Alnylam at Morgan Stanley Healthcare: Strategic Growth and Challenges

On Wednesday, 10 September 2025, Alnylam Pharmaceuticals (NASDAQ:ALNY) presented at the Morgan Stanley 23rd Annual Global Healthcare Conference, detailing its strategic transition from a loss-making entity to a profitable company. The discussion, led by CFO Jeff Poulton, highlighted significant developments in the transthyretin (TTR) franchise, particularly the cardiomyopathy market. Despite facing challenges like regulatory changes, Alnylam is optimistic about its financial strategy and future growth.

Key Takeaways

• Alnylam is focusing on transitioning to profitability with a strong emphasis on the TTR franchise.
• The successful launch of AMVUTTRA for TTR cardiomyopathy has driven significant revenue growth.
• The company is exploring international expansion, particularly in Japan and Germany.
• Alnylam is leveraging artificial intelligence to enhance commercial and research efficiencies.
• The commercial performance of AMVUTTRA is seen as a key catalyst for future growth.

Financial Results

• Convertible Note Refinancing: Alnylam issued $575 million in convertible notes to manage dilution risk, protecting against dilution up to a share price of over $800 over the next three years.
• Revenue Growth: The TTR franchise contributed over $550 million to the upgraded revenue guidance of $575 million for the year.
• Patient Volume: Approximately 1,400 commercial patients in the U.S. are on AMVUTTRA therapy for cardiomyopathy.

Operational Updates

• TTR Cardiomyopathy Launch: Rapid access unlock at provider and payer levels has been largely completed across 170 health systems in the U.S.
• Treatment Utilization: Initially used as a second-line treatment, AMVUTTRA is now balanced between first-line and second-line usage.
• Pipeline Progress: Significant advancements in pipeline programs such as mivelsiran and zilebesiran, with anticipated launches around 2030.

Future Outlook

• First-Line Positioning: Alnylam aims to establish AMVUTTRA as the preferred first-line treatment for TTR cardiomyopathy.
• International Expansion: Plans to launch in Japan and Germany in the second half of the year, with further European expansion in 2026.
• Long-Term Growth Drivers: Focus on increasing diagnosis and treatment rates in the TTR cardiomyopathy market.

Q&A Highlights

• Regulatory Landscape: No significant changes in FDA interactions; monitoring MFN policies and tariffs, with limited risk due to a U.S.-based manufacturing footprint.
• Catalyst Path: The commercial performance of AMVUTTRA and pipeline developments in CNS programs are key future catalysts.

For more detailed insights, please refer to the full conference call transcript below.

Full transcript - Morgan Stanley 23rd Annual Global Healthcare Conference:

Mike Gold, Biotech Analyst, Morgan Stanley: All right. Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I’m Mike Gold, one of the biotech analysts here, and it’s my pleasure to introduce Jeff Poulton, CFO of Alnylam Pharmaceuticals. 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, Jeff, thanks for sharing your time with us today. We really appreciate it. Maybe to kick things off, if you can just give a brief introduction to Alnylam, and then we can hop into some Q&A.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Great. Thanks for hosting and having us here today. I’m at Alnylam Pharmaceuticals, and Alnylam Pharmaceuticals is a company that developed a new class of medicines based on Nobel Prize-winning science, RNA interference. It’s been about a 25-year journey for the company. I would say the first 15 years were really around, particularly on delivery, figuring out how to get the medicines to the right parts of the body and the right cells in the body. Once that was figured out, things really started to change for the company. The way the company is positioned today is there are six products that are in the market that were discovered in Alnylam Pharmaceuticals’ lab. Four of those products are being marketed and sold by the company, on our own. The other two are through partners. We’ve got a pipeline of 20-plus medicines in the clinic, all using that same underlying technology.

