Hello, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Alnylam Pharmaceuticals.
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. Happy to have you both here.
Just a reminder, this is a fireside chat. If anyone has questions, if you raise your hand, we can try and address them in our discussion. 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/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. 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 with John. As many of you know, Alnylam is the leading RNAi 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. A real pleasure to be here to dig into the questions you may have for us.
Yeah. That's great. Thanks for that, Yvonne. You touched on it already, but you've had a very strong TTR cardiomyopathy launch. Maybe we can start there, and you can describe what's driven the success so far.
No, that's a great question. We are very proud of what we have accomplished with AMVUTTRA, particularly for patients with TTR cardiomyopathy. in Q2 this year, we crossed $1 billion of revenue in just one quarter. I think that's particularly impressive given that we achieved the cardiomyopathy indication in March of 2025. 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.
Really, I think it's been this body of evidence which we have continued to enrich with additional analyses looking at cardiac structure and function, looking at the benefits on extra cardiac manifestations, that I think really provides a compelling proposition for physicians to prescribe AMVUTTRA first line.
You put that together with a quarterly subcutaneous administration, which if you like, provides physicians with certified adherence because you are only going to get the benefits from a drug if you actually take the drug.
I think the profile of AMVUTTRA 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 have done a really good job being able to ensure that there's unencumbered access really to AMVUTTRA as a first-line therapy. Most patients are able to get access to AMVUTTRA with $0 out-of-pocket cost. We have really focused on trying to make this convenient for patients. 90% of patients can access AMVUTTRA within 10 miles of their home.
I think really strong setup from an access perspective. I think the third point is really around physician preference. What's been remarkable to us actually, is that physicians who experience AMVUTTRA, who prescribe AMVUTTRA prefer it.
We have a greater than 50% market share with physicians who have used AMVUTTRA. That's really very encouraging. The final point I'd make is just around the market. This is a rapidly growing market, hugely underserved.
Whilst we have made terrific progress with AMVUTTRA, I am really excited by how much there is ahead of us in terms of helping patients with TTR cardiomyopathy.
Yep. Makes sense. Recently on the earnings call you reset expectations around guidance for the year. 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 billion-$4.5 billion for our TTR franchise. That's a $200 million reduction at the midpoint. That was really driven by a greater understanding of the evolution of the market, particularly as it relates to second-line demand.
When we launched AMVUTTRA in 2025, there were clearly a number of patients with pent-up demand. There were patients who were progressing that were waiting for a new treatment. When we looked at the mix of our business in 2025, it was pretty well balanced between first line, so 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.
What happened as we went into 2026 is that really has normalized, if you like, and stabilized. 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 where the market is, which is 80% first-line and 20% second-line.
We're trending in that direction. Really, our focus is therefore on making sure that we continue to establish AMVUTTRA as a first-line opportunity for patients. Now, some patients who continue to progress will benefit from an alternative therapy.
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 a stabilizer, really the only opportunity is a silencer like AMVUTTRA, or they will think about this in combination.
Yep. Makes sense.
Actually, you asked me a question about the market fundamentals, and maybe just to
Sure
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
Yeah
in the U.S. and 500,000 patients around the world. A need to really help these patients get diagnosed and treated, and really also the first-line momentum that we're seeing. I think strong market fundamentals as we look out beyond 2026.
Makes sense. Also want to just touch about on 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. 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 accrue. So over time. That's really what you saw in 2025 and 2026. That's been what we said, and we see that as the outlook.
For 340B, there's a proposed rule change, and obviously that is 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. 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.
Yeah.
There are eligible accounts that anyone can purchase at 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 site of care. Those are built for volume and built for buy and bill. There is optionality on the other side of that. I would say the most important thing is we're focused on AMVUTTRA access, and we see access and utilization across sites of care.
That's the bottom line for me, that whatever happens-
Exactly
We're going to make sure that patients who need AMVUTTRA are going to be able to access AMVUTTRA.
Yeah. Makes sense. When do you think this will come to an end? Is it November? Does it keep dragging on? How does this all play out?
Historically, when there's a proposed rule change, we expect that in November, somewhere in November, is usually when those things are concluded, but it remains to be seen.
Yep. Understood. Maybe we can shift gears to another area of focus, data from the CARDIO-TTRansform study and what that means or doesn't mean for silencers. Maybe share what you've learned from the detailed results and maybe how it might impact AMVUTTRA or not.
The CARDIO-TTRansform study was really very interesting, and 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. 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 eplontersen in the study. Less than 70% mean TTR knockdown compared to what we've seen with AMVUTTRA in HELIOS-B of 81% mean TTR knockdown. That 11% is actually a meaningful difference. 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 is going back to the 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 rather than 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. We saw this in HELIOS-B actually, where patients who were at an earlier stage of their disease saw better outcomes. I think that's a really important point. Actually, in CARDIO-TTRansform, there's a similar finding there as well.
