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TD Cowen 46th Annual Health Care Conference

Mar 2, 2026

Ritu Baral
Biotechnology Analyst, TD Cowen

Thank you everyone for coming today. This is to the TD Cowen Healthcare Conference and the fireside chat for Alnylam Pharmaceuticals. I am the covering analyst, Ritu Baral, and with us from Alnylam, we have Kevin Fitzgerald, CSO, and Jeff Poulton, Chief Financial Officer. Guys, welcome. Thank you for being here. Let's start with ONPATTRO because that's where every conversation of mine starts.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Usually. Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

The revenue growth driver sustainability of growth specifically, how are you guys describing the key drivers behind AMVUTTRA's recent revenue growth, and how sustainable is this trajectory, not just through 2026, but?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

B eyond?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah. thanks for the question. I'd say there's probably two or three fundamental things that underpin our confidence in the growth going forward. One is just the growth of the category in general. This is a under-diagnosed, under-treated disease. We think probably you're at about a 20%-25% treatment rate today. If you look back two or three years when there was only a single therapy in the market, it's been growing fairly consistently the last several years, about 40% a year. We do anticipate that you're gonna continue to see robust growth on a go-forward basis. Now you've got three players in the market.

Ritu Baral
Biotechnology Analyst, TD Cowen

You're talking about treatment or diagnosis?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We're just talking about market growth treatment.

Ritu Baral
Biotechnology Analyst, TD Cowen

Treatment.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Treatment, right.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

More patients coming onto therapy.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

You know, that 40% growth in treated patients over the last several years has been with one therapy in the market.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

The standard, you know, what's been the standard of care, Pfizer's product. You've got three companies in the market today all investing behind disease awareness and driving treatment rates. That should be something that we have a lot of confidence in that that's gonna continue to grow at a brisk pace. That's one. Second is market access, which as you know, Ritu, is a, you know, pretty significant debate prior to our launch in terms of being a Part B med, you know, Part B buy and bill drug with a higher price than the other Part D products that are in the market. How is that gonna work for Alnylam? We're in the second calendar year of the launch today. I would say it's worked very well.

We have 90%-plus percentage of patients today have access to AMVUTTRA as a first-line therapy, and so we have not seen access be a headwind for the brand, and we don't think that that is gonna change over a period of time. We'll continue to stay focused on that. You know, payers and plans have the ability on an annual basis to look at policies. We feel very good about 2026 in terms of access to the AMVUTTRA. Lastly, of course, is, you know, preference, right? Market share, right? What's gonna drive the brand first in the first-line part of the market, which is really where we have been very focused since launch, is driving preference for AMVUTTRA.

It's a progressive fatal disease. Patients should be on the best, most potent therapy as early as they can. We think based on the data from HELIOS-B that we have the ability to argue that AMVUTTRA should be the treatment of choice. We shared some share data at JP Morgan through the end.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm. Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Of the third quarter that showed our share in the first line part of the market, sort of mid to high twenties. That's really been a focus for us.

Ritu Baral
Biotechnology Analyst, TD Cowen

Has that been.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Since launch.

Ritu Baral
Biotechnology Analyst, TD Cowen

Has that been increasing since then?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, we haven't given data for, you know, beyond the third quarter, but we feel very good about the positioning of the product in the first-line part of the market.

Ritu Baral
Biotechnology Analyst, TD Cowen

Was that your internal target, that level, or are you continuing to grow?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, I mean, I don't think we put out a target. I mean, what we've put out in terms of forward-looking information is on 2026-

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Revenue guidance.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We guided for the franchise, $4.4 billion-$4.7 billion, which would be 83% growth at the midpoint, which would be more than $2 billion in revenue growth on a year-over-year basis. Longer term, at JP Morgan with the Alnylam 2030 guidance that we put out, we did put a total revenue CAGR out over that period of a 25% to, you know, total revenue CAGR. That's not only product sales, that's collaboration revenue and royalty. Certainly the biggest driver of that revenue CAGR over the period is gonna be the TTR franchise.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Again, I think that speaks to the confidence that we have in terms of the positioning of the product and the ability of that product to drive durable long-term growth for Alnylam.

