Thanks. Good morning, everyone. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and we'll get started with our next presenting company. Before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and Alnylam, which are presented both at the back of the room and also at the registration desk, so, as you guys probably know, Alnylam is a leading developer of RNAi therapeutics, with a growing global commercial operations and also a rich pipeline of innovative future therapies. Positive phase III HELIOS-B data positioned Alnylam to recently file the sNDA for Amvuttra and ATTR cardiomyopathy, and Alnylam partnered zilebesiren for hypertension with Roche and has a big discovery alliance with Regeneron, among other things you guys are working on. Here with us today is Jeff Poulton, CFO, and also Sandeep Menon, who's the Chief Development Officer.
Thank you both for being with us, and Sandeep, nice to get to meet you in person.
Thank you. Thanks. Likewise.
OK, so you guys have been doing a great job growing Amvuttra under the current ATTR polyneuropathy label. Jeff, what's been driving this? And maybe you can remind us on sort of what the guidance is for this year.
Yep. Great to be here, Ted. We've been really pleased with our commercial performance this year. If you look at our results through the third quarter, so the first nine months of the year, both the Rare franchise as well as the TTR franchise both grew north of 30% on a year-over-year basis, and the strength of that performance actually enabled us to upgrade our guidance at the mid-year point. Our initial guidance for combined product sales for the year was $1.04 billion-$1.05 billion, and at Q2 earnings call, we upgraded that guidance to $1.0575-$1.1625, or I'm sorry, $1.550-$1.1625, and the midpoint of that guidance is an 11% increase from the original guidance.
If you sort of double-click on the performance, I think the area that really enabled that upgrade was the TTR business in the U.S., where, frankly, there was a little bit of uncertainty this year around the competitive dynamics and how the evolving competitive dynamics might impact our ability to continue to grow. Ionis and AstraZeneca, at the very tail end of last year, launched Wainua, the commercial name we knew at the end of the year, that's directly competitive with Amvuttra in the U.S. in that hereditary PN space. If you look at the growth of that business in Q4 last year, before the competition entered the market, we grew at 38% in Q4 last year on a year-over-year basis.
And then if you look at how we've grown the three quarters now that there's a competitor in the market this year, we grew 35% in Q1, 40% in Q2, and 37% in Q3. So very consistent growth over the course of the year. So it has not impacted our ability to grow that business. And if you look at the comments that Ionis and AstraZeneca have made, they're pleased with their launch year to date. So what's happening in the market is what we expected. When you get a second entrant, the market starts to expand, which I believe is what's happening. But the leader in the space continues to get the majority of the new patient starts. And I think that's what's happening here. So we've been really pleased with that overall.
Yeah, it's a great therapy, and congrats on the HELIOS-B data. Maybe you guys can remind us of what you reported, and sort of obviously, we now have a PDUFA date, so maybe tell us sort of what your expectations are into that.
Sure. I can take that. Thank you, Ted. So for us, we reported in the ESC positive results for HELIOS-B. More deep dive in there, right? So what we have seen is in the primary endpoint, we met both for the monotherapy and the overall population, with a significant benefit for the all-cause mortality as well. And then for the secondary endpoints, as you can see, that 10 out of 10 secondary endpoints was met with statistical significance. Now, this includes the functional endpoints. This includes the endpoints which are relevant biomarkers, NT-proBNP, and others. Now, our population here was unique because what we are seeing is the treatment paradigm is shifting to early disease. And the results were even more impressive for earlier patients, like the patients who were early in the disease. So that has been very encouraging.
And then plus, on top of TAB, which was one of our biggest subgroups, we have seen additional benefit. And that is also significant there. So we are pretty encouraged by that. And plus, the safety has been squeaky clean. We don't have any safety or tolerability issues as well. Now, what we also are doing now is we have filed, obviously, in the U.S., Europe, Japan, and Brazil. And we have a priority review voucher, which we announced last few weeks back. And PDUFA date is in March. That will come in March 23rd. So we are excited, looking forward to the next steps in this program, which is going to be very, very good for the patients.
Yeah, very compelling data set.
Yeah. So I actually have to add one more thing. Because given the data, given the totality of the data, we feel now it is compelling enough for first-line switch and add-ons, because we have got a pretty comprehensive package that will help us in the launch.
So that's a great segue into my next question. How much larger is the hereditary and wild-type ATTR cardiomyopathy market? And how do you guys envision competing with Pfizer's established tafamidis, the stabilizer, and also the BridgeBio's new recently approved acoramidis?
