Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Good day, 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 today, The Mayer Professor of Renal Medicine, the Department of Cardiovascular Sciences at Leicester General Hospital. Today's RNAi Roundtable is the first of 3 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. [Operator Instructions] 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 2 decades, Alnylam has pioneered a new class of innovative medicines. We [ now have ] 5 approved products in less than 4 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 4 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, as the green dot near the bottom of the slide, for the potential treatment of Alzheimer's disease in 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 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 ambition may be effective, which we'll talk about in details 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 other 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 to 450,000 IgAN cases in 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 University of Leicester. Professor Barratt's research is focused on a bench to best site approach to improving our understanding of pathogenesis of IgAN. He was a member of the FDA and American Society of Nephrology Kidney Health Initiative, identifying surrogate endpoint for clinical trials in IgAN Working Group. And he is 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 to 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 1 million nephrons or filtration units. And we are unable to regenerate nephrons, and therefore, the number of nephrons you're born with, it's 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 tubular interstitium 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 kidney 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 for 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- to 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 to 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, 1 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 lots 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 Eastern 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 2020, we still have severely limited treatment options for our patients. And hopefully, that's going to change over the next 5 years. And 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. So we think the main feature is the formation and the circulation of IgA-containing immune complexes listed as 5 in this diagram. And we think the main substrate for those immune complexes forming is this abnormal form of IgA. Lot of people call it Gd-IgA1 with its poorly galactosylated changes to the sugars at the hinge region, and it's a polymeric form of IgA. And we think this IgA is derived from the immune system of the mucosal tissues. So those immune cells that line our respiratory tract or gastrointestinal tract or genitourinary tract. And we think these immune complexes formed both by these IgA molecules, these Gd-IgA1 ones 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. And of course, all of this occurs against a genetic background and 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. And so 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 about kidney biopsy lighting up in green. The presence of those immune complexes trigger the resident mesangial cells to proliferate. They release pro-inflammatory and profibrotic 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 forward. 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 the 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 target IgA I'm talking about here, it's the type of IgA that we are including in all the clinical trials. We need to score the kidney biopsy with [indiscernible] score. We need to risk stratify our patients with the risk prediction tool, ideally enroll patients in the registry but most importantly of all, commence optimized supportive care. And that involves blood pressure management, maximum 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 have 3 months of optimized care, that has identified you as being a high risk of progressive kidney damage. And our first point of call reviewing all the world's literature and all treatments that have been assessed up to 2021 was the best option we found was to enroll a patient in the clinical trial because they 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 you or was unsuitable, you could consider systemic corticosteroids. But because we know of their toxicity and their poor tolerability by patients, there needed to be a thorough toxicity risk stratification before you consider them. So 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. And just how does this fit with what patients think? Well, 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, and it talked to patients about current treatments and what their aspirations were for the future. And what you can see here in the next slide is the key themes from those patients. And you can -- they talk about their symptoms, they talk about the impact on the mental health, but in particular, they talk a lot about the symptoms that the treatments actually cause rather than the disease itself. And 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, but 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 physicians 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 have systemic steroids, they will tell you they never want them again. No matter what they do for 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 GMs 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 antagonist, sparsentan and atrasentan. We have data coming out from SGLT2 inhibitors, such as dapagliflozin. If we go to the next slide. We also have a repeat of 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, NefIgArd, which is the Nefecon, which has now been approved, and the importance of that above anything else is it shows the regulators will approve the therapy on a surrogate market and 9-month change in proteinuria, which I think is fantastic for drugs like cemdisiran, where we 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 4 studies, ALIGN, APPLAUSE, ARTEMIS and VISIONARY that are in recruitment at the moment. And you will see looking at the primary interim end points 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 our IgA nephropathy. If we go to the next slide. It was identified fairly early on in the 1970s has been 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 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. And 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 shows 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 this year. 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 7 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, but 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 is being tested. The next slide, we can focus in here on the lectin pathway with narsoplimab which targets the MASP2 protease. And what you've seen from the early data here is the 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. And 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. And I think in the next slide, you'll see we're going to have new therapies for our patients. And 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 a receptor antagonist, SGLT2 inhibitors. We're going to be able to switch off the production of pathogenic IgA with mucosal steroids or B-cell-directed therapies, and critically, we're going to be able to also turn off the complement system because from the data, you'll see that this year 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 in the disease process. And that I think is going to be critical if we're going to keep our patients off 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 study. So over to you, Ishir.

Thank you, Professor Barratt. I'm Ishir Bhan, 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 and hematuria. All patients had persistent proteinuria of at least 1 gram per day and an estimated glomerular filtration rate, or EGFR, of at least 30 ml per minute per 1.73 meters squared. All patients were on stable optimal treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for at least 3 months unless they were unable to tolerate this therapy. Including patients must have been free of steroids or other immunosuppressive treatment for at least 6 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 percent change from baseline in the 24-hour urine protein to creatine ratio, or UPCR. Selected secondary endpoints included percent 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, and the population has a slight agent predominance consistent with the expected demographics of the disease. BMI was 26.8 and 30.4 kilograms per meter squared in the placebo and cemdisiran arms. And 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 1 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 demonstrate 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 urine, which are measured from a single voided urine sample instead of a 24-hour collection. This assessment demonstrated the 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 4 weeks and demonstrated an onset of effect by week 8 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 the 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, including 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 [ week 8 ]. 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 to 450,000 patients in 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 to seeing some questions come into the webcast, but please continue to put more in clicking on the 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, and I know 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 TARPEYO, which is a steroid, there are limited options for patients. Importantly, proteinuria is a well-established predictor of progression to renal failure and IgAN, so we believe a reduction in proteinuria is clinically important. In addition, we saw encouraging results on a number of secondary endpoints. It cannot compare directly to other drugs in development since as you mentioned, there are no head-to-head trial. 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 with IgAN.

