Good afternoon, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals conference call to discuss FDA approval of Amvuttra for ATTR-CM. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, March 20th, 2025. I would now like to turn the conference over to the Alnylam management. Please go ahead.
Good evening. I'm Christine Lindenboom, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Pushkal Garg, Chief Medical Officer; and Tolga Tanguler, Chief Commercial Officer. Joining us and available for Q&A is Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the slides we've made available via the webcast can also be accessed by going to the Investors page of our website, www.alnylam.com/events. Now, turning to today's call, as outlined in slide two, Yvonne will provide some introductory remarks and offer context around today's FDA approval of Amvuttra for the treatment of cardiomyopathy of ATTR amyloidosis. Pushkal will review the label and the data that supported this approval. Tolga will discuss our commercial plans for Amvuttra and ATTR-CM before opening the call to your questions.
Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?
Thanks, Christine. Thanks to everyone for joining the call. Earlier this afternoon, the U.S. Food and Drug Administration approved our supplemental new drug application for Amvuttra for the treatment of the cardiomyopathy of wild-type or hereditary ATTR amyloidosis in adults. With this approval, Amvuttra becomes the first and only FDA-approved medicine to treat both polyneuropathy and cardiomyopathy of ATTR amyloidosis. As we've discussed, we believe Amvuttra has the potential to become a new standard of care in ATTR cardiomyopathy. Our confidence stems from the success of the HELIOS-B study, which demonstrated a therapeutic profile for Amvuttra that is supportive of first-line potential. Pushkal will discuss the HELIOS-B data in greater detail, but at a high level, treatment with Amvuttra led to rapid knockdown of the disease-causing TTR protein working upstream to address the disease at its source.
This resulted in a profound benefit on CV outcomes, including up to a 36% reduction in the risk of all-cause mortality, as well as broad effects on multiple measures of disease progression, with clinical effects that were seen early. Importantly, these results were demonstrated in a population reflective of today's patients earlier in their disease progression and on substantial background therapy. Furthermore, Amvuttra is the only approved ATTR cardiomyopathy medicine that is conveniently administered just four times a year by subcutaneous injection. We believe the launch of Amvuttra in ATTR-CM would establish a flagship franchise for our company, with the potential to drive significant long-term revenue growth. With a decision by Japanese and European regulators expected later this year, as well as ongoing regulatory reviews in additional geographies, we plan to shortly make Amvuttra available for ATTR cardiomyopathy patients in multiple regions around the world.
We've been leaders in the hATTR polyneuropathy space, and we've built upon that strong foundation to prepare for a successful launch in cardiomyopathy and for sustainable growth of this franchise for many, many years to come. We believe we're positioned for unmatched leadership and longevity in the ATTR market. Importantly, we're continuing to invest heavily in this space, and that includes our next-generation TTR-targeting RNAi therapeutic, mivelsiran, which offers the potential for further innovation for patients. Of course, as you know, regulatory approval is just the first step in making Amvuttra available to patients with ATTR cardiomyopathy. As Tolga will elaborate further, we are actively in discussions with U.S. payers to help ensure that patients who may benefit from Amvuttra will have access to it.
This approach continues to leverage our innovative value-based agreements, or VBAs, and is consistent with our patient access philosophy and the access track record we've achieved for Amvuttra in hATTR polyneuropathy. This is an incredibly important and exciting moment for our Alnylam. We are confident that today's approval in ATTR cardiomyopathy will allow us to achieve our next significant wave of top-line growth. It also cements our ability to achieve sustainable profitability, as outlined in our Alnylam P5x25 goals, and importantly, to support significant reinvestment in our highly organic and productive pipeline and platform. As you heard from several of my colleagues at our recent R&D day, we believe that our organic drug discovery engine can fuel sustainable growth and value creation, so reinvesting in our pipeline and platform activities will continue to be a priority going forward.
