Salveen Richter
Goldman Sachs Group, Inc.
Great. Good morning, everyone. Thank you so much for joining us. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, and we're really pleased to be joined by the Alnylam team.
With me, we have Yvonne Greenstreet, CEO; and John Kennedy, Head of the TTR franchise. So Yvonne, before we even start, you announced some news this morning. So maybe this is a perfect time point to maybe speak to the European approval that came today and the strategy that you hope to take in Europe with TTR.
Yvonne Greenstreet
CEO & Director
Yes. So hot off the press this morning. Well, first of all, good morning, everybody. Hot off the press this morning is that we managed to secure approval in Europe for AMVUTTRA for cardiomyopathy. It's a big news for us. It means that we can move forward with our plan to take AMVUTTRA to patients with TTR cardiomyopathy in Europe. I have to do a shout out to our regulatory team because we were able to file global submissions, achieve approval in the U.S. on March 20, EU today and planning to launch in Japan and Germany second half of this year. So we really have now got some momentum, global momentum behind our TTR franchise, so very exciting.
Salveen Richter
Goldman Sachs Group, Inc.
Great. So maybe jumping back here, big picture. In 2021, you launched your P5x25 strategy outlining goals for Alnylam by year-end '25, including non-GAAP profitability, and everything has been either achieved or appears to be on track to meet. How do you think about the 5-year vision for Alnylam from here?
Yvonne Greenstreet
CEO & Director
Yes. That's a fantastic question. So you're absolutely right. In 2021, we launched what was some pretty ambitious goals actually back in 2021, really laying out the 5 years trajectory for the company. And as you said, I'm pleased to say that we're absolutely on track to meeting all of them, including achieving sustainable non-GAAP profitability by the end of this year. We haven't quite delivered them yet. So I'm going to wait until we get to the end of the year, hopefully declare victory, and then we'll be in a position to present to you our next set of 5-year goals.
Having said that, I think when you look at Alnylam as a company, it really is a unique biotechnology company where we've got robust and growing revenues, primarily driven by our TTR franchise. We've got this incredible pipeline that is spring-loaded for growth.
We have a sustainable innovation engine that continues to deliver new programs into the clinic and a very robust financial position. So in a really unique position as a company in biotech. When you think about what we need to do to continue to grow the company going forward, we clearly need to make sure that we are leaders in TTR. I think we're on -- we're really pleased with the progress with our launch with AMVUTTRA thus far, but we really need to make sure that we achieve leadership in TTR.
And we need to continue to grow through innovation and continue to maintain this incredible high-yielding pipeline with probability of success that are multiples of what are achieved in the industry.
And obviously, we need to continue to scale and build the company in a very disciplined way and continue to deliver financial performance. So those are the sort of, if you like, the 3 pillars that are important in terms of how we think about growing the company going forward. And hopefully, we are able to declare victory with respect to P5x25 at JPMorgan next year, we will share more detail around our specific 5-year goals.
Salveen Richter
Goldman Sachs Group, Inc.
Great. I want to jump in further into TTR. But before we do that, you hosted an R&D Day this year, and you really laid out a broad siRNA platform pipeline off the base of your technology. Could you walk us through what you see as the growth levers beyond TTR?
Yvonne Greenstreet
CEO & Director
Yes. No, that's an important question because we believe we're the leading RNAi company, and we think we'll deliver significant revenue growth with TTR franchise, but it's important to keep the pipeline behind that going. And I think we're making incredible progress.
Most of you have heard about zilebesiran for hypertension. But I just want to highlight a couple of areas, which are probably underappreciated. When we think about our CNS pipeline, I'm particularly excited by our program for Huntington's disease.
Huntington's, as all of you know, is a very, very debilitating condition. Patients continue to suffer from a wide array of symptoms that have been described like having Parkinson's and Alzheimer's all in one. And we have what we think is a unique approach for helping to meet the needs of these patients, an approach that not only focuses on the mutant huntingtin protein, but also the exon 1 fragment, and we believe that this is going to have a meaningful impact on these patients.
And the second program that I'd like to highlight, ALN-6400 targets plasminogen. I don't think many folks have really picked up on how exciting this could be. Essentially, we believe that this has the possibility, by targeting plasminogen, of being a universal hemostatic agent without the problems that you see with thrombosis.
And if we're right, ALN-6400 could be a little bit like VYVGART being for Argenx and really be a pipeline in an injection. So 2 very exciting programs, which have the opportunity actually of moving forward pretty expeditiously.
