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

Good morning, everyone. My name is Jess Fye, biotech analyst at JPMorgan, and we're continuing the 44th Annual JPMorgan Healthcare Conference this morning with Alnylam. Company had a lot of updates yesterday. I'm sure we'll talk about those. We're going to start out with a presentation from the company's CEO, Yvonne Greenstreet, and then we're going to go into some Q&A. [Operator Instructions] But with that, let me pass it over to Yvonne.

Thank you, Jessica. Look, it's a real pleasure to be standing here as we launch this next exciting chapter in Alnylam's history. I'm Yvonne Greenstreet, the CEO of Alnylam, and I'm delighted to be joined on stage here -- maybe stand back a bit -- by my colleagues, Pushkal Garg, our Chief R&D Officer; Tolga Tanguler, our Chief Commercial Officer; and Jeff Poulton, our Chief Financial Officer. And of course, I'll be making forward-looking statements throughout my presentation. Now as most of you know, Alnylam possesses a unique profile in the biotech industry. And what makes us so unique is that we have an established and sustainable innovation engine, coupled with commercial excellence. This has fueled our success to date, and we will continue to harness this to drive durable long-term growth. And it all begins with the leadership that we've established in RNAi with a proven organic product engine and a reproducible and modular process to developing our medicines that has resulted in outsized historical success . We also have a high-yielding pipeline with over 25 programs in active clinical development. And in addition to success and leadership that we've demonstrated on the R&D side, there are now 6 Alnylam invented medicines on the market that are collectively generating multibillion-dollar annual revenue streams and treating hundreds and thousands of patients around the world through our global footprint. So these value-creating features give Alnylam a truly one-of-a-kind profile and frankly, one which is rarely seen across the biopharma landscape. Since the company's founding in 2002, Alnylam has pioneered the RNAi and an important feature of our approach has been setting and not just meeting but exceeding pretty specific and ambitious long-term goals. Started back in 2011 when we set our Alnylam 5x15 goals, which to summarize, stated by the end of 2015, we will put 5 programs in clinical development. We delivered 7. We then followed that with our Alnylam 20x20 goals, where we said that by the end of 2020, we would have 3 approved RNAi therapeutics. We delivered 4. Most recently, we've been working towards achieving our Alnylam P5x25 set of goals. And as we stand here having concluded 2025, I'm proud to say that our efforts have resulted in 6 approved products, and we brought RNAi therapeutics to about 0.5 million patients around the world who are on an Alnylam invented medicine. We also said that we'd expand our pipeline to over 20 clinical programs. We delivered over 25. Further, we said that over this period, we would achieve at least a 40% revenue CAGR, and we greatly exceeded that too at about 50%. And finally, pending the formal announcement of our year-end results, which will happen in February, we are firmly on track to achieving non-GAAP profitability. Yes, and these strategic goals have guided us on our way towards achieving our vision of translating Nobel prize-winning science into a new class of medicines to transform human health. So let's double-click on some of the exciting highlights from 2025, which by all measures was a transformational year for Alnylam. And starting on the left, the key commercial and financial highlights include the landmark approval of AMVUTTRA for ATTR cardiomyopathy. And on a combined net product revenue basis, we generated nearly $3 billion, which represents a year-over-year growth of 81%. On the pipeline and platform side, we initiated 3 Phase III studies. We expanded our clinical pipeline with 4 proprietary CTAs in addition to the 5 that were filed by our partners. And we developed and launched a best-in-class enzymatic ligation-based RNAi manufacturing platform, which we have termed siRELIS, and this will enable us to greatly expand our capacity and bring RNAi therapeutics to more patients around the world while reducing the cost of goods. In our press release yesterday, we preannounced our net product revenues for the fourth quarter and full year 2025, delivering a breakout year with nearly $3 billion in combined net product revenues across our 4 wholly owned products. And of course, this was largely driven by the launch of AMVUTTRA in ATTR cardiomyopathy, which propelled our TTR franchise to achieve about $2.5 billion, doubling franchise revenue from the prior year and coming in more than $800 million above our original guidance. So today, I couldn't be more excited to share our next ambitious set of 5-year goals for the company, Alnylam 2030 accelerating innovation and scaling impact. These goals rest on 3 strategic pillars. And I think you'll see these pillars are pretty consistent with what drove most of our performance in 2025. It starts with achieving global TTR leadership and building a durable TTR franchise. Specifically, we intend to lead the market in TTR revenue by 2030 and also cumulatively across the 5-year period. We also plan to launch the best-in-class next-generation TTR silencer, nucresiran, first in polyneuropathy by the end of 2028 and then in cardiomyopathy by the end of 2030. The next pillar is growing through sustainable innovation. But most medicines today simply just slow the progression of disease. We want to do better than that and deliver therapies that