Now, before I hand it over to Pushkal, I'd like to take a moment to express our deepest gratitude to the patients, clinical investigators, and study staff who have participated in the Amvuttra clinical trials. Without your contribution and tireless efforts over the years, we could not have generated the evidence needed to seek label expansion for this medicine. In addition, I'd also like to acknowledge all the patients, families, caregivers, and physicians that comprise the ATTR amyloidosis community. For more than a decade now, you've encouraged us, supported us, and inspired us as we've worked to bring our medicines to all of you. I'd now like to turn it over to Pushkal to provide some additional context and to review the label and the data that supported it. Pushkal?
Thanks, Yvonne. Hello, everyone. I want to echo Yvonne's thanks to the numerous people in the ATTR amyloidosis community and at Alnylam whose contributions enabled today's approval. We at Alnylam all feel a strong sense of privilege and responsibility to be able to bring this innovative therapy to ATTR-CM patients and their families. As most of you know, ATTR cardiomyopathy is a progressive and debilitating disease caused by misfolded transthyretin protein that forms amyloid fibrils that deposit in the heart, resulting in thickening and stiffening of the myocardium and heart failure. Patients experience progressive worsening of symptoms, declining exercise tolerance, and repeated hospitalizations and urgent care visits for heart failure. Unfortunately, this disease is ultimately fatal, with a median survival of two and a half to five and a half years, a prognosis that is worse than many cancers.
By rapidly knocking down TTR in the liver, Amvuttra lowers circulating levels of the pathogenic protein, which we believe offers the potential to delay or even halt disease progression and reduce the risk of hospitalization and death. As you know, this hypothesis was successfully tested in the HELIOS-B study, which led to today's approval for ATTR-CM. It's important to note that HELIOS-B enrolled a population representative of today's patients with this disease. First, they were diagnosed earlier in their disease course than in prior studies. Second, they were being managed with substantial background therapies, namely diuretics, SGLT2 inhibitors, and notably stabilizers, which makes the HELIOS-B trial design very different from previously reported studies.
Despite this intensive treatment with what was often a cocktail of other therapies, we saw a substantial benefit of Amvuttra on cardiac outcomes: a 28%-33% reduction in the composite of all-cause mortality and recurrent CV events, and a 35%-36% reduction in the risk of all-cause mortality alone. Moreover, we saw broad benefits on a series of other parameters that are monitored by physicians and are indicative of disease progression. These included early benefits on cardiac biomarkers, improvements in cardiac structure and function, and favorable impacts on patient symptoms, quality of life, and function. These benefits, along with an encouraging safety profile and an infrequent dosing regimen that has already been associated with high rates of adherence, suggest the potential for Amvuttra to become a first-line therapy for patients with this devastating disease.
Let's now move to the updated Amvuttra label and review some highlights of the prescribing information. As you know, Amvuttra was first approved by the FDA in 2022 for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. With this label expansion, Amvuttra is now also approved for the treatment of the cardiomyopathy of wild-type or hereditary ATTR amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations, and urgent heart failure visits. The inclusion of urgent heart failure visits is unique and recognizes the effects that were also seen on this important consequence of ATTR cardiomyopathy. Importantly, the label also includes a separate safety section to describe Amvuttra's profile in cardiomyopathy, where it states that no new safety issues were identified in HELIOS-B. Let me now point out a few aspects of the label that pertain to the primary endpoint.
First, you can see here that the label includes a table detailing the primary composite endpoint. This includes data on both the overall and monotherapy populations and both components of the endpoint, including all-cause mortality. Thus, the label shows the clinically important and statistically significant benefits on the primary composite we just discussed, which were driven by equal impact on both all-cause mortality and CV hospitalizations and urgent heart failure visits. In addition, the label also includes a Kaplan-Meier curve illustrating time to all-cause mortality or first CV event in the overall population. Here, you can note the early and growing separation of the outcomes curve, a notable finding given that HELIOS-B was conducted in a patient population that was healthier than historical cohorts, and many of whom were on substantial background therapy.
Finally, the label also includes results from pre-specified subgroup analyses for the primary composite endpoint in the overall population. These data indicate that Amvuttra demonstrated benefit across the full range of patients studied in HELIOS-B. In particular, I'll note the similar benefit observed in patients using or not using stabilizers at baseline, as well as those with NYHA Class III disease, and the trends towards disproportionately greater benefit when Amvuttra was given earlier, such as in patients younger than 75 or with lower BNP values. Let me now look forward a bit to some upcoming milestones. As Yvonne mentioned, having secured approval in the U.S., we look forward to progressing through the regulatory process in other regions around the world. You can see the anticipated time of regulatory approvals here on this slide.
