The Fifth Annual Growth Conference. My name is Whitney I jem. I'm one of the biotech analysts here at Canaccord Genuity. I'm very pleased to be joined this morning by John Kennedy, Senior Vice President, Global Commercialization Lead for the TTR franchise, as well as John Vest, Senior Vice President of Clinical Research. Thank you both for being here.
Thank you.
Thank you.
We have a limited time and a lot to cover. I'm going to dive right in. Please save any questions for the end. Hopefully, there'll be some time. If you do have questions as we go, just jot them down and maybe give me a nod. I'll remember to call you at the end. Just to start off, for any of those in the room who are not familiar with the company, can you please just kind of give a brief introduction on the background and what Alnylam is all about?
Sure. Thanks. I can take that. Alnylam , for those of you who are not familiar with the company, was founded in 2002, based on Nobel Prize-winning science. In the interim, it has become the global leader in RNA interference, which is truly a generational technology that has validated and enabled an entirely new class of medications. Our leadership in RNA interference cuts across many different dimensions, but the productivity of our research and development engine is chief among those, where we have developed one of the most robust pipelines in the industry and have yielded six approved medications. We've been at this for over 20 years. The past year has been truly a watershed moment for the company. We have established three pillars that we believe will drive long-term growth and value generation. The first of those is leadership in transthyretin amyloidosis.
With the approval recently of AMVUTTRA for ATTR cardiomyopathy, we have what we believe will be a new standard of care in this very important disease. Given the outstanding clinical profile of AMVUTTRA, combined with this rapidly growing patient segment with high unmet need, we have what we believe will be a true franchise for the company that will enable long-term growth. The second of these is growth through innovation. As I mentioned, we have, through our research and development, enabled what we believe is one of the most robust pipelines in the industry. On top of this, we have a sustainable innovation engine and drug discovery platform that will enable us to continue to innovate, drive growth, and bring novel medications to patients in need around the world. The third pillar will be outstanding commercial performance.
That will be commercial execution, as well as disciplined capital allocation, which, again, we believe and are highly confident will allow us to be sustainably profitable moving forward.
Excellent. Very helpful overview. Starting on the commercial side, as you mentioned, six approved products, four commercialized by Alnylam. We are, unfortunately, only going to have time to talk about one. It is AMVUTTRA, as you mentioned, the recently approved product. I can use this word. You guys just reported a monster quarter. I can say that. With $492 million in revenues, that was 34% ahead of consensus. It's early in the launch, obviously. What do you think we were all missing on our side headed into that first quarter?
Yeah, I'll take that. For AMVUTTRA, AMVUTTRA had already been approved for the polyneuropathy of hereditary ATTR. What we recently had is the approval of cardiomyopathy for ATTR. We're just into the first full quarter. It's still early. I definitely appreciate it. It's still early, and we have lots of work to do. The first full quarter of our launch went exceptionally well. We look at multiple indicators of how we go through the launch, the things that were important to us to make sure we set up the conditions for a successful launch. We're generally tracking on or ahead of schedule on all those indicators. I think what I'd point out as most pronounced was the provider account setup. Just to back up, we do know that about 80% of the patients that present with ATTR cardiomyopathy will present to one of about 170 priority health care systems.
These are provider accounts. AMVUTTRA is the first buy-and-bill product in the category. We know that there's a setup that tends to be required for a buy-and-bill product in the category like this. That's routine. It's customary, and it tends to take several months for these provider accounts to essentially do whatever process they do, P&T committees to add a product to a formulary so that it's available for utilization for patients that flow through those systems. We've known this. It's a well-established process, but it tends to take several months for that setup to happen. We expected that would take the majority of 2025 for that provider account setup to happen. What really surprised us, favorably, was that that happened much faster than we had anticipated. At Q1, we were about, what, five, six weeks into the launch.