prevent, halt or reverse disease. This includes delivering 2 or more new transformative medicines beyond TTR that have blockbuster potential. And if we include nucresiran, that makes 3 new transformative medicines. We also aim to expand to 10 tissue types and build out a pipeline of over 40 clinical programs. In addition, we aim to invest about 30% of our revenues in non-GAAP R&D to accelerate organic internal innovation and selectively access external innovation. And the final pillar upon which our Alnylam 2030 goals rest is scaling with discipline and agility, where we plan to drive sustained profitable growth. And specifically, we aim to deliver 25% or greater total revenue CAGR through the end of 2030 and deliver an approximately 30% non-GAAP operating margin across the period. Alnylam 2030 represents our strategy to become the leading science-driven, fully integrated global biopharmaceutical company and maximize the potential of RNAi therapeutics for patients. So let's dive a little deeper into the first pillar. Our aspiration is bold. It's to transform the experience for patients living with ATTR amyloidosis. And in the process, we're building global leadership and a flagship franchise for Alnylam. While diagnosis and treatment rates have improved, especially since the introduction of noninvasive diagnostics, most patients with ATTR cardiomyopathy remain untreated. And so it's a large, rapidly growing and yet underserved category. And it's for this reason that we are driven to bring our RNAi therapeutic, AMVUTTRA to as many patients as we can as quickly as we can. We're therefore, incredibly encouraged by our early momentum. In just the first few quarters, AMVUTTRA's performance compared to the performance of some relative -- with some relevant specialty analogs suggests that we have the potential for a truly breakout launch. This speaks the cost of demand for new treatment options, the value of AMVUTTRA and our strong commercial execution as we continue to launch in ex U.S. markets, building global momentum, which will begin to manifest through 2026 and beyond. We plan to share more details around AMVUTTRA launch dynamics in a TTR-focused webinar that we plan to host in March, but I'm going to give you a little preview. Impressively, within just a few quarters on the market, AMVUTTRA has already approached parity to tafamidis in share of new starts. But it's important to note that given imperfect data sources, which evolve over time, these numbers are estimates, but one thing is clear, we're challenging standards of care. And this -- I think it's really important to note that we are making great strides in establishing AMVUTTRA as a first-line treatment. And it's the first and only approved treatment with an orthogonal mechanism of action, it's perhaps unsurprising that AMVUTTRA is the clear leader for the stabilizer progressor segment. This demand reflects health care professional and patient choice. It's also made possible by the broad access and patient affordability that we have been able to secure. Most payer coverage decisions are confirmed going to 2026 and a large majority of patients continue to have access to AMVUTTRA in first line, meaning no requirement to step through another treatment first. And most patients pay $0 in out-of-pocket costs and 90% of patients can receive AMVUTTRA treatment within just 10 miles of their home, thanks to the broad network of health systems and alternate sites of care that administer AMVUTTRA. Bottom line, health care professionals and patients are choosing AMVUTTRA and access continues to remain strong. We'll continue to drive awareness and preference for AMVUTTRA on routes to our aspiration of global category leadership, but in addition to that, we're committed to reinvesting back into the category. With so many patients still undiagnosed and untreated, we recognize our role in helping close those gaps. Our investments span evidence generation, education and awareness efforts, but also innovative collaborations to bend the curve on diagnosis rates, which include research collaborations, sponsorships, partnerships with medical societies and novel diagnostics programs. And we'll have more to share about these category growth driving initiatives at our upcoming TTR webinar in March and over the coming quarters. And of course, we're also advancing nucresiran program. Nucresiran is our next-generation TTR silencer now in Phase III, and it has the potential to offer a best-in-class treatment experience for patients by providing rapid knockdown of TTR on the order of 95% with a biannual dosing regimen and to solidify our leadership for years to come. Assuming positive results from our TRITON Phase III studies and regulatory approvals, we expect to launch nucresiran first in polyneuropathy in 2028 and then in cardiomyopathy in 2030. The next pillar is growing through sustainable innovation, where we aim to deliver therapies that not only slow disease but prevent halt or reverse course of disease. And this rests upon the truly unique innovation engine that has driven the sustainability. This is a modular process that we utilize to catalyze long-term growth. And of course, at the core of this engine is the Nobel Prize winning science of RNAi, and we're going to leverage our leadership and expertise here to continue to invest in the power of human genetics, where we now have access to more than 2 million lives through various biobanks to uncover new genetically validated targets to sustain our pipeline and leadership for the future. To expand the delivery of RNAi therapeutics into 10 or more major tissues by 2030 and to enhance the fundamental attributes of siRNAs and advance