Finally, let me close by mentioning that we look forward to sharing additional data from the HELIOS-B study at the upcoming American College of Cardiology meeting in Chicago next week. Several abstracts will be presented to further elucidate the efficacy of Amvuttra. We believe these new data further underscore the significant impact that this medicine can offer to patients with ATTR cardiomyopathy. Let me now turn the call over to Tolga, who will walk you through our commercial plans for Amvuttra. Tolga?
Thank you, Pushkal, and good afternoon, everyone. ATTR cardiomyopathy is a rare, devastating, rapidly progressive, and ultimately fatal disease. For the more than 300,000 patients around the world living with ATTR-CM, any functional capacity lost cannot be regained. Since the arrival of the first approved treatment in 2019 and the availability of non-invasive diagnostic tools like scintigraphy, we have seen a tremendous increase in diagnosis rates. Furthermore, just like with the other underdiagnosed and undertreated disease categories, we anticipate the diagnosis rates will continue to increase, driven by the introduction of new products over the next several years. Still, many affected patients remain untreated, with the vast majority of them still undiagnosed, and many who are treated with commonly used therapies continue to experience disease progression. In this rapidly growing category, there is a need for a new disruptive treatment option.
We believe Amvuttra offers a compelling and highly differentiated value for patients and physicians, as well as payers. It is the first in a new class of medicine for ATTR-CM. Amvuttra delivers rapid knockdown of TTR, working upstream at the source of disease. It is also the first and only medicine approved in the U.S. to treat both hATTR-PN and ATTR-CM, providing a unique treatment option for providers. In the landmark HELIOS-B study, Amvuttra was shown to deliver profound and consistent effects across a range of measures, from cardiovascular outcomes, including mortality, to patient function and quality of life, and even at the level of underlying cardiac structure and function. Importantly, these effects were demonstrated in a population of patients who were in early stages of disease, with about half of them on a stabilizer at some point during the study.
Finally, Amvuttra requires only four subQ doses per year. Medicines are only effective if they are taken as prescribed. As we mentioned, we've seen over 95% treatment adherence for Amvuttra and hATTR-PN today. We believe that this infrequent HCP-administered dosing regimen will give physicians, patients, caregivers, and payers the peace of mind that the disease-causing protein is being effectively silenced as intended. In the context of this rare condition, Amvuttra's strong and differentiated value proposition, and informed by our experiences in hATTR-PN, we believe Amvuttra will continue to be well-positioned for broad patient access. With these considerations in mind, we will maintain Amvuttra's current list price of approximately $119,000 per prefilled syringe. As patient uptake of Amvuttra increases over time, we will decrease the net price of Amvuttra by a rebate and value-based agreements, or we call VBAs.
Alnylam has been a pioneer in partnering with payers to implement VBAs linked to clinical outcomes. This helps to establish value and predictability for payers while enabling broad patient access. We intend to continue working with payers to execute VBAs and to maximize access for patients. Today, Amvuttra has confirmed coverage for virtually all insured patients in hATTR-PN . We expect similar broad coverage for ATTR-CM moving forward, given comparable payer dynamics and the clinical value demonstrated in the HELIOS-B clinical trial. Additionally, today in hATTR-PN , approximately 70% of patients pay $0 in out-of-pocket costs. We also expect this dynamic will continue in ATTR-CM. In parallel, we will continue investing to drive innovation in ATTR amyloidosis science and the patient experience. This includes advancing our next-generation TTR-targeting RNAi therapeutic mivelsiran.