Ritu Baral
Biotechnology Analyst, TD Cowen

As we think about commercial focus, is it really on expanding the first-line % and seeing that number.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, I mean, I think if we're successful in the first-line part of the market, which is the largest segment, that's where the.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Y ou have the opportunity to get access to the most patients. If we're successful there, then that we think will support also success in the second-line part of the market, and we've been very successful since launch in the second-line part of the market. We've really been focused on driving in that first-line share.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's been the focus.

Ritu Baral
Biotechnology Analyst, TD Cowen

How has payer contracting evolved and step edits now that, you know?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

Y ou're a growing line item.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yep.

Ritu Baral
Biotechnology Analyst, TD Cowen

T herefore are payers starting to pay attention?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, we've got 26 payer policies that are all set, and we have not seen any.

Ritu Baral
Biotechnology Analyst, TD Cowen

Not permanently, so they can always be up, right?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Every year they have the ability to do this, but the 26 plans have been set, and there hasn't been, really been any change from 25 to 26 in terms of access to AMVUTTRA. We're more than 90% of the patients today have access to AMVUTTRA in the first-line setting.

Ritu Baral
Biotechnology Analyst, TD Cowen

With no step edit?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

No step edits. Again, maybe we should just talk about the.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

P ayer mix.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, this is a, you know, given the nature of the disease, this is a heavy Medicare population. It's probably about 80% of the patients that are on AMVUTTRA, whether that be for polyneuropathy or for cardiomyopathy, are Medicare patients.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That Medicare part of the market is split roughly 50/50 between fee for service, the original Medicare part of the market, and Medicare Advantage. Just as a reminder, in the original Medicare part of the market, there's no payer policies. There's no management of that part of the Medicare market. That's obviously a very good segment for us in terms of access.

Ritu Baral
Biotechnology Analyst, TD Cowen

You mean the pay fee for service?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, the.

Ritu Baral
Biotechnology Analyst, TD Cowen

Free.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

For service. There's no policies.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yep.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

There's nobody managing that part of the market. The Medicare Advantage, which is really where there was a lot of debate.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yes.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I think coming into the launch is what you see.

Ritu Baral
Biotechnology Analyst, TD Cowen

They do cross manage the B and D.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Very, very little. I mean, we've seen.

Ritu Baral
Biotechnology Analyst, TD Cowen

Why?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Very little. Look, I think from a systems perspective to cross manage B and D is challenging for payers.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We've seen very little of that in the Medicare Advantage part of the market, so that's almost all first line opportunity. The smaller part of the market is the commercial part of the market, so that's what's, you know, 15%-20%, and that's where we did anticipate some cross management.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

B and D. We've seen some of that, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's.

Ritu Baral
Biotechnology Analyst, TD Cowen

This is where the step edits.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's where the steps are.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Right. That's where the majority of the steps are is in the commercial part of the market. Again, that's a smaller part of the market.

Ritu Baral
Biotechnology Analyst, TD Cowen

What, what kind of step edits and what sort of documentation?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, it varies by plan, right, in terms of what you have to provide to work your way through the step.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Look, we have the ability to support patients and offices when there are steps in place. It really does vary by plan.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

There's not a single approach to how those steps are put in place.

Ritu Baral
Biotechnology Analyst, TD Cowen

How do you assess the midterm competitive threat from WAINUA? I mean, it's not near term. That data's later this year, the phase III.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, look, I think, you know, one thing that's good with more competitors is what we talked about earlier, that this is still largely an underdiagnosed and undertreated patient population. The more voices that you have, the more it drives those things, and that can be good for everybody that's in the space. I think I'd start there, number one. It's hard to comment too much further until we see their data.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, I think there's a few things that, number one I'd say is just in terms of the, you know, how rapidly we knock down TTR. We probably have an advantage there.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm

Jeff Poulton
CFO, Alnylam Pharmaceuticals

In terms of time to get to.

Ritu Baral
Biotechnology Analyst, TD Cowen

A potential differentiator. That's.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Could be. I mean, we're gonna have to see the data in terms of.

Ritu Baral
Biotechnology Analyst, TD Cowen

Right.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Whether or not that translates into efficacy.

