Alnylam Pharmaceuticals, Inc. Price & Performance (ALNY)

For those of you who participated in conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website investorsaddlenylam.com/events. During today's call, as outlined in Slide 2, Yvonne will offer introductory remarks and provide some general context. Bob will provide an update on our global commercial progress. Pushover review pipeline updates and clinical progress, Jeff will review our financials and guidance, followed by a summary of upcoming milestones, before we open the call for your questions. 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 SEC. In addition, any forward looking statements represent our views only up to date of this and should not be relied upon representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne.

Yvonne?

Thanks, Christine, and thank you everyone for joining the call to 2024 was a fantastic year for Alnylam, with strong research, program development and commercial execution and significant progress across the business. This includes the highly positive results from the HELIOS B Phase III study leading to submission of global regulatory filings for vutrisiran and ATTR cardiomyopathy. We also continue to advance and expand our robust and high value pipe And we continue to demonstrate strong commercial and financial performance, achieving combined net product revenues of over $160,000,000,0.0 at the upper end of our revised guidance range and we delivered $95,000,000 in non GAAP operating income for the full year, marking a significant milestone for the company. Furthermore, we maintained our award winning culture, has been a critical enabler of our success. As we look for the year ahead, 2025 has the potential to be a landmark year for Alnylam. We believe that there are 3 core elements of our business that will drive sustainable growth and value creation not just in 2025, but for years to come. And will take our Nylem into its next exciting chapter The first is TTR leadership, where vutrisiran, if approved, has the potential to become a new standard of care in ATTR cardiomyopathy and established a flagship franchise for our company.

With the advancement of our next generation TTR asset, nucleosiran, Next is growth through innovation. Including a pipeline with numerous multibillion dollar opportunities and an R and D engine set up to deliver sustainable innovation and value creation. The third pillar is strong financial performance where we project that our robust commercial delivery and disciplined approach to capital allocation will enable us to sustain profitability going forward. All of this is underpinned by a best in class team and our award winning culture. All of this represents tremendous progress against our Niallum Pizza Fifth by 25 goals, launched back in 2021. We are now on the cusp of turning these goals into reality and believe that in doing so, we're on track to become the top tier biotech Furthermore, the progress we make in 2025 will set us up for the second half of the decade and our next era of significant growth. We are entering a new and exciting chapter in our Nylem's history and truly believe the best is yet to come. With that, let me now turn the call over to Tolga, for a review of our commercial performance. Tolga, Thanks, Yvonne, and good morning, everyone. Was another strong quarter for our commercial portfolio with our combined TTR and rare franchises delivering 30% growth compared with the On a full year basis, we delivered $1,000,000,016.46,000,000 dollars in combined net product revenue, at the very upper end of our 2024 product revenue guidance range.

Which translates to 33% growth compared to 2023.

As we continue to consistently increase the number of patients on therapy, in both our TTR and rare franchises, Let me now turn to a summary of our TTR performance. Our TTR franchise achieved $43,000,000 in global net product revenues during the quarter. Representing a 35% increase compared with the As we continue to increase the number of hATTRPN patients on our therapies. In The U. S, during our first full year of competition in hATTRPN, combined sales of ONPATTRO and ALMUTRA in the increased by 10% compared with the and finished the year with a robust 42% year over year increase driving strong growth momentum. The 42% year over year growth was primarily driven by the following: a 34% increase in demand, driven by the strength of ongoing Amutra patient uptake as well as continued switches from ONPATRA We are pleased with the growth in demand which was consistent throughout the year despite new competition entering the market at the The remaining growth in the quarter related to favorable adjustments and gross to net deductions. Which were offset modestly by stocking dynamics as inventory in the distribution channel decreased in I'd like to take a moment to reflect on our full year hATTR performance in The U. S. Where we generated $7.00 $5,000,000 in full year revenue representing 39% growth compared with 2023, and almost $200,000,000 in dollar growth.

The dollar growth in 2024 represents an increase relative to the dollar growth we generated in 2023 of $180,000,000 despite the new competition that entered the market at the beginning of the year, We believe is reflective of the leadership position we have established in the PN market over the last six years the strength of Ammutra's safety and efficacy profile which is underpinned by rapid knockdown of TTR, [indiscernible] solid commercial execution. Let me turn to our international markets. Where TTR franchise grew 12% in the compared to the an increase by 25% year over year compared with the Similar to The U. S, the year over year growth was primarily driven by increased demand for Angouchetra as patient uptake remained robust. Before we discuss our rare business, I'd like to take a few minutes to review our readiness for our upcoming PDUFA target action date and the potential expanded label and launch in We're excited about the to a patient population that is desperately in need of a product with a new mechanism of action. We've been preparing for this opportunity which may now be only weeks away pending successful completion of the ongoing U. S. Regulatory review.

