Good morning, everyone. My name is Will Pickering. I'm Bernstein's U.S. senior analyst for U.S. biotech. Very pleased to be kicking off our 2025 Healthcare Forum with Alnylam Pharmaceuticals. We have Jeff Poulton here, CFO. Jeff, thanks so much for joining us.
Thanks for having us. Good to be here.
Maybe just to start off, would you like to share some opening thoughts on Alnylam Pharmaceuticals for those who are a little bit less familiar?
Sure. We're a company that's pioneered a new class of medicine called RNAi therapeutics. It's been a 20-plus year journey for the company. There was a lot of work, probably for the first 10-plus years around delivery, but once the company figured out delivery, there's really been a steady cadence of progress. Where we are today is six commercial products in the market that came out of Alnylam's labs, four of which we're commercializing. We're certainly going to spend some time talking about the launch into the cardiomyopathy part of the ATTR market. That's sort of the big focus right now for the company. Beyond the commercial progress that we've made, we've also got a terrific pipeline, about 20 medicines in the clinic today, all based on that same underlying technology. It's a true platform company that we think has the ability long-term to serially innovate using that platform.
That's the focus of the company from an R&D standpoint. Financially, obviously a lot of focus right now on top-line growth. Again, we'll talk about the launch, but given the top-line growth, we're on the cusp of getting to profitability right now, which is a goal that we set out about five years ago. We're pleased to be on the cusp of achieving that. A lot of good things to come, I think, for Alnylam. That's how we're situated.
Excellent. Why don't we start with digging into TTR? I mean, you had an absolutely amazing quarter. What were some of the drivers of that performance?
Yeah, we had obviously a very good start. Just to sort of level set everybody, we've been in the ATTR market for the last five, six years, but we've been in a smaller part of the market. We've been in the hereditary polyneuropathy part of the market. We think the hereditary part of the market is about 50,000 patients based on prevalence, and then the polyneuropathy part of that market is probably 25,000 to 30,000. What happened with the HELIOS-B results about a year ago was really the unlock of the cardiomyopathy part of the market, which is probably 10 times larger than hereditary PN. We got the approval and the label expansion in the U.S. at the end of March. Q2 was really the initial launch into the new opportunity. As you said, we had a, I would say, a very good start.
TTR revenue globally, and this is ONPATTRO and AMVUTTRA combined, was $544 million, which was 77% growth year over year. Double clicking on the U.S., which is the only market that we were launched in, in the quarter, we reported $383 million of revenue, which was $170 million of growth from Q1. We don't have the ability to report PN and CM revenue separately, but we do have a good sort of trend history in PN. We were growing probably pretty reliably $15 million to $20 million a quarter, quarter on quarter in PN. The U.S. growth in Q2 was $170 million. Clearly, step change in terms of growth driven by the CM launch. We estimated of that $170 million, $20 million PN, $150 million CM, and we think we had about 1,400 patients on therapy for CM by the end of the quarter.
Some of the other things that we looked at and talked about on the earnings call, probably the thing that drove the faster progress than we had expected was the provider setup. This is a buy and bill drug. In addition to getting payer coverage, you've got to get the providers that are doing the buying and the billing, you've got to get them set up to be able to do that. Most of them that do the buying and billing are affiliated with what we call health systems. There's about 170 health systems, which are networks of hospitals in the U.S., where the majority of these patients that have cardiomyopathy get treated. I would say we got through almost all of that and getting the drug on formulary at those health systems. That was really the focus.
We had originally expected that that would take probably six to nine months to complete that, which is why we had guided to this really being a second half of the year story in terms of revenue. We got almost all of that done. We really unlocked that completely in the second quarter. That was really the pull forward of the revenue. We also made good progress, I think, with the payers. I think we'll talk about that later in terms of first line versus second line coverage. We also talked about the sources of demand, right? This is sort of an interesting market. There's a second line opportunity for patients that are on the sort of existing standard of care that are progressing. Then there's a first line opportunity in terms of new patients presenting, being treated for the first time.
We saw pretty good balance between first and second line in the quarter. I think we also saw good balance in terms of where those patients were treated, some in the academic centers and some out in the community. Really good start, I would say very encouraging, I think, for the company.
I'm sure a ton of work went into preparing for this launch in terms of what went according to plan versus some positive surprises. You already called out the formulary. Anything else you call out as surprises?
