Good morning, everyone, and thank you for joining us today. I'm Tolga Tanguler, Chief Commercial Officer at Alnylam, and I'm thrilled to be hosting today's webinar to update you on our leadership journey in delivering transformative therapies for patients living with ATTR amyloidosis. This past Friday marked one year since AMVUTTRA was approved in the U.S. for patients with ATTR cardiomyopathy, a pivotal milestone for Alnylam that has launched us into a new era of growth. We built a strong foundation through years of disciplined execution and are rapidly advancing toward leadership in TTR. How did we get here? In 2018, with ONPATTRO, we introduced an entirely new class of medicine, RNAi therapeutics, that silence disease at its source, bringing a transformative option to patients with hereditary ATTR amyloidosis with polyneuropathy.
We have continued to build on that foundation with AMVUTTRA, which launched in 2022 for the same indication. Exactly one year ago, we expanded into ATTR cardiomyopathy population, which, while still an orphan indication, is far more prevalent than hATTR-PN. We're now driving strong adoption across that larger patient base. We're just getting started. We continue to accelerate AMVUTTRA uptake across the world. We're advancing our next-generation TTR therapy, nucresiran, with the potential to further raise the bar. As announced today, we're investing in cutting-edge capabilities to enable earlier diagnosis, better coordinated care, and sustained long-term outcomes for patients. The strategy is clear. Lead with science, reach patients still untreated or progressing on stabilizers, and deliver durable impact for patients and value for shareholders.
Following last year's approval of AMVUTTRA for ATTR cardiomyopathy, supported by the compelling results from the landmark HELIOS-B trial, we moved quickly to drive adoption and ensure seamless patient access. Execution has been strong, enabled by our deep experience in TTR and the strength of our commercial and medical teams. That execution is translating into results. Now we more than doubled revenues for our TTR franchise in 2025 versus 2024. We beat and raised our guidance twice over the course of the year, and we're guiding to a further 83% growth in 2026 at the midpoint. This momentum reflects both the value AMVUTTRA is delivering to patients and physicians and the strength of our commercial capabilities.
Today, we'll focus on how we build on this momentum to shape the future of ATTR treatment by expanding diagnosis, advancing innovation, and continuing to raise the standard of care in an increasingly dynamic and competitive landscape. Before we begin, I want to acknowledge the ATTR patient community. It is a privilege to work alongside physicians, patients, and their families as they navigate this complex disease and to bring forward therapies with the potential to meaningfully change the course of their lives.
I'm joined today by our key commercial and medical affairs leaders who are at the center of this progress, including Mark Soued, Senior Vice President, Head of U.S., and TTR Lead, John Kennedy, Senior Vice President, TTR Franchise Commercialization Lead, Dr. Sameer Bansilal, VP TTR Disease Area Lead, and Christine Akinc, our Chief Corporate Communications Officer, who will join us to moderate the Q&A.
Let me briefly walk you through how we will shape the future of ATTR treatment and how it connects to our path to leadership. I'll start with our cardiomyopathy launch, what we learned, how that momentum is building, and how we're applying those insights to scale and strengthen our leadership position. Mark will then step back and frame the broader opportunity in ATTR amyloidosis, including the significant number of patients who remain undiagnosed and untreated. Dr. Sameer Bansilal will build on that with recent data reinforcing AMVUTTRA's differentiated clinical profile and how that translates into compelling value proposition for patients and physicians.
John and Mark will then focus on two defining potential future dynamics for the market, increasing competition within the TTR silencer class, where we've already demonstrated our ability to compete successfully in the hATTR- PN setting, and the transition of stabilizer class with tafamidis loss of exclusivity. They will outline how we are positioned to continue to compete and grow through both. Finally, John will bring it together with how we're planning to drive category growth, expanding diagnosis, increasing access, and reaching more patients at scale.
For the Q&A, please submit your questions through the webcast dialogue box. As a reminder, we will be making forward-looking statements. Looking at pace of AMVUTTRA's launch in cardiomyopathy, we're seeing strong early momentum. In 2025, performance was driven by our U.S. launch and the initial rollout in Japan, both demonstrating uptake that exceeds relevant specialty analogs. That momentum is translating into real scale. More than 12,000 patients now treated globally across our TTR franchise. A large and expanding prescriber base, including more than 1,600 unique U.S. prescribers since launch last March. This is clearly reflected in our financial performance.
Since launch in cardiomyopathy, we have delivered $2.1 billion in total global TTR revenues, and we're guiding to $4.4 billion-$4.7 billion in 2026, underscoring our confidence in continued growth. As we look ahead, it's important to start with what enables that future, the foundation we built in 2025. Our early success in cardiomyopathy reflects deliberate execution against the core fundamentals required to build a durable franchise.
First, physician preference and utilization. AMVUTTRA's clinical profile has driven a strong and compelling first-line positioning, with strong preference among physicians who have experience using it. Second, access and affordability. Innovation only matters if patients can access it. Leveraging our experience in this space, we've secured durable first-line access for approximately 90% of patients, with the majority paying zero out of pocket. Our access is broader than it was in 2025, allowing us to reach more patients.
Third, site of care infrastructure. We built a robust provider network to enable efficient administration. Today, around 90% of U.S. patients can receive treatment within 10 miles of their homes. These are not short-term metrics. They are the foundation for sustained growth. They position us to scale within a therapeutic category that continues to expand meaningfully. If you look more closely, we can see the momentum unlocked through disciplined execution against these fundamentals. As a third entrant in ATTR-CM, competing against a legacy standard of care, we achieved an average approximately 35% new-to-brand market share across the first three quarters of launch. That's a clear signal of unmet need and willingness from both physicians and patients to adopt a new treatment approach.
Importantly, we're seeing consistent patterns emerge that will guide how we scale from here. First, experience drives preference. Physicians who gain experience with AMVUTTRA increasingly choose it as their first-line therapy for new patients. Second, utilization drives depth. As physicians build confidence, they expand use, treating more patients and choosing AMVUTTRA consistently in their practice. Third, patient choice is reinforcing adoption. Patients are well-informed and asking their physicians for AMVUTTRA, now the most requested brand among surveyed U.S. TTR patients who express a treatment preference. With these dynamics, our foundational pillar is in place. Our focus now shifts to the next unlock, expanding the breadth of our prescriber base. That is a key driver of growth and a metric we will hold ourselves accountable to as we scale to the next phase of launch.