We recently announced full year 2025 product revenue guidance at [indiscernible] our guidance of over $50,000,000,0.0 in absolute growth versus 2024 is driven by mainly by our TTR franchise, that includes our anticipated label accession into ATTR and reflects our confidence and excitement about the launch. For 2025, we've guided for TTR product sales of between $160,000,000,0.0 and $17,250,000,00.,000 This would represent a 36% increase in annual revenue compared with 2024.

At the midpoint of our guidance. Reflecting an acceleration from the 34% growth our TTR business achieved in 2024. Now let me share with you a few reasons for our optimism and a sense of what's to come.

As we said before, ATTR an orphan disease. The category is rapidly growing and is still largely underserved. This will be a market growth story an opportunity to help more patients in need whether they are newly diagnosed or currently on a stabilizer therapy, and experiencing disease progression. It is a category rife for entirely new treatment option. In this context, we have the potential to introduce a disruptive treatment Assuming approval, Aultra would be the first and only RNAiSilence approved for both [indiscernible] delivers rapid knockdown of TTR, working upstream at the source of disease, demonstrated profound impacts on CV outcomes in Heliospeak, including a thirty six percent reduction in all cause mortality versus placebo, In a study population, representative of today's patients with forty percent on a stabilizer and a significant number on other background therapies like Diuretics, and SGLT2 inhibitors early and consistent preservation of functional capacity and impacts that are critically important to patients and that they can feel. All of this achieved with just four doses per year, and uniquely positioned for seamless access for patients And while there's still much work still in front of us, We are building on a strong foundation in hATTRPN.

And a demonstrated track record of consistent commercial execution as you have seen from our and full year results. As we approach this important launch, we are building for durable, long term success of our TTR franchise and building on our experience and success over the past six years in this category, This means taking the time enable smooth access and to create a seamless experience for patients, and providers alike. Toward that end, we have already been at work optimizing the access and patient onboarding experience. This means optimizing access pathways at health systems, where patients are actively managed today given eighty percent of the population is being treated at 170 Health Systems, we are focusing on optimizing access pathways at these health systems so that healthcare professionals can easily prescribe Almuthra with the knowledge that the patient will receive it at an optimal location be it an office, at an infusion center, or at home. [indiscernible] good progress laying the groundwork in this regard and it is important to note that following FDA approval for the expanded indication, it can take several months for the product to be added to the system's formulary. And for the access pathway to be fully optimized.

Which will result in a ramp up in demand as the year progresses. In parallel, we've also 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. As we previously shared at our twenty twenty four TTR Investor Day, there currently are over 1000 alternative sites of care available for patients This is in addition to health systems group practices and clinics and at home administration. Our goal is to expand these provider sites and ultimately for greater than ninety percent of patients to be within 10 miles of a treatment site. With regard to our field readiness, we've already scaled up all our customer teams cross functionally, That includes world class sales field reimbursement, fee account management and medical, and award winning patient services teams. Looking ahead to cost approval, we will pivot our focus to securing health systems formulary approval via their Pharmacy and Therapeutics Committee reviews and finalizing access pathway optimization. Which again could also take several months once we have an approved label. Expanding our value based agreement in ATTRCM we've been an industry pioneer in establishing VBA across our portfolio.

To deliver value and enable broad patient access. We are focused on expanding these existing ATTR VBA partnerships to cover our expanded label. Finally, driving disciplined and compliant execution across our teams following approval. In short, we see tremendous opportunity in this category We are on the cusp of a regulatory decision for what has the potential to become a transformational product. For patients in need.

And we have an FDA ready commercial organization deeply engaged and experienced in the ATTR market. We plan to share relevant operational details over the course of the year to provide clarity on the progress of our launch. As we aim to achieve ORXI our full year revenue guidance. Now turning to our rare franchise. And the performance of GULARI and OXLUMO. Which delivered $108,000,000 in combined product sales in the representing a 3% decline compared with the by purchase patterns, and 18% growth compared with the For July product sales decreased by 9% compared with the primarily due to the timing of a large order in the partner market in which did not recur in On a year over year basis, Givensar sales increased by 9% compared with the with the following regional highlights.