From a financial perspective, we’re at a point in time where we’re really transitioning the company from being a loss-making company to one that’s being profitable. A lot of focus right now on the transthyretin (TTR) franchise. We sort of describe that as a flagship commercial franchise, and we think we’re at the beginning phases of a lot of growth, given the expansion of the label into the cardiomyopathy part of the market. I know we’re going to talk more about that, through the fireside chat. From an innovation perspective, we continue to be very focused on internal innovation, organic growth, continuing to put money behind a platform that’s been very productive. We’re very focused on continuing to drive things forward in the pipeline so that there’s a second act beyond TTR. I think the investment community over time here is that they get more confident in that launch trajectory.

We’ll probably start to focus on that more, and we welcome that. We are focused on that. Lastly, I’m thinking about the, you know, now that we’re profitable, what does that sort of pace of profitability look like over the next five years or so? We’re in a very fortunate position right now.

Mike Gold, Biotech Analyst, Morgan Stanley: Great. Thanks for that introduction. Like you said, you’ve made some tremendous progress over the years, and lots to talk about here. Maybe before we start digging into some of that, earlier this week, you announced a finance thing, so maybe tell us a little bit about that.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. We did a transaction yesterday where we issued some convertible notes, $575 million worth. This is really a refinancing. We had done our inaugural convert financing back in 2022, and those notes matured in 2027. At the time that we did that inaugural financing, which was about a billion dollars worth of notes, we bought cap call protection on those notes when they were issued that protected us from dilution as a company up to a share price of $424 a share. Following our Q2 results, where we reported strong initial results in the U.S. and cardiomyopathy stock, you know, blew through that $424. Those convertible notes are getting more expensive now because they’re beyond the cap call protection that we have.

What we did with this transaction is with the money that we raised, obviously, on the new convert, we’re establishing a much higher price for dilution on those shares. That cash that we raised, plus the cash from the balance sheet, allowed us to retire a majority of the original convert yesterday. Didn’t get it all, and there’s probably more to do on that at some point. It really reduces us to that exposure of those notes, given where the share price was. The convert market is in a good space right now. I think we’re a high-quality issuer, so we got really good terms on the new convert as well, a 0% coupon and up to 40% on the strike price. We put a cap call on top of that that protects us to 75% of, you know, accretion from where the stock was when we issued yesterday.

These are three-year notes, so that would put dilution at over $800 a share over the next three years if it goes beyond that. We should be in a position over the next three years to retire these notes and probably be out of the convertible market at that point, given the, you know, financial profile of the company of getting the profitability. We’ll have more options in terms of the way we would finance the business if we need to go out and get external funding.

Mike Gold, Biotech Analyst, Morgan Stanley: Makes sense. While we move to TTR cardiomyopathy, I’m sure you’re familiar with that one and all the questions we get.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: I am.

Mike Gold, Biotech Analyst, Morgan Stanley: Congratulations on the strong launch so far, and maybe just talk about what the key drivers behind that have been.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. We got approval in the U.S. for the expanded label to include cardiomyopathy at the end of March. The second quarter was the initial quarter of launch activity in the U.S. Before the launch, we had really been guiding the market to anticipate that this was going to be a second half of the year kind of story in terms of when you would start to see revenues increase associated with cardiomyopathy. That’s based on the fact that this is a Part B. It’s a buy-and-bill drug. There are some things that have to happen both with the payers as well as the providers to enable that initial ordering and actually generate the revenue. I would say in the second quarter, the big surprise, positive surprise for us was how quickly we were able to unlock access both at a provider level and on a payer level.

On the provider side, the way that most of these patients get treated in the U.S. is there’s about 170 health systems, which are networks of hospitals where the majority of these patients are treated today. We expected that it would take between the start of the second quarter and the end of the year to get our drug on formulary across those 170 health systems. That was largely complete in the second quarter, which is really what the unlock was to start the ordering and start getting patients treated. That was terrific, right? The results that we reported in the U.S. for TTR reflected about $170 million of growth between Q2 and Q1. Now, that’s PN and CM combined. I don’t have the ability to report PN revenue separate from CM because it’s the same product. It’s the same SKU.