The bottom line is that our goal is to continue innovating for patients and to support the access and treatment success of all patients who can benefit from Amvuttra treatment. To that end, we have developed extensive patient support resources designed to address the needs of eligible patients across a wide range of circumstances. Our award-winning and fully owned in-house patient services program is an important strategic differentiator and is committed to helping patients seamlessly start and stay on therapy. We already have a strong track record in how quickly patients receive care coordination and appropriate support. As far as we know, Alnylam is the only company serving ATTR patients that has wholly owned in-house patient support services. This means we can quickly adjust, improve, and pivot as needed to make sure we continue to meet the needs of the ATTR patient population.
Just a few highlights of the financial programs provided include a patient assistance program that offers medicine at no cost to eligible patients who are either not insured or underinsured, a quick start program to help eligible patients prescribed Amvuttra initiate therapy quickly for any patients who encounter lengthy coverage delays or delays in treatment. Alnylam will provide the initial dose at no cost, and a continuity program that makes medicines available to eligible patients prescribed Amvuttra at no cost in cases where patients face temporary gaps in insurance coverage. In addition, we have a team of dedicated, on-the-ground case managers, field reimbursement managers, and patient education liaisons, all to support patients and physicians throughout the U.S. as they initiate Amvuttra treatment and throughout their treatment journey. As discussed on our Q4 earnings call, this will be mostly a second-half story in 2025.
We also already provided full-year guidance, including robust year-over-year growth in our TTR franchise revenues by 36% at midpoint of the guidance. This reflects our confidence in the launch and the future potential of this franchise. We are building on our experience and success over the past six years in this category and have approached this important launch with durable, long-term success of our TTR franchise in mind. This means taking the time to enable smooth access and to create a seamless experience for patients and providers alike. In preparation for today's launch, we've done a significant amount of work. As a healthcare professionally administered product, optimizing access pathways at health systems is of paramount importance. This includes the over 170 health systems where 80% of the ATTR-CM patient population is treated.
We have been optimizing access pathways at these health systems so that HCPs can easily prescribe Amvuttra with the knowledge that the patients will receive at a convenient location, whether that's in office, at an infusion center, or in some cases in the patient's home. In this severe disease, providing optionality to patients and physicians is table stakes. We have been building a broad ecosystem of alternative sites of care to expand optionality for how patients can initiate therapy in a seamless way and adhere to it. Today, I'm pleased to recognize that there are now nearly 2,000 of these alternate sites of care available for Amvuttra patients to receive their injections. This represents a doubling of the 1,000 sites that we had previously shared at our TTR Investor Day in October of last year.
These alternate sites of care are in addition to the health systems, group practices, and clinics, and at-home options available for patient treatment. We are close to achieving our goal to continue expanding these provider sites so that over 95% of patients have access to a treatment site within 10 miles of where they live. Now that we have regulatory approval in hand, our focus now pivots to working with payers to secure expanded access for Amvuttra in ATTR-CM, leveraging the strong foundations we have in hATTR-PN, including tools like our value-based agreements, and working with health systems to secure formal approval via their unique pharmacy and therapeutics committee, P&T Committee reviews. As discussed on our recent Q4 earnings call, in most cases, this is the work that can only begin after label approval and can take several months to complete.
We therefore expect our launch ramp to be more of a second-half story in 2025. In addition to our focus on launching Amvuttra in ATTR-CM, we maintain a deep commitment to advancing further innovation in ATTR amyloidosis. This includes continuing to invest in ATTR evidence generation through real-world evidence studies, research collaborations, and HELIOS-B post-hoc analysis. It also includes investing in our next-generation TTR targeting RNAi therapeutic mivelsiran, for which we will initiate two phase three studies this year. Our commitment also includes continuing to support the clinical and patient community via educational sponsorships, patient advocacy, and charitable contributions, fellowship programs, as well as genetic testing. We aim to achieve or exceed our full-year revenue guidance as announced back in January. We certainly appreciate the investor community's focus on this important launch and plan to appropriately update you on our launch progress on a regular basis.
Alnylam is deeply engaged and experienced in the ATTR community. We have been preparing for this moment to do our part to help the many patients affected by ATTR-CM and who are in need of a new treatment option that targets the disease at its source. We recognize that it takes a village to support ATTR-CM patients who face a rare, devastating condition that rapidly progresses. We would like to thank the patients, caregivers, patient advocates, and study investigators, as well as support staff who continue to work extraordinarily hard for the ATTR amyloidosis community. It is a great privilege to serve this community. I will now turn the call back to Christine to coordinate Q&A. Christine.