To double-click on the first learning, that experience drives preference, we're seeing clearly that experience with AMVUTTRA reinforces physician confidence and drives further adoption. As with any new therapy entering a competitive and established market, physicians begin with a set of practical considerations, particularly around access, affordability, and efficacy. From that perspective, real-world experience with AMVUTTRA has been highly favorable. It has broad access, most patients pay zero out of pocket, and it has a highly differentiated clinical profile that resonates with physicians, especially when they start using it. As we now focus on expanding the breadth of prescribing, bringing more physicians into that experience, we're confident this will continue to drive deeper utilization and sustained growth over time. Importantly, all of this is unfolding within a large and rapidly expanding U.S. treatment category.
We now estimate nearly 200,000 ATTR-CM patients in the U.S. alone, with more than 80% still untreated. What we're seeing is a category where the treatment volume is continuing to accelerate. As expected, increased focus and competition are driving diagnosis and treatment. The U.S. treatment category grew 56% annually in 2023 and 2024, with only a single approved therapy. With the addition of a second stabilizer and the introduction of AMVUTTRA, the first and only silencer in ATTR-CM, U.S. category growth accelerated to 77% in 2025. We expect this strong trajectory to continue in the U.S. as diagnosis expands and more patients are treated. We are well-positioned at the center of that growth, combining a differentiated approach, strong execution, and increasing physician adoption.
With that, I will turn it over to Mark, who leads our U.S. business, to outline the opportunity ahead and how we intend to capture it.
Thanks, Tolga, and I'm thrilled to be here today to discuss the opportunity ahead. Let me start by framing the ATTR-CM opportunity. Today, we're updating our latest understanding of global epidemiology. ATTR-CM remains a significantly underserved disease category. We estimate there are roughly 200,000 patients in the U.S. living with ATTR-CM, and importantly, more than 80% of those patients remain untreated. Globally, we estimate approximately 500,000 patients are living with ATTR-CM.
At the same time, awareness of the disease continues to increase meaningfully. Since 2019, we've seen prescription volume in the category grow, reflecting improvements in diagnosis, greater physician awareness, and ultimately more patients being treated. Taken together, these dynamics highlight both the substantial unmet need that still exists and the momentum already underway in expanding treatment across the ATTR-CM landscape.
To better understand how the category can continue to grow, it's helpful to look at the opportunity across three key patient segments. First, of the nearly 200,000 patients living with ATTR-CM in the U.S. today, approximately 80% or 160,000 remain untreated. This is up from the 125,000 patients that we estimated at our TTR Day in October 2024. Second, we estimate that approximately 15,000 patients per year are new to treatment. That means you have an inflow of about 15,000 new starts every year, and that's a constantly refreshed number. This is up from the 10,000 or so that we estimated in October 2024. Third, there is a meaningful opportunity among patients currently receiving stabilizer therapies who unfortunately continue to progress.
There are some observational data suggesting that as many as half of patients on a common stabilizer, suggesting roughly 15,000 patients today fall into this category, representing an important population where physicians are increasingly evaluating additional or alternative MOA treatment options. This is up from between 8,000 and 13,000 that we estimated in October 2024. Together, these segments illustrate the multiple avenues for continued category expansion, driven both by new diagnosis and optimization of treatment for patients already on stabilizers. These categories will continue to grow in number over time. Finally, it's important to consider how diagnosis itself is evolving. Prior to the availability of effective therapies, ATTR-CM diagnosis and treatment rates were extremely low. Around 2% of patients were identified, you know, before the first treatment options became available.
As awareness and treatment options expanded, diagnosis and treatment rates have improved meaningfully. Looking forward, we believe diagnosis and treatment rates will continue to increase substantially based on benchmarks from other diseases such as MS or PAH or AFib. Diagnosis rates reach around 70% over time as awareness, screening practices, clinical guidelines, and the treatment landscape all evolve. With additional therapies entering the market and a growing focus from the cardiology community, we believe the ATTR-CM treatment category is still in the early stages of formation, creating a significant opportunity for continued growth over the coming decade.
We'll talk later about how we are stepping firmly into that leadership role and ensuring diagnosis and treatment rates do indeed improve for the patients who depend on it. Stepping back, we believe the ATTR-CM category remains in the early stages of its development with significant opportunity ahead. Today, nearly 200,000 patients in the U.S. are living with ATTR-CM. The majority remain untreated even as diagnosis improves and awareness expands. When we look across the opportunity from the large untreated population to newly diagnosed patients entering treatment each year to patients progressing on stabilizers, we see multiple pathways to help patients in need and sustain AMVUTTRA's growth with durability. Importantly, if diagnosis rates ultimately evolve towards levels we've seen in other cardiovascular diseases, the number of patients actively treated could actually increase substantially within the decade.
In short, we believe ATTR-CM represents one of the most significant remaining opportunities in cardiovascular medicine to improve diagnosis and expand treatment options for patients who are largely underserved today. You'll hear more about what we're doing to grow the category later on in today's presentation.
With that context on the size of the opportunity and how the category is evolving, I'll now turn it over to Dr. Sameer Bansilal, who will walk through AMVUTTRA's clinical value proposition. Over to you.
Thank you, Mark. That clearly highlights the opportunity in ATTR-CM. The next question is what defines clinical value, and how does vutrisiran stand apart? From a clinical perspective, I'll focus on the data and the experience that matter most for cardiologists and patients. My name is Sameer Bansilal. I'm Vice President of Global Medical Affairs, TTR Disease Area Head at Alnylam. I'm also a practicing cardiologist at the James J. Peters VA Medical Center in the Bronx. Over the course of my career, I've worked as a clinical trialist and outcomes researcher at Mount Sinai, NYU, Brigham and Women's Hospital, and the Harvard School of Public Health.