By then, already half of these priority accounts, health systems, had added AMVUTTRA to the formulary. As of the Q2 earnings call, we shared that essentially the market is broadly set up. That allowed us to realize demand much earlier than we had expected. Originally, we thought it was going to be mostly a second-half story. Because of that faster-than-expected setup, we saw more of that demand manifest earlier than we expected.
Excellent. Excellent. OK, perfect. Another key discussion point, I guess, in the ATTR space is sort of diagnosis and treatment rate amongst these patients. Where are we with both of those in the U.S. and worldwide at the moment?
Yeah, generally speaking, we're still early. There's been tremendous improvements over the last several years in terms of diagnosis and treatment rates. We're still early. Just to kind of back up, globally, we estimate that there are more than about 300,000 patients affected by ATTR cardiomyopathy. In the U.S., just a crude rule of thumb, call it about half, so 150,000 patients affected by the disease. Globally, about 80% of these patients remain undiagnosed. Certainly, the vast majority of these patients are untreated. Yes, there's been some progress over the last several years because of better diagnostic or easier diagnostics and treatment choices. We're still early. There's still a significant amount of growth to be had. There are so many patients that we can help.
OK, perfect. Moving forward, the growth for you all will continue with penetration into those existing patients, but then increasing the existing patient pool by increasing diagnosis rate, etc. Yes, OK. As that rate increases, do you expect there to be a shift in the type of patients that are coming on to therapy? If we're looking harder for patients, are we going to find earlier ones or less severe ones? How do you think about that?
Yeah, generally, we think of a couple of different segments of patients where there's opportunity. There are these new-to-treatment patients. They're, on an annual basis, more of these patients presenting to a physician for that very first treatment choice, that first-line treatment. That's one patient segment, the new-to-treatment patient. In the U.S., we assume that there's about 10,000 of those patients coming in on an annual basis. Globally, about 18,000 of these new-to-treatment patients. A second segment are stabilizer progressors, so patients who have been treating with a stabilizer. Regrettably, some of those, we see estimates in the literature anywhere 30%- 50% of those patients may continue to progress and may be available for an alternate treatment option. Then there's the remainder of those patients that are still undiagnosed and will continue to flow in. With regards to what we're seeing, there has been a shift.
I mean, there's still so much more to do to improve on diagnosis. It's not like we're catching these patients uber-early. I think there's still more that we can do. If you think about the patients that were studied in the first clinical trial in this space, compared to what we're seeing as those first-line treatments today, these patients are generally a little bit earlier in the disease and are generally on substantial background treatments. I say that because if you look at the HELIOS-B patient population, that is the patient population that we studied, patients that are generally earlier in the disease and also with substantial background treatments. If there's a question, can these patients benefit from early and aggressive treatment? HELIOS-B says resoundingly, yes. There's absolutely a tremendous amount of benefit for treatment early with AMVUTTRA in this patient population.
Got it. OK. Just one follow-up on that. For the stabilizer progressors, those are the patients that are on the oral approved stabilizers but still progressing, as aptly named. Are those patients coming off the stabilizers and moving over to AMVUTTRA? Are they doing combination therapy? What does that look like?
Just to kind of quantify it, globally, we think there are about 45,000 patients that are actively treating on a stabilizer. Again, rule of thumb, U.S., call it about half of that. In the literature, we've seen somewhere in the ballpark of 30%- 50% of patients on the common historical stabilizer have experienced progression. We are the first and only alternate treatment option in terms of the mechanism of action and orthogonal option. It's really just an obvious option for these patients that have been progressing on a stabilizer. In terms of utilization patterns, look, we're one quarter in. I think it's a little early. We see some examples of combination therapy, but I would say, generally speaking, we expect this is going to be a monotherapy treatment market for the foreseeable future.
I think what could change dynamics is when you have a tremendous loss of exclusivity, which Pfizer has said they expect at the end of 2028. That could be kind of an unlocking event in terms of more combination therapy. I think until then, we'll likely see more monotherapy.