A 14% increase in The U. S. Primarily driven by growth in new patients on therapy, with additional growth driven by inventory stocking dynamics a 1% decrease in our international markets, where demand growth in our European markets was offset by gross margin adjustments in our partner markets. For OXXULMO, product sales increased by 8% compared with the primarily due to continued demand growth. And increased by a solid 33%. Compared with the with the following year over year regional dynamics. Despite emerging competition, a 77% increase in The U. S. Primarily driven by strong demand growth with additional growth driven by favorable gross to net pricing adjustments and inventory stocking dynamics, a 12% growth from rest of world markets primarily driven by strong growth in patient demand. In conclusion, we delivered strong results in the with both our TTR and rare franchises, driven by continued robust growth in patients on therapy. Which enabled us to close the year at the upper end of our 24 product revenue guidance range. With that, I will now turn it over to Pushkal, to review our recent R and D and pipeline progress. [indiscernible] Thanks, Tolga, and good morning, everyone. As you all know, 2024 was a very exciting year for our TTR franchise.

We shared the landmark results from Helios B at several conferences throughout the second half of the year. Together these data presentations highlighted VUTRISSE rands potentially transformational profile in today's population of patients with benefits across a comprehensive series of assessments. Based on these compelling data, we've completed several regulatory submissions that are now under review. In The United States, we have a PDUFA date of March '23 and parallel filings were achieved in all major regions. Including Europe and Japan. Our goal is to bring this new and important therapeutic option to patients around the world as quickly as possible. We also continue to look ahead and innovate in TTR beyond guttersiran, with new creosiran. Formerly known as ALNTRSC-four. At in Nov. 0, we presented updated Phase 1 results showing rapid knockdown of serum TTR that was robust and highly durable. Greater than ninety percent at six months. Supporting the potential for an annual or biannual subcutaneous dosing regimen and an encouraging safety profile. Which in addition to offering convenience for patients could enable broad payer coverage. Together, we believe these data support a potential best in class profile.

I'm also happy to announce today that the FDA has granted the nucleosiran orphan drug designation for ATTR amyloidosis encompassing both polyneuropathy and cardiomyopathy.

As Yvonne announced at JPMorgan, we plan to quickly advance nucrisiran to a Phase 3 study in ATTR amyloidosis with cardiomyopathy that is expected to start in the Additional details regarding the study design will be shared at our R and D Day on February '25.

Beyond TTR, our 1 of the most robust pipelines in the biotech industry today, positioned to deliver strong growth and innovation across a broad range of disease areas and indications, at all stages of development. In the we continued to make great progress in advancing our pipeline. Let me highlight a few key milestones.

We continue to advance Zalbisseran an investigational therapeutic for the treatment of hypertension, through Phase II and towards initiation of a Phase III cardiovascular outcomes trial expected to start in the In fact, as announced this morning, we have recently completed enrollment in the CARDIA3 Phase 2 study. Nvelsiran, our investigational therapeutic for the treatment cerebral amyloid angiopathy in Alzheimer's disease continues to proceed as well. We presented multi dose data showing high levels of knockdown with single and multiple doses along with good safety and tolerability.

We have an ongoing Phase 2 study in cerebellumab luteangiopathy and plan to start a Phase 2 study in Alzheimer's disease in the second half of the year. And we started 4 new Phase I programs last year, The first was for Huntington's disease where we have a unique exon one targeting approach that non human primates has shown deep and sustained knockdown with encouraging safety and tolerability. The Phase one trial is ongoing in The United States Canada, and The UK. The other programs initiated in includes zalbesiran plus Reversir for hypertension, Puts us in a great position to have a strong self sustainable pipeline that can deliver meaningful impact to patients for many years to come. I encourage you to join or to tune in to the webcast of our R and D Day that we will host on February 25. Where we will provide more comprehensive reviews of the programs I've described and also highlight continued RNAi platform innovation that will drive the next era of Alnylam's growth. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. [indiscernible] Thanks, PushCall, and good morning, everyone. I'm pleased to be presenting Alnylam's full year 2024 financial results and providing our complete financial guidance for 2025.

