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

Good morning, everyone. Thank you so much for joining us for day 3 of the UBS Healthcare Conference. Very happy to have Alnylam Pharmaceuticals here with us. By way of introduction, I'm Ellie Merle. I'm one of the biotech analysts here at UBS. Very happy to have Alnylam with us for a fireside chat. Joining us from Alnylam is Pushkal Garg, Chief Medical Officer. And with that, thanks for joining us.

And maybe before we dive into lots of fun APOLLO-B questions, high level, maybe can you frame the Alnylam pipeline and strategy and where you see the company in 3, 5 years from now?

Absolutely. Well, thank you, Ellie, for having us here, and thanks to UBS for inviting us to the conference. I'm happy to be here and to see so many folks. Yes, look, Alnylam -- we're actually reaching our 20th anniversary this year, and the company's vision, mission and purpose has not changed in those 2 decades, which is to really transform human health and bring an entirely new class of medicines, RNAi therapeutics forward. And we're really proud of the progress we've made both in terms of the foundational biology and chemistry of RNA interference and optimizing delivery mechanisms and now having brought 4 and, hopefully, soon 5 medicines to patients around the world with serious unmet need. We focus on diseases where there's genetic validation, where there's a high unmet need and where there's a clear path to registration. We focus on medicines right now based on our delivery approach that target liver directed -- liver-expressed genes, but we are now broadening into new tissues. We just started our first CNS program earlier this year. We have programs for ocular disease, and so we are really just at the first couple of innings of what we think RNAi therapeutics can do. And Alnylam hopes to be at the forefront of that. Last year, we announced our P5x25 goals, which is really to become basically a top 5 biotech by 2025, to be profitable in that range, and so we're very excited and all aligned internally along that mission to really bring RNAi therapeutics forward and achieve that goal.

Great. Maybe you obviously have APOLLO-B data coming out quite soon. In terms of thinking about expectations, I guess, what are you looking to see both on 6-minute walk and potentially the placebo side of things on 6-minute walk as well, as well as potentially thinking about some of the secondary end points? We know it's not powered for stat sig on some of these cardiovascular mortality or hospitalizations, but what could we potentially see in terms of trends? And what are you looking for?

Yes. So maybe just to take the step back for everybody, right? We are bringing forward -- we've established patisiran or ONPATTRO, which is an IV-administered therapeutic. It's given every 3 weeks in hATTR-PN. Vutrisiran is a follow-on molecule, which has also shown positive clinical data in hATTR-PN and under regulatory review right now. We are -- the APOLLO-B study -- both studies -- both drugs are being evaluated for the cardiomyopathy aspects of ATTR. APOLLO-B is looking at ONPATTRO for that disease. And as you said, Ellie, it's a study that was originally designed for 300 patients and actually got over-enrolled to 360 patients, and it has a 12-month end point of 6-minute walk test. The study is powered for that 6-minute walk test end point. It's also powered for the first secondary end point, which is the Kansas City Cardiomyopathy Questionnaire, the KCCQ. And so look, we feel very good about the way that the study has been designed, and we feel good about the way the study is being executed. And we are looking forward to the results in the middle of this year. As you noted, there are additional end points related to cardiovascular outcomes, but the study is not powered for those at all. And so I think those are captured. But I would just remind folks that this is a smaller study, for example, than ATTRACT, which was over 440 patients. It's -- but more importantly, it's a much shorter study. Outcomes develop over time, and separation outcomes take time to develop. And so a 12-month end point, I would not have high expectations to see outcome separation at that point. I'll remind folks that even in ATTRACT, hospitalization separation started to show up a little bit at 9 months, and mortality separation didn't occur until around 18 months. So APOLLO-B was not designed for that. We do have HELIOS-B with vutrisiran, the other agent. And that is a longer-term study. We can talk more about, but that's actually designed and powered for those outcomes.

