Alnylam Pharmaceuticals, Inc. (ALNY) September 2026 Conference Transcript

All right. Hello, everyone, and thanks for joining us at the Morgan Stanley Global Health Care Conference. I'm Michael. It's one of the biotech analysts here. It's my pleasure to introduce the team from El Nilem Pharmaceuticals. Up to my left, Yvonne Greenstreet, CEO, and to her left is John Kennedy, Senior Vice President of Global Commercialization and lead of the TTR franchise, which I know a lot of people are interested in, so happy to have you both here. But just a reminder, this is the fireside chat. If anyone has questions, if you raise your hand, we can try and address them in our discussion. But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com backslash research disclosures.

If you have any questions, please reach out to your Morgan Stanley sales representative.

And with that, maybe I'll just hand it over briefly to Yvonne to make some comments, and then we can hop into the Q&A.

Well, thank you so much. It really is a pleasure to be here, to be here with John. As many of you know, our NILM is the leading R&AI company. We have a commercial stage TTR franchise business that's growing very rapidly. We have a rich pipeline with a number of potentially transformative medicines that will be delivering some exciting catalysts over the next year or so. And a real pleasure to be here to, you know, dig into the questions you may have for us.

Yeah, that's a great, thanks for that, Yvonne. And you touched on it already, but you've had a very strong TTR cardiomyopathy launch, so maybe we can start there and you can describe what's driven the success so far.

Yeah, that's a great question. Yeah, we're very proud of what we've accomplished with Amvutra, particularly for patients with TTR cardiomyopathy in Q2 this year. We crossed a billion dollars of revenue in just one quarter, and I think that's particularly impressive given that we achieved the cardiomyopathy indication in March of 2025. So really, really strong progress, and I think that's driven by a number of key drivers. I think the first is the strength of the data that we generated from the landmark Helios B study where we delivered impressive results with respect to all-cause mortality in all the different subgroups in the study and severity types and patients receiving stabilizers or not. And really, I think it's been this body of evidence which we've continued to enrich with additional analyses looking at cardiac structure function, looking at the benefits on extra cardiac manifestations, that I think really provides a compelling proposition for physicians to prescribe Amvutra first line. And then you put that together with a quarterly subcutaneous administration, which, if you'd like, provides physicians with certified adherence, because you're only going to get the benefits from a drug if you actually take the drug. And I think the profile of Amvutra has been very well received by physicians and supports its position as first-line monotherapy. I think the second key driver is really around access. Again, it's great to have delivered a successful study and have a medicine that's safe and efficacious, but patients have to be able to receive the medicine. I think we've done a really good job being able to ensure that there's unencumbered access, really, to Amvutra as first-line therapy and most patients are able to get access to Amputra with zero dollars out-of-pocket costs. And we've really focused on trying to make this convenient for patients. And 90% of patients can access Amputra within 10 miles of their home. So I think really strong setup from an access perspective. I think the third point is really around physician preference. and what's been remarkable to us actually is that physicians who experience Amvutra, who prescribe Amvutra, prefer it and we have a greater than 50% market share with physicians who have used Amvutra so that's really very, very encouraging. And the final point I'd make is just around the market. This is a rapidly growing market, hugely underserved And so, you know, whilst we've made terrific progress with Amvutra, I'm really excited by how much, you know, how much there is ahead of us in terms of helping patients with TTR cardiomyopathy.

Makes sense. And recently on the earnings call, you know, you reset expectations around guidance for the year. So maybe talk about some of the dynamics behind that and what you've been seeing as the launch progresses.

