Alnylam Pharmaceuticals, Inc. Wells Fargo 21st Annual Healthcare Conference

Thanks for having us. Excellent.

Yeah. Thank you for that. Maybe I'll just start by characterizing the launch, what we see when we look back, and then what that means going forward. We'll talk about the guidance along the way. First and foremost, we're about 18 months into this launch for cardiomyopathy. AMVUTTRA was already approved for hereditary polyneuropathy. We added cardiomyopathy in March of 2025. We're about 18 months in, and the launch has gone exceptionally well. Just a single headline, if you think about the last quarter, we passed a billion-dollar quarter for the TTR franchise. This is very, very strong. Now, when we look back, there are several things that we were really focused on to make sure that this had the fundamentals in place for sustainable growth, and they're there. Generally speaking, the first area of focus for us has been access.

That is both provider access but also payer access, and the access is very, very strong. Generally unencumbered access to AMVUTTRA, particularly in first-line, with the majority of patients paying $0 in out-of-pocket cost. That has allowed us to focus on demand. Now if we look at physician experience and demand, since the launch of the cardiomyopathy indication through the end of last quarter, we have seen more than 1,700 physicians have a first experience with AMVUTTRA. There is tremendous uptake, especially in a rapidly growing category where more physicians are coming in. Now what we look for is what is that experience, and a great indicator of that experience is if we look at those physicians that have experience, we have north of 50% share of new starts with those physicians. In other words, trial results in a favorable experience and in preference for AMVUTTRA.

That is all very, very strong and encouraging. Of course, this is in a category that has grown. It has grown for the last 6, 7 years. It will continue to grow when you think that the majority of patients, unfortunately, are still untreated. So those are all the fundamentals that we are very, very confident in and give us quite a bit of runway for opportunity moving ahead. Now, as it relates to the guidance, one of the things that we talked about was just the learning in terms of the contribution of the AMVUTTRA source of business. To back up a little bit, there is a first-line segment and a second line. First line are these newly diagnosed patients. They are looking for that very first treatment choice. First line has, from the very beginning, been our strategic area of focus.

We want to establish AMVUTTRA as a first-line choice, knowing that, again, the vast majority of patients in this category are untreated. They will come in and seek that first-line treatment choice. So long term, that is a significant part of the opportunity, and that has gone very well. There is a second component, which is second line. What we have seen from real-world evidence data sources is that patients treated with stabilizer unfortunately continue to progress. There was one analysis that looked at more than 800 patients treated on a stabilizer, mostly tafamidis, and what we saw was that within about a year on average, about half of those patients experienced cardiac worsening. So these patients continue to progress, and they will be looking for another treatment choice. Now, we are the first and only alternate mechanism of action in cardiomyopathy, and so we are a natural option for those patients.

Going back to the guidance, what we saw early on the launch is we had many of these high-volume prescribers start using AMVUTTRA, which is a good thing. With those higher volume physicians, they had more of these patients that had been treated with a stabilizer for some period of time. As you can imagine, many of those patients were progressing. So what we saw in the first several quarters of launch is those physicians moved more of those patients to AMVUTTRA in a second-line opportunity, and that was a robust part of the opportunity. So early on, it was relatively balanced where our source of business was coming from that first line and the second line. Now take a step back if you look at the category at large, this is more of a first-line category.

Now, part of that is because there hadn't been another option for a long time, but switching behavior is a relatively new behavior. That will take some time to really form and unlock. When we look at the category, generally about 80% of new treatment initiations are first-line treatment initiation. It's the minority, it's about 20%, that are second line. As you can see, when we started, we have more of a balanced contribution across both lines of therapy, but with those higher volume physicians that were earlier adopters, they moved more of those patients to AMVUTTRA, and what we saw is that second-line inflow has normalized. There's still robust inflow of second-line starts. It's still an opportunity, but it is normalized so that it's less of a contribution in terms of the AMVUTTRA source of business.

Now, the good news is our volume has continued to grow, and it just means that a greater proportion of our volume is now in first line, which strategically was the priority for us. The guidance is to reflect this change where there's a normalized volume of second-line inflow. It is different than what we saw in the first several quarters, and that was a learning for us. We had to adjust the guidance to reflect that normalized flow of second-line volume starts. That's on us in terms of the guidance, but again, just the context is prior to us, there really wasn't a second-line market. That was the newest part of this category where we had to observe and just see how that would play out.

Yeah. What we're looking at for the initiations of AMVUTTRA, what we're seeing is it is still very balanced across these centers of excellence and the community. Just to step back, this is a category that is growing. It's growing very, very rapidly in terms of patient volume, in terms of RX volume, but also in terms of physicians that are active in the category, meaning they're diagnosing and they're initiating treatment. There's an expansion of the physician growth. About half of that growth is coming from these more community centers as opposed to the centers of excellence. We still have a robust business in the centers of excellence. We continue to see depth of penetration. That's a good thing. But in terms of the growth, we're also seeing quite a bit come from the community. Again, we're seeing balanced utilization of AMVUTTRA.

The reason for that is because AMVUTTRA is very widely accessible. I talked about the beginning. Access is a function of both provider and payer. On the provider side, if a community cardiologist chooses to engage in buy and bill, that's fine. That is a relatively well-tried and easy experience. By the way, we're not the only ones that are engaged in that space. Think of LEQVIO in the lipid-lowering category. There are more experiences that cardiologists are having engaging in buy and bill. But if there's a physician that says, "I don't want to get involved for some reason," that's okay, too.

Because we've established a very, very broad network of buy and bill alternate sites of care, such that about 90% of patients anywhere in the U.S., about 90% of patients can receive AMVUTTRA within about 10 miles of their home, whether that's in the physician's office, in a site of care that's part of a large integrated network that the physician is part of, or one of these clinics that is often down the street from where the patient lives.