Starting with a summary of our P and L results for the full year. Total global net product revenues for 2024 were $1,646,000,000 dollars representing 33% growth versus 2023 with both our TTR and rare franchises reporting strong growth 3429% respectively. These results came in at the top end of our 2024 product revenue guidance which we had raised more than 10% at midyear from our original 2024 guidance. For the full year, net revenue from collaborations was $510,000,000 including a $60,000,000 sales milestone in Q4 from Novartis due to Lecvio exceeding $600,000,000 in annual sales. Compared with 2023, collaboration revenues decreased 7% primarily attributed to differences in certain revenue items between 2023 During 2023, we recognized $310,000,000 of revenue from the upfront payment received from Roche in connection with XH execution of our Zalbisiran collaboration. In comparison, during 2024, we recognized $185,000,000 in revenues associated with the modification to our Regeneron collaboration, driven by providing Regeneron an exclusive license develop, manufacture and commercialize semdesiran as a monotherapy. Royalty revenue for the full year was $92,000,000 or more than double what was recognized in 2023, driven by higher royalty 81% for the full year, representing a 3% increase compared with 2023.

The improvement in margin was primarily due to non recurring prior year expenses associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory. These decreases were partially offset by an increased rate of royalties payable and net [indiscernible] For 2025, we expect a decrease in gross margin on product sales, as the average royalty rate payable to Sanofi on IMbutra is expected to be higher as sales of IMBUTRA continue to increase. Our non GAAP R and D expenses increased 10% for the full year compared with prior year primarily due to increased costs associated with our preclinical activities as we develop our clinical pipeline of RNAi therapeutics targeting multiple tissues, increased clinical trial expenses associated with the Zalvisiran Cardia III Phase two study, and increased employee compensation expenses. Our non GAAP SG and A expenses increased 24% for the full year compared with 2023 primarily driven by increased investments in support of our TTR polyneuropathy business and in preparation for the potential launch of Ambutra for cardiomyopathy. Along with increased personnel costs. For the first time, we achieved full year non GAAP operating profit of 95,000,000 representing a $156,000,000 improvement compared with 2023 primarily driven by strong growth in product sales.

This is a significant milestone for the company as achieving non GAAP profitability has been a key goal associated with our P of the 5x25 growth strategy. This achievement will enable further investment in our R and D pipeline as we strive to deliver sustainable long term top and bottom line growth. Finally, we ended the year with cash, cash equivalents and marketable securities of 2,700,000,000.0 compared to $2,400,000,000 at the end of twenty twenty three, with the increase primarily driven by improved operating performance and net proceeds received from the issuance of common stock in connection with employee stock option exercises. Now I'd like to turn to our 2025 financial guidance. Starting with net product revenues, we are reiterating our combined net product revenue guidance from ONPATTRO, AMBRUITRA, GIVLARI and XULUMO that was communicated in our JPMorgan press release dated January 12, 2025. We anticipate combined net product sales for our four commercial products will be within a range of $2,050,000,000 to $2,250,000,000 representing combined full year growth compared to 2024 of 31 more than $500,000,000 in growth. On a franchise level, the guidance is broken down as follows. Total TTR $1,600,000,000 to $1,725,000,000 representing full year growth compared to 2024 of 36% at the midpoint of the guidance range.

Importantly, this guidance assumes approval and launch of INVUTRA for ATTR cardiomyopathy in The U. S. By the PDUFA date of March 23. Additionally, we assume launches for IMbutra and ATTRCM in Germany and Japan in the second half of twenty twenty five. Total rare, dollars four fifty million twenty twenty four of 15% at the midpoint of the guidance range. Our guidance assumes foreign exchange rates as of December 31, 2024, which are noted in the footnote of our guidance slide. We are also providing constant exchange rate growth guidance for our net product revenues with a projected range of 26% to 39%. Collaboration and royalty revenue guidance range is $650,000,000 to $750,000,000 representing 16% growth compared to 2024 at the midpoint of the guidance range. Our guidance assumes achievement of a $300,000,000 milestone payment from Roche, associated with the initiation of our Phase three study for zolvysiran, we anticipate will occur in the second half of the year. We also expect that collaboration revenue associated with our partnerships Roche and Regeneron as well as LECTBIO royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2025. Our guidance for combined non GAAP R and D and SG and A expenses is a range between $2,100,000,000 and $2,200,000,000 with the midpoint of the range representing 17% growth compared with 2024.