Thanks, Tolga. Operator, we will now open the call for questions. As a reminder to those dialed in, we ask that you limit your questions to one each and then get back in the queue for any additional questions.
Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star followed by the number one on your touch-tone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press star followed by the number two. If you are using a speakerphone, please lift the handset before pressing any keys. Your first question comes from the line of Ritu Baral from TD Cowen. Your line is now open.
Hi, guys. Congratulations on the approval. A quick question on some specific language in the label. Tolga, what value do you see the urgent heart failure visit reduction language presenting to payers, especially as you contemplate frontline coverage for Amvuttra in this indication? Thanks.
Yeah, thanks for the question, Ritu. I mean, clearly, we're absolutely delighted with the Amvuttra label. And we're particularly pleased that the label reflects the robust data that we generated from HELIOS-B, where we delivered 10 out of 10 on all the endpoints and really helping patients live longer and healthier lives. This is truly a monumental moment for patients in Alnylam. We're particularly pleased with some aspects of the label, including the urgent heart failure visit. Tolga, Pushkal, perhaps you can start off by providing your clinical perspective on why this is an important aspect of the label.
Yeah, happy to do that. Thanks, Ritu, for your question. I think this actually is a really important aspect of the endpoint that we crafted for HELIOS-B, recognizing that increasingly care is moving to outpatient settings around the world. That was highlighted, for example, during the pandemic, but it's now increasingly happening where patients are being managed for heart failure exacerbations in the outpatient setting. It was important for us to demonstrate that not only did this medicine reduce mortality, reduce hospitalizations, but actually reduced outpatient visits for heart failure exacerbations as well. That is really what this indication indicates, that we're not trading off inpatient hospitalizations for outpatient urgent heart failure visits. We're actually having a beneficial effect on all of these consequences of worsening heart failure. This is an important thing.
We think that it's something that increasingly, with time, you will see increasing pressures to kind of put patients and treat them in outpatient settings where it's also more convenient for patients. This is an important differentiating aspect of the label, something we were able to demonstrate, and I think good for patient care. Tolga.
Yeah, I mean, look, Ritu, what we're really excited about is, first of all, it's a really great day. You can tell how excited I am. Look, what's really great about this label, it really reflects everything that has been laid out by HELIOS-B. The HELIOS-B data set, as Pushkal highlighted during the call, provides really a complete picture of how this disease should be treated.
The fact that we are the only product with PN and CM indication, the fact that we're the only silencer that actually knocks down the disease-causing protein at its source, the fact that we only have four subcutaneous injectables over a year, which not only ensures that patients get the full effect of the medicine, but secures that it's actually patients are adhered. In the totality of this, of course, we're excited about urgent heart failure visits, but the totality of data is what's so exciting.
That's great. Thank you very much, Pushkal and Tolga. Next question, please.
Your next question is from the line of Jessica Fye from JP Morgan. Please go ahead.
Hey, guys. Good evening. Thanks for taking my question. In the past, you've talked about 5,000-10,000 cardiomyopathy patients initiating treatment in the U.S. each year at an increasing rate. I'm curious, if we look out, say, five years from now, where do you think that 5,000-10,000 per year initiating treatment is going to go?
Yeah, that's a great question. I mean, clearly, as Tolga described in his presentation, there are huge unmet medical needs here. I mean, only 20% of patients are diagnosed. Those diagnosis rates have gone up. They've actually increased 10 times over the last six years. We believe that there are still many unmet needs and many patients that need to be diagnosed and treated. Perhaps, Tolga, you could provide some additional color.
Yeah, thank you, Jessica, and thank you, Yvonne. Look, I mean, obviously, we don't have a crystal ball, but what we can tell you is that when you see, especially an entirely new medicine, like in multiple sclerosis, this happened, a new medicine is introduced to the mix, certainly diagnosis rates start going up. Now, that diagnosis rate is obviously a system issue. We believe from 2% to 20% happened in five to six years. It's going to continue to go up. What the steep of that curve is going to look like is something actually we're going to have to wait and see. I can assure you, we will be an important part of that ecosystem and making sure that disease awareness goes up. I'm sure so will others.