Ritu Baral
Biotechnology Analyst, TD Cowen

That's one nuance.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's one. I think we're gonna be very interested to look at the safety data in that study. I mean, there's been, you know, renal tox issues with ASOs in the past.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

This is clearly a different molecule, this is a, you know, in the cardiomyopathy setting, this is an older, you know, frailer population, so it's gonna be interesting to see if there are any safety signals there that could have an impact. In terms of how these products are dosed, we're a once a quarter dosed. We're Part B, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's physician administered. They're Part D, once a month, so 4 times a year versus 12. Majority of patients would prefer fewer injections to more injections.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

You can get our product at home. You can have it ad-administered in the home. That's one differentiator. Lastly, I think maybe it's instructive to look at what's happened in the polyneuropathy space since they came into the market. In the U.S., they launched in polyneuropathy at the start of 2024, and if you look at the growth of our PN business prior to their launch, post their launch, you really didn't see any change in the trajectory of the polyneuropathy business. I think what's happened over time is with the second entrant in the polyneuropathy part of the market in the U.S., the pie started to expand faster, just as what I said.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Before in terms of another voice. We're getting majority of that business. We've probably gotten 70% of the new patient starts since they launched in polyneuropathy. That leadership position that we had.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That kind of firmly established position was very helpful in polyneuropathy. We believe that we're gonna have a similar situation in the cardiomyopathy part of the market with the head start that we've had on them.

Ritu Baral
Biotechnology Analyst, TD Cowen

One thing you've been able to do to really lock in that PN market was contracting, whether it was I'm still not sure, but I inferred there was certainly ex-US contracting, national orders, national pricing in place. Is that a strategy you can adopt for cardiomyopathy, whether US and ex-US?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, I mean, we're not doing any contracting in the US today per se, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm. Yep.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I don't think that that's gonna be part of the plan going forward in terms of competition with WAINUA.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Ex-US, again, the dynamics are obviously a little bit different around sort of pricing and access.

Ritu Baral
Biotechnology Analyst, TD Cowen

Right.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Than they are in the U.S.

Ritu Baral
Biotechnology Analyst, TD Cowen

Population sizes as well.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yes.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, the polyneuropathy part of the market, it's a much more mature market outside the US because tafamidis got approved outside the US for polyneuropathy and really built that part of the market.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That didn't happen in the U.S. We were really building the polyneuropathy market in the U.S. with ONPATTRO many years ago.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

The dynamics are just a little bit different in polyneuropathy.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

U.S., ex-U.S.

Ritu Baral
Biotechnology Analyst, TD Cowen

Got it. How do you hope next gen will evolve into the TTR landscape? This is nucresiran.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

How's enrollment in TRITON going?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah, I mean, we're early days, but I would say enrollment's on track in terms of.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm

Jeff Poulton
CFO, Alnylam Pharmaceuticals

The plans that we had. You know, we're really excited about this opportunity. This is a next gen, so uses different chemistry and allows us to dose less frequently. We're looking at twice-a-year dosing, so once every six months, and deeper knockdown and a, I would say, sort of less variability around that deeper knockdown. Our, you know, our belief is that that could translate to better efficacy. We're looking at 95%.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Knockdown versus mid-80s knockdown.

Ritu Baral
Biotechnology Analyst, TD Cowen

Is that gonna be?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Tighter spread around 95% than it is around 85%.

Ritu Baral
Biotechnology Analyst, TD Cowen

Do you think that's gonna end up representing sort of a linear improvement in outcomes?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Again, I think it's hard to say. I think the best data that we have in looking at deeper knockdown and what efficacy benefits that you see are, is in polyneuropathy on mNIS+7, and we do see certainly a relationship with deeper knockdown leads to better efficacy. I think we're hopeful that we'll see that. We've got two studies underway with nucresiran two phase III studies right now, a polyneuropathy study that is very similar in design to what we did with HELIOS-A. That will read out.

Ritu Baral
Biotechnology Analyst, TD Cowen

With the same APOLLO A control arm?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yes.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah. That would be a 2028 launch is the expectation. We've got an outcome study for cardiomyopathy that's largely gonna be a study that's gonna be run on top of tafamidis. Much bigger study than the polyneuropathy study. This is about a 1,200 patient study.