Yeah, just again, why do we think the unlock on the provider side happened faster than we anticipated, which was really the positive surprise? I mean, I think it was ultimately two things. I think the fact that we've been in this market for five plus years on the polyneuropathy part of the market, we have relationships with these health systems, the majority of them. They understand the technology already. That certainly probably facilitated things a little bit. I do want to compliment the commercial organization at Alnylam. I think they really did a very good job. They understood that we needed to move as fast as we could to make the early experience that physicians were having with prescribing the product.
We wanted that to go well because sometimes if you get out of the gate where that's a challenge, that can then make them hesitant to prescribe the product. We couldn't get this stuff done until we had the approval and the label to take into these formulary discussions. The team did as much work as they could in advance to prepare for that. I think that they deserve credit for that. In terms of the things that maybe went as we expected, we didn't talk as much. I didn't talk as much about what happened on the payer side. This is largely a Medicare market. Probably in PN, we've had about 80% of the patients that are getting access to the drug being Medicare patients. That's split between Medicare Advantage and fee-for-service roughly, fairly evenly. The majority of the rest of the market is commercial.
In the fee-for-service part of the market, there's really frankly not much to do. Once you have the approval, the drug gets covered to label. There's no policy that has to get put in place there to enable access. We probably got out of the gate fastest there in terms of patients that had fee-for-service. Medicare Advantage and commercial plans, you have to work with the plans to get policies in place. You can get access to the drug before policies are in place, but it's a little more cumbersome. There's a little more work required from the physicians. We made really good progress in getting those policies in place in Medicare Advantage and commercial Medicare Advantage. Almost all the policies that were written in the second quarter enabled first line access, which was critical for us. We expected that, but it was nice to see that pull through.
On the commercial side, majority also first line access. Some step edits were put in place again, which we expected. I think you really need to look at the policies and the way they're written to understand how challenging that might be to still get access. Most of that is really going to be at the physician's discretion to determine whether or not the patient's progressing. If they are, there's going to be an ability to access there. Payer side, I think went as expected. I talked about the demand. I think our expectation was that we were going to see demand both from a second line and a first line perspective. We're really focused on the first line, but we expected that we would get both. I think that's very positive.
I think among the three players in the market today, we're probably uniquely positioned to have really two sources driving growth, both the first line opportunities as well as the second line. It was nice to have that go well. We expected it, but nice to see.
Could you talk about the mix of first line and speech and how that evolved over the course of the quarter, and sort of what you're expecting in the back half of the year?
Yeah. You know, right out of the gate, it was mostly second line, which probably is indicative of there probably was some warehousing going on where patients and physicians were waiting to get access to an orthogonal mechanism of action. We did see that right out of the gate that most of the early demand was second line. Over the course of the quarter, however, the first line demand was building. By the end of the quarter, it was pretty balanced in terms of where we were seeing that, you know, sources of growth coming from. That's what we would expect on a go-forward basis is both will be drivers of growth. We're really focused on first line. Maybe I should talk a little bit about the segments and how large they are. On a first line, you know, this is a disease that's pretty significantly undertreated today.
We think it's about 20% treated today. In the last few quarters, I think our expectation is there's actually, it's over the course of a year, there's about 18,000 new patients we think that are presenting to get access to therapy. With new entrants into the marketplace, I think we have an expectation that you might see an acceleration of that. It's a little early yet to call that, but that's what it's been historically with tafamidis and the market. The second line opportunity is, you know, Pfizer's not reporting patient numbers, but you could probably back into it, making some assumptions around prices, probably 40,000 to 50,000 patients on therapy. There's different estimates on how many of those patients might be progressing. We think about half. So there's probably a second line opportunity of about 20,000 patients.
Again, we're really focused on first line because long term, given that it's only about 20% treated, that's really where the growth is going to come long term in this segment. We want to be positioned well and compete effectively there. It's a progressive fatal disease. Our expectation is that physicians and patients are going to want to go on the best product as early as they can. It's not the kind of disease where you want to try something, see how it goes, and then maybe switch to the best product because what you lose, it's difficult to get back with this disease. It's our job now, obviously, to take the data that we've got and make the case that we have the best product. I mean, we've probably talked a lot about the HELIOS-B results.