Got it. OK. Given this competitive dynamic, as you mentioned, with the kind of existing oral stabilizers, what is your pitch to docs? Like when a salesperson shows up to the doctor's office, how are they presenting AMVUTTRA? I guess that's relative to the stabilizers. Is there also anything you're doing in the near term relative to the potential future availability of a related silencer called vutrisiran?
Yeah, I think we're in a unique position. We are the first RNAi silencer that's approved for ATTR cardiomyopathy in the U.S., the first and only treatment that's approved for both polyneuropathy of hereditary ATTR as well as cardiomyopathy of ATTR. We're the first and only that's approved for both manifestations. We're in a really unique position. What we hear from customers, physicians, and patients alike is it makes intuitive sense. If you know the disease-causing protein, to rapidly knock down the protein, essentially working upstream or at the source, that intuitively makes sense. Now, if you ask, what is the implication of rapid knockdown of TTR? We know the results. That's what we showed in HELIOS-B. What we saw in that study was a profound impact on outcomes. In particular, it's noteworthy we had all-cause mortality, a profound impact on all-cause mortality as a pre-specified standalone statistically significant finding.
On top of that, to be able to demonstrate preservation of functional capacity and quality of life, and then delivered with four subcutaneous doses per year. Altogether, that's a value proposition that resonates. Physicians will tell us it's peace of mind to know that the patient is receiving the treatment as intended. It is a very compelling first-line value proposition. In terms of a future competitor, I think it remains to be seen if and when they come to market with what data package. I don't want to be presumptuous and speculate. I do feel like what we're doing right now is establishing AMVUTTRA as a first-line treatment option. That's the best thing that we can do. We have a wonderful data package that we can continue to educate on with some lead time.
If I were to look at hereditary polyneuropathy, we have been competing against another silencer for now well over a year. What we see in that space is that more voices expand treatment options or diagnosis. We've seen an expansion of that category. That's a net positive for patients. We have retained a resounding lead in first-line treatment choice in hereditary ATTR polyneuropathy, even in the context of competition. We feel good. We've got a lot of work to do, but we can establish AMVUTTRA as that first-line treatment choice.
Perfect. Sticking with that competitive dynamic question, you spoke about the oral stabilizers and kind of where they are now. What are you hearing from both doctors and physicians, I guess, particularly in that front-line setting, on the appetite for, yes, an oral stabilizer versus a subcutaneous injection or versus maybe some of the next-next-gen kind of one-and-done gene editing approaches?
Yeah, so just unpack that a little bit. I think in terms of just the choices that are available today, it's really, this is a condition where it's rapidly progressing, devastating. It's an efficacy-driven decision. We can go through the HELIOS-B data set. I think we have a really, really compelling and robust clinical data package coupled with a treatment regimen, this quarterly dosing that aligns with when most patients will see their physician, gives that peace of mind that the patient is actually receiving the medicine as intended. What we've seen with daily oral treatments in this category and others is that daily oral treatment is not perfect in terms of adherence and persistence. It's all part of the value proposition that is relevant.
With regards to future competitors, even gene editing, I would say fast forward, don't forget that we're continuing to drive innovation that involves evidence generation for AMVUTTRA today, but also advancing our next-generation RNAi silencer, vutrisiran. By the time there may be a gene editing competitor, it's likely in the time frame when we would have vutrisiran available to market as well, if all goes to plan. Vutrisiran has the potential to deliver 90%, 95% knockdown of TTR with incredible durability, about two doses per year. I think it really, the question is, what's being brought to market by the competitor that we're not already providing for patients?
Yeah, fair enough. OK, perfect. You are also getting your ex-U.S. launches off the ground. This wouldn't be a contemporaneous panel if we didn't ask about MFN. To what extent is MFN a concern? How are you thinking about that as you look to the ex-U.S.?