As clinicians, our goal is simple. We want our patients to live longer, better lives and remain on therapy long enough to realize those benefits. Historically, it has been difficult to achieve all three simultaneously. With our RNA silencing platform at Alnylam and continued commitment to ATTR-CM patients, we believe we have the opportunity to deliver across each of these goals. We ask cardiologists who treat TTR patients what attributes matter most when selecting a therapy for patients with ATTR-CM. What you see on the left side of this slide is their rating for the patient outcomes that are most important to them. Their top priorities include reducing mortality, reducing cardiovascular-related hospitalization, and having a positive impact on patients' quality of life.
What you see on the right side is the cardiologist rating of vutrisiran on these attributes. As you can see across the board for the outcomes that are most important to them as they make choices for their patients, AMVUTTRA rates very highly for mortality, for hospitalizations, and also quality of life.
Let's take a closer look at all three of these in terms of the data that drives these high ratings. To start, let me walk you through the clinical rationale and evidence supporting our expectation that this therapy can help patients live longer. The mortality data. In the HELIOS-B trial, during the double-blind period and the extended follow-up during the open label extension, vutrisiran has shown a definitive and increasing benefit on all-cause mortality to nearly 40% in the monotherapy population. When identified early and treated, as we did in HELIOS-B, vutrisiran has the potential to bring patients close to their estimated age-adjusted mortality, which is remarkable for a disease that the survival rate over five years was extremely low only a few years ago.
A patient's experience with the treatment is often undervalued in our system. In reality, it's one of the top priorities for patients and cardiologists treating them. How patients feel day to day matters. It can influence things like being able to take a walk with a friend or play with grandchildren. It matters to patients, and it directly influences treatment decisions. That's where targeting TTR production at its source makes a meaningful difference for patients. Gastrointestinal symptoms are one of the most common and burdensome extracardiac manifestations of ATTR-CM, affecting the majority of patients, whether hereditary or wild-type, with prevalence rates reaching as high as 70% in some populations.
In HELIOS-B, we saw that patients treated with vutrisiran have self-reported 40% fewer of these symptoms, and depending on the specific GI side effect, as much as 65% lower incidence. What is noteworthy because we inhibit the protein at source, the lower incidence of these extracardiac manifestations were observed early and the difference grew over time. This is in contrast to the effects noted with stabilizers. How are we impacting mortality and morbidity? What is the relevance of this inhibition at source? One specific proof point that is unique to vutrisiran, and this is important data from the National Amyloidosis Centre in the U.K., is that we have been able to show in HELIOS-B with serial cardiac MRI imaging in the monotherapy population, we observe not only a reduction in the amyloid burden, we also see it translate into improvement in structure and function.
In fact, when we compare regression of amyloid protein, as noted in the LV mass change here and paralleled by ECV and multiple other measures, we see amyloid regression in 22% patients in the vutrisiran group, in contrast to over two-thirds of patients progressing in the placebo arm. The improvement in LV stroke volume is quite striking and has not been previously seen in terms of an improvement in myocardial structure and function, and we do believe that this is due to the inhibition at source. These were both observed in a small subset of patients, and we continue to study these measures in ongoing and future studies. Patients can only realize these benefits if they take their medicines correctly, well, and for the long term.
Another note for the feature of vutrisiran is its once- every- quarter healthcare professional- administered dosing, which is associated with a persistence and adherence profile that is quite exceptional. We have previously shown in real-world analysis of hereditary ATTR peripheral neuropathy patients that quarterly HCP administration represents a significant benefit, and we see a meaningful difference as it relates to vutrisiran persistence and adherence versus old stabilizer therapy. Similar data in the ATTR-CM population will be presented at upcoming congresses.
Finally, we are continuing to expand the evidence base to further strengthen and vutrisiran's differentiation and support sustained growth. Building on the strong clinical foundation established by HELIOS-B, we are continuing to generate real-world evidence through the DEMONSTRATE observational study now enrolling globally. We are capturing a range of patients and will be able to not only look at further clarifying the benefit, effectiveness and safety of vutrisiran as a first-line therapeutic, but we shall also be able to look at comparative and combination treatments as patients accrue.
Let me wrap up with what I just shared with you in terms of what this all means for patients through outcomes that align with what clinicians prioritize most when selecting a therapy. With vutrisiran, we are able to help ATTR-CM patients live longer, to the point of them living nearly as long as they would without this disease. With this TTR inhibition at source, vutrisiran mitigates extra cardiac adverse effects while positively impacting cardiac structure and function. Finally, the reason we think this happens quite consistently across the board with vutrisiran is our once every three-month dosing.
With that, we have been able to get to more than 90% persistence and adherence over more than a two-year period. That's all translating into the benefit which we hope to capture in an observational study and many other studies that we are launching. With that, I will hand over to John Kennedy.
All right. Thank you, Sameer. I'm John Kennedy, Senior Vice President, TTR Franchise Commercialization Lead. Let me shift to the competitive landscape within the silencer class and how we think about sustaining leadership going forward. We're competing against eplontersen in the hereditary ATTR polyneuropathy category today, and that experience has shown us two things. The first is that the category expanded. Our volume growth continued unabated, and the total treatment category grew. The second, we maintained leadership. More than a year after competitor entry, we maintained about 70% share of new starts and more than 80% of the total market share. We established this preference for AMVUTTRA before having the cardiomyopathy approval, meaning we were competing effectively before the benefit of label expansion.
This reflects the strength of AMVUTTRA value proposition, including the favorable access dynamics that Tolga referenced, the adherence and persistence that Sameer mentioned, and the customer preference built during our lead time. We believe these dynamics are all transferable to cardiomyopathy as well. Another consideration when thinking about the silencer landscape is how these therapies are used alongside stabilizer therapy. AstraZeneca has focused their commentary on the combination data they expect from CARDIO-TTRansform. Remember, HELIOS-B showed consistency of AMVUTTRA treatment effect with or without tafamidis background. We have the data. It's reflected in the label. In fact, we're already seeing meaningful volume of use in combination and in the real world. That means customers are gaining experience using combination mechanism of action, and we'll be able to continue generating even more data from real-world data sets.