When orders come in, it’s for AMVUTTRA, not for PN or CM. We do have a nice long history of what the PN business was growing at. If you look back over the last four or five quarters in the U.S., that was growing quarter on quarter, about $15 million or $20 million a quarter. Obviously, a major step up in terms of growth. We went up to $170 million. We attributed $20 million of that to the PN business and $150 million to CM. A really very, very strong start. We estimated there were 1,400 commercial patients that were on therapy. None of those patients were patients that came out of the trial, right? The HELIOS-B trial. Those were all new patients, new to therapy for AMVUTTRA.

That 1,400 patients, based on pricing, again, sort of, you know, syncs up with the $150 million in revenue that we attribute to the CM business in the U.S. The strength of that result and the fact that we really accelerated revenue into the quarter allowed us to upgrade the guidance for the year. Our top-line revenue guidance went up $575 million, which was a massive increase, almost all of that driven by the transthyretin (TTR) franchise. I think the TTR franchise went up north of $550 million. We’re excited about the start. There’s still a lot to do here. There are a couple of additional markets that we’re opening up right now outside the U.S. Mostly the international opportunity is going to be more of a 2026 kind of unlock in terms of when we’re going to see access and reimbursement. We’re off to a good start.

I know you’re going to have some other questions about understanding the source of that business, so I’ll hold comments on that.

Mike Gold, Biotech Analyst, Morgan Stanley: Yes. I wanted to get your sense of, you know, early treatment, you know, utilization, where that’s happening, front line, second line, combo, etc.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. I think initially what we saw, the initial start forms, which is kind of the prescription for these high-cost medicines, it was mostly second line. These are patients that were on tafamidis that were probably waiting, ultimately waiting for the approval, that were probably not doing well on tafamidis. Right out of the gate, it was mostly second line. As the quarter progressed, the first-line business progressively over the quarter was growing. By the end of the quarter, it was pretty balanced in terms of the sources of the business, first line and second line. We do expect that that’s likely going to be the profile going forward, which I think is actually a very good place for us to be, that we’re going to have two sources fueling growth, both first line and second line. We’re probably going to be unique in that regard in the market today.

Tafamidis has really had the market to themselves for the last five years. Bridge launched last November. We launched at the end of March. I think what we’re seeing on the second line opportunity is when patients are not doing well on tafamidis, obviously, you have a choice. You could switch into another stabilizer, or you could switch into an orthogonal mechanism. What we’re finding is the vast majority are choosing to switch to an orthogonal mechanism, which makes sense with the way cardiologists like to treat their patients. I think that’s going to be a source of business for a period of time for us. We’re really focused, actually, on the first line opportunity because long term, that’s really where growth in the category is going to come from. Today, TTR, we think in the cardiomyopathy part of the market, it’s about 20% treated.

Long term, that’s really what’s going to drive the growth of the category is increasing diagnosis and treatment rates. We want to compete effectively there. I think we got off to a good start. There’s more to do there. This is a progressive, fatal disease, right? Patients and physicians want to choose the best, most efficacious product as soon as they can. This is not one where you want to try this one, see how they do, and then put them on. Once you progress in this disease, it’s hard to get back what you lost. You want to get on the best product right away. It’s our job now, based on the HELIOS-B data, to work with the physicians, educate them, and make sure they understand the profile of the product, which we think, based on the data from HELIOS-B, is the best product.

That’s obviously something that we need. We’ll see how that plays out over time. Just to remind people about HELIOS-B, I would say it had the highest bar in terms of challenge to show an efficacious product because that was a study that was run in what we describe as a contemporary patient population. These were generally less advanced in the course of the disease than prior studies. For sure, they were better treated. I mean, 40% of the patients in the study had baseline around tafamidis, and then you had another 10% of those that added on tafamidis during the course of the study. The fact that we showed efficacy in the overall population and the monotherapy population, which were the way that the study was segmented, we hit endpoints on all those. If you look at the combination part of the study, patients did well.