I would, you know, there's no head-to-head studies across the category, but I do think that the HELIOS-B study was the sort of highest bar in terms of what needed to be met to have a successful study. The patients that went into that study were less advanced in the disease relative to the other studies that have been run in this disease. Secondly, they were heavily treated with other therapies, including 40% of the patients in the study at baseline that were on tafamidis, an approved product for the disease. In spite of all of that, we delivered across, you know, every endpoint in the study, both from an outcome perspective, which was the primary endpoint, which is ultimately what I think patients and physicians most care about, but also on the quality of life and functional metrics.
That's really what we have our commercial team focused on is educating and making the case that when you have a new patient, this is the product that you should reach for.
Could you talk about the competitive dynamics you're seeing with AMVUTTRA and how that's different across different either patient or payer segments?
Yeah, I mean, it's a competitive category. We've only got, obviously for us, only one quarter so far. There's probably not too many definitive conclusions we can draw yet. I would say in the first line, I think what we saw in the second quarter is the majority of the patients are probably still going on tafamidis, which I think at this point is expected. I mean, they were the only product in the market for five plus years. BridgeBio got on the market with their product towards the end of last year, and this was our first quarter. There is an unmet need here. I think we saw that also in the first line setting, that physicians were very interested in trying these new products.
I think by and large in the second quarter, the physicians that were trying something new were roughly splitting between BridgeBio and our product and starting to get some experience there. This is why we're really focused on first line and driving clarity on the data that we've got from HELIOS-B so that we can continue to drive a greater share there on a go-forward basis. From a second line perspective, we talked about the number of patients that might be progressing. I think now physicians really have a choice to make if the patients are not doing well on tafamidis. They can switch them to another stabilizer, which is in the same class as tafamidis, or they can switch to an orthogonal mechanism, the Silencer, which is obviously our product.
Based on the way cardiologists like to do this, the vast majority are switching them to a new orthogonal mechanism. I do think that we're going to continue to do very well in the second line setting.
Going into the launch, there was a lot of investor debate about the Part B versus Part D dynamics. Can you talk about what you're seeing now that the launch is underway?
Yeah, I mean, maybe a couple of things. We talked about the payer progress already. Really, first line in Medicare Advantage and the majority of first line in commercial, that's what we expected. We're not planting the victory flag on that. We're not done forever. These plans have the ability over time to review and make adjustments to their policies. When we launched, we kept the price the same as what we had in PN, but we communicated that we anticipated that price would come down gradually over time. We said on the second quarter call that we did see an increase in gross to nets in the second quarter, and we expect 2025 versus 2024 mid-single-digit reduction in net price. That should be the expectation in terms of direction of travel. We believe that will enable us to maintain the type of access that I talked about over time.
Maybe just to talk a little bit about the pricing decision and why we made the decision that we did, probably two or three factors into that. First of all, this is a rare, progressive, and fatal disease. Sometimes people forget a little bit about the fact that it's an orphan disease. Typically with payers, with a rare and a fatal disease, they're hesitant to get really involved and manage those types of categories aggressively. That was part of the calculus. Secondly, I think it's based on the data. I've already talked about the strength of the data. We've got the broadest label in this space. We're the only product that's got both hereditary PN as the full opportunity in cardiomyopathy. The data we think sort of supports it.
Lastly, in terms of what's the impact of the way we price the drug on patients, what we saw in polyneuropathy is what we're seeing already in cardiomyopathy, which is the majority of the patients are not paying anything. About 70% of the patients that have been on the product, first in polyneuropathy, had zero out of pocket. We're expecting the same thing in cardiomyopathy. Even though this is a high-cost drug, from a patient perspective, it's an affordable opportunity. Those were the things I think that went into the decision to price it the way that we did. Thus far, so far, so good. This is clearly an area that we're going to need to continue to focus as time passes.
Turning to the guidance, you raised net product revenue guidance by $600 million at the midpoint, which is a very substantial increase. On the other hand, by my math, you could grow sequentially maybe a little over $100 million for the next two quarters and still hit the top end of that guidance. Maybe talk about some of the puts and takes or how you expect growth to look in the back half.
Yeah, maybe just talk about the sort of the sequencing of the guidance that we gave. We actually guided it at JP Morgan this year. Historically, we've given product sales guidance combined for TTR and sort of our rare products together. This year, we decided to break them apart. We wanted to provide more visibility to our expectations on TTR. Again, we guided at JP Morgan, which was two or three months before we even had an approval on a label. Obviously, we were confident based on the data we had and the progress that we were making with the FDA. Part of that was also wanting to get a little bit ahead of the sell side because it was clear that a lot of the sell side hadn't spent a lot of time on their models yet and thinking about numbers for 2025.