Yeah, no, that's a really great question. Yes, we revised our guidance on our Q2 call to $4.2 to $4.5 billion for our TTR franchise. That's a $200 million reduction at the midpoint. And that was really driven by a greater understanding of the evolution of the market, particularly as it relates to second-line demand. You know, when we launched Ambutra in 2025, there were clearly a number of patients with pent-up demand. There were patients who were progressing, they were waiting for a new treatment. And so when we looked at the mix of our business in 2025, it was pretty well balanced between first lines, the patients that had just been diagnosed with TTR cardiomyopathy and getting a treatment for the first time, and patients who were second line, who were already on a treatment. And, you know, what happened as we went into 2026 is that really has normalized, if you like, and stabilized. So we've gone from a mix of business that's been pretty well balanced between first line and second line to now a business that's really approaching, you know, what the market, where the market is, which is 80% first line and 20% second line. So we're trending in that direction. So really, our focus is therefore on making sure that we continue to establish Ambutra as a first-line opportunity for patients. Now, some patients who continue to progress will benefit from an alternative therapy. And some physicians, when they have to think about how to best treat these patients, will think about either adding in an additional therapy, and if they're on stabilizer, really the only opportunity is a silencer like Amputra, or they will think about this in combination. Makes sense. Actually, you asked me a question about the market fundamentals, and maybe just to touch on that a little bit, because I think it is worth emphasizing how strong the market fundamentals are. I've already talked about access. I've already talked about the needs in the marketplace with 80% of patients yet to be diagnosed and treated in a market that has roughly 200,000 patients in the U.S. and 500,000 patients around the world. And so a need to really help these patients get diagnosed and treated, and really also the first-line momentum that we're seeing. So I think strong market fundamentals as we look out beyond 2026.

Makes sense. And I also want to just touch about some of the pricing dynamics and maybe how that's evolved through the launch and then this 340B question that's coming up now.

Yeah, John, do you want to touch on pricing and 340B?

Yeah, absolutely. So in terms of pricing, we have said since launch, and we've been very consistent, that we anticipate a modest and gradual reduction in net price just as the volume and experience accrues over time. And that's really what you saw in 25 and 26. And so that's been what we said, and we see that as the outlook. For 340B, there's a proposed rule change. And obviously that has gone through the comment period. There's been quite a few voices that have spoken up about that. Particularly on the provider side, there's some very strong voices against that. And so I think it still remains to be seen what will actually come from that comment period and actually what happens with the proposed rule change. That said, even if that were to move forward, I think the other variable is how providers will change their behavior. And there are options. So there are eligible accounts. Anyone can purchase that list price. There are also these alternate sites of care, which we have really built a robust network to make sure that patients have optionality in terms of the site of care. And so those are built for volume and built for buy and bill. So there is optionality on the other side of that. And I would say the most important thing is we're focused on Amvutra access, and we see access and utilization across sites of care.

So that's the bottom line for me, that whatever happens, we're going to make sure that patients who need Amvutra are going to be able to access Amvutra. makes sense.

And when do you think this will kind of come to an end? Is it November? Does it keep dragging on or just like, does this all play out?

Historically, when there's a rule, proposed rule change, we expect that in November, somewhere in November is usually when those things are kind of concluded, but, you know, it remains to be seen.

Yep. Understood. Maybe we can shift gears to another area of focus, you know, data from the cardio transform study and kind of what that means or doesn't mean for silencers. Maybe share what you learned from the detailed results and maybe how it might impact Amvutra or not.