It wasn’t powered statistically to show statistical significance, but in that combination part of the study, on every endpoint, it favored AMVUTTRA, right? AMVUTTRA and tafamidis compared to tafamidis alone. It was a high bar, and we met that threshold. That’s really now what we’re doing in terms of educating the community, both with our medical team as well as our commercial team, to make the case that this should be the product, the first product that you reach for when you have a patient with this disease.

Mike Gold, Biotech Analyst, Morgan Stanley: What kind of feedback are you getting early in the launch here?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah, it’s early, obviously. We’re one quarter in, but I think the things that we’re hearing first from an efficacy standpoint is they’re impressed by the all-cause mortality data and from Helios B, right? That was an outcome study. That’s probably the thing that patients most care about, is what’s the impact on the heart outcomes. Physicians like that data. I think they like the breadth of the label. We’re the only product in the space in the U.S. that’s got the full disease in the label, right? We’ve got hereditary PN. We’ve got CM in both the hereditary as well as the wild-type population. We’re the only product of the three that has that. The other two just have the cardiomyopathy piece. They don’t have the polyneuropathy piece. We’ve got the full breadth of the label. I think that they like the route of administration, the once-a-quarter profile.

It sort of ensures compliance, right? Sometimes, even with a progressive fatal disease, patients aren’t disciplined around taking the medicines, right? Daily orals, either once or twice a day. I think it gives the physicians, and ultimately, the payers like that too because they’re paying for these drugs, and they like to know that the patients are going to get the benefit of it. I would say the last thing, and this really speaks to, I think, the commercial execution that we talked about earlier in terms of the earlier unlock. Physicians have found it easy to get patients on the drug, which is super important, right? Given the competitive nature of this space, we’re the only drug right now that’s a buy-and-bill drug. You don’t want that to be creating additional complexity for physicians when they want to put a patient on drug.

That’s really where I think the team did a lot of good work in advance. As soon as we had the label, the ability to go out and get the drug on formulary, I think we also benefited because we’d been in polyneuropathy for five years. We’ve got the buy-and-bill sort of infrastructure in place. We’ve just expanded that. That’s gone well, and physicians appreciate that. Their time is limited. They don’t want to have to get tied up in, you know, fighting with insurance companies and doing a lot of paperwork to get these patients on therapy when they want to put them on. So far, so good on that front.

Mike Gold, Biotech Analyst, Morgan Stanley: Yep. Can you talk a little bit about what you’re seeing in combination use?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah.

Mike Gold, Biotech Analyst, Morgan Stanley: I just asked because KOLs we talked to seem to be excited about that.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: If you look, there’s interest in that. I think, fortunately for us, because we had that pretty sizable segment in Helios B where 40% of the patients were on Taf at baseline, we have some pretty good data there. Actually, if you look in the clinical trial section of the label, there’s a forest plot that shows the various segments in the study across the primary endpoint. You can see it there, right, that it favored the combination. Compared to Taf alone, it wasn’t stat-sig. I think that’s helpful, right, as physicians and patients think about the possibility of combination therapy. They’d like to do it.

I think it’s going to be difficult to do it broadly until the path goes generic because at least in the commercial part of the market and the Medicare Advantage part of the market, most of the payers are putting policies in place that restrict combination use. The original fee-for-service part of the market is probably where it’s happening today because there aren’t policies that would restrict that. I can’t quantify it, but I know that there is some combination experience that’s taking place. We do think that when Taf goes generic, and our expectation, I think, is consistent with what Pfizer has messaged historically, that they expect generic entry by the end of 2028. That would sort of open up the opportunity for more combination use more broadly. I think we’re well-positioned based on the results for Helios B and the data that made its way into the label.