Yeah, so first, really excited. We have regulatory approval in Europe, in Brazil, Japan, and so international launches will continue afoot. In almost all countries outside the U.S., there is a pricing and reimbursement process we go through, which is after the regulatory approval. That's still a process to work through. In many countries, that can be a little bit of a protracted process. For that reason, the ex-U.S. launches is really a 2026 story for the most part, and that's still work in front of us. Now, as regards to Most Favored Nation, MFN, I think it's really, really hard to speculate. There's so much uncertainty around what that policy may be, how it may play out. It's very difficult to try and read the tea leaves in terms of where it's going. We'll just use the latest information as we go forward with those ex-U.S. launches.
Again, I'll say most of those decisions in terms of pricing, reimbursement, and launch are still in front of us. We retain degrees of freedom while we learn as much as we possibly can about MFN. Again, it's really hard to speculate with so much uncertainty.
Yes, definitely. You're not actively slowing down any launch processes, ex-U.S.?
We continue to move forward.
OK, excellent. Perfect. Tariffs, I guess. Is there anything that we should ask about or be thinking about in that regard?
Nothing particularly noteworthy. I think it's been talked about. I don't know that I have much more to add.
Excellent. Excellent. OK, perfect. All right. I could ask a bunch more questions on the commercial side. I will move to the pipeline now. Sticking with the cardio side of things, zilebesiran, can you talk about the current unmet need in high blood pressure? What's the TPP?
Yeah, so the zilebesiran program is just, as a cardiologist, incredibly exciting and we believe has the potential to truly redefine the treatment of this very important disease. Unmet need, hypertension, despite the numerous available therapies, remains the leading addressable or reversible cause of cardiovascular morbidity and mortality. It's estimated that up to 80% of patients who are on therapy are not meeting their blood pressure targets. There is a huge, huge unmet need for one of the most common problems that we encounter in medicine. In addition to just lowering blood pressure, there are a number of factors that feed into the morbidity and mortality that go along with hypertension. One is adherence to medication. That's a huge problem.
There's variability in blood pressure control, where patients may be controlled one day, not the next, controlled for part of the day, but not for the second half of the day. In particular, loss of blood pressure control during the nighttime hours. These are major problems that factor. When we look at this, we see a real need for something that could have tonic control of blood pressure, very infrequent dosing, two doses a year, 24 hours a day, seven days a week, 365 days a year, tonic control of blood pressure, and address many of these deficiencies, potentially improve adherence as well. Those feed into what we're looking for in the profile of this drug.
OK, perfect. If I forget to take my blood pressure meds, or I won't have to. It's only twice a year. That's the idea. Yes. You, as mentioned, have another approved product that is commercialized by Novartis, inclisiran, that was developed for another kind of larger cardiovascular indication. From a clinical development and maybe kind of early commercial experience with inclisiran, what were the learnings there as you looked to kind of design the plan for zilebesiran?
Yeah, yeah, so I think the fundamental learning is inclisiran launched, and as you're pointing out, a very common indication for control of lipids without outcomes data. I think that Novartis learned from that early experience in the launch. Certainly, as we thought about going into this other very prevalent common indication of hypertension, we and our partners at Roche felt that it was critically important that we bring this to the market with outcomes data. That's what we're planning on, starting a cardiovascular outcomes trial that we intend to start later this year.
OK, perfect. In terms of the clinical development plan, what are the other key questions? There are several studies ongoing, I guess. Can you talk about what are the kind of key questions or key data points you're looking to generate with the various studies?
Yeah, we'll be at the ESC Congress in Madrid in just a couple of weeks here. We will be releasing the results of our KARDIA-3 study. This is a phase II study of zilebesiran in patients at high cardiovascular risk on a background of two to four background antihypertensive medications. There will be very important learnings from that study. It will inform us. It will confirm the dose that we want to take forward into the phase III study. It will inform details around inclusion/exclusion criteria, and we'll confirm power and size of the cardiovascular outcomes trial. Really, really exciting, important data that we're looking forward to sharing in just a few weeks here.
OK, perfect. Remind me, the cardiovascular outcomes study is on track to start before the end of the year. Is that right?
Yes.