If CARDIO-TTRansform demonstrates the benefit of dual mechanism of action approach, that would corroborate what we've already seen and bolster the case for even more combination treatment. Now, it's not surprising there's been conversation about what CARDIO-TTRansform will show. In fact, our market research has shown that the large majority of cardiologists believe favorable combination treatment data will support a broader class effect. Again, it would corroborate what we've already seen from HELIOS-B. Ultimately, when clinicians reach for a silencer, they're looking for depth, duration, and consistency of knockdown. Today, AMVUTTRA delivers on that with the fewest doses per year. Of course, our next-generation candidate, nucresiran, is designed to extend that durability even further into the future with greater than 95% knockdown in just two doses per year.
Finally, we've also heard questions relating to pricing or access implications with a new silencer competitor that will be covered under pharmacy benefit. Remember, today, we're already competing against two ATTR-CM medicines, both covered under pharmacy benefit. We know AMVUTTRA has excellent access, approximately 99% coverage overall and 90% coverage in first line, and the majority of patients paying $0 in out-of-pocket cost for AMVUTTRA. From an access perspective, we believe AMVUTTRA is already well-positioned within the current coverage environment. Having another pharmacy benefit medicine in the mix does not change the calculus. Pulling it all together, competition in the silencer class is a net positive for the category and for patients. ATTR cardiomyopathy remains significantly underdiagnosed and undertreated. An increased attention in the disease ultimately expands awareness and accelerates category growth.
We're already competing today in the silencer class in the hATTR polyneuropathy market. Competition has expanded that category. Despite that competition, we've retained clear leadership. Ultimately, when physicians choose a silencer, they're looking for depth, duration, and consistency of knockdown to drive meaningful outcomes for patients. We're well-positioned to sustain differentiation with AMVUTTRA. Additionally, our next-generation candidate, nucresiran, is positioned to extend that leadership even further. With that, I'll turn it over to Mark to speak about the second competitive event in ATTR-CM, the genericization of the stabilizer class. Mark?
Thanks, John. Okay, let me now turn to the anticipated genericization of the stabilizer class, specifically tafamidis. Importantly, our trajectory is not dependent on the timing of tafamidis' loss of exclusivity. AMVUTTRA's differentiated profile is already driving demand and shaping physician preference today, and we expect that momentum to sustain and build both before and after the stabilizer class transitions. As we think about how the market may evolve, we see several dynamics that we believe will support sustained growth for AMVUTTRA. First, we are already seeing meaningful traction against the incumbent in new patient starts, despite entering the market several years later. Within just a few quarters of our U.S. launch, AMVUTTRA has delivered steady share gains in new starts, reflecting growing physician and patient interest in differentiated upstream silencing. Importantly, that early adoption is translating into preference.
Among physicians with experience using AMVUTTRA, we're seeing a clear shift towards selecting it for new patients, and this dynamic is critical. As preference builds, then it's driving demand, and establishing that foundation ahead of tafamidis' LOE positions us well for sustained growth over the long term. The second important consideration is access. If you look at the U.S. payer mix in ATTR-CM, we should not assume that genericization will lead to universal step edits for AMVUTTRA—i n fact, it will not. For patients already on treatment at the time of tafamidis' LOE, we expect continuity of care to remain the priority, meaning many patients will continue therapy without payer disruption.
It's also important to remember that in Medicare fee-for-service, which is our single largest payer segment and represents approximately half of our business today, AMVUTTRA is covered to label with no step edits, and we would expect that dynamic to continue following tafamidis' LOE. Again, this segment represents nearly half of our business today.
Of course, it's possible we'll see step edits, particularly in the commercial segment of the market. Even when there is a step edit today, we've seen that when a doctor and a patient determine that AMVUTTRA is the right treatment, patients can usually access it, whether through appeals or a relatively rapid progression through a step. Let's not forget that many ATTR-CM patients may progress on tafamidis and therefore require a switch or add-on treatment. Because of AMVUTTRA's orthogonal mechanism of action, we are well-positioned to address that need.
This leads to another important opportunity following tafamidis' LOE, which is the potential to more fully unlock dual- mechanism treatment strategies. Cardiologists are already accustomed to adding on and combining therapies in cardiovascular disease. This is how they practice. As John spoke about earlier, as the body of clinical data supporting silencing therapy continues to grow, including evidence emerging from studies like CARDIO-TTRansform, we expect increasing confidence in combination approaches using both stabilization and silencing. At the same time, the availability of generic stabilizers could significantly reduce the cost of dual- MOA treatment, making these strategies more accessible in clinical practice.
Taken together, this creates an environment where AMVUTTRA will play an increasingly important role. When we step back, we believe AMVUTTRA is extremely well-positioned in a post-LOE environment. We're already building first-line demand and physician preference today, years ahead of anticipated genericization. We expect durable access across key payer segments with continued need for therapies that offer an orthogonal mechanism of action. The tafamidis LOE may actually accelerate adoption of dual- MOA treatment strategies supported by a growing body of clinical data. Taken together, these dynamics reinforce what we believe is a sustained opportunity for AMVUTTRA growth.
Let me turn it back over to John to discuss how we'll accelerate our investments to drive category growth.
Thanks, Mark. Let me close by focusing on the opportunity ahead to further accelerate growth in ATTR-CM. We've already talked about the strong momentum in the category, but we see a clear opportunity to build on that and do it in a deliberate, focused way. As we continue to scale our role as a category leader is not just to participate in the growth, but to help shape it, expanding diagnosis, increasing treatment rates, and ultimately helping more patients. We think about the diagnostic journey, there are really three stages: awareness, suspicion, and diagnosis. Diagnostic tools already exist. Nuclear scintigraphy provides non-invasive, accurate, and accessible confirmatory diagnostic test. That's not really the primary barrier. The real opportunity is earlier recognition of disease, which requires much greater awareness and clinical suspicion upstream, so more patients are identified and diagnosed sooner.
By increasing recognition of the disease and improving identification of these patients, we can help ensure more patients reach confirmatory testing and ultimately receive appropriate treatment. That's where we're investing. The first pillar of our strategy is expanding patient awareness and engagement, including our direct-to-consumer efforts. We're already driving meaningful interest from patients today.