Growth drivers for R and D expense in 2025 include increased clinical investment across our early, mid and late stage programs, including the initiation of pivotal Phase three studies for Zalvisiran and Nucrisiran. Growth in SG and A will primarily be driven by the launch of Ambutra for ATTR cardiomyopathy in The U. S, Germany and Japan, assuming regulatory approvals. Finally, as discussed last month at JPMorgan, we anticipate delivering non GAAP operating income profitability in 2025. Let me now turn from financials and discuss some key goals and upcoming milestones for early twenty twenty five. As PushCall mentioned, we will host an R and D Day on February 25 in New York Citi. The PDUFA target action date for the sNDA for VUTRISRAN is 03/23/2025. Please note that given the materiality of this decision, we will be entering a quiet period beginning on March 1.

We intend to initiate a Phase three study of nucrisiran in patients with ATTR amyloidosis cardiomyopathy in the first half 2025. And our partners at Sanofi have a PDUFA target action date for fotuciran of 03/28/2025. Let me now turn it back to Christine to coordinate our Q and A session. Christine? Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.

Thank you. Ladies and gentlemen, we will now begin the question and answer session. And your first question is from Tazeen Ahmad from Bank of America. Your line is now open. Hi, good morning. Thanks for taking my question. I wanted to get a sense from your team about how long you think it's going to take to establish payer policies after the approval?

Of Voutree? And how do you think that could impact the initial trajectory of the launch?

Thanks.

Thanks, Azim. That's a great question. I mean, clearly, we're in a strong position, having already TTR franchise supporting patients with polyneuropathy and this really gives us a strong foundation on which to build. Tolga, perhaps you could ask a specific question around time to [indiscernible] approvals Yes. Hi, Suzy. Look, obviously, we're really excited about the upcoming potential launch. And our Frankly, excitement is confirmed by the guidance that we've already provided. Now when it comes to the payer policies and formulary uptake, I think as you can see from my prepared remarks, this is really going to be a second half story.

We're very much committed to the growth that we've already committed to. [indiscernible] we have value based agreements that we know is going to be extended. Some of these payer policies that's going to accelerate But the formulary piece takes a little bit time. So I would expect the uptake really to be meaningful in the second half of the year. Thanks, Sazeem.

Thank you. And your next question is from Kostas Beliaris from BMO Capital Markets. Your line is now open.

Thanks for taking our question. A quick one on Ambutra from us. If we assume premium pricing for Ambutra compared to silences, which are approved already, What are your thoughts around step edits for commercially insured patients? Who represent about twenty percent of the ATTR cardiomyopathy population. Thank you.

Bogota, that's a question for you.

Yes, great question. Look, I mean, first and foremost, we really appreciate and like the product profile that Amutra has to offer. Which is underpinned now by the Helios B results. And in our engagements with payers at the pre pricing discussions, We're also encouraged that they see one, obviously, the value of this product can bring to the market. Second of all, the predictability.

Of how we are actually being positioned as a Part B product. So all these combined we actually expect our uptake to be very consistent with what we have seen in the past with PN in terms of how payers will cover this product, And as we've already shared, very much committed to the guidance that we provided, which again underpins how we really see the growth, which is going to be accelerated in 2025.

Thank you. Your next question is from Gina Lang from Mark Your line is now open.

Thank you. I know you cannot comment on the actual price for Ambulco, we'll wait until the approval date. But wondering if you can share the key factors that impact your decision? On pricing adjustment for Envutro. And related question, I know a few already asked, Can you share with us what percentage of the current sites already have a J code in place that you can use for Ammutro in ATTR cardiomyopathy?

Thanks. Thanks, Gina, for the question and recognizing that it's too early to be specific about price. And as you know, we have patient access principles. And when we think about price, we obviously consider the value that a product is bringing to patients and the ecosystem as well as assuring optimal And I think we've done a great job in PN along with the dimensions and we continue plan to do an equally good job for Centimeters, don't we, [indiscernible] answer to your last point. We already have a J code Amutra, which is going to be used. Therefore, we don't expect any changes or any disruption on that. And in respect to our coverage, Look, as we shared earlier on our TTR Day and other forums, The current makeup of our business from Medicare perspective as well as commercial, expect that to remain the same. And therefore, which we believe is going to result in rather [indiscernible] coverage for our product As Ivan indicated, we're really excited about orthogonal mechanism and how that's going to actually bring additional value and alternative, the disruptive treatment for payers as well as patients. And then I frankly, most importantly, The affordability for the patient.

As you know, seventy percent of our patients currently pay zero co pay and we expect that dynamic to remain the same, which we believe is going to be an important driver for our patient uptake. Thanks, Salda.

Next question?

Thank you.

Your next question is from Murray Raycroft from Jefferies. Your line is now open.

Hi, congrats on the progress and thanks for taking my question.