Got it. And there's been a lot of debate around 6-minute walk and whether this is the right end point or not. Curious your thoughts on that. But also say we have a missed primary on a 6-minute walk from APOLLO-B, maybe taking a step back from APOLLO-B and thinking about vutrisiran and HELIOS-B, how would you think about that outcome in terms of the long-term success of the ATTR franchise and thinking about the expansion to cardiomyopathy?

Sure. So obviously, until probably about 5 months ago, there wasn't a lot of controversy around the 6-minute walk test end point. Now there's a lot of controversy for understandable reasons. And look, it's difficult to say exactly what happened in the acoramidis study until we kind of see the data, and I'm sure the company is working through that. What I can say is that it's a very well precedented end point. It's been around for quite a long time and used in a lot of studies, both in heart failure and in pulmonary arterial hypertension. We studied that end point quite a bit as we implemented it in the study. We are working with experienced experts who've helped us implement that test in the context of the study, including qualifying sites and their ability to perform the test appropriately, training the sites and then monitoring as tests are done to make sure they are performed properly. So I feel good about all the things that we put in place to conduct that test properly. There have been talks about -- for example, is there a training effect, et cetera. We've done a number of -- we put in measures to minimize the number of, for example, baseline assessments to try and minimize that effect. So we're aware of the biases. It is a -- there is some variability in that test. We know that. But it's something that we've accounted for in both -- in how we're implementing the test and in our statistical assessments and power calculations for that assessment. So all in all, I feel very good about it. I think the second part of your question was just how does this read through to HELIOS-B if there was, unfortunately, if it didn't hit on that end point. And look, what I would say is we'll have to look at the totality of the data. I think that we have to remember that this is a short-term study, looking at a couple of end points, functional end points, quality of life. But there's now an abundance of data that appears to suggest that RNAi silencing can actually have a favorable effect on CM, right? Where does that come from? We have post hoc analysis from the original APOLLO study. We have study -- analysis coming out of the HELIOS-A study of vutrisiran in polyneuropathy. We have post-marketing studies published out of the U.K. and out of the Netherlands. All of those are showing favorable effects on echocardiographic parameters of the heart, cardiac stress biomarker, NT-proBNP, walking ability, post hoc analysis of survival and hospitalization. And most recently, now on a couple of things, including from our HELIOS-A study, evidence that actually with silencing, you actually can cause regression or reduce technetium uptake in the heart, which might suggest that there's actually amyloid being pulled out of the heart, right? All of those things suggest a favorable impact of silencing on CM. And so I remain optimistic about HELIOS-B independent of APOLLO-B for that reason. And I'll remind folks that it's a much longer study. It's actually -- there's a bit of a misunderstanding. It's not a 30-month, it's actually a 30- to 36-month study. So we have actually a pretty considerable follow-up in that with this variable follow-up. The last patient will have 30 months of follow-up. The first patients in that study will have 36 months of follow-up. So it's a graded duration of follow-up. So I think that's going to help us a lot in terms of accumulating outcome events and hopefully resulting in an ability to detect a good efficacy signal.

And in terms of the number of events, another debate that I think has become maybe more topical recently after BridgeBio is how the natural history of the disease might be changing both through the availability of tafamidis, increased diagnosis as well as potentially just the patients that are likely to be enrolled in the studies today. I guess, first, how are you thinking about the natural history and how this is evolving? And second, how are you thinking about the impact of tafamidis use on the event rates that you're potentially going to see in both APOLLO-B on a shorter basis but then longer term with HELIOS-B?