Now, if you're not one of our target audience, you may not have seen our ad, but I can tell you our target audience is seeing it and it's working. Already today, we're the most requested ATTR-CM therapy by patients. Second, we continue to expand the HCP prescriber base across cardiology and heart failure specialists. We've talked about the breadth of prescribing. We'll continue to increase that just as we have so far in our launch. We're built to cover the potential of the market with our field force, and we're engaging more physicians.
The third pillar of our strategy is advancing AI-enabled diagnostic technology, importantly, with an emphasis on practical implementation. We're partnering with nationally recognized organizations to identify patients earlier in the course of disease. Earlier today, we announced a set of strategic collaborations designed to accelerate earlier recognition and improve care coordination for ATTR-CM patients. One of these is our collaboration with Viz.ai, a leader in AI-powered disease detection and care coordination. Together through the AWARE study, we're developing ATTR-CM care pathways at five large U.S. integrated health systems, integrating FDA-cleared Eko AI algorithm with electronic health records designed to help clinicians identify patients earlier in the disease and guide appropriate diagnostic evaluation and referral. The pathway will coordinate care across cardiology and heart failure teams.
This AWARE study is the first multi-system prospective implementation study designed to evaluate how AI-enabled screening can be incorporated into real-world clinical workflows, improve diagnostic timelines and care coordination. The initiative will help generate real-world evidence to inform broader, scalable adoption across health systems in the Viz.ai network. The goal is simple: identify patients earlier and connect them to care before potentially irreversible disease progression occurs. The fourth pillar of our strategy is to enable end-to-end health system engagement, working directly with the large integrated health systems to improve care pathways.
Also announced today, we're working with the American Heart Association to strengthen systems of care for ATTR cardiomyopathy. This three-year initiative will convene a national learning collaborative of multidisciplinary health systems to evaluate current care pathways and identify ideal models of care for diagnosis and managing ATTR cardiomyopathy. Participating centers will assess processes across diagnosis, referral, treatment, and follow-up to improve coordinated care and patient outcomes. We'll disseminate insights generated through this program nationally to enable broader adoption of effective care models. Now remember, we're already engaging approximately 190 accounts that drive about 80% of ATTR cardiomyopathy patient volume. With our new collaborations, we believe we can strengthen ATTR-CM care delivery across the healthcare system nationally.
Finally, we continue to expand global access for AMVUTTRA to ensure that patients around the world have access to this important therapy. We've launched in Japan and Germany, and more recently in Austria and the U.K. We continue to advance additional regulatory submissions and pricing and reimbursement negotiations to expand access in markets around the world. Stepping back, the opportunity in ATTR cardiomyopathy remains significant.
We're establishing leadership with AMVUTTRA, a differentiated therapy, and we're building strong physician and patient preference. We're investing to accelerate diagnosis all while expanding access globally. Taken together, we believe these efforts position us to continue driving meaningful growth while improving outcomes for patients living with ATTR cardiomyopathy. With that, I'll turn it back to Tolga.
Thank you, John. As you've seen today, Alnylam is well positioned to continue driving long-term growth with our TTR franchise. This is enabled by a treatment category that is under-penetrated and rapidly growing. All told, by 2030, we could see upward of 75,000 patients being treated for ATTR-CM in the U.S. alone. It'll be a competitive market, but one in which AMVUTTRA is poised to stand out and be the revenue leader in TTR by 2030. We're confident in our ability to achieve that goal, driven by continued focus on these three key foundations we discussed earlier: driving differentiation preference, knowing that experience drives utilization, ensuring seamless patient access and affordability, and setting up a broad care network. With these elements in place and helping to deliver remarkably strong results out of the gate, we look forward to unlocking the next phase of launch.
As we look ahead, we're focused on scaling what we built, driving sustained category growth, expanding our prescriber base, and maximizing the strong adherence and persistence we're already seeing. These are the key drivers that will shape our next phase of growth. What you heard today is a plan for leadership in a category with a tremendous amount of opportunity. We're advancing the field with continued investment in TTR, including our next-generation therapy, nucresiran, which has the potential to raise the bar. We're also investing in new technologies to identify patients earlier. All of this with the goal of continuing to bring real transformative therapies to patients at scale. As you can tell, we're incredibly excited about the opportunity ahead. With that, let's head to our Q&A session.
Good morning, and thank you, Tolga, Mark, Sameer, and John. We'll now begin the Q&A portion of our webcast today. Just as a reminder, please enter your question in the dialogue box in the chat, and we will get to as many as we can in our 20-minute session. Just as a quick reminder, the focus of today's session will be the presentation that was delivered earlier today, and we will hold any questions related to quarterly progress for our Q1 call.
With that, let's go to our first question. We have a number that have been queued up at this point. You've said a lot about expanding the prescriber base. Can you tell us who has prescribed so far, and are all of them former PN writers?
Great question. Indeed, we are focusing on that. Before I turn it over to Mark, let me point out the fact that what's really great about this first year of learning is the fact that once doctors experience AMVUTTRA, they really enjoy it, they use it, so there are no real hurdles in terms of prescribing the drug, and they start seeing the results. Therefore, what's really left is to continue to differentiate the asset as well as to continue to expand the prescriber bases. Mark?
Yeah. No, I think you said it well. I mean, if we look at our prescriber base today, it's quite broad and balanced. Actually, 75% of our prescribers today for AMVUTTRA are new prescribers. As Tolga said, once they get experience with AMVUTTRA, we found that there's actually a preference developed for AMVUTTRA. That's why it's really important that we continue to expand that prescriber base, and we use that to essentially unlock the next wave of growth.
Great. Let's go to our next question. What do you expect your share of the 75,000 treated patients in TTR in the U.S. to be in 2030? And can you translate that into a peak revenue number for us?
Yeah. What we've done, Christine, is obviously, we guided the market for 2026 revenues, which is at midpoint over 80%, anywhere between $4.4 billion-$4.7 billion. That obviously is built on the great momentum that we've been able to build in 2025. Now, in terms of the 75,000 number, one other key aspect of this is obviously our 2030 ambition. We certainly look forward to being the leader in terms of revenue by 2030, and 75,000 number is being incorporated into that. Maybe JPK, you can actually expand on that.