Salveen Richter
Goldman Sachs Group, Inc.
Could you also speak just overall from a pricing dynamic with regard to Most Favored Nation pricing? And if that were to be implemented, how that factors into your plan for the ex U.S. launch from AMVUTTRA in cardiomyopathy? And help us understand this in the context of what's playing out with polyneuropathy currently.
Yvonne Greenstreet
CEO & Director
Yes. Look, I think it's really difficult for anybody to speak with any degree of knowledge with respect to what's going to happen with MFN. There's just so much uncertainty at the moment that I think it's quite difficult for us to really predict specifically what the impact on our business is going to be.
I think one of the advantages that we have at Alnylam is all of our products are for rare diseases. They have orphan drug designation. And so when it comes to negotiations like the IRA, that orphan status has actually helped position Alnylam relatively well. But we'll see how things unfold with MFN.
Salveen Richter
Goldman Sachs Group, Inc.
On the TTR front, specifically in ATTR cardiomyopathy, on your 1Q earnings call, you outlined that greater than 50% of the 170 priority health systems that treat about 80% of these patients have the drug on formulary, of which over 75% have begun treating patients. And so one could assume you've treated over 65 to 75 patients at this point. Could you discuss the drivers behind this rapid progress within the first 5 weeks post approval and how we should think about that on the forward?
Yvonne Greenstreet
CEO & Director
I think it really helps having a medicine out there with AMVUTTRA treating patients with polyneuropathy. And actually, 45% of patients with polyneuropathy are actually diagnosed by cardiologists. So we're able to get off to a running start, if you like, with AMVUTTRA in cardiomyopathy. I think the reasons for our great progress are probably twofold. I think one is actually just the strength of the data that we generated with HELIOS-B. I think it's a very compelling value proposition across the board for payers, for physicians, for patients. And I think the profile that we have with AMVUTTRA has really resonated within the ecosystem. So we're delighted with that.
Salveen Richter
Goldman Sachs Group, Inc.
And how are you thinking about the cadence of P&T committee meetings and patients starting treatment into year-end?
Yvonne Greenstreet
CEO & Director
Yes. We haven't given specific details around that. But John, perhaps you want to say a few words about how we're thinking about that.
John Kennedy
Yes. One of the things that we have said pretty consistently is that this is a buy-and-bill product. So there's an initial setup that we have taken very seriously. We've been laser-focused on that. And so I think that what we saw with the first quarter earnings is a reflection of how focused we've been to make sure that we have that proper setup that really unlocks that momentum in the second half.
So in terms of the cadence, we obviously haven't really committed any kind of velocity kind of metrics. What we have confirmed is our expectations for revenue. And so we fully expect that we're going to be able to meet or exceed guidance. That's what we aspire to do.
I think it's very encouraging that you had so much progress as of that first quarter earnings call. So that is certainly in track, if not a little bit ahead of our expectations for that initial setup. That allows the demand to actually fall through. And we do know that there's demand in the market.
Salveen Richter
Goldman Sachs Group, Inc.
And on that guidance front, you provided guidance this year for TTR of $1.6 billion to $1.725 billion, which is roughly 36% year-over-year growth at the midpoint. Given that the polyneuropathy segment is still growing, can you help us understand, a, whether this guide is conservative in the context of what you provided, but b, where the growth on the polyneuropathy still lies?
Yvonne Greenstreet
CEO & Director
Yes. No, that's a tremendous question. And we're delighted with the performance of our business in PN. I think it speaks to a number of things. As I said, the profile of AMVUTTRA and the strength of our commercial team, but the fact that there's actually a lot of patients out there and the market is continuing to grow even with competition.
Now we've been growing the PN business between 28% and 34% on a quarterly basis year-on-year. So that's actually robust growth. And we expect to see obviously growth over and above that with cardiomyopathy. One thing we won't be able to do is to split out polyneuropathy and cardiomyopathy sales directly because we sell to distributors, and we can't actually provide that granularity.
But given that we understand the growth rates that we're seeing with polyneuropathy, I think it's not going to be too difficult when we share our progress with our TTR franchise in our next earnings call to get a sense of actually what the growth ramp is going to be for cardiomyopathy.
But John, do you want to say anything about the polyneuropathy business and why you think that remains so strong?
John Kennedy
Yes. I think in polyneuropathy, there are some similarities to cardiomyopathy. This is still a rare disease, generally underserved. So there's a lot of growth to be had in polyneuropathy. We see that. And I think one of the things that we're seeing is competition. That's just more voices. That helps diagnosis.