Yes. So let's maybe take those one at a time. So first of all, natural history. What I'd say is the -- this is a disease that's really just been diagnosed and been really known about in the last several years more commonly, right? Medical practice doesn't change quite as fast as that. It would be great if it did, but it doesn't. We still have a lot of patients with cardiac disease who don't get beta-blockers or an aspirin, right? And so to think that this disease is so dramatically changed in such a short period of time, I think, doesn't make a lot of sense. The best data we have actually on natural history comes out of ATTRACT. And if you look actually at the published data, even patients with milder disease, NYHA Class I and II in ATTRACT, actually had progression on their 6-minute walk test, that was actually comparable to that seen in the more -- patients with more advanced illness. And in fact, the treatment effect on 6-minute walk test was largest in those patients with NYHA Class I and II. So that's point one. So I don't think the natural history is likely to have changed dramatically. And I think even in a somewhat milder population, you would still see a benefit. That's what the best natural history data out there would tell us. Now in terms of the impacts of tafamidis, certainly, as we design both of these studies, we were very conscious about the potential of tafamidis. We've taken, as we've talked about, in previous settings, measures to control the amount of background tafamidis use. So in APOLLO-B, up to about 30% of patients were permitted to be on background tafamidis. In HELIOS-B, that number is around 50%. And we were able to manage that very effectively with the geographic deployment of the studies. And so -- and our power calculations, we're very conservative around that background rate of tafamidis use. We certainly want to generate data looking at our drugs, both as monotherapy and in combination with tafamidis. So we think we'll be able to do that with the way these studies are designed but still have very conservative assumptions that will hopefully yield a positive study result.

Is there any color you can give us on the statistical assumptions around tafamidis?

There's -- I think we've not sort of delved into the details of all the powering assumptions, et cetera. But look, I think what I would point to is our track record in studies in TTR and in porphyria and in primary hyperoxaluria and other diseases where you can see we take pretty conservative assumptions in terms of how we power these studies.

And if you're able to comment, I guess, what's the latest that you're seeing in the degree of tafamidis drop-ins throughout the studies as well?

Yes. So what we've commented is that we obviously monitor that very carefully, and we remain very encouraged by what we're seeing, which is very low rates of drop-in in tafamidis.

And in terms of just thinking longer-term labeling, long-term commercialization relative to a potential generic tafamidis, how are you thinking about what type of effect size is needed commercially? And how is this impacted, if at all, by say, having a perhaps up to 50% of the placebo arm on tafamidis when physicians ultimately might compare the effect size across labels? How do you think about that and think about what's needed from physicians to say, hey, look, the silencers might be better or hey, look, the combination might be better. What does that look like in terms of a data generation perspective?

Yes. So look, it's obviously very early to talk about what a label might look like. We have to look at the trial results. But what I'd say is I think these studies are going to allow us to actually understand a number of different facets that are going to help inform clinicians in terms of prescribing, right? We will, as I said, generate data both as a monotherapy and as a combination, and there will be -- we'll present those data as they arise. But I think the studies are designed to enable that. And so clinicians will have that at their fingertips and being able to understand the data. Obviously, these are not designed as head-to-head studies with tafamidis. So I can't -- there's not going to be any controlled head-to-head experiments. And so -- but clinicians will have to look at those data sets separately to look at how they might think about the 2 therapies. And certainly, the studies that we're doing will allow us to show the effects of silencing both as a monotherapy and as a combination. But I think clinicians will look at the overall effects. I imagine they'll look at the onset of effects. They'll look at effects on all the other end points that are captured and sort of be able to make an overall assessment. I would expect, as we see in many chronic diseases and many difficult diseases that, ultimately, there will be some amount of combination used that will be going on. We're already seeing that in some patients because we know this is a multi-systemic disease out in the community today. And so I would expect that there will be some amount of combination use going forward.

How should we think about the mechanistic rationale for combination? Are there certain types of amyloid plaques or certain types of being able to reduce the amyloid burden? Help us understand mechanistically the role of stabilizers versus silencers and how to think about the added benefit?

Yes. So look, I think what we know -- again, we don't -- this is all sort of speculation at this point because we don't have formal clinical data. We know that with our silencing approach, we can reduce hepatic TTR production by about 85% or so. And we've seen, certainly in polyneuropathy that, that can lead to a halting or even reversing of the polyneuropathy aspects of the disease. As we've talked about, we'll see what it looks like in CM. Now the question is, with that residual amount of TTR that's still being produced, does a stabilizer potentially have some additive benefit? And that's what we'll kind of start to understand over time.