Yeah, it's substantially larger. I mean, we're in the hereditary PN part of the market today. And we think the hereditary prevalence is probably about 50,000 patients. And then within that hereditary population, those that are predominantly PN or mixed phenotype PNCM, it's probably 25,000 to 30,000 patients that are addressable today by our current label. The expansion into cardiomyopathy, we think, is probably 300,000 plus. And so you're looking at a market opportunity that's probably 10 times or so larger than the part of the market that we're labeled for today. So substantially larger opportunity. And when you look at that larger opportunity, it's only about 20% diagnosed today. And of the patients that are on therapy, on tafamidis today, based on the literature, there's a relatively high percentage of those patients that are continuing to progress on therapy.
There's a significant unmet need, whether you look at patients that are not diagnosed or whether you look at the patients that are on therapy that may benefit from an alternative therapy. The way we're thinking about the opportunity is, as Sandeep mentioned, first-line, second-line, add-on. I think the primary focus of that launch for us is going to be in that first-line patient setting. Let me talk a little bit about how we think about what the size of that looks like today. We think today, on average, there's about 18,000 new patients a year that are starting therapy. We would anticipate that as you have new entrants into the market, that will expand and grow. Why we think that we will compete effectively in first-line is because of what Sandeep summarized before in terms of the clinical data that we produced in the HELIOS-B study.
Remember, this is a progressive fatal disease. Physicians and patients want to reach for the best product, the most efficacious, the most potent product as early as they can. We think, based on the Helios B data, if you look at the outcome data, the consistency across the subgroups, what we saw in the stabilizing, the functional, and quality of life endpoints, that we're going to compete very effectively there based on that data. Additionally, some of the practical considerations that we think will allow us to compete effectively there: convenient, four times a year, sub-Q dosing administration. From an access and a patient cost burden perspective, based on what we've experienced in the hereditary part of the market, the vast majority of the patients, around 70%, have $0 out of pocket.
All of those things we think will allow us to compete effectively in first-line. We certainly think second-line is also an opportunity. We think if we're successful in first-line, it's probably going to pull that second-line business in as well. The second-line opportunity I mentioned previously is related to patients that are on the existing product that maybe are not adequately responding. If you look at the literature, there was a presentation at AHA recently that followed 800 patients in the U.S. through claims data and electronic health records. Over a 12-month period, we saw progression of about 50% of the patients on different cardiac markers of the disease. If you got around 40,000 patients today on TAF globally, half of those, you're looking at an opportunity today of about 20,000.
I think given the fact that we will have an orthogonal mechanism, given the fact that we showed pretty compelling data on top of tafamidis in that subgroup and HELIOS-B, we're going to be well-positioned in that segment. I think the question about that segment are two things. One is, are patients and physicians wanting to add-on, or are they comfortable with switching? And the add-on opportunity is likely going to be challenged from a cost and a payer perspective until tafamidis goes generic. And then the other element of this is there's not really a switch dynamic in the marketplace today, because there hasn't. There's only been one product. And so there needs to be some work done to help the physician community understand and know what to look for in terms of progression.
But we do think this will be an opportunity to grow the business as well.
Yeah, that's really, really helpful. So I'm going to just pause and see if there's any questions. At AHA, you guys reported phase I data on nucresiran.
A tough one.
Yeah, I haven't pronounced that one yet. Or ALN-TTRsc04.
That's the one most people know it by, sc04.
Yeah, sc04. How do you pronounce it? I'm putting you on the spot now.
Nucresiran.
Nucresiran. There we go. Thank you. So remind us what you presented. And where does this fit into sort of product life extension for the TTR franchise?
Thank you, Ted. I guess what we presented was the phase I data at AHA. But in general, the way we think about this one is we have this platform called IKARIA, which is basically we don't need a lot of dosing now. It could be once in six months or once in a year in terms of the dosing. So it's going to be much more durable. The second point of this is this is going to be much more deeper knockdown, which is going to be sustained over a long period of time. And we have seen that in the phase I data, which was about 90%, 90% of or more than 90% knockdown in 15 days. And by the time it is in the 29th day, actually, it was like close to the maximum knockdown was close to 96%, which was very encouraging.
So what happens is with that kind of a knockdown, the variability also is shrunk, because the interpatient variability is much more lower. That helps in the efficacy in the long term. So that is our differentiation. And we want to be the leaders in TTR franchise. And this is our next generation, which is going to be even more promising in terms of both the TTR knockdown and the efficacy. And to help us with that, both from a commercial perspective as well and financially, because we don't have any royalty here. So that helps us go a long way in terms of the upside for Alnylam.
I'll emphasize that point. I mean, the royalties that we owe on global sales of Amvuttra to Sanofi range between 15% and 30%, and that sort of ramps up over time as the sales grow, so it's a heavy royalty burden and would make Alnylam gross margin not at benchmark from a biotech perspective. This would allow us to address that issue when we're able to launch, assuming that we've got a profile that would incentivize switching from Amvuttra to sc04, so that's a big focus here. The other thing that we're thinking about is how do you, what's the design of the phase III study? And we've talked about providing color on that to the market early next year. We're really thinking about the long game here. Amvuttra's got IP protection until 2036. TTR sc04 would have IP protection until 2042.