Wondering if there's any perspective you can provide on label discussion progress And in addition to reduction of mortality in hospital [indiscernible] sections such as wording related to preservation and quality of life and functional capacity.

Yes. Thanks, Maury. Look, first of all, we're really very enthusiastic about how the FDA review is going and we've been fully on track and for an approval date by the PDUFA. So we're excited about the progress that's been made in that front. In terms of the label, look, we believe that the study was designed and clearly demonstrated a benefit on mortality and hospitalization events and we expect that there'll be that will be reflected in label as well as the ancillary benefits that we saw in terms of preservation of functional ability, quality of life, and benefits across a series of endpoints there. So at the end of the day, we want a label that reflects the study that was designed and where we saw statistically significant results and predefined endpoint across a whole series of attributes that we think are a benefit. And and that we were able to actually then go and educate providers and patients on And so we look forward to sharing that when an eventual approval occurs.

Got it. Okay. Thanks for taking my question.

Thank you. Your next question is from Aritu Baral from J. D. Cowen. Your line is now open. The question. My question is actually a really good follow-up to Maury's on label language. Toga you think about the language in the label, this specifically mortality, but potentially having that mortality clinical data later in the label in the clinical data section what sort of potential advantage could that give you or or not either detailing the product or with [indiscernible] Okay. Hi, Ritu. Look, we have a pretty clear view understanding of how we're going to be able to promote, communicate this Mainly, obviously, what Pushkal indicated We had reached significant results on all pre specified endpoints. 10 out of 10. And our ability to communicate that is going to be relatively smooth. We're pretty confident in how we can actually differentiate the product from a product profile perspective. Given that this is an orthogonal mechanism of action that rapidly knocks down the disease causing protein. And has the ability to actually then demonstrate those clinical outcome benefits on both mortality as well as hospitalization coupled with the fact that we actually have four times a year subcutaneous injectable that really provides great adherence as we've seen on polyneuropathy as well as our relatively smooth access given that seventy percent of patients pay zero co pay.

All those perspectives will be carried through how we're going to actually communicate this exceptional medicine to the prescribers, which are very much in need of a disruptive treatment.

Do you still expect that to be in the the actual labeling language though? Those data?

Look, at the end of the day, we think that the label will reflect the things that we've shown in the clinical trial. That's traditionally what is done and we would expect this as we've said, Ritu, that we had a whole series of pre specified endpoints that show the impact of this drug on this disease. And so we would expect that to be generally reflected in the label. And again consistent with labeling, TOLVIA team, our medical teams will be able to speak about those attributes and the results of the Helios B study to providers and patients and payers.

Thank you. Your next question is from Greg Harrison from Scotiabank. Your line is now open. Good morning. This is Theresa Vitale on for Greg Harrison. Congrats on all of the updates and thanks for taking our question. I was just curious to hear what your expectations are for Nutriseran's potential revenue mix among naive patients. In the first line setting versus switches? [indiscernible] Still got that question for you. Yes. So I think our best of our abilities, we were able to provide a pretty clear and ambitious guidance that really shows how we're going to actually accelerate this RTTR franchise and post 36%. Now how that mix is going to happen is, look, we believe this is a product well positioned to be a standard of care and to be considered first line.

But like any categories, we do also know that there is a need of another product with an orthogonal mechanism of action beyond the stabilizers. So we certainly expect a good mix of patients, some from naive patients that are coming in the door that are newly diagnosed and some perhaps eligible for switches. Or in rare instances some combination. So we do expect that and obviously as we built our [indiscernible] all these elements were incorporated.

Great. Next question?

Thank you. Your next question is from Gary Neskrum from Laurentian. Your line is now open.

Hi, good morning. Maybe you could talk about the [indiscernible] in polyneuropathy With both products growing at this point, and how is the difference between Part B and Part D playing out And how you think that's going to translate over to cardiomyopathy with that approval?

Thanks for the question. I mean clearly we're very pleased with our strong TTR performance in 2024, and that was with competition in the market. So I think we're doing a good job continuing to build the business. Tolga, perhaps you want to add some color to the specific dynamics?

Yes. So we just posted our full year results for 2024, which happened to be the first year actually we faced competition in this relatively narrow category where we always said this is going to be a growth story, category growth story, And I think what you can see particularly in our U. S. Numbers, where U. S. Business from a pretty good healthy base grew 42% year over year and that was with the competition. And as far as I can tell, Waianuya also getting their fair share of growth, which is again very consistent with the with the growth story that we've been telling all along. We believe we have a highly differentiated product profile versus Waenuya given that it's four times a year, and it's CEP administered. And we had not seen any significant access headwinds. And we anticipate frankly, this type of dynamic continue as we expand our expand the education to cardiomyopathy.