So it's actually been a category-expanding event. I think you'll see very similar dynamics in cardiomyopathy. The majority of patients, globally, about 80% of these patients are untreated. So it's a category expansion opportunity. The fact that there are now multiple treatments, more voices in the market, I think, is helpful. So if you look at the guidance, it is an acceleration of the growth, but there's a lot of opportunity to be had.
Salveen Richter
Goldman Sachs Group, Inc.
Is there any granularity you can give us in terms of the breakout between treatment-naive and progressors for the patients who are starting treatment here?
Yvonne Greenstreet
CEO & Director
So right now, I think what's really encouraging about the launch is just the broad utilization across patient types, both patients starting treatment for the first time and those that are already on treatment. I think there's breadth of the prescriber base in terms of community physicians and academic centers. And so we're really encouraged actually by the broad uptake that we're seeing thus far with AMVUTTRA.
Salveen Richter
Goldman Sachs Group, Inc.
And apart from sales numbers that will be provided on the 2Q and 3Q calls, are there any other metrics that you'll provide that will help us understand?
Yvonne Greenstreet
CEO & Director
Absolutely. By the time we get to Q2 call, we'll have had a little bit longer with the AMVUTTRA launch under our belt, and we'll be able to provide some more specifics. Clearly, I think revenue is going to be the most kind of critical number for many folks that kind of watch the space. But I think we'll provide some granularity on some of the things that I've just shared in terms of the nature of prescribers, the nature of patients. So I think there'll be quite a lot more that we'll be able to share in our Q2 earnings call.
Salveen Richter
Goldman Sachs Group, Inc.
And you've spoken about your efforts of expanding alternative sites of care and overall providing optionality to where patients can be dosed, including miles from injection site in home. Just walk us through how that's playing out, right?
Yvonne Greenstreet
CEO & Director
Yes, I'll start, and John may have some additional points to make. So at our last earnings call, we said we had 1,000 sites set up for patients, and the plan is to double that, and we'll double that. And we intend to make sure that 90% of patients are within 10 miles of an infusion center. And obviously, also patients can also receive the administration at home, which I think is really helpful to patients that want that.
I also think that the quarterly subcutaneous regimen is a real actual advantage for AMVUTTRA in that it aligns pretty well with physician visits, but also physicians can be sure that the patients actually receive the treatment. With all therapies, their major compliance issues and for progressive severe condition like TTR cardiomyopathy, you're only going to get the benefit of a treatment if you actually take the treatment.
And we've been really pleased with our adherence rates in the polyneuropathy setting in excess of 95%, and we expect to see exactly the same thing with cardiomyopathy.
John, anything to add?
Salveen Richter
Goldman Sachs Group, Inc.
Speak to the reimbursement front here. So you've initiated treatment across payer mixes without step edits. Are you seeing a difference in access for patients on Medicare Advantage where cross management with stabilizers has been a point of debate?
Yvonne Greenstreet
CEO & Director
Yes. No, I think I'll start and then I'll hand it to John. I think what is encouraging about this launch is that we're seeing initiations across all payer types. So fee-for-service, Medicare Advantage and commercial. There being no barriers to access. John, anything specific...
John Kennedy
What I'd add to that is in addition to seeing utilization across all payer segments, the majority of patients are paying $0 out-of-pocket cost. So if you remember, we're really informed by the experience that we've already had in polyneuropathy, where 99% of patients have access to AMVUTTRA and the majority of those patients have 0 out-of-pocket costs.
The payer mix is very, very similar in cardiomyopathy. So it's incredibly encouraging. So far, we're seeing utilization across all of those payers, whether it's Medicare fee-for-service, Advantage or commercial. And again, the majority are paying $0 out-of-pocket cost. So it's very encouraging.
Salveen Richter
Goldman Sachs Group, Inc.
And how are you overlaying the free drug program on top of all of this?
Yvonne Greenstreet
CEO & Director
I think that's one piece. I think this is an important point to clarify. I think again, there's a little bit of confusion around exactly how our program operates. I'll just start off by saying that we provide a very holistic service to support patients. And this is just one -- what we call the QuickStart program is just one component of that. John?
John Kennedy
Yes. I'll talk more broadly about our patient services organization. So it is fully owned. It's a part of our organization, and that's relatively unique in the industry, certainly in this category. So it's an important part of how we support this community.
We've had a patient service organization for a long time, a range of support services or offerings. QuickStart is one of those. So we've had this for years. It is not a new initiative, but we continue to maintain it here to support this launch.