You know, the cardio transform study was really very interesting. And, you know, I think the outcome was driven by a number of key factors. I think one was the depth of TTR knockdown that was achieved in the study. I think the second was around the patient population that was enrolled in the study, and I think the third was around endpoint selection. What I think was probably most surprising to people was actually the relatively poor TTR knockdown that was achieved by Eplon-Turston in the study. I mean, less than 70% kind of mean TTR knockdown compared to what we've seen with Ambutra in Helios B of 81% mean TTR knockdown. And that 11% is actually a meaningful difference. And to me, what I think is really quite interesting is that probably what we've seen is a little bit of a dose response set of studies, if you like, in this space for patients with TTR cardiomyopathy. Clearly, better knockdown leading to better outcomes. less good knockdown leading to less good outcomes. I think the other aspect, just going back to the sort of patient selection for the study, that it's quite clear that when you're thinking about a stabilizer, the best opportunity for patients is to treat patients early. You're treating them with a stabilizer. When the heart's already had a lot of deposition of amyloid, it's obviously going to take longer for that to resolve. And we saw this in Helios B, actually, where patients who were at an earlier stage of their disease saw better outcomes. And that's a really, really important point. And actually, in CardioTransform, there's a similar finding there as well. In the cohort of 900 patients who were NAC stage 1, so earlier stage of their disease, actually Epilontes was able to deliver a positive result, which would have achieved statistically nominal significance. So I think there's something around patient selection that is really, really important. And the last point is around the endpoints. I mean, the Helios B looks at an all-cause mortality endpoint. Now we know that TTR cardiomyopathy is a multi-system disease. It affects the heart. It affects other parts of their body. And people die from the broad aspects of the disease. If they have heart failure, they get pneumonia, they die, they're weak, they fall. And so if you're going to have an endpoint, I think it's helpful to have an endpoint that is able to measure all the aspects that impact mortality. And I think the other thing is having an event-driven endpoint is also helpful, so you can make sure you crew enough events and you're able to see a difference.

I guess what feedback have you gotten more recently from physicians since the detailed results is there any impact on Ambutra or not and I guess we did our own doc call and the view was no impact so just curious what you're hearing out there I'd just like to say a little bit Helios B does stand alone in this study it was a landmark study delivered very impactful results and I think the other point to make is that silencers are not all silencers.

You have ASOs and you have siRNAs. And what's been quite interesting, actually, when you've looked at a number of programs, AGT, APOC3, PCSK9, and now eplontersin, is that actually siRNAs perform better than ASOs. And I think people are beginning to understand that, that different study, different drug, Not surprising if you get a different result. So I think, you know, as we speak to physicians, and we've done some surveys, they're really not seeing huge implications to their daily practice based on the CardioTransform study. But obviously, you know, it's our job to make sure that we're able to get out there and educate physicians on the strength of what we have in the Helios-B study and the compelling profile for Amfutra.

What about this dynamic between the stabilizers versus the silencers? Is that kind of the same view, like no real impact or change there?

Yeah, I mean, I think there are some that are trying to characterize the study as something that it wasn't designed to do. But in terms of just general practice, maybe the way I can answer it is we actually did a survey of cardiologists, general cardiologists that are caring for these patients in this category, and we actually did it between the press release announcement of the failed trial and before ESC. So if you think about it, that was the moment of probably the highest uncertainty. And we did a survey and essentially asked, does anything change, especially with regard to your current behavior and your perception of silencing? And the short answer was overwhelmingly no. Now, since we went to ESC, we now have so much more data, and I think the conclusions are generally what we see. It probably worked. Silencing worked, but it matters how well you silence, and we have a better product, and that came across, I think, very clearly at ESC.

Yeah, makes sense. maybe you can talk about some of the OUS dynamics you're seeing and how that might play out this year I'm thrilled that we're able to make Amvutra available to patients around the world I think the launch has gotten off to a great start in markets like Germany and Japan we recently effected a commercialization agreement with B1 to make sure that we can work towards making Amvutra available to patients In China, obviously, we need to get through the regulatory process first. And whilst these are all different geographies and they have their different systems, their different pricing and reimbursement systems, different access considerations, I think one thing is clear that patients with TTR cardiomyopathy are not sufficiently diagnosed and not sufficiently treated. And so there's a huge opportunity as we think about building this business. obviously in the U.S., but also around the world to meet the needs of so many patients.

Makes sense. Maybe shifting a little bit related, but Nucraceran, obviously, lots of questions around that and implications of the cardio transform. You shared your views on the data, I guess, on this study. How are you thinking about the implications there?