Mike Gold, Biotech Analyst, Morgan Stanley: Can you talk a little bit about access? You touched on it a little bit. It is very easy to get the drug. I think before the launch, just given the pricing, there was a little bit of concern about that. Maybe how have you been able to manage that? Does that become an issue as you keep launching the drug or not?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. So far, so good. Maybe just a little bit of thinking behind the price. I mean, I think the first reason that we chose to price it the way we did, which is we didn’t change the price. We had a price in the market for polyneuropathy, so when we expanded the label in the U.S., we kept the price the same, which is higher than the other products that are in the market. There are, I think, two or three things that led to that decision. First is the data from Helios B that we’ve talked about. We think it was really strong, hit every endpoint in the study, and that in combination with the fact that we’re offering payers value-based agreements, which essentially is our commitment to the payers that the patients are going to stay on the drug and get the benefit of the drug.

Payers are willing to pay for drugs like this when they know the patients are going to get the benefit of it and then stay out of the hospital, stay out of events occurring that cost them more money. With the commitments that we’re making with the value-based agreements, that really helps with the payer community. The other thing is that this is a rare disease. People forget that a little bit because they like to talk about this being such a significant opportunity, but it is a rare disease. We got an orphan designation, and it’s a progressive and fatal disease. Typically, payers are hesitant about, in these types of diseases, getting very involved in forcing patients on one product or another. That was part of the calculus.

Lastly, what’s really important to the community and the physicians as well is what does this cost the patients to get on the drug? Because this is a Part D medicine, what we saw in polyneuropathy is about 70% of the patients have zero out of pocket, right? The remaining 30%, it’s about $3,500 per year in terms of median. That’s before potentially them getting third-party support to help pay for that. From a patient perspective, this is an affordable medicine, even though it’s a high-cost drug. Those were the reasons that we chose to price it the way we did. So far, so good, right?

I think that we commented on the Q2 results call that on the payer side, where payers have put policies in place in Medicare Advantage and in commercial now, most of those are first line that are enabling first line access, meaning there’s no step edits in place that require you to go through one of the other medicines in the space. There are a couple of examples on the commercial side where that did happen. That’s expected, not a surprise to us. We think we can continue to manage and work through that. I will say that this isn’t permanent. This isn’t we’re done. These are policies that can be reviewed and revised on an annual basis. This is something that we’re going to have to continue to work closely with the payer community to make sure that we have the drug positioned as a first line drug.

Mike Gold, Biotech Analyst, Morgan Stanley: Makes sense. Maybe just going back to the price a little bit and gross-to-net over time and just what you’re seeing there and your expectations.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. When we, on the approval call, when we announced that we were keeping the price the same, we did say that we anticipated that gross-to-net dynamics would increase gradually over time, meaning net price will come down gradually over time. I still think that’s the right guidance for the market. On the Q2 call, we did talk about what happened with gross-to-net dynamics in the second quarter itself. We did see an increase in gross-to-net dynamics in the quarter, and there were a couple of things that drove that. One was increased 340B utilization, and there are rebates that you pay on that. That was driven by the cardiomyopathy launch, and we expected that. The other thing that happened in the quarter is, actually, part of our business gets processed as a Part D sale, even though we’re a Part B product.

That’s the home care part of the market, which is about 20% or 25% of the business. Given the IRA redesign in terms of who pays for what with these high-cost medicines, 20% of that cost is the responsibility of the manufacturer. For that part of our business, we saw an increase in gross-to-net dynamics. What we guided to was that we thought we would see gross-to-net dynamics increase about mid-single digits this year on a full-year basis versus 2024. Beyond that, I would say, 2026 and beyond, we continue to expect that we’ll see a gradual increase in gross-to-net dynamics over time.

Mike Gold, Biotech Analyst, Morgan Stanley: Gotcha. Maybe last question on TTR.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah.

Mike Gold, Biotech Analyst, Morgan Stanley: Obviously, you’re early in the launch, having success. As you move through the next few quarters, what are the key drivers in your view, or how do things sort of progress?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: It’s really about focusing on driving demand in that first-line positioning for the product. We talked about the importance of that, given where the market is in terms of treatment and diagnosis rates. Given that that’s really what’s going to drive long-term growth in the category, we’re really focused on that first-line positioning. We’re one quarter in, and you know, physicians have these patients coming in every day now, and they have to make choices on what products they want to put their patients on. That’s really where we’re focused, and that’s something that we’ll be tracking carefully over time. I think the other thing is we mentioned that we’ve got a couple of additional markets that we’re launching in the second half of the year, Japan and Germany.