Ritu Baral
Biotechnology Analyst, TD Cowen

What % do you think is gonna be on top of tafamidis?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Most will be on taf, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Like 80-90% most?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I don't think we've put out a %, but it's certainly gonna be mostly gonna be on top of Taf.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I think, look, the confidence level that we're gonna have a successful study there is based on what we saw in the combination, you know, subgroup in HELIOS-B, where we actually saw very good efficacy on top of tafamidis. Actually, that's one of the things that we think sort of speaks to the potency of our mechanism of action, that on top of tafamidis, which was 40% of the patients in HELIOS-B, we saw really good efficacy on every endpoint in the study, right? It certainly seems that the stabilizers are leaving some efficacy on the table. We've designed this, the cardiomyopathy nucinersen study.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

W ith, you know, in terms of assumptions around powering with really good data from HELIOS-B to support the assumptions that we're making.

Ritu Baral
Biotechnology Analyst, TD Cowen

Going back to WAINUA for one second.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

You just reminded me of something. One thing that the WAINUA developer has been saying, is that they, based on the design of the study.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah

Ritu Baral
Biotechnology Analyst, TD Cowen

T hey will be able to show stat sig improvement on all outcomes, I believe, all cardiac outcomes.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

V ersus Taf background.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yep.

Ritu Baral
Biotechnology Analyst, TD Cowen

You have similar data, but not exact data. Can you.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

S aying that's their differentiator, what do you have.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, they've got a powering, the their study is powered, right? They've got, I don't know, 1,400 patients in the study. 50% of those are the tafamidis subgroup. It's a much larger study. We had 40% of the patients in HELIOS-B. It was 655 patients in total. 40% were on taf at baseline, so a much smaller.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

sample size. They've got a powering advantage, right? I think our expectation is that they will show stat sig in that subgroup. We have data in our label on that.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Subgroup of patients.

Ritu Baral
Biotechnology Analyst, TD Cowen

It's a different endpoint, but yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

I mean, the primary endpoint is very similar, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We have data that shows in that subgroup that there was an advantage. It's in the label.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That should be supportive of patient, of physicians using that product in combination. We are seeing some combination use today. That's more restricted, I would say.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

from a payer standpoint, and we don't think that that'll open up more broadly until Taf goes generic. Look, we think that based on that data, that we can compete in that part of the market when combination therapy becomes more open from a payer standpoint. The nucinersen study that we talked about earlier is powered, right, in that patient population on top of tafamidis based on the way we've designed that study.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

The cardiomyopathy readout and launch would be expected in 2030. We feel comfortable that we're gonna be able to compete effectively, even in the combination part of the market, first with AMVUTTRA based on the data we have, and then certainly with nucinersen to follow.

Ritu Baral
Biotechnology Analyst, TD Cowen

Last question.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

On TTR before we move to Kevin and the pipeline. How do you see nucinersen in terms of how we model things? Are you looking at it as sort of continuation of market expansion and sort of keeping the growth going? Or at that point in 2030, are we looking at sort of duration of franchise as an asset and sort of consolidation?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah. I mean, I think it'll consolidate the TTR business if it has the profile that we think it will.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Patients would certainly prefer to be on a you know, less frequently administered product.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

P articularly if we have efficacy that looks like it has an advantage. I do think it'll consolidate the TTR business, which is gonna be very good for us from a financial perspective, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

A margins perspective.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

No royalty burden. We've talked about, you know, 30% operating margins through 2030, and then the ability to really expand to probably at least mid-40s% with.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

A successful nucinersen launch. I think it will also continue to grow the franchise longer term. Again, this is a large rare disease that's undertreated today. Beyond 2030, there's still gonna be plenty of opportunity to be driving penetration rates deeper, and I think nucinersen will position us to continue to not only consolidate the AMVUTTRA business, but continue to grow the franchise overall beyond 2030.

Ritu Baral
Biotechnology Analyst, TD Cowen

Got it. With that, we're gonna move to the pipeline, and the biggest topic that I get talking to investors about the pipeline, this is what I call my airport lounge bar conversation when we're all delayed on flights. What asset in the pipeline should we be focusing on now? What's an internal priority for Alnylam amongst the myriad? I mean, this is the downside of having such a rich pipeline, right?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