In the cohort of 900 patients who are NAC stage 1, so earlier stage of their disease. Actually, eplontersen was able to deliver a positive result, which would have achieved statistically nominal significance. I think there's something around patient selection.
that is really important. The last point is around the endpoint. I mean, the HELIOS-B was 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. People die from the broad aspects of the disease.
They have heart failure, they get pneumonia, they die, they're weak, they fall. 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. I know the other thing is having an event-driven endpoint is also helpful, so you can make sure that you accrue enough events and are able to see a difference.
Yeah. I guess what feedback have you gotten more recently from physicians since the detailed results? Is there any impact on AMVUTTRA or not? I guess, we did our own doc call and the view was no impact. Just curious what you're hearing out there.
Yeah. I mean, I'd just like to say a little bit, the HELIOS-B does stand alone-
Right
as a study. I mean, it was a landmark study, delivered very impactful results. I think the other point to make is that silencers are not all silencers. You have ASOs and you have siRNA. What's been quite interesting actually, when you've looked at a number of programs, AGT, APOC3, PCSK9, and now eplontersen is that actually siRNA perform better than ASOs.
I think people are beginning to understand that different study, different drug, not surprising if you get a different result. I think 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 CARDIO-TTRansform study. Obviously, 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-
Yeah
for AMVUTTRA.
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 think there are some that are trying to characterize the study
Right
as something that it wasn't designed to do.
Yeah.
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.
Yep.
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.
Yep. Makes sense. Maybe you can talk about some of the OUS dynamics you're seeing and how that might play out this year.
We're thrilled that we're able to make AMVUTTRA 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 ViiV Healthcare to make sure that we can work towards making AMVUTTRA 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 out there.
Yep. Makes sense. Maybe shifting a little bit related, but nucresiran obviously lots of questions around that and implications of the CARDIO-TTRansform. You shared your views on the data. I guess on this study, how are you thinking about the implications there?
Yeah. That's a really good question. I think the first thing to say around nucresiran, we are obviously evaluating nucresiran, a study that's called TRITON-CM. It's a large cardiomyopathy study. Nucresiran has 95% TTR knockdown. That's the best of any program that's out there. We think that's going to play through into improved outcomes.
We definitely have a molecule that is incredibly potent. I think that's the first thing to say. I think the second is that we've been developing medicines for patients with TTR amyloidosis for many, many years and have 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.
We've actually built in a lot of the learnings that were then validated when we saw the data from CARDIO-TTRansform in terms of patient selection, in terms of the endpoint. We feel that we're in a really, really good place with respect to 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, so we're going to sweat the details as we always do.
Yeah.
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.
Those are decisions that we would have to make pretty soon whilst we're still in this enrollment period. 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. 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 later in the course of the study.
I think it's really important to just, I think, underscore that actually, the learning from CARDIO-TTRansform to a certain extent has actually strengthened our conviction
Yeah
around the design of the TRITON-CM study.
If you decide to make some fine-tuning to the study, I guess when would that happen? 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?
If we do anything different with enrollment, 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. 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.
Yeah. Increase in the confidence, is that about monotherapy effect? Is that combo effect? Is there some limit on background tafamidis you can have to be successful? I know these
It's important to just say what we're trying to achieve
Yeah
with this study was actually to affect a broad label
Yeah
for mivelsiran the way that we have done for AMVUTTRA, and therefore it's going to be important that we study a range of patients in the 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.
Yep. Another question that comes up for TTR cardiomyopathy is just the impact of generic tafamidis in 2031, and maybe you can just share the latest thinking there and the impact to your functions.
Yeah. We'd originally thought that generic tafamidis would become available in 2028, and now we understand it's more likely to be 2031. Actually, that's a pretty good thing for AMVUTTRA.
It reduces the pricing pressure of having a generic come into the market sooner, and it allows us more time really to establish AMVUTTRA, to continue to establish AMVUTTRA as 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 nucresiran and the TRITON-CM study because we will be delivering data for the polyneuropathy TRITON-PN in 2028, and then for TRITON-CM around about 2030. So it actually all comes together rather nicely.
Yeah. Maybe last question on TTR. I guess as you look 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? Where are the key?
I think if I think about it, I'll step back and then I'm sure John Kennedy 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 AMVUTTRA as first-line monotherapy, and obviously doing that in a number of ways in terms of continued evidence generation, continued education of physicians, continued support around patient identification, diagnosis, and helping patients get through the various care pathways so they can actually receive treatment. 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. 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. I said physicians who use AMVUTTRA prefer it. We're currently addressing about a third of the prescribers out there, and there's a lot of runway.
We're investing in broadening the prescriber base as well as obviously also deepening prescribing within physicians who are already prescribing AMVUTTRA. Then you touched on markets outside the U.S.
We'd like to continue supporting patients who live outside the U.S., and continued geographical expansion is going to be very important to us. We spent a little bit of time also talking about nucresiran.