Yes, OK, perfect. Excellent. All right. I could ask more here, but in the interest of time, I'll move on. Everything we've been talking about so far is cardio, kind of liver-targeted. Moving over to CNS on the CAA program, can you talk a little bit about CAA as a disease, the mechanism, kind of the tissue target, sort of differential route of administration there?
Yeah, so this has to do with our mivelsiran program, which is targeting APP, or amyloid precursor protein. As the name suggests, this is a fundamental part of amyloid that deposits in the brain and has been genetically validated in two different very important diseases. One is Alzheimer's disease, which has to do with deposition of the amyloid precursor protein in the parenchyma of the brain. The other is CAA, which is the point of your question, is cerebral amyloid angiopathy, where there's deposition of the same amyloid precursor protein in the blood vessels of the brain. Again, it's this genetically validated target. We do have a program going on in Alzheimer's disease as well. CAA is a highly underserved area. This is one of the leading causes of intracerebral hemorrhage or stroke where there are currently no approved therapies.
These are patients that live with a very, very high—once they've had an intracerebral hemorrhage, their chance of a second or then multiple bleeds is extremely high, about six times as high as it would be with other causes of intracerebral hemorrhage. A real, real unmet need here. We have an ongoing phase I trial, CAPRICORN, where we're looking at two different populations. One is a sporadic population. These are patients who tend to be a little bit older, in their 60s, 70s, who developed intracerebral hemorrhages due to this mechanism. The other is a genetic population of Dutch cerebral amyloid angiopathy. This is much rarer. This is a more severe form of the disease and one that happens much earlier in life. These are patients who may start experiencing bleeds. This is a genetically defined population in their 40s or 50s.
You can imagine if you are somebody who carries the genetic risk for this, maybe have a young family living every day with the knowledge that today could be the day that you have your stroke. Really a horrible disease with no good treatment options. We're really, really excited about this opportunity moving forward.
OK. When will we get the next update there? For Alzheimer's as well?
Yeah, we have not said anything, disclosed anything about when we'll update on the CAA program. With the Alzheimer's program, we will be starting, we hope, a phase or we're intending to start a phase II trial by the end of the year.
Perfect. OK. Yes, very clear unmet need and maybe more straightforward on the commercial side in the CAA space relative to Alzheimer's. Alzheimer's is obviously a huge, huge opportunity and also a huge unmet need. We're going to stick with that sort of huge, huge opportunity and move over to the medical side and talk about MASH, where you have a phase II program. Can you talk a little bit about the target and the mechanism there? Again, kind of TPP and when we'll get the next update?
Yeah, I can't. MASH is out-licensed to Regeneron, and we're not permitted to answer questions about that. What I can speak to is the rest of—we have other very, very exciting programs in our cardiometabolic profile targeting both type 2 diabetes as well as obesity. In type 2 diabetes, we have an ongoing study with the GRB14. This is a novel insulin sensitizer, something that hasn't been developed in this space in decades, and one that we believe has a differentiated profile that avoids the weight gain that's associated with other insulin sensitizers. It's something where we see real opportunity. In obesity, we're planning for the end of the year to start a study with ARCV1, which will be our first adipose. This is not a hepatic target.
This will be an adipose target, where we think we have a differentiated potential to not only focus on the quantity of weight loss, but also on the quality of weight loss with preservation of lean mass and in an area where we believe we can add to and improve on what's currently being achieved with incretins.
Got it. OK. In the last 30 seconds, everything at Alnylam is homegrown at this point, as you mentioned, a robust kind of technology platform to generate new medicines. Is there any appetite to look externally to either add capabilities, technology, or new programs?
In short, we really are focused on growing the business and investing in our internal efforts and in our internal pipeline and our internal R&D engine. Certainly, we will always survey the landscape and look for any opportunities that we might have to build on what we're doing. Our focus is on growing in-house.
Perfect. Excellent. Perfect timing. Thank you so much.
Thank you.
Appreciate it.
Thanks.