Thanks, Togo. Next question please.

Thank you.

Your next question is from Jessica Fye from JPMorgan. Your line is now open. Hey, guys. Good morning. What do you think the early accoramitous scripts imply for the TTR Cardiometabolic, the market dynamics, market expansion and interest in agents beyond tafamidis as it relates to AMVUTRA And folks have been kind of trying to ask this in a few different ways, but maybe just to try one more time. What's the right way to think about the evolution of Ambutra's net price as you move into this much larger patient population? Thank you.

Okay.

I mean two questions there. Tolga. I mean clearly as Tolga said, I mean we believe that this is a market growth opportunity, which makes it a very exciting category to be playing and obviously become tachycardia, obviously, with a strong track record in the TTR space. Okay. Perhaps that's the color for the first question and then the specific question around the evolution of net price. Yes.

I mean, I think look, the first sentiment that comes to mind is encouragement. Effectively seeing another stabilizer coming into the market And Dave shared some numbers on the prescription that are early innings, obviously, [indiscernible] We're very encouraged because if another stabilizer that is four times a year would not release significant clinical data Obviously, Dave, they've actually shown shown that this is actually a growth category. Now when I think about Amutra product profile, that has really strong clinical profile as well as the fact that it's four times a year. Annual dosing. With really well positioned to be in the access we're very excited about what on which we can do given that the category is going to be continue to be growing. Given the undiagnosed patient numbers.

Thank you. Your next question is from Paul Matteis from Stifel. Your line is now open.

Hey, thanks so much for taking the question. On payer dynamics and how they evolve in this category, are you expecting the average insurer to cross manage between Part B and Part D? And I think, again, the underlying question that everyone trying to get to on pricing is you're at a significant premium right now, does that have to go down or not? There's a lot of moving parts, right, like the payer liability on Part D is one of them. But just as it relates to how insurers are going to manage their formularies in this space, like could tafamidis or acaraminis actually be a step at it or is that just not something that normal in practice at this point? Thank you. [indiscernible] Thank you for the question. Look, I mean, there's a lot of noise around how the payers will be managing this. What we've seen is is a rare condition, highly devastating condition, and we expect the payers to cover the product And how the market is going to evolve, I think we have a pretty clear eyed view given how have been actually managing pulmonarypathy as a Part B product, and how Vynula has launched in a Part D product.

We expect similar dynamics in terms of our and we do anticipate that given the given the patient affordability is a key driver, of how patients stay on therapy is to be very favorable for Amutra.

Thank you. Next question?

Thank you. Your next question is from Sylvain Richter from Goldman Sachs. Your line is now open. Good morning. Thanks for taking my question. You plan to initiate a Phase III study for nucrasiran in in ATTRCM in the first half.

How are you thinking about the timing of enrollment and events availability of new options and how do you plan to conduct an interim here?

Yes. So thanks for the question. I mean clearly we'll be providing more detail around [indiscernible] at R and D Day at the end of this month. Frisco, maybe you can share a little bit about how we're thinking about moving forward in the crease, which we're very excited about. Yes. Salveen, look, I think the Crease RAN, the profile that we've seen so far really sets it up. We think be a best in class therapy for patients with this disease, building on what we've seen with Vutrisiran, this now is a de risked asset. We think we can get deeper knockdown. We've already shown that over ninety percent, ninety five percent knockdown. Less frequent administration and we think that's going to help patient outcomes. When we think about the development plan for it, I think there's a number of factors. A, we want to develop bring this to market as quickly as possible because of the value that it brings. Two, want to think about how do we develop a clinical profile for that and a label that allows for broad uptake and a very durable franchise, right? And so you'll see those how we've kind of brought those factors together at R and D Day, we will talk more about the development program there in Centimeters and PN and our overall approach to this disease.

So tuned, it'll just be a couple of weeks and we'll be able to share more.

Next question.

Thank you. Your next question is from Ellie Marlow from UBS. Your line is now open. Hey, guys. Thanks so much for taking the question. Just a couple from me. So how would you characterize the mix of growth in the TTR guidance from polyneuropathy versus cardiomyopathy? And then Tolga, you mentioned that post approval you'll be finalizing value based agreements in cardiomyopathy Can you elaborate a bit on how these could work and what this could look like for cardiomyopathy relative to polyneuropathy? Thanks. [indiscernible] polyuria, cardiomyopathy and then a little bit more detail on how we're thinking about buying Bell post approval.