I think as we move into 2026, given that the access and reimbursement timelines in other major markets in Europe, we’ll start to add more markets in Europe next year as well. That will be a bigger contributor in terms of growth. One point of clarification for people on the ex-U.S. launches, it’s very likely that in most of these launches or markets when we launch, we’ll be launching at a lower price than what we’re at today, given the way access and reimbursement negotiations work ex-U.S. That means for the polyneuropathy business ex-U.S., it will be a headwind when we lower price, and you probably won’t have the same step that you saw in the U.S. There’ll be a little bit of bite taken out of that initially.

Certainly, the volume is going to be more than enough to make up for that, and we’ll ultimately see good growth ex-U.S., but it might be just a little bit slower in terms of the impact because of that. Just trying to manage expectations on that front. The international part of our business in the transthyretin (TTR) franchise has historically been a significant contributor to the overall franchise. It’s been 40% to 50% of the polyneuropathy business has come ex-U.S., so we do expect this will be a meaningful contributor longer term ex-U.S. as well.

Mike Gold, Biotech Analyst, Morgan Stanley: Yep. Makes sense. Maybe we can move to mivelsiran real quick and maybe talk about how that’s different from AMVUTTRA and kind of what the advantages are of getting that to market.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. This would be our third-generation TTR product. Probably most of you are familiar. The first product was ONPATTRO. Again, it’s a silencer, every three-week IV infusion, so very high burden of treatment. AMVUTTRA was a huge step in terms of convenience advantage to once-a-quarter sub-Q. What this third-generation product, zilebesiran, offers is a couple of things: deeper knockdown and more consistent knockdown. AMVUTTRA and ONPATTRO, both we get to about 85% knockdown and obviously very good efficacy with that. What we showed in the phase one study with zilebesiran is we get it to 95% and hold it there. Actually, the variability around 90%, it’s a sort of tighter spread than what we see around the 85%. Deeper knockdown typically translates into better efficacy. Our anticipation and hope is that we’re going to see better efficacy with this product because of the deeper knockdown.

The other benefit, which is something that patients always welcome, is the durability is longer. This is an every six-month dose product, so twice a year rather than four times a year. There are some additional sort of business advantages of the drug as well. We’ve got a pretty significant royalty that we pay to Sanofi on sales of AMVUTTRA that’s between 15% and 30%, and it ramps up to that 30% level pretty quickly. There’s no royalty burden to Sanofi on sales of zilebesiran, so obviously a substantial margin advantage of this product. It’s also got intellectual property that pushes out into the 2040s. AMVUTTRA is 2036, so hopefully it extends the franchise and expands the franchise both. It’s an important program for us. We’ve initiated the phase three or the pivotal study for cardiomyopathy.

That’ll be an outcome study, 1,200 patients, likely 2030 is what we’re talking about in terms of launch. The polyneuropathy study, we intend to initiate that before the end of the year, so in the next few months. That’ll be a quicker-to-market kind of study, probably a couple of years quicker than the CM study would be.

Mike Gold, Biotech Analyst, Morgan Stanley: How do you think about when that gets to market, how do you transition patients? Obviously, better profile, but are there other things you can do to increase that in any way?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: I mean, if you look at what happened with AMVUTTRA when we launched, right? That went from, again, every three-week IV to once-a-quarter sub-Q. We did not have to work very hard, right? Very similar efficacy profile. We didn’t have to work very hard to switch that business. That was preferred very quickly by patients. Here, hopefully, we’ll have better efficacy and more convenient. I think if that’s the profile, I think there’s going to be a high demand from patients that are on AMVUTTRA to want to switch. I think we can switch that business, obviously, ultimately, depending on the outcome of the study.