That's a really good question. I think the first thing to say around Nucreceran, we're obviously evaluating Nucreceran, a study that's called Triton-CM. It's a large cardiomyopathy study. Nucreceran has 95% TTR knockdown. That's the best of any program that's out there, and we think that's going to play through into improved outcomes. So we definitely have a molecule that is incredibly potent. I think that's the first thing to say. I think the second is that, you know, we've been developing medicines for patients with TTR amyloidosis for many, many years and have, you know, real insights from all the studies that we've got. We've got patient-level data from our Helios B study. And that allowed us to be really thoughtful about the design of Triton-CM. And, you know, we've actually built in a lot of the learnings that were then validated when we saw the data from CardioTransform in terms of, you know, patient selection, in terms of the endpoint. And so, you know, we feel that we're in a really, really good place with respect to, you know, Triton-CM. We're obviously continuing to enroll that study. Obviously also very thoughtful about the fact that this is an incredibly important study for the company, and so we're going to sweat the details, as we always do, right? And we're going to think about whether there's anything that we need to do to modify the study, which really falls into two buckets. One is thinking about the patients that we enroll and enriching for certain types of patients potentially, maybe increasing the size of the study. That's another option. And those are decisions that we would have to make pretty soon whilst we're still in this enrollment period. And obviously, if we make those decisions, we'd communicate that broadly. The other approach might be to think about the analytical plan, a little bit like we did with Helios B. And that's a decision that we can make at any point in time over the duration of the study. It's probably something that we think about kind of later in the course of the study. But I think it's really important to kind of just, I think, underscore that actually, you know, the learning from CardioTransform, to a certain extent, has actually strengthened our conviction around the design of the Triton cardiomyopathy study.

If you decide to make some fine-tuning to the study, I guess, when would that happen? And then, I guess, related to that is obviously there's a lot of interest in probably the baseline characteristics because those are going to matter as we try and think about the probability here, I guess. When might you share those, or what's the thinking there?

So if we do anything different with enrollment, I mean, you know, if you remember, I think it was earlier on this year, we announced that we were upsizing the study. We're adding another 500 patients to the study, and we announced that as soon as we'd made that decision. So if we're making any changes to enrollment, that's something that we would communicate before the end of the year. But as I said, if we're refining the stats plan, we can do that at any point in time, so I wouldn't expect that we would be communicating anything on that front in the near term.

The increase in the confidence, is that about monotherapy effect? Is that combo effect? Is there some limit on background TAF you can have to be successful?

It's important to just say what we're trying to achieve with the study is actually to affect a broad label for Nucleasra and the way that we have done for Amvutra. Therefore, it's going to be important. We study a range of patients and study both monotherapy and combination. therapy. Really, the goal is to make sure that we deliver a successful study, which can then meet the needs of patients with TTR cardiomyopathy, whatever types of patients those are.

Another question that comes up for TTR cardiomyopathy is just the impact of generic tefamidus in 2031, and maybe you can just share the latest thinking there and the impact to your Yeah, we'd originally thought that generic tefamilis would become available in 2028, and now we understand it's more likely to be 2031.

And actually, that's a pretty good thing for Amvutra. It reduces the pricing pressure of having a generic come into the market sooner, and it allows us more time, really, to establish Amvutra, to continue to establish Amfutra is the foundational therapy for patients with TTR cardiomyopathy. So we think it's actually a good thing for us. The other thing is actually the timing juxtaposes really nicely with Nucresteron and the Triton-CM study because we will be delivering data for the polyneuropathy Triton-PM in 2028 and then for Triton-CM roundabout 2030. So it actually all comes together rather nicely. Yeah.

And maybe last question on TTR. I guess as you look sort of near term through the next couple of years, just the key drivers of growth to really push the frontline use up, is it just helping find more patients more quickly? Is it more education around the profile? You know, what are the key?