What I would say is if you look at the polyneuropathy business, there's generally been limited utilization of it because there hasn't been a need for it. So essentially, the way it works is if a patient has challenges getting initial access, we'll provide that first dose with quarterly dosing, that gives a 3-month lead time to work through that.
And so again, we've had this offering for a long time, generally have had limited utilization. So far in cardiomyopathy, it's a very similar situation. We provide that offering, but it's been limited utilization. And it hasn't been an issue because we're seeing that utilization come through.
Salveen Richter
Goldman Sachs Group, Inc.
And maybe provide color on the cadence at which you'll manage AMVUTTRA's net price over time and how this will be accomplished because you have always had this ability to kind of adjust based on policies.
Yvonne Greenstreet
CEO & Director
That's right. So we've indicated that we will see some modest adjustment to AMVUTTRA pricing over time, but we haven't gone into specifics of that at this point in time. I think it's way too premature. But as you said, we have the levers to manage this in the marketplace.
Salveen Richter
Goldman Sachs Group, Inc.
You touched on this earlier with the first question, but speak to the timing and expectations for your first ex U.S.
John Kennedy
Yes. I mean we're obviously very encouraged that we've got a product that is unique in having a regulatory approval in multiple countries, U.S. included across both hereditary polyneuropathy and cardiomyopathy.
So our goal generally is to make AMVUTTRA available as broadly as we can, as quickly as we possibly can. What we've talked about so far in the second half of this year is that we expect to launch in Germany and Japan. There will be other launches to follow likely throughout 2026, which is a function of both the regulatory review in certain countries, but also that pricing and reimbursement process that does exist in many countries.
Salveen Richter
Goldman Sachs Group, Inc.
And one last question here, but you presented some data and analyses at the Heart Failure Conference this year. Can you speak to the key takeaways that played out here and how that factored in physician education efforts or how it is factoring in physician education efforts?
Yvonne Greenstreet
CEO & Director
So the key takeaway from my perspective is that with HELIOS-B, we have a very rich data set, which we will continue to interrogate. And the more we interrogate the data set, the more it becomes clear to us that AMVUTTRA has a significant magnitude of impact as well as consistency of impact across all patient types.
So we continue to provide more information. So I think that helps to educate physicians and give them a greater understanding of what they can expect to see as their patients take AMVUTTRA. But there are a few key, I think, additional data sets that we shared. So yes, John, do you want to touch on what you find most exciting?
John Kennedy
Yes. What we showed from the primary analysis, first and foremost, is this is a very rigorous trial. I mean these were patients generally earlier in the disease progression with substantial background treatments in the active and placebo arm. So it was a really robust test of effectiveness.
And in that, we did see a magnitude of outcome impact that was profound, including that 36% reduction in all-cause mortality as a stand-alone prespecified endpoint in addition to that preservation of function and quality of life with quarterly dosing. So what we're now seeing with additional analyses just reinforces a lot of the same themes. So we've seen additional outcomes that have reported out. For example, in addition [indiscernible] 33% reduction in CV mortality.
More recently, we saw there was a 46% reduction in urgent heart failure visits. So again, magnitude and consistency of those outcomes, coupled with that preservation of function. So we've seen remarkable biomarker data, some imaging data, for example, echo parameters like diastolic function, which suggests not just an improvement versus placebo, but in some of these parameters, improvement versus baseline. So it just reinforces the value proposition that we've seen, and it just gets richer and richer with more data analyses.
Salveen Richter
Goldman Sachs Group, Inc.
Moving over to the pipeline here, and I'll start with vutrisiran. So you plan to initiate a Phase III study in the second quarter this year. Speak to us about how you're thinking about the overall trial design in order to elucidate the benefit that you see with this drug, not just from potentially dosing dynamic and then also how you manage for concomitant medications that could impact these trials in the future?
Yvonne Greenstreet
CEO & Director
So hot off the press. We've actually now initiated TRITON-CM, so a little bit ahead of schedule. So yes, we're really delighted to have kicked this program off because we do see vutrisiran bringing additional benefits to patients with TTR cardiomyopathy. It's also a testament to Alnylam's commitment to these patients to commit to continue to innovate for these patients with a program that has the opportunity not just for increased convenience with biannual dosing, but also much greater TTR knockdown. So we couldn't be more excited about the study.
I think one thing to note about the study is it's an event-driven study. So we'll continue the study until we have a high degree of confidence that we have a result. And it's an outcomes study. So we will be following these patients for at least 24 months because we think that as we consider the evolving treatment of patients with TTR cardiomyopathy, it's really important for us to bring vutrisiran to patients with the most compelling profile that we can deliver.