And to the extent you can comment, I guess, are you aware of the event rates on a blinded basis, I guess, HELIOS-B and perhaps APOLLO-B trials?

So look, we have teams, as every sponsor does that looks at blinded data, to monitor the quality of the data, to ensure study integrity, to monitor safety, et cetera. So we have people in our clinical and stats and clinical operations teams who look at those data. But that's really to ensure trial integrity.

Absolutely. And I guess, I mean -- the reason I ask is how should we think about things like hospitalizations in an era of COVID where people might be, say, more reluctant to go to the hospital and say, "Oh, we are not feeling so well. I don't know if I want to get COVID, if I go to the hospital." I mean if that's an end point in the trial, just I mean, from an operation perspective, how are you thinking about that?

Yes. So actually, our end point structure includes not only deaths and hospitalizations but also urgent heart failure visits. So it captures patients who may go into a doctor's office or other settings for an urgent visit where they have been exacerbation of their heart failure. So I think we feel good that we're going to be capturing the totality of events that are clinically meaningful to these patients.

Absolutely. And thinking from kind of a biomarker perspective, such as NT-proBNP, you mentioned sort of the technetium scan. What are some of the markers that at an early time point at 12 months we can debate what we'll see with 6-minute walk, but what are some of the other measures that you see as perhaps highly reliable on their own that we should be focused on as well?

Yes. Look, I think you're talking about APOLLO-B?

Yes. And I guess the clinical trials generally, but yes.

Yes. Look, I think we've seen already coming through from a variety of sources that we see benefits in terms of echocardiographic parameters at around 12 months, 12 to 18 months. We've seen NT-proBNP changes, as you've mentioned. I think the technetium data that are emerging for silencing are actually really quite remarkable. We just recently published -- presented at the -- at a French meeting, SFNP. I think, in January this year, the cardiac data coming out of the HELIOS-A study, and that showed that in the majority of patients, you actually have reduction in technetium uptake in their heart, signifying amyloid regression. There are, again, no head-to-head comparative studies, but KOLs we talk to say that's really kind of remarkable. And then we just presented actually earlier this week, put out data in the cardiac subpopulation and even in patients with high-grade Perugini scoring. And again, there, we saw that the majority of patients have improvement. So I think it's a very amazing mechanism by targeting upstream and some of the effects that we're seeing, and they all point to evidence of a beneficial effect on the cardiac aspects of this disease.

We'll stay tuned for data. It's an exciting space. Maybe beyond ATTR cardiomyopathy, what are you most excited about in the pipeline?

Well, I love all our children. Can't single out favorites.

I tried.

But look, I think there's a number of exciting things going on in the pipeline. I'll point to a couple of them that I think are probably at the forefront in some ways. One, as we've kind of evolved and understood the profile of RNAi therapeutics, which is very potent, but also durable silencing. This is a very unique pharmacology profile and a well-tolerated safety profile, we've been able to go into more prevalent diseases. And so inclisiran, now marketed by Novartis, really was the forefront of that, right? Going into hypercholesterolemia by targeting PCSK9. But we're advancing zilebesiran, which targets angiotensinogen for high blood pressure, and we can talk more about that. But that's incredibly exciting, and I think it truly has the opportunity to transform one of the most common and highly morbid health conditions around the globe. And I couldn't be more excited about what we might be able to do to affect human health by that. And then second, I would point to our first CNS program, ALN-APP, which targets amyloid precursor protein. And that also shows the ability to take RNAi therapeutics into different tissues. So this year, we basically initiated the first time RNAi therapeutics have been introduced into the CNS and we'll be -- and very excited about this first program, which hopefully will show the benefit of this therapy in terms of silencing APP and hopefully having beneficial effects that will translate into clinical benefits for Alzheimer's disease, but also another disease called cerebral amyloid angiopathy.