And so we're thinking about a life of an asset across that period, including how the dynamics in the market will evolve and change. And we need to have a package of data and a label that would support it from a demand and from a payer perspective, payers being willing to pay for it and reimburse it. So that's really what we're thinking about as we're thinking about the phase III design. Fortunately, Sandeep and his team have a wealth of really good data from HELIOS-B to think about what's the best way to design this study. So more to come on that.
We are in discussions with regulatory as well. It's been very, very positive.
And I think you guys have guided that to provide that phase III design early next year at some point. So we'll look forward to that. And also, I was just thinking about in a way, a patient I don't even think will know they'll go from getting it four times a year to getting it two or once a year. And it'll probably be.
That'll be great.
Barely even know that they're on a new medicine. So that seems really logical. I want to switch gears, because I think one of the biggest trends that we've seen with the safety and now, obviously, the long-term durability with RNAi therapeutics is this move from what have been predominantly orphan diseases to really much broader diseases. And I think Leqvio with Novartis is sort of the quintessential example that kind of started that. I want to talk about zilebesiren with Roche, which I think is a really, really compelling therapy. Maybe you can kind of tell us about this target and some of the data that you've reported. And remind us, why did it make sense to partner this one with Roche?
Do you want to start with the data first?
Start with the data. So we have currently completed two studies. And the third one is ongoing. And we have a plan to start a CVOT, which is going to be a large phase III study next year. So the first study was the phase II study, which has got like hundreds of patients, was on monotherapy, where patients were on just one treatment, mild to moderate hypertension. The second one was, again, mild to moderate hypertension, but on background medications and mostly standard of care. And what we have seen is we have seen a good reduction of blood pressure. The key thing, Ted, is for a lot of these blood pressure medications, the variability is not controlled over a period of time. And there is a nighttime dipping that happens in normal people without hypertension. That is not happening effectively.
This helps, given our mechanism of action and durability. It helps the 24-hour blood pressure control. Plus, the bigger piece there is also adherence. You just need one shot in six months, and it takes care of it. The phase II data from what we call the KARDIA-2 study basically validated all of that. It has been safe in terms of anything that we have seen so far. Then the last study that it's ongoing is now it's on high-risk patients, high CV risk patients, patients on background medications between two to four background medications. What helps now, we are slowly going from a monotherapy. We have added medications in the second study and the third study. Now it's a high-risk patient. That is going to read out second half of next year.
Once that is done, we are very excited to partner with Roche and continue our partnership with Roche and start our big CVOT study next year. We have so far seen whatever data we have seen in terms of both safety and efficacy has been very, very encouraging.
Yep, excellent.
So we established the partnership that Sandeep referenced with Roche mid-year last year. I would say the primary reason for the partnership was around accessing capabilities that we didn't have in-house to maximize the value of the program, in particular commercially. So given the broad international global footprint that they've got, given the track record that they've got in launching highly innovative therapies in competitive markets, and given the fact that they've got a lot of experience with buy and bill medicines, which this will be, that made Roche an attractive partner to us. So it's a co-development, co-commercialization deal. They will fund 60% of the cost development from a development perspective on a go-forward basis. Milestones, there was a $310 million milestone upfront when the deal got signed. There was a $65 million milestone when we started the KARDIA-3 study, which Sandeep referenced.
There's a $300 million milestone when we initiate the CVOT, which we expect to do by the end of next year. From a commercialization perspective in the U.S., they lead commercialization. But we have the opportunity to co-promote alongside them. And it's a 50/50 profit split in the U.S. ex-U.S., they lead the commercialization. And we're a royalty and milestone player ex-U.S. So I think given the size of the CVOT study, having somebody fund 60% of that for us has also allowed us to invest more broadly across the pipeline. It's one of the things, frankly, that enabled us to announce what we called our 2-2-5 strategy, which was really about expanding into two new tissues by the end of next year. We talked about muscle and adipose, bring forward at least two new CNS programs, and at least five liver programs.
The partnership with Roche certainly enabled us to afford to be able to do that.
Yep, absolutely, and you said the cost, you're only on the hook for 30%.
40%.
40, sorry.
50/40 split on development cost.
On cost and 50/50 in the U.S. That's great.
Exactly.
I definitely want to get to the pipeline. One of them, you guys have this big partnership with Regeneron right now. One thing I've never really gotten a good explanation. How does sort of candidate selection go there? How are you guys working with Regeneron? Do you both sort of put targets in that you want to work on? Does that evolve over time? Is there a picking strategy? Maybe you can share with us a little bit how that works.