So I think if I think about, I'll step back and then I'm sure John will add some color, but if I think about, okay, what are the key drivers of the business over the next period? And you're absolutely right. I think the really important thing is to establish Ambutra's first-line monotherapy and obviously doing that in a number of ways in terms of, you know, continued evidence generation, continued education of physicians, continued support around, you know, patient identification, diagnosis, and helping patients get through the various care pathways so they can actually receive treatment. So that's really, really, really important. I think the second area is around continuing to help grow the market. When you've got a market where 80% of patients are undiagnosed and untreated, I think it's a really important opportunity and obligation for us to continue to educate physicians and improve the diagnosis rates and improve the treatment rates. So investing in helping to grow the market is also very important. I think when we think about educating physicians, I think what we also need to do is to broaden the prescriber base. So as I said, physicians who use Ambutra prefer it. We're currently addressing about a third of the prescribers out there, and so there's a lot of runway, and so we're investing in broadening the prescriber base, as well as obviously also deepening prescribing within physicians who are already prescribing in Vutra. And then you touched on markets outside the U.S., and we'd like to continue supporting patients who live outside the U.S., and so continued geographical expansion is going to be very important to us. And we spent a little bit of time also talking about Neucristra. I think Amputra is a very important medicine for our nylon. It actually is a medicine that's going to allow us to fund the very exciting pipeline that we're developing and build the company. So we really are aspiring to ensuring that we're leaders in the TTR space. And we'd like to be leaders for a long time. And so developing our third generation with Neucristra, much better, much 95% TTR on lockdown is another important aspect as we think about the long-term opportunity for the TTR franchise and Amvutra. David, was there anything else?

You covered all the levers. Just for a color commentary, what I'd say is this category is rapidly expanding. That's patient volume, but it's also just the number of prescribers that are involved in the category. That's why being able to expand their prescriber base is important. we're doing more. So we're actually, we have more physician engagement with more people in the field, more investment. And then the other investments to drive diagnosis, we're not doing this alone. We feel compelled as, you know, we aspire to be the leader to do more to drive diagnosis, but we're doing that in partnership with others. This AI is, you know, an AI provider is one example, the American Heart Association, et cetera. So those are partnerships we're building.

Yeah. And Yvonne, you brought this up pipeline, which, you know, we got about eight minutes left here, so maybe we can dig in there a little bit, and you've got a bunch of updates later this year, but maybe just high level, maybe just talk about pipeline and kind of what you think investors should focus on there.

Yeah, I'm really excited about the progress of the pipeline. As I said, a number of important catalysts this year. So I'll start with the first, which is our Huntington's program, and I know I don't have to convince any of you here how much unmet need there is for patients with this disease. It's been described as being a combination of ALS and Parkinson's and Alzheimer's, and there's really nothing out there for these patients. And we have at Arnylam a program which we believe has a really important mechanism of action where we're able to address not just the full-length Huntington gene, but also the exon 1 fragment, which has increasingly been implicated in the pathophysiology of the disease. So we think we've got something in our hands that could be really impactful. And I think this has been supported by some of the data from Unicure and Natural History Study, which showed the importance of actually having this exon 1 fragment. And this is a program. It's administered intrathecally. It's probably going to be a couple of times a year. and we'll be getting phase one data in October. So it really is imminent, and we're hoping that they will be able to demonstrate safety and tolerability. We'll be able to demonstrate, you know, we'll be able to understand PKBD. We'll be able to measure Huntington's luring through CSF. And so if this program is successful, we think we'll be able to move it very quickly into phase three. I think there'll be, you know, a lot of support for trying to progress this medicine towards patients. So something that we are kind of very excited about, and we hope to be able to move rapidly forward. And there'll be more information being presented at the EHD meeting in October, so just around the corner. So I would ask you all to stay tuned. That's a really, really exciting program. Probably the second program to touch on is called ALN 6400. It's what we call our plasminogen program. It's for bleeding disorders. And really it's got, again, a really interesting approach where it can stabilize clot, and the potential here is to be able to stabilize clot and therefore reduce bleeding without any thrombotic risk, and there's some good genetics and biological evidence for this. And the other kind of exciting thing about this program is the mechanism of action could apply across a range of different bleeding disorders. So, you know, we're starting with a study in patients with hereditary hemorrhagic telangiectasia, and I'll talk a bit more about that. But we're also then in a phase two for patients with von Willebrand's disease. So you can see how, start off with one indication, and we start to kind of go after one indication after the other with bleeding disorders. So we have a Phase II ongoing in patients with HHT, and there we're measuring numbers of bleeds in this patient, severity of bleeds. These are patients, actually, that have incredibly severe nosebleeds, GI bleeds, and they're often anemic, they require transfusions. There's actually a really significant unmet medical need for these patients, which we hope to address with this particular program. And we'll be able to, you know, complete this phase two study shortly. And, you know, if we're able to move this program into phase three, it's something that actually could also move very quickly. You don't need large outcome studies to measure bleeding. So we're pretty excited about this.