Awesome. I guess, starting with hypertension, can you tell us a little bit more about this target biology and where this fits in, in the treatment landscape for hypertension?

Yes. So let me take it in 2 parts. First of all, we're targeting angiotensinogen, which is at the very top of the cascade of the renin-angiotensin system. And it's a genetically validated target for hypertension. And we've already shown in our Phase I studies that it can reduce blood pressure by more than 15 millimeters of mercury, and not only that, but it can actually sustain that benefit for more than 3 months and up to 6 months. So a very exciting profile. Now why is that profile so exciting? If you think about hypertension, why are these guys developing a drug for hypertension, there's so many medicines out there. Hypertension, not by my words, but by the AHA, is the #1 addressable cause of cardiovascular morbidity and mortality around the world. There's 100 million people with high blood pressure in the United States, 40 million of them are at highest risk because they have concurrent cardiovascular disease. And why isn't their blood pressure being controlled? It's because most patients can't get to goal and the goals keep getting more and more stringent. There's tremendous variability in blood pressure control, time of day, day to day, week to week, month to month. And three, people don't actually stick with their blood pressure medicines because of side effects or other things, adherence is poor. And so after a couple of months, the majority of people actually don't even refill their medicines anymore. So what's the solution to that? Wouldn't it be great if you had a blood pressure medicine that you could take once every 3 months or every 6 months that led to tonic control of your blood pressure? Now you can get people to goal, you can reduce variability by offering tonic control and you can improve adherence. And so that's why zilebesiran is so incredibly exciting. And so we're already -- the data that we've generated in Phase I is incredibly encouraging in terms of both its efficacy profile, but also the early safety profile of this medicine. And we're now studying it in a large Phase II program.

And how is enrollment going in the KARDIA-1 and 2 studies? And how should we think about the time frame there?

Yes. So we have 2 studies, KARDIA-1 and KARDIA-2. KARDIA-1 is looking -- is it about a 375-patient study, looking at zilebesiran as a monotherapy. That's really a dose-finding study. So it's really to establish the dose and regimen. Is it 150 milligrams every 3 months? Is it 300 milligrams every 6 months? So we'll get that dose and regimen out of that study for pivotal trials. And then the second study is KARDIA-2, which is looking at the drug in combination with other agents. We know that in blood pressure management, multiple drugs or classes of agents are used in combination. And so we are looking at zilebesiran with a calcium channel blocker, with a diuretic or with an angiotensin receptor blocker. And so that's a larger study of 800 people. We recently announced -- updated the guidance on those studies at our Q1 call that we ran into some headwinds with KARDIA-1, it was deployed initially in the Ukraine and also between that, obviously, and then COVID, we've had to actually broaden the geographic footprint of that study, made some protocol modifications. And so we're forecasting now that, that will complete enrollment in early '23. And then KARDIA-2, we're forecasting the completion of enrollment at or around year-end of this year.

And can you tell us more about the data that you'll be looking to see from these studies?

Yes. I mean, first -- we'll be looking at -- both of these are designed to look at efficacy, so we'll be looking in KARDIA-1 and efficacies of monotherapy. We also really want to be looking at the durability. Is this an every 3-month drug? Is it every-6-month drug? And what's the dose? And then in KARDIA-2, we really want to see what are the additive or synergistic effects on top of the calcium channel blocker, on top of a diuretic and importantly, on top of an ARB. We were very encouraged that in our Phase I study, we looked at a small cohort of patients who are given zilebesiran and an angiotensin receptor blocker. And what we found is that there was an additive blood pressure effect and importantly, no adverse safety consequences. And that's very encouraging. And so we're going to be looking at that in a much larger patient population in KARDIA-2. So those are some of the things we'll be looking for along with safety, of course.