our capabilities with continued platform requirements. As I said, Alnylam is unique. And here, we've a demonstrated track record of success. We believe that the seamless integrated approach enables us to do all of this with high quality and probability of success at scale. And this has helped us build out this robust and high-yielding pipeline, industry-leading pipeline, that you can see here across rare, specialty and prevalent indications and spanning multiple therapeutic areas. I want to highlight a few of these programs, which represent the next wave of transformative medicines, each of them with multibillion-dollar potential. These include programs that span the cardiovascular metabolic space, neuroscience and hematology. Zilebesiran targets angiotensinogen with the aim of achieving continuous control of blood pressure. With just 2 doses a year, zilebesiran could address significant unmet need for over 60 million patients with uncontrolled hypertension who are at high cardiovascular risk. We're also advancing assets for metabolic disease, which represents a substantial global unmet medical need. And we see a compelling opportunity to address significant gaps in treatment left by GLP-1s. ALN-4324 targets GRB14 with the potential to be a novel insulin sensitizer for patients with type 2 diabetes. And ALN-2232 is our first RNAi therapeutic directed towards an adipose target ACVR1C, with the potential to lead to durable and fat-specific weight loss. Turning to neuroscience. Mivelsiran targets amyloid precursor protein for the potential treatment of cerebral amyloid angiopathy and Alzheimer's disease. Mivelsiran has the potential to prevent amyloid deposition, both in the vasculature of the brain to prevent the life-threatening clinical sequelae of cerebral amyloid angiopathy and in the parenchyma of the brain to impact the progression of Alzheimer's disease. ALN-HTT02 targets the Huntington gene to reduce the progression of Huntington's disease. Our exon 1 targeting approach has the potential to lead to deep and widespread lowering of HTT in the brain. With over 100,000 symptomatic Huntington's patients globally, this also represents a multibillion-dollar market opportunity. We look forward to sharing initial Phase I data in the second half of this year. ALN-6400 targets plasminogen to address a wide range of bleeding disorders. There are over 3 million people in the U.S. alone estimated to be living with an inherited bleeding disorder. The first indication we're pursuing is hereditary hemorrhagic telangiectasia, affecting approximately 70,000 in the U.S. Our Phase II trial in HHD patients is already underway, and we also plan to start a Phase II in a second bleeding disorder later this year. Now since our founding in 2002, we pioneered the RNAi revolution, solving hepatic delivery, proving the platform. This has resulted in 6 approved RNAi therapeutics. We intend to build on this foundation as we drive towards our vision for 2030 and beyond. We plan to accelerate innovation and build on our competitive advantage by delivering to 10 or more new tissue types and utilizing potential combinations and polygenic approaches. We'll also look to continue our leadership in platform enhancements while selectively pursuing complementary modalities through business developments. Now let me conclude with our 2026 guidance and goals. In our press release yesterday, we provided 2026 net product revenue guidance. Specifically, we're expecting total combined product sales between $4.9 billion and $5.3 billion, driven by our TTR franchise guidance of $4.4 billion to $4.7 billion or 83% growth at the midpoint. And really, what this does is indicate our strong conviction in the opportunity and reflects robust growth and excellent commercial execution. Let me now turn to our 2026 pipeline goals, which will drive our next phase of growth. We've got an exciting year lined up in which we expect 4 clinical data readouts advancing 3 Phase III studies, initiating 3 Phase II studies and filing 3 to 4 new INDs. But of course, it's not just about this coming year. We're building Alnylam for the future. We believe we have a generational technology, which has the impact, the possibility of impacting potentially millions of patients. And our Alnylam 2030 strategy positions us for continued long-term growth and becoming the leading high-science global biopharma company. And as we look out over the next 5 years, if we achieve our aspirational goals, this is what we believe the profile of the company could look like in 2030. We expect to deliver substantial impact for human health around the world across a diverse range of diseases, as I said, potentially helping millions of patients. By 2030, we aspire to be generating well over $10 billion in annual revenues, driven by multiple blockbuster products and enabled by a best-in-class commercial organization. We plan to maintain our industry-leading pipeline by continuing to reinvest in programs with the potential to transform human health. We also expect to substantially increase our manufacturing capacity and lower our production costs to support our rapidly expanding pipeline and commercial portfolio. Moreover, we want to be a company recognized for our commitment to social responsibility. If we do all of this, we believe that we will build substantial value creation for shareholders. This is our vision, and thank you for your continued support up to this point in our journey. We hope you share the excitement that we have for building a leading global biopharma company and transforming human health. And we truly believe that we're in the early innings of RNAi and the best is yet to come. Thank you.