Thank you, Tolga. Next question.
Your next question is from the line of Tazeen Ahmad from Bank of America. Please go ahead.
Hi, good evening. Thanks for taking my question. This is probably for Tolga. Can you give us a sense? You've talked a lot about your focus on frontline new patients, but as the launch is going to progress, how should we be thinking about switch patients or add-on patients? I guess in the label, there doesn't seem to be reference about how to use it in combination with stabilizers. Does that impact at all your view of the opportunity beyond frontline? Thanks.
Yeah, let's start by Pushkal providing a perspective on the label. Then, Tolga, you can follow up with your view on the commercial perspective.
Yeah, Tazeen, maybe I want to just correct you a little bit. I think what the label here shows, and if you look at the forest plot, actually, is it shows importantly that there were consistent benefits of Amvuttra, whether given in a monotherapy setting without background stabilizer or in the sizable proportion of patients who were studied in this clinical trial who were on a background stabilizer. That is clearly represented. I think the fact that it is clearly represented highlights the regulator's belief that that is a clinically significant finding that is informative to prescribers. Moreover, there is no prohibition around using the combination. This label actually does allow full use of this drug as a monotherapy or in combination with a stabilizer.
There is no limitation of use around that at all. The label clearly reflects the benefits that were seen in the clinical trial in both populations. I just want to put that out there and maybe turn it over to Tolga to answer the rest of your question.
I mean, I think you covered most of it. The only thing I would add is what's really important for patients, and physicians know this, and we were told this, that the cardiac function that you lose, you never gain it back. The real choice here is to make sure that physicians want to put the treatment that they believe is the most optimal treatment. We believe with this data package and the total profile of Amvuttra really positions us well to be a first-line treatment. As Pushkal highlighted, this does not mean that we cannot be used as a switch or a combination agent. The label certainly supports that.
Thanks. Great. Next question.
Your next question comes from the line of Paul Matteis from Stifel. Your line is now open.
Hey, thanks so much and congratulations. I wanted to ask a little bit more about your thought process behind pricing. When you've engaged with Medicare plans, to what degree do you think that the Part B book of business is truly looked at in a vacuum? I guess, is your thinking that the price of Amvuttra shouldn't really be comped or, I guess, won't be comped by insurers to the price of tafamidis and acoramidis? I guess that is sort of what I'm ultimately wondering here is what gave you the confidence to price and maintain price at a significant premium? Thanks so much.
Thank you, Paul. Look, I think what you're really asking is, are we going to be step-edited? What I can tell you is we believe very firmly that the majority of cases, we will not be stepped through tafamidis or any other stabilizer. The bottom line is that is the label itself. I mean, what we've been able to demonstrate, not only that we are uniquely positioned as the only PNNCM agent, not only do we have this unique mechanism of action, but also all these results that you've seen have been achieved through a high bar of those patients that have already been half the patients that are nearly on a stabilizer. We've been able to still demonstrate that. We are very confident that given where we are and how we're positioned, the majority of the cases will not be stepped through tafamidis.
Now, in the minority of the cases where payers do put us in second line, we certainly have demonstrated our capabilities of how we work with payers through value-based agreements and other means to be able to manage so that patients can get on the therapy as quickly as possible.
Thank you. Next question.
Your next question is from the line of Kostas Biliouris from BMO Capital Markets. Please go ahead.
Hello, everyone. Congrats on the approval. Thanks for taking our question. One question from us on recent real-world evidence data from tafamidis, which showed that the discontinuation rate is actually very high, 30%-40% between 12 and 24 months. We would be interested in hearing your thoughts around what can you do to secure that those patients who are discontinuing tafamidis, they prefer to come to a silencer versus another stabilizer. Also, although Tolga mentioned some of those, any measures you are taking to avoid such high discontinuation rate with Amvuttra? Thank you and congrats again.