Exciting. And maybe turning to ALN-APP. You mentioned this is exciting and that sort of bringing RNAi to the CNS.

Yes.

How should we think about your confidence level in the ability to deliver beyond the liver and certainly a new frontier for RNAi. And yes, your confidence in the preclinical data and what we should be looking for in the initial data?

Yes. So ALN-APP targets very far upstream in sort of the amyloid pathway in the CNS. And this is an intrathecally administered agent and that will then deliver the RNAi agent into the CNS. The preclinical data, first and foremost, have been very encouraging, and we've published all this on the Capella portion of our website. But through a pretty extensive series of both rodent study and non-human primate studies, toxicology and pharmacology studies, what we've shown is that with the C16 modification that we add on to the RNAi therapeutic that we can actually penetrate all different regions of the brain, not just the cortex, cerebellum, but deeper structures in the striatum and thalamus. And so we feel very good about that. Point two, we see that these therapeutics can actually get into various cell types. So not just neurons, but astrocytes, glial cells, dendritic cells and the CNS. So that really tells us we can actually have that widespread distribution that we need to have a favorable effect on the targets that were -- and silence the targets that we're after and hopefully have a beneficial effect on the diseases that we're pursuing. And then the third thing is, as I was talking about earlier, one of the really exciting things about the pharmacology of these RNAi therapeutics is the extended durability. And we're seeing that same phenomenon that we saw with liver silencing translate into the CNS, right? So we can expect quarterly dosing, every 6-month dosing with our new IKARIA platform, maybe even annual dosing for some of these disorders. So obviously, that's really exciting, but that translates from the liver into the brain. And so those are the -- so I think all the preclinical data give us a lot of optimism about how this will translate into humans. And so that's -- the APP program will be the first foray into that. In terms of the program itself, again, I think it's a great target for us to be pursuing because it really targets very high upstream in this APP -- in the amyloid pathway. Amyloid has actually been implicated as we commonly think about in Alzheimer's disease, but also in another related disease called cereberal amyloid angiopathy where instead of having parenchymal accumulation of amyloid, you actually have it on the vascular walls and that leads to hemorrhages, microhemorrhages and macrohemorrhages in the brain. And so by targeting upstream and amyloid, or APP, we think we can potentially affect both of these disease pathways. And in contrast, antibodies, which really target certain structures of amyloid that -- the tertiary structure of amyloid and certain forms of amyloid in the extracellular space by targeting upstream, we can address all different isoforms of amyloid, but also intracellular, as well as extracellular. So a lot of reasons for encouragement. So we have a Phase I study that's going on right now, it's an early-onset Alzheimer's disease. We think that's a great population to be looking at because it's a high unmet need, but also not a lot of other confounding clinical comorbidities that might impact our ability to detect both either side effects or safety or efficacy. But the first study is really to look at safety and initial pharmacology. And so we expect to have some data by the end of this year, looking at safety and silencing in the CNS.

Exiting. I certainly think that the intracellular silencing will be quite interesting in the neuro space. Maybe just from -- there's 2 questions. One, the ability to deliver to the CNS, but then also the target biology. Maybe just in terms of the delivery itself, how should we think about what we'll learn from that and how you're measuring that?

Yes. So as I mentioned, our -- the preclinical data suggests that the C16 modification that we've put under the siRNA really does allow us to deliver pretty broadly in the CNS across tissue types and across cell types. And so we're looking to see how that will translate into CNS. We'll be able to measure that pretty readily, I think, good thing with APP is that there are downstream biomarkers that we can measure in the CNS -- in the CSF rather, and the cerebrospinal fluid. So we can look at soluble APP alpha and soluble APP beta. And I think that will give us a good indication about whether what we're seeing in preclinical experiments in terms of silencing is translating into humans. There's a number of other parameters that we'll be looking at in that study, including imaging parameters. We've been doing some functional assessment on patients, but I think the really primary thing to focus on is safety, tolerability and then silencing through soluble APP alpha and beta. And I think this is very important for us because not only does it guide us in terms of this particular program, but with our colleagues at Regeneron, we actually are working on a whole host of other CNS targets. And so this really becomes a gateway to help us sort of understand and optimize those programs as well.