We wanted to help, frankly, sell side and manage expectations. We did believe this was going to be a second half of the year story in terms of the CM launch. We talked about the strength of the Q2 numbers. If you look at where TTR was halfway through the year based on the Q2 results, we were a little over $900 million. The guidance that we gave back in January for the TTR franchise revenues this year was $1.6 billion to $1.725 billion. Clearly, we had to upgrade the guidance based on where we were at Q2. We upgraded it more than $550 million in TTR to $2.175 billion to $2.275 billion. That's more than a 30% upgrade from the original guidance at the midpoint. It's based on one quarter of results.
I would sort of point people to that in terms of expectations for the second half of the year. Just to frame a little bit more in terms of the growth that that implies for the franchise on a year-over-year basis, if we hit the midpoint of that guidance, the TTR franchise in total, so PN plus CM, will grow about $1 billion in revenue compared to 2024. In 2024, when it was PN only, the franchise grew $300 million. Right. You can see the accelerating effect of the TTR or the CM opportunity in just nine months in the U.S., right? We are going to start to launch in additional markets outside the U.S. We've just started in Japan and Germany, probably not significant contributors this year. That'll be more of a 2026 story. We'll start to unlock more markets outside the U.S. next year as well.
There's a lot of long-term growth potential here. In terms of the guidance, I mean, again, I think that was based on one quarter. I would point the market to that in terms of expectations for the second half.
Oh, U.S. How should we think about the timing of when those approvals and reimbursement starts contributing to revenue?
Yeah, I mean, I just mentioned, I think it'll be a fairly modest contribution from Japan and Germany this year. Then we'll start to unlock more of the markets in Western Europe next year. The one thing that'll be different outside the U.S. from the U.S. is pricing and what that should mean in terms of the sort of the growth ramp in CM. We've talked about in the U.S., we didn't make any change to the price when we launched in CM, and we have a single price for the franchise as a whole. Obviously, as you start to add new patients in the U.S. for CM, that's all additive to growth. Outside the U.S., it's likely going to be a different story. These are single-payer markets, so you're negotiating with the governments to establish price.
Typically, the way price works is you're benchmarked against what's in the market for that disease. In this case, it's tafamidis, and so we'll get benchmarked against that. I'm simplifying this a bit, but typically, they look at your clinical data compared to the clinical data of the product in the market. If you're better, you may get a premium to existing product. If it's determined it's very similar, it'll be probably similar in price. If it's not quite as good, you're going to have a discount. That'll be lower typically than the price that we're at for PN, and so there will be an impact on the PN business in terms of a headwind as you lower that price and launch into CM.
Now, the volume, as we've already talked about in terms of the size of the opportunity, is so significant that the volume in CM is obviously going to more than make up for what you're losing in PN. It will impact the, again, the initial uptake. In the U.S., we talked about that sort of stairstep effect. We grew 80% in the U.S. between Q2 and Q1. Right. We won't have that kind of growth stairstep in the international market. They'll contribute, but it'll just be sort of a little bit of a different sort of profile when that starts next year.
Could you talk about your expectations for the longer-term evolution of the TTR market and what that means for Alnylam? For example, in a couple of years, you may have another Silencer on the market. In a few years, potentially tafamidis generics. What does all that mean for your franchise?
Yeah, maybe we'll take those sequentially. There are three products in the market today, one Silencer and two stabilizers. You mentioned it, there's another Silencer that's in the clinic for cardiomyopathy. That's the Ionis AstraZeneca product. They're already on the market in polyneuropathy. I think their study is expected to read out second half of next year. Maybe second half of 2027, I think, is what they're guiding to in terms of when they would potentially be on the market. Maybe talk about the experience that we've had in PN, where in the U.S., we really had the PN market to ourselves for four or five years and really built and established that market. The AstraZeneca Ionis product, Wenua, got approved at the start of 2024.
If you look at what happened to our PN business over the course of 2024, there really was no change in the growth trajectory from the year prior. I think they were probably happy with the progress that they made in the launch. What's fairly typical in these rare disease type opportunities is when there are multiple or new voices coming into the market, driving disease education and awareness, the market starts to expand faster. That is what happened last year as the market started to expand faster. As the leader in the category, we were probably getting two-thirds to maybe 70% of the new patients that were coming on to therapy, which is what allowed us to continue to grow at the same pace. You didn't see a switch dynamic really between our product and their product. We're a once-a-quarter sub-Q, they're a monthly injection.