Where do you focus? What's the next lever?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Let's talk about the pipeline in general. You know, zilebesiran, right? We'll talk about the cardiometabolic franchise in general. We've got zilebesiran for blood pressure. We've got REV-14 , which is for diabetes, right? We have, you know, recently put into clinic ACVR1C for obesity. We'll start with zilebesiran, and we can also talk a little bit about how you might combine some of those.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Zilebesiran is this product that Literally takes blood pressure down and holds it there, right? What, you know, we know similar to how it's linear between lowering LDL cholesterol and outcomes, blood pressure, if you lower it and keep it down, you do better on outcomes. In fact, when we've looked at the human genetics, the variability in blood pressure, if you go up and down, say you are taking your medication, you're off, or it wears off, and you spike in blood pressure, it's those spikes actually that are bad for the blood vessels. Overall, the profile of something that comes down, you know, it's unique in the industry and keeps your blood pressure low, we think is really, really exciting. We're in a phase III outcome trial to show that, right? That over time, that benefit accrues.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're very excited about that program. If you look in the, you know, REV-14 , there hasn't been a new novel insulin sensitizer in years, right? There's a program where, you know, the human genetics is clear that if you lower this protein, you actually prevent that type 2 diabetes. I think it's an insulin sensitizer, and then it controls the level of the insulin, of the insulin receptor itself.

Ritu Baral
Biotechnology Analyst, TD Cowen

When are we getting proof of concept here?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're in phase II. We're gonna look for data in diabetics.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

By the end of the year.

Ritu Baral
Biotechnology Analyst, TD Cowen

By the end. That proof of concept.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

That proof of concept. Right.

Ritu Baral
Biotechnology Analyst, TD Cowen

That endpoint, are you just looking at HbA1c or fasting glucose?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're also doing clamps, actually.

Ritu Baral
Biotechnology Analyst, TD Cowen

Clamps. Okay.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Both. There's a subpopulation where we're doing clamps. We have our program targeting plasminogen, which, you know, that's a program where again, the human genetics, we set out looking for something that could be a universal hemostatic agent without thrombotic risk. As you look across the targets that people have chosen over the years, most of them genetically carry thrombotic risk because when you change that pathway more towards clotting, that can be a risk.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

This particular target, plasminogen, what we found, you know, profoundly was that, you know, individuals could lower their rates of bleeding without a thrombotic risk. Now we're in a number. There's about 3 million or more, you know, patients that have bleeding disorders, and only a small segment of them with hemophilia really have treatments. We're very excited about we've gone into HHT.

Ritu Baral
Biotechnology Analyst, TD Cowen

What % does that, like, non-hemophilia bleeding disorders.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

It's the majority of them.

Ritu Baral
Biotechnology Analyst, TD Cowen

It's like 95+ now?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

90+.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay. 90%+ of that $2 million.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Of that. Yep, $3 million.

Ritu Baral
Biotechnology Analyst, TD Cowen

$3 million.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Yeah. you know, we started out in an indication HHT.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Which these individuals actually have fragile blood vessels, and so they bleed constantly. They can have nosebleeds that last for, you know, 2 hours at a time.

Ritu Baral
Biotechnology Analyst, TD Cowen

What's that particular prevalence for HHT?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

there's about, we probably think between 40 to 90,000.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

You know, of those individuals, a lot of them actually need to have transfusions. This is not just, you know, they bleed from their gums.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're in a phase II trial. They're now in patients. Again, we'll be looking to have data by the end of the year, around how that's impacting them. Then, we're filing, you know, in a second indication that we haven't yet named. You know.

Ritu Baral
Biotechnology Analyst, TD Cowen

You've discussed some additional indications.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

Can you walk us through those and the market space?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Again, there's a number of them.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

You know, there's things like hemophilia, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

There's things like von Willebrand disease.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

There's a couple others that are smaller, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're gonna walk through them because we think that this really is gonna have benefit in all of those patients.

Ritu Baral
Biotechnology Analyst, TD Cowen

How do you think of the development path for this asset? Is this something where, like, you could have two trials in similar or different but similar disease populations that could support, you know, one an approval for the drug with.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

I mean, I think we're going to do, you know, for y ou know, the good news is that a lot of the readouts are sort of binary, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

You have really hard outcomes, which is bleeding, no bleeding. As you walk across them, we'll probably do, you know, somewhat standard trials in some of them, and as you get to the more sort of the less prevalent diseases, you might think about something like a basket trial.

Ritu Baral
Biotechnology Analyst, TD Cowen

You have a phase I-B Huntington's.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Yes.

