Alnylam Pharmaceuticals, Inc. Morgan Stanley 24th Annual Global Healthcare Conference

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.

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.

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.