We didn't see a lot of switching between the two products. Fast forward to cardiomyopathy in terms of the Silencer part of the market. I guess we would expect that's a pretty good proxy for what we would expect when they come into the market. Obviously, this is all pending data from the study and understanding what that looks like. The other dynamic that you're asking about is tafamidis generic. I know there's a sort of a big debate about timing of that. I think our view is consistent with what Pfizer has guided in terms of likely timing in the U.S. We think it's the end of 2028. We think what that means for now is that it's largely going to be a monotherapy market because payers are going to make it difficult to get two products for the same disease reimbursed at this point.
There is some combination therapy going on today, and there frankly is interest in that. I think cardiologists are frankly very comfortable combining products. I think the data from the HELIOS-B study wasn't designed to have a statistically significant result in that combination setting, but the trends were really pretty favorable. There's some really interesting data in there in that combination setting. In every endpoint in the study, it favored the drug, the combination compared to tafamidis. There are some very positive trends. That's in the clinical trial section of the label. I think there's a desire to do combo. I think it'll be more limited until tafamidis goes generic. Once tafamidis goes generic, I do think you're going to see a lot more combination therapy.
For us, I think we're encouraged by that because I think that reflects the fact that we think this will be a very durable franchise that can grow through tafamidis going generic. I think, again, it'll be mono primarily until then, and then we think it'll be probably more of a combo market. I know we're going to talk about ALN-TTRsc04 a little bit, but we think the design of the ALN-TTRsc04 study will also position the franchise well for that post-tafamidis generic period as well.
That was where I was going to go next. Yeah, that's going to be one of the other really important developments in the market, you know, five, six years from now. Maybe talk about what the product profile is that you're hoping to achieve and why it's important for the business.
Yeah. This is our third generation TTR product. First generation was ONPATTRO, which was an every three-week IV, then AMVUTTRA, which is a once-a-quarter sub-Q. Both of those get to knockdown of about 85% on average. ALN-TTRsc04 (nucerisiran) is that sort of, again, I would say we're continuing to improve the chemistry, which is allowing us to dose it at higher rates, which is leading to better knockdown. In the phase one study, we saw knockdown quickly and getting to about 95% and sustained for out to six months. The increased knockdown, we believe, could lead to better efficacy, 85% to 95%. Typically, more is better in this kind of disease. The duration of the dosing once every six months compared to once a quarter, I think certainly from a convenience standpoint, would be preferred by patients.
That's the profile that we're going for. There are some other elements of this that are attractive from a financial standpoint. There's a pretty heavy royalty burden on AMVUTTRA that's payable to Sanofi. That's between 15% and 30%, and you get to that upper tier fairly quickly. There are no royalties that would be due to Sanofi on ALN-TTRsc04 (nucerisiran). Even if you just switch the existing business, the impact from an earnings and a cash perspective is pretty substantial. We don't think this is just switching the existing business. I talked about the profile. We think it's something that will sustain growth longer term. Longer term here means IP that goes out into the early 2040s. We're looking at AMVUTTRA probably 2036 in terms of when you'd see generic entry there. It extends the life of the franchise as well.
There's a lot to be excited about here, I think, with this particular product and why we're very focused on it.
You're just now getting the study underway. One of the questions that I get is, they have trouble enrolling the study given AMVUTTRA is a very compelling product. Anything you could say about that?
Yeah, I don't think so. I mean, I guess I don't think that we'll have a problem enrolling it because this gives patients the opportunity, frankly, to get on combination therapy because there's going to be no limitation for patients to be on a background stabilizer to come into this study. I talked about the fact that right now combination therapy is difficult from a payer perspective in the U.S. I think there will be patients that will be very interested in that. I also think that the experience that we have and the data that we put up, both with ONPATTRO and AMVUTTRA, gives physicians and patients confidence in this mechanism that this is going to work. They know based on the phase one data that we're getting to deeper knockdown. I don't think we're going to have a problem enrolling it.
It's also a space that we know very well. We've been in this space for 10 plus years. The design of the study, frankly, was we're confident in it based on the HELIOS-B results. We talked about 40% of the patients in HELIOS-B being on background tafamidis at baseline. I mentioned the positive trends that we saw in that patient subgroup in the study. That's really the data that we used to design this study because we're not going to have any limitation on background tafamidis in this study. Most patients are probably going to be on tafamidis. It's an outcome study. We do think that long term for this to be reimbursed, you need the outcome data from a payer standpoint. It's what the physicians and the patients care about. We are looking at an endpoint very similar to what we had in HELIOS-B.