Well, we'll certainly stay tuned for the data later this year, exciting. Maybe turning to another program that I think doesn't get a lot of airtime, but OXLUMO and recurrent renal stones.

Yes.

Can you help me understand sort of biology of this, obviously, approved drug, potentially could be a much broader patient population, probably similar in size to ATTR cardiomyopathy, which I know we talk a lot about. Help us understand the biology of how this could potentially work in a broader patient population?

Sure. I'm glad you brought up, it doesn't get a lot of attention, as you said. So look, 1 in about 11 people has a kidney stone. About 1/3 of those are recurrent, 80% of kidney stones are oxalate kidney stones. And so when you kind of do all the math, that winds up in about 2.5 million people in the U.S. who have recurrent oxalate kidney stones with elevated urinary oxalate. So that's a large pool of patients who have a very troubling medical condition and would really benefit from a new therapy. So lumasiran, we've developed in an orphan disease, called primary hyperoxaluria type 1. These patients have a genetic mutation in a gene called AGXT that leads them to accumulate oxalate, that precipitates in the kidney as oxalate stones. It causes calcification in the kidney called nephrocalcinosis. And so -- and we know that lumasiran therapy, as you said, has now been approved OXLUMO to reduce those oxalate levels. And actually, we're seeing now in some exploratory analysis, very small numbers of patients, but we're seeing encouraging signs in terms of potential benefits in terms of stone formation and therefore calcinosis improvement actually in a couple of our studies. So all of that leads us now to go well, if we can work -- if this drug works in this genetic subpopulation of patients who are overproducing oxalate, perhaps it can work now in the general population of patients who lack the mutation, but who are forming oxalate stones. And so what we'll be looking for is in this Phase II study that we're doing is reduction of urinary oxalate because that will portend well for a potential than downstream benefit in terms of stone formation. And so we've kicked off a Phase II study in recurrent patients with recurrent oxalate stones. It's a 120-person study. We're looking at 2 different doses of lumasiran versus placebo. And the end point is a 6-month end point looking at urinary oxalate reduction. And if we see reductions in oxalate there, that should give us a lot of optimism about the potential to actually then have a benefit on stone formation overall.

And when can we expect to see that data?

So we've said we plan to complete enrollment by the end of this year. So -- and it's a 6-month end point. So you can kind of do the math forward, it's 2023.

And I'm sorry if this is a dumb question, but I mean the biology seems straightforward, unless maybe I'm missing something, why not start this study earlier? Are there certain questions that are maybe outstanding around the biology or study design or patient population?

I think -- look, I think we really benefit from having seen the profile of this medicine in PH1, and we were very focused on bringing forward that this medicine into that population with high unmet need. And also, as we understood the safety and tolerability profile, the pharmacology profile, how to dose it, et cetera, that then gave us the impetus to now look in this broader, more less acutely ill population over time. And so I think this is just part of strategically as we kind of think about -- how we kind of think about life cycle extension and opportunities for therapeutics. I think this was sort of a natural progression of that. So.

Awesome. Well, before I ask about C5 and gout with a little under 4 minutes left, I want to turn it to the audience if anyone has any questions. All right. Well, maybe just in terms of gout, can you tell us a little bit about the target biology there and how we should think about the timelines from here?