I think AMVUTTRA is a very important medicine for Alnylam Pharmaceuticals. 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. We really are aspiring to ensuring that we're leaders in the TTR space. We'd like to be leaders for a long time.
Developing our third generation with nucresiran, as I said, much better, 95% TTR knockdown, is another important aspect as we think about the long-term opportunity for the TTR franchise.
Yeah
AMVUTTRA.
Yeah. JP, is there anything else?
You covered all the levers. Just for color commentary, what I would say is, this category is rapidly expanding, so that is patient volume, but it is also just the number of prescribers that are involved in the category, and that is why being able to expand the prescriber base is important.
We are doing more. So we have more physician engagement with more people in the field, more investment. Then the other investment is to drive diagnosis. We are not doing this alone. We feel compelled, as we aspire to be the leader, to do more to drive diagnosis, but we are doing that in partnership with others. Viz.ai is an AI provider.
Yeah
is one example. The American Heart Association, et cetera. Those are partnerships we're building.
Yeah. Yvonne, you brought this up. Pipeline, which we got about 8 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 what you think investors should focus on there.
Yeah. No, I'm really excited about the progress with 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. 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.
We have, at Alnylam, a program which we believe has a really important mechanism of action, where we're able to address not just the full-length Huntingtin 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.
I think this has been supported by some of the data from uniQure, a natural history study, which showed the importance of actually having this exon 1 fragment. 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 I 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 understand PK/PD. We'll be able to measure huntingtin lowering through CSF.
So if this program is successful, we think we'll be able to move it very quickly into phase III. I think there'll be a lot of support for trying to progress this medicine towards patients. So something that we are very excited about, and we hope to be able to move rapidly forward.
There will be more information being presented at the EHDN meeting in October, just around the corner. I would ask you all to stay tuned. That is a really, really exciting program. Probably the second program to touch on is called ALN-6400. It is what we call our plasminogen program.
It is for bleeding disorders. It has, 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 is some good genetics and biological evidence for this. The other exciting thing about this program is the mechanism of action could apply across a range of different bleeding disorders.
We are starting with a study in patients with hereditary hemorrhagic telangiectasia, and I will talk a little bit more about that, but we are also then in a phase II for patients with von Willebrand disease. You can see how we start off with one indication, and we start to go after one indication after the other with bleeding disorders.
We have phase II ongoing in patients with HHT. There we are measuring numbers of bleeds in these patients, severity of bleeds. These are patients actually that have incredibly severe nose bleeds, GI bleeds, and they are often anemic, so they require transfusions. There is a really significant unmet medical need for these patients, which we hope to address with this particular program.
We will be able to complete this phase II study shortly, and if we are able to move this program into phase III, it is something that actually could also move very quickly. You do not need large outcome studies to measure bleeding. We are pretty excited about this.
Can you just quickly touch on the bar for bleeding? What is a meaningful decline in the bleeding rate or any particular bar you are looking for?
We'll come back on that as we get the results. But clearly we only want to progress a program that's going to have a significant benefit to these patients. It's not just the numbers of bleeds, but it's also the fact that these patients are anemic. They often require transfusions. You also have to think about are you able to reduce the hematological support that these patients require.
Got you. If we just keep going with the pipeline, just the obesity program and your strategy there and when we might see some data.
Yeah. A lot of people are excited about obesity.
Yeah.
There's a lot going on. We're hoping to be able to demonstrate that we're able to deliver our siRNA into adipose tissues. That'll be a first for us. That in itself will be a significant milestone. When we think about what the opportunities are in obesity, it's really thinking about beyond incretins. How can you think about better quality weight loss?
As we think about our strategy, it'll be thinking about the monotherapy, it'll be thinking about in combination with other siRNA, we'll be thinking about in combination with incretins as well. We're fortunate at Alnylam 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. Again, we'll be getting proof of concept data.
Yep
later on this year. We're eagerly looking forward to that.
Yep. Great. Maybe we keep going with the pipeline. Zilebesiran, maybe just give us a quick background there, and I think you're going to have a webinar later this week.
Yeah. No, the webinar's coming up.
Yeah.
I'd encourage you all to tune into it. Look, I think zilebesiran 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.
One of the other issues with patients who are receiving treatment for hypertension is around adherence. They just don't take their tablets. Here we can conceive of infrequent dosing of subcutaneous zilebesiran 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. We have a large outcome study ongoing where we hope to be able to demonstrate this over the next few years.
Yeah. Great. Maybe I can ask on another hot topic, the AI topic.
Yeah.
John, you mentioned some ways you are using it in diagnosis. Are there any other ways across the company you are using it to accelerate development or things like that?
Well, we are using AI broadly across the company.
Yeah
as many organizations are to improve our efficiency, improve our productivity. Obviously, some of the approaches that John touched on the commercial side of our operations. We are 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 siRNA 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 are just about out of time, so why don't we end it there.
Thank you.
Yvonne and John, thanks so much. Appreciate your time.
Oh, thank you. A pleasure. Thank you so much.