We're also going to be kicking off our study in polyneuropathy with vutrisiran second half of this year. And that gives us an opportunity to bring vutrisiran to patients in a much shorter time frame. So we couldn't be more excited about vutrisiran.
And the opportunity that provides Alnylam as a company is really for kind of durable revenues out to the 2040s in what is, as John has said, a large and growing market. So a really important part of the TTR strategy.
Salveen Richter
Goldman Sachs Group, Inc.
Can you lay out for us from a data perspective or event perspective, what you're most focused on from the pipeline over the next 12 months?
Yvonne Greenstreet
CEO & Director
Wow. I mean there's a lot that's happening in the pipeline. Zilebesiran, I think we're really excited about zilebesiran. We will be sharing data from what we call our KARDIA-3 study, where we're assessing zilebesiran on top of patients who are taking 2 to 4 antihypertensives, who are at high risk of cardiovascular disease.
And that study will -- is powered to show a 6-millimeter of mercury reduction in systolic blood pressure. Actually, it's been demonstrated if you're actually able to reduce blood pressure by 5 millimeters of mercury, you actually have a significant impact on cardiovascular outcomes. But not only does zilebesiran reduce blood pressure, but also provides continuous control. And we believe it's going to have a lot of ancillary benefits that are also going to drive improvement in outcomes. So we hope to be able to share the KARDIA-3 data with you second half of this year. And then we will be kicking off a cardiovascular outcomes study. So I think that's pretty exciting.
We continue to progress mivelsiran. It's a Phase I study ongoing in patients with early onset Alzheimer's disease. We continue to get more information from the multi-dose portion of our study as we go through the year. Very excited about that program.
We've already kicked off the program with mivelsiran in patients with cerebral amyloid angiopathy. I think that's an indication again that people should pay attention to. It's underrecognized. Diagnosis is growing as patients have more and more MRIs with the introduction of antibodies for Alzheimer's.
And we believe it's got a really kind of strong probability of succeeding in this patient group. So we're pretty excited about that. And what I continue to be really excited about for the company is actually the innovation engine that we have that continues to deliver 2 to 4 new INDs per year. And we're now able to deliver to the liver, the CNS muscle, heart, adipose tissue. Really one of our goals is actually to deliver siRNA technology to every single major tissue in the body.
So again, Alnylam [indiscernible] when we think about the trajectory of revenues for TTR, very exciting when we think about the clinical pipeline. But I think what we're building here really is a company that is really just getting started.
Salveen Richter
Goldman Sachs Group, Inc.
Could you touch on your strategy in obesity and diabetes and when those programs could enter the clinic?
Yvonne Greenstreet
CEO & Director
Yes. I think, look, our platform is actually really well suited to addressing the needs of patients with metabolic disorders and obesity, just given clamp PD, the fact that you can get infrequent administration. And so we believe that we should be able to provide benefits to patients in these 2 disease states. And we started to share some of the progress that we're making with our programs. One program is GRB14 for patients with diabetes.
The real opportunity here is actually to provide an insulin sensitizer without any weight gain. So we're pretty excited about moving that forward. And I told you now in adipose tissues, we've got another program that's actually targeting ACVR1C, which I think is going to have a really unique approach to treating patients with obesity. There's quite a lot going on in that metabolic obesity pipeline. It's a really exciting space.
Salveen Richter
Goldman Sachs Group, Inc.
Could you talk to capital allocation and BD strategy here. Do you feel -- I mean, you clearly have a lot going on, but do you feel a need to use your cash here and look at external options to bring in?
Yvonne Greenstreet
CEO & Director
I think as you pointed out, we have a very rich pipeline. And our first order of business is to progress the pipeline that we have. We believe that there's some really transformative medicines that have the opportunity to be multibillion opportunities in the medium term. So we really must make sure that we focus on those and move those through.
And again, continue to invest in our platform. We continue to make platform enhancements, talked about getting into different tissues. So there's a lot that we believe we can do at Alnylam to create substantial value for many, many years to come. But we are in an ecosystem where it continues to be innovation that gets driven by other companies, and we keep a close eye on what's happening in the landscape. But I think it's going to be a pretty high bar, at least at this point in time for us to do any significant BD.
Salveen Richter
Goldman Sachs Group, Inc.
Great. Well, with that, thank you so much. Really appreciate the time today.
Yvonne Greenstreet
CEO & Director