Mike Gold, Biotech Analyst, Morgan Stanley: Yep. Makes sense. Maybe we can switch to zilebesiran.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah.

Mike Gold, Biotech Analyst, Morgan Stanley: You recently presented some data there, phase two data, CARDIA3. Maybe give us some key highlights and next steps for that program.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. I mean, let me just talk about what we’re trying to do here in this space, and then we can talk about the results with CARDIA3. This is a program for hypertension. There are plenty of effective therapies on the market for hypertension, a lot of them generic. The challenge with those products is they’re oral. Patients don’t take them religiously on a daily basis. They don’t stay on the meds, right? You don’t get the benefit or advantage of the medicine. For the patients that stay on them, again, it’s intermittent in terms of how they’re taking these. What that creates is variability in blood pressure control. That variability is a risk factor for hypertension. This is a medicine that could be given once every six months, turn it on for six months, and you get that tonic control of blood pressure.

You get the blood pressure lowering, which should reduce risk for these patients, but you also get a higher quality control of blood pressure because you reduce that variability. You get tonic control both at day and night. We think that is another factor that will lower risk for these patients. That’s what we’re trying to do with this program. The CARDIA3 data, I would describe it as a warm-up act for the outcome study. This was a study that looked at zilebesiran in combination with two to four of these background meds. What we found is we got clinically meaningful blood pressure lowering of 5 millimeters of mercury. That in and of itself gives us confidence to take the drug forward. The things that we learned that we’ll apply to the phase three study, number one is the dose that we’re going to take forward.

The 300 milligram dose is the right one to take forward every six months, one injection every six months. We also learned some about inclusion-exclusion. That 5 millimeters of mercury, if you look at the patients that were on diuretics that were in this study, you saw like 7 to 9 millimeters of blood pressure lowering. That’ll be an inclusion criteria in the phase three study or in the pivotal study, the outcome studies that will want patients on diuretics. Also, just based on the results from the study, it helped us sort of fine-tune the powering assumption. This will be an 11,000-patient study. The reason we’re running this as an outcome study rather than just a blood pressure lowering study is what I described before.

We think the benefits of this are twofold, not only the blood pressure lowering, which will reduce risk, but it’s the quality of the blood pressure lowering and that tonic control. That in and of itself should also be risk-reducing. The only way to show that is to run an outcome study and see what you get in terms of lowering, you know, of a MACE-type endpoint. That is what we’re going to do. We think that would then position the drug well for an attractive commercial launch.

Mike Gold, Biotech Analyst, Morgan Stanley: Just talk about timelines.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. It’s an outcome study, 11,000-patient study. A lot of this is going to we can fine-tune as we see how enrollments go in. Our estimate is that this is a, you know, around the end of the decade kind of launch. We’ve got to run this a long time to accrue enough events to see the benefit here. Yeah, it’s probably 2030.

Mike Gold, Biotech Analyst, Morgan Stanley: Gotcha. Maybe in the last few minutes here, I can ask you a couple of macro questions.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah, sure.

Mike Gold, Biotech Analyst, Morgan Stanley: We’ve been asking for a topic, only been asking all our companies. We’ll start maybe with China’s rise in biotech innovation. You know, how are you thinking about your competitive position here? Will this influence your R&D or BD strategy going forward? What was the first part of the question?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: China’s threat.

Mike Gold, Biotech Analyst, Morgan Stanley: Yeah.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. We don’t have an investment in China today, either commercially or from an R&D standpoint. I think that’s something that we’re thinking about carefully. Certainly, we’re monitoring and seeing all the innovation on the R&D side that’s happening very rapidly in China today. I think our feeling is that we need to get closer to that. That’s something that we’re exploring in terms of what that could look like. I would say just kind of TBD on that.