About 1,200 patients to get the powering right on this. Again, I would say that we're confident in that based on the HELIOS-B results. That study is underway. We do think, oh, and the other element of the endpoint is it's an event-driven endpoint. That's another learning from HELIOS-B. The event rates in HELIOS-B were much lower than what we'd seen in prior studies. We were white-knuckling that a little bit, obviously, up into the end, just like everybody in the market. We learned from that. These will be patients that are earlier in the progression of the disease. As I said, they're going to be on background meds. We've got an event-driven endpoint, which also I think takes some of the risk out of the study of being positive. The study is underway. 1,200 patients. We think this is likely an approval and a launch in 2030.
We will also start a polyneuropathy study before the end of the year. That'll be a smaller and a quicker study to run, and we think that'll get approval first, probably a couple of years ahead of CM. Likely in 2028, we'll be launching the product in PN. Again, that's also the expected timing of when we believe that tafamidis will go generic. We'll be getting this on the market at about the time that'll be happening.
Great. I want to spend a bit of time on other parts of the pipeline. You presented some data at ESC for zilebesiran. Maybe if you want to recap some of the data that you shared and also just sort of what that product could mean for the growth of Alnylam in the 2030s.
It's a good question. This is our hypertension product. Zilebesiran targets angiotensinogen. What we're trying to do here in hypertension, which is the number one modifiable risk factor for cardiovascular disease. There are lots of products available for hypertension, orals, daily orals. Actually, a lot of them are, they're effective and they're cheap. A lot of those are generic. The problem with those products is, first and foremost, patients don't stay on them. They're not adherent to therapy, and they're not getting the benefit of the product. Secondly, the patients that stay on the product, given the pharmacodynamics of those products, you get a fair amount of variability over a 24-hour period in terms of control of blood pressure. That variability is also a risk factor for cardiovascular disease. We think the profile of this product addresses both of those issues.
This would be a once every six month administered product. Think about that. You don't have to worry about adherence. You get a shot, you're good for six months in terms of blood pressure control. Given the clamp pharmacology, you get control continuously over a 24-hour period. You're getting the benefit both during the day and at night. That nighttime dipping is really important, and you don't get very good control of that with the daily orals. This is a product that we think both from a quantitative perspective in terms of the ability to lower blood pressure, as well as the qualitative elements of it in terms of that continuous control, it's really going to reduce risk in this patient setting. That's how we're thinking about this program. We presented data at ESC a couple of weeks ago in a phase two study.
I would talk about this phase two study as kind of a warm-up act for the CVOT. It was done in the same patient population. This is a high-risk CV patient population, and it was done on top of two to four of these other standard of care medicines. The data that we reported at ESC, we showed about a 5 mm mercury blood pressure lowering at three months, which is clinically meaningful. It wasn't statistically significant, even though the P-value in the 300 mg dose that we're going to take forward was statistically significant. The way the stats were designed, we couldn't claim statistical significance. What was important with Cardio3 are things that we learned.
I mentioned it's a warm-up act for the CVOT, which will be about an 11,000 patient study that will run over multiple years, which is why you really want to learn as much as you can before you design and launch that study. The things that we learned were the dose to take forward. Again, it's going to be an every six-month dose. We learned about inclusion-exclusion criteria. Looking at the patients and how they did across the different types of patients that were in the study, those that were at 140 or greater in terms of systolic blood pressure that initiated the study and were on a diuretic, we saw much better blood pressure lowering, seven to nine millimeters of mercury. That's a learning that we'll take into the CVOT, and that'll be part of the inclusion criteria in the CVOT.
Lastly, we learned about the powering, how to power the study. I mentioned 11,000 patients, and we're kicking that off now. This is another drug that probably will be to market around the 2030 timeframe. This is a program that we're doing in partnership with Roche. We put a partnership in place a couple of years ago. That was mostly about, frankly, from our perspective, the need to work with somebody who had commercial capabilities to launch this successfully. We just didn't feel like that was something that we could do on our own at this point. It really wasn't a financial decision. It was more about capabilities to maximize the value of the program. That'll give us an opportunity to co-promote it alongside Roche in the U.S. and hopefully learn from them. That'll be a 50-50 profit split in the U.S.