Great. Thanks for the presentation. [Operator Instructions] We spent a lot of time kind of going through those 2030 goals. What gives you the confidence to kind of lay out sort of these ambitious targets today?

That's a really great question, Jess. Now as I said, we we have this history. We have a 15-year history of setting these long-term 5-year goals. And the reason why we do this is that it really helps rally the organization. It creates focus. It creates accountability. And as you've seen, we've got a track record here. We have met or exceeded every single set of 5-year goals that we've delivered and most recently, piece of it by '25. And we've built our next set of 5-year goals based on what has been an incredible year in 2025, where we've seen real momentum across the business in R&D, in commercial, in manufacturing. And so we feel that we have in our hands the opportunity to really impact human health and are going to set ourselves these bold goals on that journey. And I think it's important to say that we've set the goals, but we also have plans to ensure that we're going to be able to deliver them.

And when you're kind of setting goals that far out, how much buffer do you bake into kind of long-term targets like that?

So I'm not sure that's the right way to think about it actually because what we're trying to do here is set goals that are ambitious, okay, but that we feel we have plans that will allow us to achieve those goals. So by definition, it's not about buffers. It's about understanding the underlying assumptions behind our business and then developing goals that provide us with the potential to really impact patients across a broad range of diseases and build a substantial business. But Jeff, you may want to talk a little bit more.

I mean the only thing I'd add to that is, I think the goals are probably almost more important for internal purposes than they are for external because of what Yvonne has touched on that the organization is very accountable. So when we establish something like this, the desire sort of to galvanize the organization to drive that performance is real. I mean that's why we've continued to do these 5 sets of goals. So that's how we think about it. It's really about driving performance.

And then turning to the 2026 guidance you provided, specifically on the TTR franchise. Can you just talk a little bit about the AMVUTTRA drivers like underlying that guidance and how they may be similar or different from last year?