Do you want to talk about how the target sort of selection process works?
So the selection process is by science, basically. At the end of the day, you put the targets together. We brainstorm together and making sure that depending upon our strategic fit and scientific fit, we take programs together. So it is a CNS and an ocular partnership. And the bottom line is let science drive it. And then we look at the synergies in the development. And based on that, we select who is playing the lead role and vice versa.
On the ocular side, they lead development and commercialization. And we're just royalty and milestone player there. On the CNS programs, the leadership alternates between the companies. And the non-lead party has an option to either opt in as a 50/50 or not opt in and just be a royalty and milestone player.
Excellent. That's really helpful. One of the programs that fits under this that I think is really interesting is mivelsiran. And you guys just started the phase II CAPRICORN-1 study in cerebral amyloid angiopathy. I think you have plans to start a phase II in Alzheimer's disease. Maybe you can describe why this RNAi mechanism may prove superior to antibodies going after these targets. And what data have you reported today?
For us, currently, we have got enough data in the early-onset Alzheimer's disease. Our differentiating factor is we switch off APP, which is the amyloid precursor protein. Now, this is almost like the source of all the amyloids that come in later. Based on all the amyloid species that come in that antibodies mop up, actually, we are switching off the APP. That is our differentiating factor in terms of how we are therapeutically differentiated. The other piece is so far whatever data we have seen, both in our phase I single ascending dose and the multiple ascending dose, it's well tolerated. It is very safe. We have a good knockdown of the biomarkers, especially the target engagement biomarkers and the disease species biomarkers, which is directly related to the disease pathology.
We showed in the last earnings call, we knocked out about 90% of the soluble APP beta within the first one month, which is significant in terms of the disease progression. From our perspective, we are excited about it. We are collecting more data. We'll be sharing more data in the relevant conferences coming soon. Regarding the CAA, which is the second leading cause for hemorrhagic stroke, we have started the study. We are still recruiting patients. We'll be sharing more data in the coming months, depending upon how we are progressing on the study.
That's really exciting. I like that program a lot. Jeff, you mentioned we've got a story here with growing top line. I think you've done a really good job containing costs, driving to profitability, but yet still very robust investment in the expansion of the pipeline. I think you mentioned nine wholly owned, as many as 13 partnered INDs over the next 18 months or so. Just kind of looking at the balance sheet, you guys had cash of about $2.4 billion. Owed debt, I think, of just over $1 billion. How do you think about funding the company with all of this going on? Do you have enough cash right now to reach profitability?
We do. And frankly, this goes back to a couple of things. One, in JPMorgan, January 2021, we put out a set of goals that we called P to the fifth by 25. One of those goals was related to reaching non-GAAP profitability within that five-year window so the company could be sustainable from a financing perspective. And it frankly also goes back to the deal that we did, the strategic financing deal that we did with Blackstone, where we monetized half of the Leqvio royalty that was due to Novartis. At the time that we did that deal, we said there was $2 billion financing, that that was it, that we didn't need to do any more financing. And I absolutely feel that way. I think my confidence level and our ability to get to profitability next year is as high as it's ever been.
That's based on the strength of the base business. We talked about that upfront in terms of the upgrading of the top line guidance. I feel really good about that as we're heading into 2025. That's certainly the strength of the HELIOS-B results and what that means in terms of our ability to launch next year and start to grow as we move into the cardiomyopathy part of the market. Again, the exciting part about that is we're getting the profitability not by squeezing cost. We're getting there by the growth of the top line and frankly continuing to invest in the pipeline. It's the success of HELIOS-B that's frankly going to enable our ability to afford to do 2-2-5 and bring all these programs into the clinic. I do think that investment is appropriate.
If you look at the history that the company's had in terms of the success rates that we've had in bringing forward programs that are genetically validating using this incredible platform, we should be spending this kind of money on future development. And we're not seeing a shortage of high-quality targets. And we're really expanding the opportunities by moving into new tissues. So we're excited about the future. I feel very good about the balance sheet. And there's no need to go out and finance. There were a lot of people that wondered after HELIOS-B if we're going to go do a financing. We don't need to do that. So we're good.
Great. Well, Jeff, Sandeep, thank you for being with us. Excited for upcoming approval and the launch and just continued pipeline expansion. Thanks for being with us.
Thank you.
Thank you, Jeff.
Thanks, Ted.
I just want to also say one thing that we'll be sharing more information on our R&D Day next year. Just for all of.
February 25th. It'll be in New York. Yes. I'm glad you reminded me. R&D Day.
Feb 25th.
February 25. You got it. Thank you.
2-2-5-2-5. Got it.