Ritu Baral
Biotechnology Analyst, TD Cowen

With O2 reading out in the second half too. Can you walk us through, those key endpoints and how you see the interpretation of that mechanism evolving, given the, you know, overlap of the mechanism with uniQure's gene therapy and therapy efficacy data?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Yeah. Let's start out with Huntington's, you know, devastating disease, and, you know, we are going in with a very specific mechanism, which is that we're hitting this thing called exon 1, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Yep.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

There's exon 1, and there's the full length. This is a disease where, you have, you know, both of those playing an important role. You really wanna hit exon 1, and it wasn't known in the field for a long time that exon 1 was important. But now, you know, as this evolved, it's very clear that exon 1 is part of that disease. You know, we have a unique mechanism here where, you know, we have an RNAi that targets that. It took us a little bit extra time to actually figure out how to do that, but we've got a really nice molecule that does that. We're in phase I.

We're looking at, you know, lowering in patients, have data by the end of the year that will look at safety of that molecule as well as the degree of lowering. We're looking for something maybe 40%, 50%. That's where the field thinks there'll be significant benefit for.

Ritu Baral
Biotechnology Analyst, TD Cowen

40%-50% knockdown.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Knockdown. Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

You know, I think the uniQure data, I don't like to comment on other people's data, is a very small trial, but I think if anything, that if you sort of read the tea leaves, it does look like that's the only other thing out there that's an exon 1 mechanism.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

I mean, it did maybe seem to have some hints. I think the FDA has come back and said they wanna see a bigger controlled study, but that's, you know.

Ritu Baral
Biotechnology Analyst, TD Cowen

Putting the landscape together, and if you do target this 40%-50% knockdown for the next study, speculating obviously on contingent data, but speculating, how long do you think you need to treat before you start moving the endpoints that FDA cares about?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

I mean, I, you know, I'm not gonna speculate on our phase II design, but I think we're still looking at the data. There are natural history studies.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

That are coming out of the progression of the disease.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

There are neurological endpoints that you're gonna wanna look at.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

We're in the midst of sort of figuring out exactly, you know, how long and what those endpoints should be with all the KOLs in this.

Ritu Baral
Biotechnology Analyst, TD Cowen

In our last 5 minutes, I wanna talk about next 5 years and long term. This is the conversation that I have with the generalists.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

That are really looking on the long term. Are you gonna be focused on maintaining and growing profitability or more on pipeline development and expansion into new therapeutic areas? I mean, you guys used to be the R&D engine. You had a huge pipeline.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

And absolutely no profits, and a huge R&D budget, which you reined in from some of your first few years. We've had that conversation. How is that balance evolving?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah. This is where I think the Alnylam 2030 set of goals that we shared a couple months ago is really helpful because I do think it sort of gives a picture of where we're going. Just to recap, I mean, that's really focused on three things. One is leadership and TTR, which we talked about earlier. Two is about, like, frankly expanding the pipeline and creating opportunities to grow durably beyond TTR. We can talk about that more in a second.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

It's really about how we're gonna scale the business financially. We talked about the top line growth expectations, right? We set a 25% CAGR, and then we provided our view of operating margins across the period.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

And we're looking at 30% across the period. Let me walk through that 'cause there were a lot of questions about that, and frankly.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We anticipated that because the market, if you looked at consensus going into JP Morgan and you looked out five years, the market's expectations in terms of profitability were frankly much higher.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

They were at about 50%, actually better than 50% operating margins.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's really difficult, if not impossible, with the gross margin.

Ritu Baral
Biotechnology Analyst, TD Cowen

With the 30%.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

With the cost and the royalty. Yeah. Our gross margins are at about 75%, so to have operating margins at 50% when you're frankly starting at 75, that just doesn't leave enough room for investment in SG&A and R&D to be at that level. We needed to be really clear about that with the market, and one of the things that we clarified is how we intend to invest in R&D across the period, and we did set a goal of 30% of revenues reinvested in R&D.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We think that's a prudent allocation of capital. Kevin talked about a lot of the things that are in the pipeline today that are gonna drive that growth in the years ahead. Primarily, this is gonna be focused on internal innovation.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Again, I think that's smart given the success that we've had with the platform and the approach that we've taken historically in terms of how we use genetics to drive targets and things that we bring into the clinic. That's not gonna change. We're very focused on opening up new tissues, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We've got a goal to be in 10 tissues by 2030, and the, maybe the harder R&D goal that we gave, very specific goal, was to have 2 plus new therapies either in the market or a line of sight to being in the market that can drive substantial growth that are beyond TTR, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We're focused on protecting and growing TTR, we wanna make sure that we can diversify the business. That's why we've selected 30% as the place that we see the right investment rate to drive that kind of growth in the pipeline and innovation across the period.