Can you just quickly touch on the bar for bleeding, like what's a meaningful decline in the bleeding rate or any particular bar you're looking for?

We'll come back on that as we get the results. But clearly, we only want to progress a program who's going to have a significant benefit to these patients. So it's not just the numbers of bleeds, but it's also the fact that these patients are anemic. They also require transfusions. So you also have to think about, are you able to reduce the hematological support that these patients require.

If we just keep going with the pipeline, just the obesity program and your strategy there and when we might see some data.

Yeah, so a lot of people are excited about obesity. There's a lot going on. We're hoping to be able to demonstrate that we're able to deliver our SIRNAs into adipose tissues. That will be a first for us, so that in itself will be a significant milestone. And when we think about what the opportunities are in obesity, we're really thinking about beyond incretins. How can you think about better quality weight loss? And as we think about our strategy, it'll be thinking about monotherapy. It'll be thinking about in combination with other siRNAs. It'll be thinking about in combination with incretins as well. So we're fortunate that we're able to think about how we can progress our pipeline in creative ways to meet the emerging needs of patients with obesity. And again, we'll be getting proof-of-concept data later on this year, so we're eagerly looking forward to that.

Great, and maybe we keep going with the pipeline, so Zobisiran, maybe just give us a quick background there, and I think you're going to have a webinar later this week.

Yeah, the webinar's coming up, so I'd encourage you all to tune into it. Look, I think Zalbisran really has the potential to transform how hypertension is treated because hypertension is not just about lowering blood pressure. It's about the durability of lowering blood pressure. It's that continuous control. And one of the other issues with patients who are receiving treatment for hypertension is their aderterence. They just don't take their tablets. And here we can conceive of infrequent dosing of subcutaneous LBs trying to really maintain continuous control for these patients, restore nighttime dipping, reduce variability. And we believe that all of this will lead to better outcomes for patients. It's not just about blood pressure lowering. It's about improving outcomes for patients. So we have a large outcome study ongoing where we hope to be able to demonstrate this over the next few years.

Great. So maybe I can ask on another hot topic, the AI topic. John, you mentioned some ways you're using it in diagnosis, but, you know, any other ways across the company are you using it to accelerate development or things like that?

Well, we're using AI broadly across the company, as many organizations are, to improve our efficiency, improve our productivity. Obviously, some of the approaches that John touched on, you know, on the commercial side of our operations, We're also very excited that we signed an agreement with a company called Inceptive Nucleics who are helping us think about how we can combine their frontier models with all the data that we have with respect to sRNAs and actually see whether this can help us accelerate innovation and be able to move our incredibly already productive R&D engine even faster.

Yep.

Okay.

Great. Looks like we're just about out of time, so why don't we end it there? Yvonne and John, thanks so much. Appreciate your time.

A pleasure. Thank you so much.