Yes. So we announced a program that we kicked off this year called ALN-XDH. It targets xanthene dehydrogenase or xanthine oxidase is the other isoform of that enzyme. This is a genetically and clinically validated target for gout. Gout affects 14 million to 18 million people in the United States. Now anyone who has had gout, it's really disabling to people, accumulations of uric acid in various joints that cause pain, disability and ultimately can cause joint destruction as well. There are therapeutics for gout. Allopurinol is the most commonly prescribed that actually target xanthine oxidase, but they're not all well tolerated. And so a minority of patients actually get to goal uric acid levels, which is under 6 milligrams per deciliter. And so patients are at constant risk of acute attacks and joint destruction. So -- and again, another disease, a chronic disease where because of side effects and other reasons, adherence is poor and it makes patients vulnerable. So again, we're taking forward a molecule that we think can have extended durability and hopefully bring more people down to goal. And so we've kicked off an early study. The first portion of the study, Part A is in healthy volunteers, which will just be looking at uric acid lowering. And and then Part B will be going into gout patients. And so a very exciting program, and hopefully, we'll have some data from the healthy volunteer portion. We know that uric acid lowering and healthy volunteers should correlate well with uric acid -- the magnitude of uric acid lowering in gout patients. So hopefully, those healthy volunteer data will reveal a good pharmacologic effect that will then allow us to move quickly into Part B and into patients.

I always think it's interesting how much more time people spend on RA than gout, but I understand there's more, I guess, therapeutics there currently. Maybe in terms of when you move to Part B in gout patients, how are you thinking about the patient segmentation, whether it's before KRYSTEXXA, after and the types of patients that would be studied first?

Yes. So I think we're going to be going after -- we are looking in Part B in a couple of populations. We'll be looking at the drug as a monotherapy, we'll also be looking -- which I think will help us more firmly establish sort of again, dose regimen, the magnitude of effect. And then -- but we also have a portion of that study, we'll be looking at it in combination with allopurinol, which is a very commonly used agent as well. So I think that will then further elucidate the profile quite a bit.

That’s helpful. Excited to see that data. And then turning to the C5 program, broad biology in terms of the number of potential indications. I guess, how are you working in collaboration with Regeneron, thinking about the potential indication set, particularly with targeting C5 in the liver?

Yes. So look, the number of diseases where complement has been implicated is longer than sort of a medical textbook it seems like. But we are targeting C5, which in terminal complement cascade, which we've shown, we have very, very potent silencing with cemdisiran, 99% silencing. And what we've done with our colleagues at Regeneron is we know that there are certain diseases where you literally need to basically control complement close to 99.9%. And so for some of those diseases, PNH being the most prominent, our colleagues at Regeneron who have an anti-C5 antibody, pozelimab, we're looking at the combination. And we know from Phase I studies that we did, the combination of cemdisiran with an antibody can lead to a very, very potent silencing or reduction in C5 levels that can have a beneficial effect. So they're studying the combination in PNH. They're also looking at the combination along with a monotherapy cemdisiran in myasthenia gravis, which is another validated disease for complement inhibition. We ourselves are studying the monotherapy in a Phase II study in a disease called IgA nephropathy. This is the most common inflammatory disease of the glomerulus of the kidney and a leading cause of end-stage renal disease and complement has been implicated in that disease as well. So we have a Phase II study. It's a 30-patient study with a 2:1 randomization, looking at cemdisiran in IgA nephropathy and we're looking forward to data actually shortly, we've said in the first half of this year, and we'll really be looking to see if we see reductions in proteinuria. Proteinuria is shown to correlate with progression to end-stage renal disease and a 20% to 25% reduction in proteinuria is considered clinically significant. Other agents have actually received accelerated approval based on reduction of proteinuria. And so we're really eagerly waiting those data as well because not only would that potentially show a path forward in this disease of IgA nephropathy, which is, as I said, very common, but also potentially open up other inflammatory renal disorders that we might be able to go into with this drug.

Awesome. Looking forward to seeing the data. It's very near term in the first half coming to a close.

Yes.

Well with that, I think we're out of time, but thank you so much for joining us today. It was a great learning more all about ATTR, as well as the many things beyond ATTR.

Thanks, Ellie. I enjoyed it.

Awesome.