Sure. Look, '25 has been an exceptional year for us. As we shared with you, if you look at the fundamentals of the market, we really set up an exceptional business where we're gaining preference in market share, underpinned by the very much untapped market demand and the growth that continues to go from a category perspective. So in light of that, we obviously would like to be able to continue to build that market preference. And what you'll see is where we're actually going to be accelerating the growth opportunities as well. So we want to be able to increase more diagnosis rates as we are actually continue to differentiate the product that's already been well received, both by payers, physicians as well as actually from the patient's perspective. So we just need to continue to elevate that and as we are growing the category.

So with AMVUTTRA writing, it sounds like you're seeing both in the academic and community settings. What are you kind of learning about prescriber behavior or patient characteristics in the different channels? And how do you use that information to kind of maximize frontline use?

So when you look at the fundamentals of the business and why we think it's actually very strong is because it's balanced, durable and there's a depth to our business, both from academic centers as well as from the community centers, the business that we're driving is more or less the same in terms of the quality. And what's also really important for us is how the community physicians and academic centers are experiencing the prescription. Are they getting easy access? Are there patients actually being able to access the medicines and getting their injection conveniently? What's been the experience both in the academic centers and the community centers once the product is actually being used. And when we look at that across the board, we see a very similar dynamic. And what's, I think, really important for us, and you've seen in the numbers is to drive first-line preference. And that has been going really well. We're being very competitive, and we need to continue, obviously, that journey. So just the bottom line is it's a balanced business, and we're really not seeing a one particular patient type that's preferring one or the other.

What's your latest thinking on what eventual tafamidis generics will mean for the AMVUTTRA business?

So we've heard from Pfizer that tafamidis is losing patent protection 2028 in the U.S. From an Alnylam perspective, this isn't really a big deal for us. We're already approaching parity to tafamidis, as I described in my presentation. And actually, the real potential impact of tafamidis going off patent is that it really unlocks the opportunity for combination use. And when we think about AMVUTTRA, we have all that we need in this regard. I mean, we have data from HELIOS-B, which shows benefits in combination with tafamidis. It's on our label. And so we think that the introduction of generic TAF will actually likely accelerate a little bit of combination use.

Within that 2026 TTR guidance, how should we think about the contribution from international cardiomyopathy sales? And maybe you can expand a little bit on your expectations for price outside the U.S. where you've kind of commented a little bit before?

Yes. No, that's a really great question. Jeff, do you want to take that?

Yes. I mean I'm happy to take the question. The expectation is as we launch in markets ex U.S., you're not going to have split indication pricing. Price will likely come down, which will have an impact on the existing polyneuropathy business. Over time, the volume growth in the cardiomyopathy parts of these markets will more than offset that. But in 2026, it likely means you're not going to see an acceleration of growth outside the U.S. relative to the growth that we saw in 2025.

What are you guys going to be watching for in the eplontersen CVOT data coming out this year?

Yes. And obviously, we're waiting for the data to be released. But Pushkal, why don't you take that one?

Yes. I mean, look, we'll obviously be watching. I think we want to see the efficacy. We also want to see the safety, right? This is an ASO in a large, older population. I think we want to understand what the safety profile looks like as well. As we kind of think about the readout, just, it's probably also -- as we kind of think about, okay, how does -- it's another silencer type of mechanism in the disease. We kind of look at what we've established with HELIOS-B, which is 85% knockdown, 30% plus reductions in all-cause mortality, comparable reductions in hospitalizations. We're seeing some evidence of disease reversal on cardiac MRI, and we're seeing benefits on extracardiac manifestations like GI, et cetera, with 4 times a year dosing. So I think when we look at the profile that's going to emerge for eplontersen, I think I would -- my instinct is that it will be somewhat similar to that. I don't expect it to be materially different. That said, I think there's been a lot of discussion around, well, they've got a larger population of patients on combination and is that going to mean anything. And I think as Yvonne just alluded to, we already have established benefits in combination using HELIOS-B, which is now reflected in the label. So while they may have greater statistical precision around that estimate, I don't expect that, that's going to result in a materially different claim, for instance, because we already have that established HELIOS-B, as Yvonne mentioned.