They'll have full responsibility for launching the drug outside the U.S., and we'll just get royalties on that. An exciting program for us.
Great. You are now sort of at the final year of the P to the Fifth program. Do you plan to set new targets in 2026? How are you thinking about what the shape of those should be?
Yeah, maybe just to talk a little bit about P to the Fifth before I talk about what's next. The company's had a history of putting five-year goals out into the market. This was the P to the Fifth, was the third iteration of those. That was launched at JP Morgan in 2021. It looked at five different things, two of which were financial goals. That was the first time the company had included financial goals in these five-year goals. I think that's because the company was just starting to build the commercial part of the business. The two financial goals were around a growth rate, revenue growth rate across the period. We committed to at least a 40% CAGR across the period. Based on the guidance that we've given for this year, we're going to beat that handily in terms of what the CAGR will be across that period.
We committed to getting the non-GAAP profitability, which frankly took a little bit of courage. We were a long way from profitability and there was a lot to do to get to that point. I think it actually really helped us that we made a public commitment to do that. I know that internally we felt real accountability for that as a result. I think it created a dynamic where we were making choices at times about things that we were going to do. We couldn't afford to necessarily do everything and achieve that goal. We've also got it to get into profitability this year. I'm confident that we're going to do that. I would say we're likely to do this again in terms of setting out another set of five-year goals. I think it's been part of the Alnylam story.
A lot of times when companies do this, I think these are aspirational types of goals that maybe they're not really committed to achieving. We've really taken the opposite approach. These have been pretty bold goals typically when the companies have put these out. Over the last 15 years, companies really achieve what it set out to do. We don't want to walk away from that. I do anticipate that we'll do it. I'm not ready to tell you what those are today, but I could generally tell you probably the areas that we're going to focus on. I don't think any of this will surprise people, but leadership and TTR obviously were one quarter into this CM launch. Clearly, the expectations for growth here are a big driver for where the stock is right now.
That's likely going to be an area that we'll talk about in terms of some goals over that five-year period. Secondly, it's around innovation, really sort of driving towards what I would call a second act, like what should people be confident in could be a driver of growth beyond TTR. We want to lay out some things that we anticipate achieving and accomplishing there. Lastly, from a financial profile perspective, you know, now that we're at profitability, how do we expect that to evolve? Maybe in terms of operating margins over the period. Those are the types of things that we're thinking about. Stay tuned. I do think that's something that Yvonne will likely be talking about at JP Morgan in January.
How do you think about capital allocation from here, and in particular, the potential role for external innovation now that you have more financial flexibility?
Yeah, I mean, things that we're focusing on right now in terms of investment are clearly on the commercial side. We're investing behind the launch in TTR. We had a foundation in PN. We're obviously building and scaling that up. We've done that in the U.S. and we'll continue to do that as we launch X. On the R&D side, the platform's been a really productive platform for the company. That's going to continue to, as a result, be the primary focus of innovation, continuing to invest behind that amazing platform that we've got. We talked in February at our R&D day as an example that we're going to, by 2030, hope to and expect to unlock every major tissue in the body. As you unlock new tissues, that opens up the opportunity for a variety of new diseases to target with the technology. That'll be the primary focus.
You highlighted the fact that the company, from a financial perspective, in terms of top line growth and profitability, is really moving into a place that will enable more flexibility. External innovation will probably also start to become part of the story. I don't have a lot to share in specifics right now, but I do think that'll probably start to become more of the story. I would point you back to internal innovation being the primary story.
Great. One more, if I may. One of the things that I hear a lot now is Alnylam Pharmaceuticals, fantastic story, but I feel like I missed it from a stock perspective. What would you say to those folks that know the story well, want to know what they're playing for from here?
I guess a couple of things. I get it, right? I mean, we've had a really nice run-up post the launch, but we're one quarter into the launch, right? We've got a long way to go on the launch, and we do expect that this is going to drive, you know, long-term growth for the company. Secondly, we're a true platform company. A lot of companies talk about it, but we really do have the ability to serially innovate. A lot of times when companies get this initial flagship commercial franchise, the real challenge becomes what's next. I think we're going to have the ability to solve that because we've got this amazing platform. I would tell people to start taking a look at the things that we've got in the pipeline.
I think over time, hopefully, we're going to deliver more data that's going to give people more confidence in that. I do believe we're going to have the ability long-term to drive diversified growth as well.
Great. Jeff, thanks so much for joining us.
Thank you.