Yes, of course, it's great that you've identified this unmet medical need where, as you said, patients continue to progress. Clearly, we're going to make sure that we're able to engage appropriately with the physician and patient community to educate them on how to think about managing patients with progression.
Yeah, thank you, Yvonne. Look, Kostas, it's good to see that you clearly picked up on that. It's an area where we certainly have seen anecdotally as well as through various data points.
Look, we don't have a single standard definition of progression in ATTR-CM today, but there are multiple and relatively simple ways to be able to actually compel physicians to start looking whether their patients are actually advancing in a stabilizer. Change in NYHA classification, increasing cardiovascular events or related hospitalizations while they're on stabilizer treatment, increasing use of standard care approaches like increased use of diuretics. I think Pushkal can attest to this, simply how patients feel while they're on treatment. This is an area where obviously we're going to continue to work and make sure that we generate evidence where the physicians will be able to identify quickly if they're actually progressing on a stabilizer so they can actually use another option that is unique.
Good. Next question.
Your next question comes from the line of Maury Raycroft from Jefferies. Please go ahead.
Hi, I'll add my congrats and thanks for taking my question. I'm just going to ask about the patient assistance program and initial free dose if there's coverage issues. What are your expectations for this at the start of launch and how could this evolve over time? Maybe just provide more perspective on that.
Yeah, that's great, Maury. I mean, we're really proud of our Alnylam Assist, our patient support service. And as Tolga pointed out, I think actually very differentiated in our Alnylam because it's fully owned. Our people are absolutely dedicated to making sure that they can meet the needs of patients, really with the goal of making sure that all patients get appropriate care. Tolga.
I mean, the only thing I would add, Yvonne, is we're not new to this. We've been actually managing very similar programs across all of our launches. Maury, just to be specific, for patients that have lengthy delays in their insurance for approval, which frankly, in some cases, we do not expect that, we offer an initial dose at no cost that gives them three months to work out our insurance coverage. We believe this is a pretty good, flexible option that gives plenty of time for our teams to be able to help navigate the insurance system.
Thanks, Tolga.
Thank you.
Your next question comes from the line of David Lebowitz from Citi. Please go ahead.
Thank you very much for taking my question and congratulations on the approval. On pricing, while you're maintaining the current list price and you're going to be making use of rebates and whatnot to lower the net price over time, I'm curious to start with, what type of differential might there be between cardiomyopathy and polyneuropathy at the get-go relative to these rebates and aspects on net pricing? Will that actually differentiate over time with polyneuropathy maintaining a more premium approach and then cardiomyopathy potentially having more of an impact?
I'll take that. Yeah, look, essentially, we have one label, one product, and we have agreements, value-based agreements that will cover both sides of the aisle. I would expect the exact same approach both between PNNCM.
Great. Next question.
Your next question is from the line of Gena Wang from Barclays. Please go ahead.
Thank you. Also, congrats on the early approval and it was a strong label. Regarding the net price, you mentioned that it will be decreased over time. How much does net price impact your 2025 revenue guidance, especially given it is a $1.22 billion revenue in 2024 in polyneuropathy?
Hi, Gena, this is Jeff. I'm on the line. The guidance that we, let me just sort of recap so everyone remembers what the guidance is that we gave for the year on TTR. The guidance for this year is $1.6 billion-$1.725 billion. Tolga mentioned this in his prepared remarks. That represents 36% at the midpoint growth. In terms of impact on price, I mean, I think Tolga, again, in the prepared remarks talked about gradual reduction in net price over time.
I think that's probably all we're going to say about it at this point, but I think you probably can infer from that a reasonable assumption around impact on price this year.
Thank you.
Your next question is from the line of Gary Nachman from Raymond James. Please go ahead.
Thanks. And my congrats as well on the approval. Understanding this is more of a second-half impact on the launch, what type of metrics will you provide to give us a sense of how the CM launch is going in terms of payer access, patients treated, physician prescribing, or anything else that you could talk to to give us a sense of the launch? Thanks.
Gary, that's a great question. I think probably the most important metric is the one that actually Jeff has just shared, which is the guidance that we've committed to for this year for TTR net product revenues. I think that underscores the confidence that we have in the profile of Amvuttra, the label that we have, and the commercial capability that we've built. I know that you may want to say a little bit more about this, Tolga?