Yeah, absolutely. I think you talked about some of the core elements. We did provide TTR guidance for 2026. That's robust growth. For the 2030 aspirational goals for the company, obviously, we did provide some commentary about TTR. One component of that was to achieve leadership share of revenues for the category by 2030 and across the period. Then the second component that we talked about was our total revenue for the company would grow at about 25% CAGR over the period of time between now and 2030. Now, that's total revenue for the company, so more than TTR alone. Again, consider TTR as a significant driver of it. That gives you a sense of the potential that we see.
Again, it's all grounded in how many patients there are in the U.S.—u nfortunately, still untreated today. There's significant opportunity. We're seeing momentum. That's great, but there's still a lot of opportunity ahead.
Super. We actually have a three-part question for our next one. Are you seeing any changes in step therapy requirements as a part of restrictions to first-line AMVUTTRA? How are payer discussions going for 2027 policies? What gives you confidence in your ability to maintain this level of first-line access beyond 2027?
Yeah. As Head of U.S., Mark, you'll probably need to take this one. What I'll say is, look, this has been a hot topic since we actually had our first TTR Investor Day back in 2024 in October. There was a lot of debate about are we gonna be covered? What the prior burden on the co-pay for the patients is going to be? Are we gonna be step edited? In 2025, obviously, we've been able to demonstrate that we get great coverage, nearly all patients actually not having any co-pay. In 2026, in fact, the numbers have been actually better in terms of our coverage. Maybe Mark—
Yeah.
You can give additional color on that.
Indeed, you know, in October 2024, I think leading up to the launch, there were a lot of questions. You know, at that time, I think we shared our expectations for favorable access based on AMVUTTRA's clinical profile, but also based on the dynamics between Part B and Part D. Our expectations have become reality. Today, we have over 90% of patients with confirmed first-line access. The majority of patients pay $0 out of pocket, and that, by the way, is with two, you know, Part D competitors in the market. As we look ahead and we sort of see and think about how this is gonna unfold, all those fundamentals remain the same. That's regardless of whether another Part D competitor comes into the market.
I'll point out that, you know, today we are competing with WAINUA in polyneuropathy, and we have, you know, virtually unrestricted access. I mean, one other point here to think about as we think ahead is also the LOE of tafamidis. If we think about what that means, we believe that's actually a tailwind. We'll see the price of tafamidis come down. We think that'll help unlock combo usage, which I think this is something that you know the cardiology community would wanna do. Bottom line is, you know, we think we're very well positioned from an access perspective, and we actually think that those dynamics that allow us to have that access today will persist into the foreseeable future.
No, you covered it very nicely. I think this is going to continue to be an ongoing effort on our side, but, looking ahead, we're very confident about how we're gonna be actually able to manage that.
Thanks, Mark and Tolga. While there's no universal definition of progression, what are some of the common guideposts or indicators that physicians are citing as meeting the bar for combo therapy or are switching patients to AMVUTTRA?
Yeah. Maybe Sameer, you should take that as the only clinician in the panel of today. Go ahead, please.
Thank you, Tolga. That's an important discussion, really draws a lot of interest in the clinical and academic community. While there are guidelines on both sides of the Atlantic, I think the more we speak to clinicians and researchers, the answer is always the same. This is as much art as it's science. At the end of the day, we have to talk to our patients, and we have to bring our clinical judgment in, and that's driven by multiple variables, which come from the guidelines in terms of imaging, biomarkers, and other clinical outcome measures.
I would say, though, I think far more important, even though there are data from health systems and from observational data that point to nearly 50% progression with stabilizers, that the broader need is really to identify these patients early, because this is a very progressive disease, and treat them with an effective agent. I would argue in this case, vutrisiran has shown very definitive data that we can really help bring down everything from mortality to hospitalizations and more.
That's nicely captured. What's really exciting about this first year is also being able to see that now doctors do have an option, an orthogonal mechanism. And therefore, I think we've been able to really help physicians to start identifying those patients early and as they progress, and therefore they can actually end up being with AMVUTTRA.
Thank you both. We've gotten a few questions about the collaborations that were announced earlier today. Can you tell us about these collaborations, and do these collaborations give you access to new or different patient segments that you're not currently penetrating today?
Yeah. John, I'll have you take this one. But let me say a few words. First of all, we're really excited about these collaborations, and there will be more to come. The point of this is, we did lay out that 2030 is our goal for leadership, and we're acting like leaders. A leader does actually what others don't, which is set up the right ecosystem, making sure that we're actually connecting the dots to make sure that more patients are getting treated as the awareness and options are continuing to increase. So, John?
Yeah. Absolutely. You know, these are a couple initiatives that have already announced today, and yeah, we're very excited about them. At the most simple terms, this is about increasing diagnosis and ideally the timeliness of that diagnosis and then facilitating care coordination. Bear in mind, we already know the numbers. Unfortunately, too many patients are overlooked, not diagnosed, and/or not treated. Unfortunately, for many patients who are diagnosed, it happens later than it likely should. This is really about facilitating timely and accurate diagnosis for more patients. Now you asked a question in there about specific segments.
What I would say is if we look at the utilization of AMVUTTRA so far in the launch, it's been broad and relatively balanced, whether it's wild type or variant patients across the spectrum of disease severity, academic center or community, we're seeing broad and balanced utilization. It's not really about unlocking a specific segment per se, but more just increasing diagnosis, ideally timely diagnosis, so more patients can find their way to appropriate treatment.
Thanks, John. Can you expand on the meaning of the 35% of new- to- brand starts? Does this mean that AMVUTTRA is 35% of all new patient starts?
Yeah. Look, we're incredibly excited about the number itself. Given the fact that as a third entrant to this category, in less than 12 months, we've been able to actually essentially secure about a third of the net new patients for AMVUTTRA. That's quite remarkable. Those of you may be familiar with how the market dynamics work. I'll have Mark maybe expand on that, how that number is calculated, what does it really mean.