Maybe just building on that, I think we're going to have a head start as well. And I think we've demonstrated in the PN market segment, but we've been able to maintain a leading market share compared to eplontersen in the polyneuropathy indication. So we feel we're well set up with the data that we have for HELIOS-B and looking forward to seeing the data come out of CARDIO-TTRansform, but as Pushkal said, we don't believe it's really going to change the game.

And what about for nucresiran? What are the most important differentiators from AMVUTTRA? And I guess, how do you think about the transition or maybe like coexistence of that product with AMVUTTRA?

Yes, nucresiran is a really important opportunity for the company. And that's why we're really expediting development and delivering the PN indication, hopefully, by 2028 and CM in 2030. But Pushkal, why don't you speak to the specific...

I can speak to the profile and then Tolga, you want to speak to the -- how we're going to bring it forward. I mean I think we're very excited about nucresiran. As Yvonne highlighted in her presentation, we can get about 95% knockdown with nucresiran, AMVUTTRA delivers about 85%. That's going to lead to more patients getting that deeper level of knockdown, which we think is a benefit both in polyneuropathy as well as in cardiomyopathy, less variability, so more patients getting there. It's twice a year dosing. So we think it's going to offer greater patient convenience. And so at the end of the day, our hope is that this will really be now the new sort of standard of care for patients with this disease, where we need to hit them strongly with the best available therapy. Tolga, do you want to comment on this...

Yes. I mean the only thing I would add is our ambition for 2030 obviously includes nucresiran, which we're really excited about. It's the target -- the product profile is really exciting. In terms of how the switch is going to happen, it's probably too soon for us to really articulate that. We've obviously managed through ONPATTRO and AMVUTTRA, although they're not exactly the same. And again, we're really excited about nucresiran, and we hope to be able to -- once the product is in our hands, we're going to be able to provide a lot more clarity around how the category is going to be developed.

And just I think also important to note that this really gives us a durable franchise. So we are committed to patients with TTR amyloidosis. We're committed to continuing innovating for these patients. And it really gives us a sort of durable long-term growth franchise here.

Just one comment here on nucresiran and the importance of it financially. From a margin perspective, we've guided to 30% operating margins through 2030. Nucre, we're talking about CM launch 2030. That will really drive a margin enhancement post 2030, assuming that we've got a successful product launch.

Okay. So the nucre transition could be sort of like a tailwind for the 2035...

Very soon, very soon after 2030. I don't think we'll need to wait to get to 2035 for us to see the impact.

The royalties -- the average royalty that we'll be paying on that is going to be high 20s. So if you can obviously switch that business from AMVUTTRA to nucresiran where you won't have the royalty burden, I think it should substantially benefit our margins.

So I guess, put differently, the 2030, 30% operating margin does not really reflect much of a transition?

Correct.

No, you won't get that in this period. It's really beyond this period, right? Because the CM launch is really what would unlock that.

Another element of that long-term guidance. When you talk about expanding into 10 tissue types, what sort of -- what counts as an expansion into a new tissue? It looks like you've brought something into the clinic or you've got preclinical proof of concept? What sort of...

Yes. This is a really important part of our strategy because we believe that the expertise and experience that we've built up in working in the RNAi field for more than a couple of decades now really helps us come up with strategies for accessing additional tissues. And that's why we set the target at 10 each tissue that we unlock, think about it acts as a value multiplier for the business. But Pushkal, maybe you want to talk a little bit specifically about how we're thinking about the different tissues?

Yes, absolutely. I think -- look, I think it's important to note, RNAi is an evolutionary concerned process. It's in every cell of our body. It's in every tissue of our body. And so if we can deliver into a particular tissue like we did in the liver now that we've done in CNS with our colleagues at Regeneron, that opens up now a wealth of possibilities. And so in terms of new diseases to go after or new targets to pursue. And so we've identified and we'll be pursuing at least 10 tissues that we want to get into where we think that there is a preponderance of disease as well as a preponderance of genetically -- genetic targets that we can pursue to ameliorate that disease. As Yvonne said, that then allows -- that's a value multiplying concept for us where we can go after in that tissue, but also start to think about multiplexing across tissues, right, to really address polygenic and more complex chronic diseases. In terms of what counts, we've talked about -- what we're really talking about is things that are either in the clinic or sort of IND-enabled at that point. That's really what we're looking for through NHP studies, et cetera, so that we have a strong confidence that they're going to work...