Look, unusual to our tradition, we actually at JPM broke down our guidance between TTR and rare But I think we'll stop there. We'll obviously continue to provide more color about how the launch is going. In the particularly in the second half of the year where we do see where we do anticipate the growth to take place. Now the can you remind me the second question?

First approval, how we're thinking about buy and build? Well, the value based agreements, right. So look, we're very, very proud about the value based agreements that we set out Approximately, we have about 60% of the lives that are currently covered under PN is dependent on the value based agreements. And the value based agreements are actually essentially really provides our commitment to the clinical outcomes. So we have this experience already with PN. And we anticipate that to actually also carry over in most instances for cardiomyopathy, which should provide a level of predictability for the payers about how the product is going to perform and the clinical outcomes that the payers expect us to achieve. So I think that's a great one of the great best practices that we've established over the years and we anticipate that to carry over with our cardiomyopathy indication in most cases.

Thank you.

Next question is Your next question is from Manny Korungar from Leerink Partners. Your line is now open.

Congrats on great results commercially and otherwise. I know that there's probably 20 more questions about Ambutra and pricing. In the line. So am going to ask an actual financial question.

Could you clarify the driver of the tax benefit that was noted here? And would that be recurring? Is this NOL Dynamic OUS? If you could just dig into how what drove that benefit [indiscernible] how it might recur or not over the course of the year? Jeff, it's a question for you.

Good question, Manny. We noted in the press release that we had a release of evaluation allowance ex U. S. And that's really related to our Swiss entity. This is something that have to do every quarter with our deferred tax assets as we have to assess whether or not it's more likely than not that that value is going to ultimately recognized. And the Swiss entities had profitability for a number of periods now. So that gave us the confidence to release that.

We've not released all the valuation allowances either in Switzerland and we've not released anything in The U. S. Yet. It's very difficult at this point to predict further. Manny. So I'd probably just leave it at that for now. [indiscernible] I think we've got time for one more question. I think we've got our last question coming up.

Yes. Your last question is from Luca Ypsi from RBC Capital Markets. Your line is now open.

Great. Thanks so much for squeezing me in. Maybe I follow Manny here, I guess, But Jeff, how should we think about gross margin here going forward? I mean, the same Fe royalty fee is very meaningful at 15%, 30%, but we obviously don't know the exact tiering of that royalty fee. Do you think that modeling gross margin compressing from 80% now, I think it's low 80s now to like low 70s or even upper 60s debt, a reasonable assumption in your mind color there, much appreciated. Thanks so much.

Yes, I appreciate the question. So in my prepared remarks, I mentioned that we expect gross margin on product sales to be lower in 2025 You're right, 2024, our gross margin on product sales was was 81%. And I do think that'll be the direction of travel for a period of time, really driven by two things that relate to Ambutro. One is it's our lowest margin product right now given the royalty burden to Sanofi.

It's our fastest growing product. So that will put pressure on margins as we move forward. And secondly, as that business grows, we also start to move up higher in the royalty tiers. So the average royalty rate will likely also increase over time. The royalty that we paid on average Across 2024, for Ambutro is 21% Again, my expectation is this moves forward is over time that number is going to probably be mid to high 20s. So that's the sort of the incremental amount that I would expect. Now there's a couple of things that will move the other way. I would say on margins. If you look at our gross margin on a total revenue basis, that also includes the impact of collaboration and royalty revenue. That's revenue that's very high margin. Probably close to 100% As an example, in 2024, the margin on product sales was 81%, but if you looked at margin on total revenue, it was 86%. So that uplifted it.

And then secondly, I think the most important thing is that the issue with this high royalty burden if we're successful in in developing Nucrisiran. We'll hear more about that at R and D Day as PushCall said. There's no royalty burden to Santa on that. So that would obviously offset this in the future. If we're successful in bringing that to market. So hopefully that gives you a little more clarity on direction of travel on margins.

That's super helpful. Thanks so much.

Very good. Well, look, thanks everybody for joining the call. 2024 is really a very good year. From '9. And they're really, as I said, just the beginning, of the success we believe we're on track to realize in 2025. So thanks everybody and have a great day.

Ladies and gentlemen, the conference has now may all disconnect your lines.