That's new- to- brand Rx. To your point, Tolga, that captures the totality of the patients that are coming onto AMVUTTRA. I think, you know, having a third of all those new starts within, you know, nine months of launch actually is pretty impressive. I think we're very happy to see that. It's very encouraging. I think it speaks to AMVUTTRA's clinical profile and also frankly to a once a quarter HCP-administered therapy, which allows for, you know, validated adherence and ensure that the patients actually get the medicine to get the efficacy. You know, now the goal is to really unlock this next wave of growth, as I mentioned before, and really expand that prescriber base.
Great. Thank you. We've gotten a couple of questions about the CARDIO-TTRansform study. If AstraZeneca shows statistically significant results in the combo arm and lowers their price , how will you compete? Conversely, if CARDIO-TTRansform does not hit stat sig in the subgroup of patients on background tafamidis, how do you expect greater restrictions from payers, and how would this potentially impact your commercial strategy?
It's a two-parter. I'll have Sameer, who's himself a trialist, expand on what we expect from CARDIO-TTRansform, and then I'll have John comment on the latter part of the question. What I'd like to say is, look, as we laid out in terms of our silencer strategy, there's nothing new, essentially, in terms of our label, in terms of our, you know, data set and the experience that we're already building with patients and physicians both. We're already establishing AMVUTTRA. Yeah, and given its actually unique profile, deeper knockdown and longer duration, we're already highly differentiated in this class. Let me turn over to Sameer, and maybe he can expand on what we expect and how we're gonna continue to compete.
Absolutely, Tolga. Thank you again. Let me first of all remind everyone, I think for HELIOS-B, almost two years back, in our primary paper, we showed very clearly that vutrisiran provides benefit regardless of tafamidis as a background therapy. That's our anchor data on combination therapy. That is the data that is available today. We have shared that broadly in multiple roundtables that many of us, in fact, led personally. I would say in those conversations, the data resonates. People already know of this data that vutrisiran in combination with tafamidis does provide benefit from that perspective.
I would say that I think when you start thinking about what happens with CARDIO-TTRansform, we have had those conversations as well, and I think the belief set is only going to be that it's a class effect, and that's our best guess at this point based on what we expect with CARDIO-TTRansform later this year.
Yeah. Part of the question there was about what do we expect for pricing and access, and I had shared some of those thoughts earlier today. Just restate it. If you think about it, already today, we're competing against two pharmacy benefit-covered products. You see the AMVUTTRA access. It is really unencumbered. We have about 99% coverage, about 90% of that is in first line, with the majority of patients paying $0 in out-of-pocket cost. We don't really see a dynamic that changes here. I think the other thing I'll go back to is it is instructive to think about the experience that we've had in hereditary ATTR polyneuropathy. Don't forget, we've been competing against a silencer already today.
In polyneuropathy, past a year of competition with another silencer, we saw two things happen. Number one, the category expanded. More patients were being treated. The second is we retained leadership. Obviously, we do know that competition is generally helpful for the category. At the end of the day, when a physician is reaching for a silencer, they're looking for that knockdown profile. AMVUTTRA today delivers about 87% mean reduction in TTR with four doses per year. Nucresiran, which is still a development candidate, promises to have the potential of delivering 95% knockdown with just two doses per year. Again, we're well positioned for the competition.
Great. What should we expect as far as quarter-over-quarter growth for the remainder of 2026?
Yeah. As you highlighted, it's a good question, but it's a question that we're not gonna be able to answer, and we'll actually address this in the Q1. What I can tell you is this. We've laid out our guidance at JPM, and what we laid out was due to the couple facts. One is we could see how the product is performing competitively. We can see how the category is growing very in an accelerated fashion. Last but not least, we have concluded our 26 negotiations with the payers. All these three important dynamics were green.
That gave us even further confidence to actually provide it a guidance that's over 80% in midpoint to $4.4 billion-$4.7 billion for a year. That's building on over 100% growth that we've been able to achieve in 2025. We're very confident that we're gonna be able to continue that progress. In Q1, we'll discuss more of the details on the Q1 and what you'll obviously see for the remainder of the year, how we intend to meet and hopefully exceed that guidance.
Great. We've actually gotten a number of questions about the tafamidis LOE, so I'm gonna ask a couple of parts to this, to this one question here. When do you think tafamidis will go generic, and what does that actually mean for AMVUTTRA? Is the availability of a generic alternative going to be a headwind for all players in this space as payers will step out at generic tafamidis first or be a tailwind as it would unlock combo use? And then how do you weigh the potential headwind of first-line access versus a tailwind on combo use?
That's a long question.
It's a many-part question.
Yeah, exactly. Well, look, I'll have Mark address this, and he, I think, did a phenomenal job in the way he laid out how we're gonna compete against the potential genericization of the stabilizer class. What's great about where we are today, though, is it really doesn't matter because essentially we have an orthogonal mechanism of action that have already established its competitiveness in less than a year. Whether tafamidis goes generic by end of 2028, that's what Pfizer has stated, or one may speculate that it may happen later. It really doesn't matter in the way we are competing. Maybe in terms of the granular detail, Mark, you can provide more perspective.
Yeah, yeah. I will say, you know, Pfizer has publicly stated they expect the U.S. LOE for tafamidis to be in late 2028. We think we're really well-positioned, to your point, Tolga, to continue to manage AMVUTTRA in that era. There's strong demand, as I just shared a moment ago, in terms of our NBRx. There's strong demand for AMVUTTRA, and that's because it's a therapy that knocks down TTR at the source, and we're seeing that physicians and with patients that really resonates. Additionally, I'll just reiterate, we have strong access today, right? As JPK pointed out, you know, over 90% first- line coverage, 99% total coverage, most patients pay zero out of pocket.
We expect those dynamics, those fundamentals to persist post tafamidis LOE. We really see the tafamidis LOE, frankly, as a tailwind because we think this unlocks the ability for physicians and for patients to use combo therapy if they want. I'll remind you, as Sameer pointed out, that, you know, we show from our HELIOS-B results similar effects with tafamidis or without tafamidis, and we'll see what the AstraZeneca, you know, WAINUA data look like, but that's almost certainly gonna provide a tailwind for the category. At the end of the day, our fortunes are not tied to whether tafamidis is generic at the end of 2028 or not. We do think this is an unlock for the class big picture, and so we look forward to it.