So for the ALN-HTT data coming up, can you talk about what would represent success in that update? What would be kind of especially exciting when you unveil those results?

Yes. I mean, I think ALN-HTT is an incredibly exciting program. I don't think I have to describe the harness nature of Huntington's disease, which has been described as ALS and Parkinson's and Alzheimer's altogether. It's a devastating disease. We've got a unique approach, which I think is now being really supported by the academic science, which is targeting this exon 1 fragment is felt to be necessary to have an effect on this disease. We've been going through Phase I studies. So we'll be sharing some data later this year. I think -- look, there have been, unfortunately, for the patient community, real setbacks with past programs that have looked this disease where they've actually had some deleterious side effects. So first and foremost, we want to ensure that we get good deep knockdown as well as good safety. And that's really what the primary focus is going to be. Obviously, over time, we'll be looking at other measures, biomarkers and clinical measures of efficacy. But the first and foremost is we want to make sure that we have a safely administered drug that really does what we're hoping to from a pharmacology perspective and allows for infrequent dosing, we anticipate probably twice a year.

And maybe turning to mivelsiran. What are the data for that product that you're kind of most excited about so far? And what should we look for in the next update?

Yes. I mean I think this kind of connects again to what I just talked about with Huntington's disease. What's really remarkable is that in the few years, we've now taken the C16 delivery platform, and we're able to now actually have these discussions about how we can affect these really horrendous diseases, which I think kind of only imagined just a few years ago, right? And so with mivelsiran now, that is -- targets amyloid precursor protein, and we're really bringing that forward for 2 different indications. One is a blue ocean opportunity, which is cerebral amyloid angiopathy, the second leading cause of hemorrhagic stroke. We've got that in the Phase II study, which is enrolling well. But that's really a potential blockbuster and really entirely blue ocean. And then we'll be coming forward with our plans in Alzheimer's disease shortly in terms of how we're going to pursue that indication. So these are very exciting opportunities. Again, what's amazing is we want to share more data in terms of the levels of knockdown that we're achieving, the safety that we're seeing now with some patients on drug for over 2 years. And then again, we'll start to share some data over time in terms of biomarker imaging, et cetera, that gives us confidence in this approach.

With our last minute, what would you flag to investors as the next kind of most exciting upcoming pipeline data readouts look out for?

I think -- look, I think as Yvonne highlighted, we now have 25 programs in the clinic. We're putting 3 to 4 molecules in the clinic every year. So there's going to be really a steady sort of flow of data coming out of the pipeline. We've highlighted a few things that we're going to share about some Huntington's data that we've talked about, some data on plasminogen, some data on ACVR1C for overweight and obesity. But I think there'll be more data as well over time. Understandably, we're keeping some things a little closer to the chest these days than we may have in the past. It's getting competitive out there, but you can see that we're incredibly excited about what we have in our hands and continue to build an amazing portfolio across a range of diseases.

Yes. And Jess, if we think about where we are as a business, we could not be more excited about what's ahead. Thinking about the growth trajectory with AMVUTTRA, we doubled TTR revenues this year. We set ourselves some bold guidance to be the market leaders by revenue by 2030, and all the business fundamentals are strong. So we're very excited about driving that through. Pushkal has talked about this very rich pipeline with a number of really important and exciting multibillion-dollar opportunities that we're going to be prosecuting over the next few years. And so we really have a business that is humming and we're going to use this 2030, 5-year set of goals to really accelerate our innovation and scale our impact and hopefully have significant impact on human health and build, I think, what is already a remarkable business, and we're determined to become the leading science and biopharmaceutical company.

Great. Well, thank you.