Great. Thanks, Ishir. Maybe going to Professor Barratt. So 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 had went through quite a bit, but why do you believe complement inhibition? And maybe specifically, C5 inhibition could be a promising strategy for the treatment of IgAN?

Thanks. Yes. 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 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. But what we need is an urgent quick treatment that will reduce inflammation quickly. And that's where complement inhibition is going to be key. And C5 clearly fit -- 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, and we've seen with the avacopan data, that very small study I mentioned that, that can have very positive effects. And we're also going to stop the production of the membrane attack complex, which we know is present in the glomeruli IgA nephropathy. We know at sublytic concentrations that 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 asymptomatic disease. So kind of maybe walk us through little bit if the 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?

Yes. So unfortunately, most of the time the patient hasn't got clue there, and they've been picked up by chance because I've had the 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 5 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 2 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 a fairly large numbers of prevalences theoretically out there, but how many of those patients roughly do you think were seen in clinic?

So 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 UK Biobank, which has 0.5 million 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. And we reckon that 1 in 5 of those people had IgA nephropathy as a cause, it just wasn't diagnosed. And we're talking about many thousands of patients here in terms of just from the UK Biobank alone. So I think we are -- there is a massive under diagnosis of IgA nephropathy out there.

The other part of the previous last thing you meant was kind of chronic kidney disease presents substantially chronic treatment. So what would be your thoughts about long-term treatment of IgAN with complement inhibitors, such as cemdisiran?

So 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 the induction remission. I think they are very fit very nicely into treatments of relapse. And 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 an unchartered 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. But of course, all the clinical studies at the moment finish at 2 years. That's the data we will have. But in my view, we will have induction therapy, then we will have maintenance of remission and 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 use cyclically, definitely use for relapses and -- but I think it will vary from patient to patient.

Excellent. Another question came in a little bit more on the disease itself. So once treatment is 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 respond to treatments that we've used so far?

Yes. 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 have kidney failure, but the kidney failure wasn't due to IgA nephropathy. So they had a normal circulating IgA system. What happens is when those transplant kidneys were biopsied, some 3, 6, 9, 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 their 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. Look, questions are 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. Well, proteinuria improvement is slightly waning. So I think this is for Ishir looking at the Phase II data. So maybe I'll go to you first. It looks like the results kind of flattened between weeks 16 and 32. Any insights on that? Is that kind of the maximum effect we should expect? Or how would you think about interpreting those data?

Well, I think what we see is fairly consistent results from week 16 to week 32. It's important to remember these are -- this is a small study. So there are expected to be fluctuations over time, but those are not necessarily statistically meaningful. And what we've seen so far is that both from the spot year and 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.

It's a great point. Always an interesting point, right? So up to how many years do we continue to follow those patients?

So currently 3 years.

3 years. Okay. So we'll see that long term. 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 on to cemdisiran in that open-label extension.

Okay. So you see that transition. That's great. Maybe related to that Ishir, you mentioned some additional analysis. What else do we think we would plan to disclose at future medical conferences?

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. It's not compared, as I mentioned, we're looking at a number of biomarkers.

Great. Another question just came in. Can Dr. Barratt comment on how he thinks about long-term safety of complement inhibition in IgAN patients. And maybe that's kind of related to the earlier question on long-term treatment, but maybe specifically on the safety is 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 this -- we clearly have to think about immunization for encapsulated organisms. And that is part and parcel of the protocol, a routine and part of the course. But as 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 -- mediated disease, maybe last 2 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 on why do you think that combination may be necessary or effective in PNH and MG, but not required in IgAN, we believe.

Yes. 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 a complement system available [ in the fleet ] and target pathogens. So I think we have the good situation here where IgA nephropathy, if 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 and 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 Controversies meeting, which I'll be attending in Florence on Thursday, which is looking -- which is dealing exclusively with the role of complement and 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, old ANCA-associated vasculitis. We've got to get all of the diseases where there is already some headway in terms of complement therapies. But actually, there's a whole work stream looking at diabetic nephropathy, and FSGS, which are 2 diseases, not traditionally thought of as complement mediated, but there is data starting to accumulate that the complement system may be important in these 2 diseases. And so I would ask anyone on the call who is interested in this area to look out for this conference. There will be a publication that will come out, which really synthesize the current state of art in the evidence of these diseases being mediated by a 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.

Ishir, maybe back to you on the Phase II data set. Do 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.

Yes. 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 may you can go a little bit deeper into what that relationship is and kind of how we split up the portion 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 needs 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. And maybe a final point on that somebody asked a question about what is it that Regeneron's providing, in particular, those programs were there leading that we couldn't have ourselves essentially? And I think probably the monoclonal antibody is the obvious answer here, 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, few second 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 our 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 and IgAN.

Excellent. 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 2 more upcoming roundtables over the coming weeks. The next will be on October 21, where we'll discuss the Alnylam Engine for Sustainable Innovation, and then on November 1, we'll discuss GalNAc 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 15 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 day.