Great.
Thanks. How do we think about phasing of ex-U.S. TTR revenues as you roll out across additional geographies?
Sure. First of all, look, we're quite excited because we're a company that is obviously, and despite its early stages of commercialization, has been a global, you know, organization. We have footprint across the world, and we've been able to commercialize first ONPATTRO and then later AMVUTTRA with the PN indication quite successfully. As we move forward with the making this product available across the world, we're gonna actually have important, you know, steps. As you already know, we shared that Japan launch is going extremely well, even better than most analogs and other launches, regardless of the therapy area.
We also did indicate that, you know, in Q1, we're gonna see a little bit of a headwind, given the fact that we're actually going to make a price adjustment to further compete in the cardiomyopathy, which has much larger prevalence. Now, that softness in Q1 is good news. It's good news because essentially we're building up volume that's going to be able to actually overcome some of those headwinds in the full year. John, you already shared with the slide that shows how those, you know, rest of the world launches are going, starting with obviously Japan, Germany. Can you give a little more context?
Yeah, absolutely. Again, Japan, well underway, great momentum. Excited about that. Germany, we started with the provisional launch while we were working through the pricing reimbursement process, but now that's underway and you're spot on in that Q1 will reflect the new negotiated cardiomyopathy price in Germany. For the PN volume in Q1, there's an adjustment, but we'll more than make up for that in growth. Bear in mind, the prevalence of cardiomyopathy is tenfold greater than polyneuropathy, so we'll make up for that in volume growth after the initial transition. Today, I shared that we've also launched in Austria and U.K., and we have several other countries staggered throughout the remainder of this year and into next year.
You know, the goal is simple, bring AMVUTTRA to as many countries as we can, as fast as we can. In terms of the revenue contribution, it'll be more kind of back half of the year weighted, just given these transitional dynamics, but tremendous opportunity and we continue to move forward.
Thanks, John. What are the AMVUTTRA persistence, adherence you see in real world for ATTR-CM so far, and how do you anticipate these evolving over time?
I'm so glad somebody picked up on the adherence point because as I closed the presentation, there are three key metrics along with obviously our, you know, other metrics that we've been talking about. There are three key metrics that we're going to be updating the Street. One is obviously the category growth. The other one is adherence rate. And essentially what we're going to make sure is that our highly differentiated product profile comes across very clearly. With that, John, do you wanna—w as it Mark you—
I'll take it.
Yeah, sorry. Yeah.
Yeah.
You take it. Sorry.
Yeah. Just building on your point.
Yeah.
If we think about polyneuropathy. We've seen adherence rates, you know, in the 90% range, upwards of 90%. Obviously, it's early days here on cardiomyopathy. You need enough time to measure, you know, adherence. We're seeing very similar numbers in terms of cardiomyopathy. An important point here, though, is obviously with cardiomyopathy, that tends to be an older patient population. Sadly, you know, there are more of those patients that expire over time. It's still a small percentage, but obviously that's on an increasingly large, you know, patient base.
That's why, you know, coming back to the bigger question here, that's why we think AMVUTTRA really has a compelling and frankly advantageous profile in terms of once- quarterly HCP, you know, validated HCP administered and validated dosing where you're ensuring that the medicine gets into the patient. You know, with nucresiran as JPK pointed out, there's an opportunity there to have every- six-month dosing, which I think will be even more compelling. Anyway, this is something we're gonna report on, you know, regularly as we've committed to. So far things look pretty similar in CM as they were in PN.
Great.
Thanks, Mark. We have a number of questions that have come in, but we have time for one last question. What are some of the channels you're using to reach patients to become the most requested treatment?
That's a great question. Who's gonna take that one? JPK, was it?
Do you want to jump in? I can jump in. I can take it.
Yeah, yeah.
I mean, what I'll say is, you know, patients and physicians, we know they're very involved in their treatment and, they're very active, especially in cardiomyopathy. You know, we use a number of means. We certainly do a lot of direct-to-consumer, and that may be with television, that may be with social, that's with search, that's with radio. What we've seen is that, you know, it really works. You know, patients are asking for AMVUTTRA now, very regularly. In fact, what we've seen in our Q4 research is that AMVUTTRA is the most requested brand by physicians, which tells you something. You may be wondering, why don't I always see the ads on television?
That's because we have a more targeted approach to actually placing the AMVUTTRA advertisements where the patients really are. We've seen it working and we also have a you know, an in-house patient services organization that includes nurse educators that are able to engage directly with patients you know, in an appropriate manner. I think all of those things help to ensure that patients you know, are educated. Do you wanna add anything to that, John?
I think maybe I'll just point to some of the initiatives that we have at scale. We talked about some collaborations that have been announced. One of these, just to give another example, is this sponsorship of American Heart Association initiative, which really brings together a consortium of organization health provider accounts that are integrated systems. It's really designed to identify what are these best practices for engaging customers so that we can actually work through the diagnosis and the care coordination process as efficiently as possible. That's working at kind of a system scale, which complements some of the work that you're talking about in terms of direct patient engagement or physician engagement as well.
Thank you guys both. What's really exciting about this category is, you've seen the growth has already been pretty robust when Pfizer alone actually introduced the first option available, and now it has significantly accelerated with the addition of AMVUTTRA. Part of the reason is not only actually communicating and creating awareness with the physicians, but also actually communicating directly with these patients. Patients are really aware of this disease once they're diagnosed, and they are actively engaged in their treatment. That's where we see actually a clear preference for AMVUTTRA.
But more importantly, before. As John actually laid out, before the diagnosis, there is a longer period of suspicion and awareness, and this is the part where I think we've been playing a very important role and clearly, again, we have a very targeted, very selective approach to reaching those patients. Once we do, I think our narrative really resonates with them and this is one of the reasons why you see the results that you see today.
Great. That's all that we have time for today. Thank you to our speakers and to everyone who joined us on the webcast. The replay will be available on our website later today, and we look forward to keeping you updated on our progress on our next quarterly earnings call. Have a great day.