Ritu Baral
Biotechnology Analyst, TD Cowen

Speaking of potential in licensing, like, what therapeutic areas are you looking into, or is it going to be more of a technology delivery-?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah..

Ritu Baral
Biotechnology Analyst, TD Cowen

focused thing to open up new tissues?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Maybe I'll specify what we said about business development, then I'll let Kevin maybe comment further on the types of things that we might be interested in. That 30% reinvestment rate of revenues into R&D we said primarily is gonna be driven by internal.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm

Jeff Poulton
CFO, Alnylam Pharmaceuticals

R&D.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Our, you know, focus on RNAi. We said that we would start to add, you know, selective business development into that mix. That's included in that 30% reinvestment rate.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We do think that we will start to look at external innovation.

Ritu Baral
Biotechnology Analyst, TD Cowen

That's within the 30%?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

That's within the 30%.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Right? We've left ourselves headroom.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

For external innovation in that 30%. Maybe I'll let Kevin talk about.

Ritu Baral
Biotechnology Analyst, TD Cowen

Yeah.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Sort of our approach and how we might think about external innovation.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Yeah. I'd say we're, you know, I'm a drug hunter, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

In a lot of ways you're looking for both things that can enhance your technology, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Delivery.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

What's that? Sorry.

Ritu Baral
Biotechnology Analyst, TD Cowen

Delivery, like.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

Well, either delivery or a modality that maybe you can combine, right?

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

With an RNAi. As you start to think about things like that, there are. You know, for instance, our, you know, our cemdisiran program with Regeneron, for certain indications, it's an antibody with an SI, right? You can get very creative about how you take RNAi as a foundation and maybe add something to it, as well as if you start to think through delivery to 10 different tissues, there may be somebody that has a delivery modality that they're using for something else, that you can repurpose for delivery to RNAi.

Ritu Baral
Biotechnology Analyst, TD Cowen

Any favorite therapeutic areas or strategic approach to therapeutic areas? I mean, you've obviously evolved from, like, an orphan company to targeting much larger indications. You know, the TTR is incredibly cuspy if you look at models on whether it's orphan or not. Your partner programs are large. Are you looking for commercial synergies for the marketing force as you look at the pipeline?

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

I would say as we look at assets, even internally and externally, if there's something that fits within, you know, a franchise.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

A therapeutic area

Ritu Baral
Biotechnology Analyst, TD Cowen

It gets some weight?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

It gets a little bit of weight, I think.

Ritu Baral
Biotechnology Analyst, TD Cowen

Okay.

Kevin Fitzgerald
EVP and Chief Scientific Officer, Alnylam Pharmaceuticals

On the other hand, I'm always looking for what can be the next franchise, right? We're gonna be very opportunistic. If there is, you know, another large indication where there's high unmet medical need where we think we can really make a huge difference, we'll go there.

Ritu Baral
Biotechnology Analyst, TD Cowen

There is the willingness to spend on the SG&A in the midterm on all that?

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Yeah. I mean, I think the external opportunities that we're looking at probably you know, earlier stage is probably much more likely at this point.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Again, we've given a pretty robust top line growth expectation across the period.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

We don't need to buy near term revenues.

Ritu Baral
Biotechnology Analyst, TD Cowen

Mm-hmm.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

It's more likely that we're gonna see things that are earlier in development that we'd be investing in.

Ritu Baral
Biotechnology Analyst, TD Cowen

That would be a longer term investment.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Likely, yeah.

Ritu Baral
Biotechnology Analyst, TD Cowen

on the SG&A side. Great. With that, we are a little over time. Thank you, guys. Thank you, Jeff. Thank you, Kevin.

Jeff Poulton
CFO, Alnylam Pharmaceuticals

Thank you.

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