Yeah, I mean, look, we're really excited that I think in this category, we're the only ones that really committed to year-end guidance that we believe is realistic, and we certainly want to be able to exceed that. Look, progress on some of the things, Gary, that you highlighted, we need to set up the right access both at the provider and payer level. We want to be able to provide you that.
Some color around essentially whether this is an academic or more community start points, we would like to be able to do that. Category growth is another area we would like to be able to provide. Especially in the early days, qualitative customer reaction in response to the launch are areas where we would like to provide. We appreciate that this is an important launch and we'll provide as much color as we possibly can in the early days. Wonderful.
Next question.
Thank you.
Your next question comes from the line of Luca Issi from RBC Capital Markets. Please go ahead.
Oh, great. Thanks so much. Hey, thanks so much for taking the question. Congrats on the approval. I know it's a long journey, so congrats. Maybe Tolga, a quick one for you. It feels to me that this drug is going to do really well at top academic centers, especially given the favorable buy-and-bill economics for the hospital. Maybe it will be a little bit harder in the community settings where maybe such economics are less of a factor and maybe where patients and physicians may prefer the convenience of an oral pill, especially if the patients live kind of far from an amyloidosis center. Would you agree with that characterization? If so, what's the strategy to capture market share across both urban and more rural areas there? Any comment? They're much appreciated. Thanks so much.
Sure, Luca. No, it's a great question. I would probably characterize it slightly differently. That would be really based on our experience in polyneuropathy. We've already been calling about 60% of these centers, and they're not necessarily just academic centers in major metropolitan areas. They're at the regional centers as well as at local centers. Essentially, how we've been actually generating prescription in those markets has been 50/50. The reason is because we've been able to actually provide a lot of alternative site of care where the patient actually is able to get their injection, where the injection center actually gets on the liability, and is able to actually administer the product without having the cardiologist in their local office establishing some of those capabilities that you highlighted. This is actually an area where we've made great progress.
As I shared with you, we had actually back in October at the TTR Day, we talked about this, that 95% of our patients are already using different venues to be able to actually secure their treatment. That number of 1,000 centers has just been doubled now at this point from 1,000 to 2,000. We are very much on track of providing a lot of optionality for patients so that if the academic center or the local doctor wants to prescribe this medicine, they can go and be able to get this product at an infusion center maybe a few miles away from their home.
Great. Thanks so much.
Okay, I think we have our last question coming up.
Your last question comes from the line of Ellie Merle from UBS. Please go ahead.
Hey, guys. Thanks so much for taking the question. Just in terms of combination use, one of the payers said about this in your initial conversation here. In terms of the platform infusion option that we mentioned, what's the utilization for Amvuttra polyneuropathy? How do you expect that to compare in cardiomyopathy?
Ellie, it was actually really challenging to just hear you. Do you mind paraphrasing your question again? It seems like we've lost Ellie. Is that Ellie? I think we could probably wrap with that. Yeah, apologies if Ellie is still on the line, but we couldn't hear the question properly here, and it's probably time for us to.
I can simply just answer that first part of the question as far as I could understand. I think you asked whether actually payers will be amenable to using a combination therapy. I mean, I think we've been pretty consistent about this that until TTR genericization, this will primarily be a mono market. In instances where patients may have access, obviously our label allows it, our data allows it. We believe actually monotherapy and the first-line standard of care therapy is the way right now the label reflects how it will be used. You're probably right. Combination therapy is not going to be the common use until what we would expect the TTR genericization.
Yeah. Thanks for doing your best to answer some of that question, Tolga. Thanks again to everyone for joining us today. It's an incredibly exciting and important moment for Alnylam. As you could hear, we're looking forward to making Amvuttra available to patients living with a cardiomyopathy of ATTR amyloidosis who are really in need of new treatment options. In doing so, establish a flagship franchise for our company. Thanks to everybody and enjoy the rest of your evening.
This concludes today's conference call. Thank you very much for your participation. You may now disconnect.