Mike Gold, Biotech Analyst, Morgan Stanley: Gotcha. Second question, you know, how are you currently leveraging artificial intelligence or thinking about AI’s future disruption?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Yeah. I mean, I think we’re probably doing a lot of the things that a lot of other companies are doing in terms of just improving the efficiency of certain processes using AI. That’s probably not that exciting. We are doing that kind of stuff. I think the stuff that’s more strategic that could be more meaningful to the overall business. On the commercial side, we are using AI in terms of sort of directing our salesforce efforts. I think that we’ve had some success with that. I think on the research side, we’re certainly doing some stuff with AI around target, you know, mining genetic databases for targets and things like that. Probably more to come on these types of things. Those would be the two areas I think strategically that we’re investing more time and energy.

Commercially, it’s patient finding and then helping us sort of find the right targets to go after with our technology.

Mike Gold, Biotech Analyst, Morgan Stanley: Okay. Maybe last macro question, what has been most impactful for Alnylam from the regulatory side? Would it be changes with the FDA, MFN, or tariffs?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: I would say, first of all, maybe I’ll go through this one by one. I think in terms of interactions with the FDA, we haven’t seen any changes. I think maybe we were fortunate, but I’m happy we got approved with the Helios B right when we did, which was at the end of March. We really haven’t seen any changes in the interactions there. So far, so good. MFN, I think you’re probably hearing from everybody. We’re managing or watching this very carefully. We’re trying to understand where this is going. We understand what the administration is trying to achieve. If we were, you know, asked to participate in that, we would constructively engage. We’ve not been one of the companies that’s gotten one of these letters. For now, it’s kind of watch and wait and try and understand where this may be going.

Right now, there’s not a lot of specifics. I think on the last point about tariffs, I think we’re in a pretty good position in terms of the vast majority of our manufacturing is done in the U.S., and the intellectual property for where it sits geographically, most of that sits in the U.S. as well. We don’t see a significant risk to our business associated with tariffs as a result.

Mike Gold, Biotech Analyst, Morgan Stanley: On MFN, since you’re more rare disease, does that maybe?

Jeff Poulton, CFO, Alnylam Pharmaceuticals: That’s a good point. I mean, I think on the IRA, if you’ve got an orphan designation, you’re actually not subject to price negotiations in the future. I don’t know how MFN is going to work if it can continue to work its way forward. Could there be a carve-out for orphan products? Maybe. If so, obviously, we’d be in a good position. All of the products that we’re marketing and selling in the U.S. are orphan designation products. If that were the case, that would obviously be good for us.

Mike Gold, Biotech Analyst, Morgan Stanley: Maybe just last minute, I’ll ask just one last question in terms of, you know, we talked about some of this already, but the catalyst path here. As we look over the next year, maybe walk us through some of the key catalysts.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: I mean, the biggest catalyst here without a doubt is going to be commercial performance with AMVUTTRA. That’s where the market is really focused, and we understand that. Internally, we’re putting an amazing amount of focus on that too, and we’re investing behind that launch to drive success. That’s the biggest catalyst. Again, I talked earlier, I think at some point, as people, we get a few more quarters behind us and people get more confidence in that revenue trajectory, people are going to then start to turn to the pipeline. We’ve talked about a number of the things, late-stage programs, mivelsiran, zilebesiran. We’ve got a lot of interesting things going on in other parts of the pipeline, including CNS. You know, that’s the next tissue that we’ve started to unlock.

We have demonstrated with the first program, mivelsiran, that we can get it into the brain, we can get knockdown, and we can do it safely. What we haven’t delivered is any proof-of-concept data yet, and that’s what we’re working on right now. We’ve got a number of additional interesting programs that we’ve moved into the clinic for in the CNS as well, including our Huntington program. Let that data mature a little bit, and then hopefully, we’ll show some proof-of-concept there. That hopefully will start to get people more enthusiastic about the potential of those programs. We’re excited about that.

Mike Gold, Biotech Analyst, Morgan Stanley: Great. Looks like we’re out of time. Thanks so much, Jeff. Appreciate it.

Jeff Poulton, CFO, Alnylam Pharmaceuticals: Thank you. Appreciate it.

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