases, immune diseases. Maybe I'll ask two kind of related questions. Earlier, we presented that PNH and MG are being studied by our partner, Regeneron, but using a combination with a monoclonal antibody. With IgAN, we've shown here monotherapy efficacy data. Maybe, Professor Barratt, if you had any thoughts or opinions, why do you think that combination may be necessary or effective in PNH and MG but not required in IgAN, we believe?
Yeah. So I think both of those diseases you mentioned are exquisitely sensitive to small levels of complement activation. And that is, in my view, why you need to be getting 99% plus inhibition of complement to prevent hemolysis, certainly in PNH. IgA nephropathy is a bit more of a sluggish machine. It's not as highly strong. And therefore, you don't need to get that 99% inhibition to have clinical effectiveness. And it's just the nature of the disease. And it doesn't surprise me at all. In fact, I wouldn't want to inhibit the complement system 100% in IgA nephropathy. I'm very happy with the levels of complement inhibition we're seeing across the studies because, of course, if we're not getting that degree of inhibition, it means there is still complement system available to treat and target pathogens.
So I think we've got to ensure we have the good situation here where IgA nephropathy, its efficacy is not dependent on complete inhibition of complement activation, which therefore means we reduce that risk of infection because we have complement activity to deal with pathogens. But I think it's the very nature of the disease. But it doesn't surprise me with PNH where you can get breakthrough hemolysis really with very little disturbances in overall complement activation.
Excellent. Very helpful. And then maybe from your perspective, thinking about other renal diseases beyond IgAN, where else could you think about complement inhibition being clinically useful?
So people may or may not know, but I would just signpost this. There is a KDIGO's controversies meeting, which I'll be attending in Florence on Thursday, which is dealing exclusively with the role of complement in complement-mediated kidney diseases. And this is going to have a variety of work groups. And we're going to be looking at IgA nephropathy, IgA vasculitis, membranous nephropathy. We're going to be looking at C3G, atypical hemolytic uremic syndrome, lupus, antiphospholipid syndrome, all the ANCA-associated vasculitis. We're going to be looking at all of the diseases where there is already some headway in terms of complement therapies. But actually, there's a whole workstream looking at diabetic nephropathy and FSGS, which are two diseases not traditionally thought of as complement-mediated. But there is data starting to accumulate that the complement system may be important in these two diseases.
So I would ask anyone on the call who's interested in this area to look out for this conference. There'll be a publication that will come out, which will really synthesize the current state of the art in the evidence for these diseases being mediated by complement and where complement therapies may fit in. But this is something that will be happening in this coming week. But there's a whole range of glomerular diseases where I think complement therapies are going to prove themselves to be really useful in the future.
Thank you. Ishir, maybe back to you on the phase II data set. Did we capture any data on the patient-reported symptoms and some of the challenges that Professor Barratt had mentioned earlier? Do we have any data on that or anything we can share at this moment?
Nothing to share at this moment. That is something we'll be looking at. But as Dr. Barratt mentioned, patients are generally asymptomatic with this disease. So that is one of the limitations of assessing patient-reported symptoms.
Yep. Okay. That makes sense. A few more minutes left, so please send any more last-minute questions you may have. Maybe I'll turn to Sonalee now. And if you could just, you mentioned Regeneron as our partner, but maybe you can go a little bit deeper into what that relationship is and kind of how we split up the portions of this program?
Sure, Eric. The development of cemdisiran as a monotherapy, such as in IgAN, is conducted under a Co-Co agreement where Alnylam is the lead party. Regeneron has contributed to the cost of running the current phase II study. Regeneron leads the development of cemdisiran in combination with pozelimab in PNH and MG. Alnylam does not contribute to development expenses. However, we will receive commercial milestones and royalties in connection with commercial sales.
Okay. Thanks. And maybe for a little bit finer point on it, somebody asked a question about what is it that Regeneron's providing, in particular those programs where they're leading, that we couldn't have ourselves, essentially? And I think probably the monoclonal antibody is the obvious answer, right?
Yes. That's right, Eric. I think, again, as Dr. Barratt said, right, we need potent inhibition of C5 for PNH and myasthenia gravis, and adding a monoclonal antibody to cemdisiran allows for that.
That's great. Okay. Any last questions? Please take a few seconds here to send it in. Otherwise, I think we're getting pretty close to the end. Maybe one more for you, Sonalee, then. Kind of what are the next steps for cemdisiran that we're taking?
Absolutely. As we said, we are very excited about the phase II data, and so we are doing further analysis of our phase II results and discussing with Regeneron that will inform future steps in IgAN, as well as help identify other potential opportunities for cemdisiran. We believe the phase II data are robust and, as such, support further development of cemdisiran in IgAN.
Excellent. I think we've gotten through most, if not all, of the questions, so maybe at this point, I'll again thank everyone for your questions, for attending this session. Thank you to Sonalee and Ishir for presenting on our side, and of course, to Professor Barratt. I think excellent presentation and great depth of knowledge on the disease and really helpful for us, so with that, I will turn it over to Chris for a few closing comments.
That's great. Thank you very much, Eric. And thanks again to all of our speakers this morning. That does conclude today's RNAi roundtable. As always, you can visit the Capella section of Alnylam's website to access a replay of the webinar along with slides and a transcript when available. I'd also like to remind you that we have two more upcoming roundtables over the coming weeks. The next will be on October 21st, where we'll discuss the Alnylam Engine for Sustainable Innovation. And then on November 1st, we'll discuss CNS delivery and ALN-APP in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. Then we'll wrap up 2022 with a virtual R&D day on December 15th for a deeper dive into other pipeline programs and platform activities, including advancements in our TTR franchise. So save the date and stay tuned for additional details there.
That concludes today's event. Thank you all for joining, and have a great.