Alnylam Pharmaceuticals, Inc. Q3 FY2024 Earnings Call

Good day, everyone, and welcome to today's Alnylam Pharmaceuticals Q3 2024 Earnings Conference Call. At this time, all participants are in a listen-only mode. Later, you will have the opportunity to ask questions during the question-and-answer session. Please note this call is being recorded, and I will be standing by if you should need any assistance. It is now my pleasure to turn the conference over to the company.

Good morning. I'm Christine Lindenboom, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Medical Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review 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 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 would like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. The third quarter of 2024 marked a period of continued progress for Alnylam on all fronts. Commercially, we achieved 34% year-over-year growth in global net product revenue, generating $420 million across our four marketed products. We made great progress with our TTR franchise, sharing additional results from the HELIOS-B study of vutrisiran and filing regulatory submissions in the U.S. and EU. We also hosted a TTR Investor Day to highlight our preparations in anticipation of a potential launch in ATTR cardiomyopathy next year. We believe that AMVUTTRA and our broader TTR portfolio will serve as our flagship franchise, similar in potential impact to what EYLEA has been for Regeneron or what the cystic fibrosis franchise has been for Vertex, delivering to those companies durable growth and enabling those companies to invest in R&D, new product development and portfolio diversification for the long term. Lastly, our early pipeline saw continued momentum as well, particularly our efforts in CNS. We initiated a Phase 1 study of ALN-HTT02 in Huntington's disease, and we're pleased to announce today initial results from the multi-dose portion of the Phase 1 study of mivelsiran in patients with early onset Alzheimer's disease. These results are encouraging for our CNS platform as they provide early evidence that multiple doses of an intrathecally administered siRNA are well tolerated. We're continuing to progress towards achieving by year-end 2025 our Alnylam P5x25 goals and are steadfast in our belief that we're on track to become a top-tier biotech developing transformative medicines for patients around the world with rare and prevalent diseases driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering strong financial results. 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. Q3 was another strong quarter for our commercial portfolio with our combined commercial portfolio delivering year-over-year growth of 34% compared with the third quarter of 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 third quarter TTR performance. Our TTR franchise achieved $309 million in global net product revenues, representing a 34% increase compared with the third quarter of 2023 as we continue to increase the number of hATTR polyneuropathy patients on our therapies, particularly noteworthy in the U.S. given the competitive environment. We are approaching 5,000 patients on treatment with ONPATTRO or AMVUTTRA globally, and there is still a significant growth opportunity given our belief that 25,000 to 30,000 patients across the globe suffer from this devastating disease. Now let me provide highlights of our U.S. and Rest of World TTR performance. In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 8% compared with the second quarter and a robust 37% year-over-year as momentum in new patient adds continues to drive strong growth. The U.S. 37% year-over-year growth was primarily driven by the following: a 31% increase in demand driven by the strength of ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO who have switched to AMVUTTRA. We are pleased with the growth in demand, which has been consistent throughout the year despite new competition entering the market at the end of 2023. Favorability is also driven by gross to net adjustment. Now let me turn to our international market, where TTR franchise growth decreased by 9% compared to the second quarter of 2024, yet our quarter-over-quarter patient demand remains strong with 6% growth. The 9% quarter-on-quarter decrease was driven by a gross to net adjustment in Portugal that was booked in Q3 and large orders of ONPATTRO in our partner markets in Q2, including Australia, where we built inventory as we launched ONPATTRO in this market. On a year-over-year basis, the TTR business in international markets grew by 31% compared with the third quarter of 2023. At our recent TTR Investor Day, we shared our plans for the promising potential of vutrisiran in addressing ATTR cardiomyopathy pending regulatory approval. We're confident in our journey towards leadership in this field, driven by several key factors. ATTR cardiomyopathy is a rare and progressive disease where there is significant unmet need and substantial number of patients remain undiagnosed or not optimally treated. With HELIOS-B, we've shown very compelling results across key endpoints in a population reflective of today's patients. We have a track record of success in polyneuropathy and experience operating in a competitive environment. Our dedicated focus on ATTR will be instrumental as we scale for a successful launch, building Alnylam's flagship franchise and ushering a new phase of growth. Now moving to our rare franchise, the performance of GIVLAARI and OXLUMO, which delivered $111 million in combined net product sales during the third quarter, representing an 8% increase compared with the second quarter of 2024 and 34% growth compared with the third quarter of 2023. For GIVLAARI, Q3 product sales increased by 14% versus Q2, primarily due to the timing of orders in partner markets and a robust 31% compared with the third quarter of 2023 with the following year-over-year regional highlights: a 9% increase in the U.S., primarily driven by growth in new patients on therapy, and a 79% increase in our Rest of World markets, primarily driven by the timing of orders in our partner markets, primarily Brazil, and increased demand growth across European markets. For OXLUMO, Q3 product sales were relatively flat versus Q2 2024, while delivering robust 40% year-over-year growth compared to Q3 2023 with the following regional dynamics. This includes a 54% increase in the U.S., primarily driven by strong patient demand growth, and a 33% growth from our Rest of World markets, primarily driven by strong patient demand growth across both EU and our partner markets. In conclusion, our third quarter results reflect consistent strength with both our TTR and rare franchises achieving impressive patient and revenue growth. This performance positions us well to meet the midpoint of our full year revenue guidance, which we updated and raised during our second quarter earnings call. We remain intensely focused on preparing for a potential ATTR cardiomyopathy launch next year. And with that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Thanks, Tolga, and good morning, everyone. As you all know, Q3 was very exciting for our TTR franchise. We shared the full results from the pivotal HELIOS-B study at ESC in August and additional exploratory findings at HFSA in September. Together, these data presentations highlighted vutrisiran's potentially transformational profile in today's population of patients with ATTR cardiomyopathy with benefits across a comprehensive series of assessments. This started with rapid knockdown of TTR, characteristic of the RNAi mechanism of action. We then saw favorable impact on cardiac biomarkers as well as echocardiographic assessments, reflecting impact on the underlying pathophysiology of this disease. This was then followed by impact on a number of important clinical measures of function and health status, indicating delays in disease progression. Ultimately, we saw profound benefits on outcomes with a greater than 30% reduction in all-cause mortality. Based on these compelling data, we've now completed regulatory submissions in the United States, where we've used a priority review voucher and in the EU with additional global regulatory submissions to follow in late 2024. Turning now to another important program for Alnylam. We're excited today to share new results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with early onset Alzheimer's disease. As you recall, mivelsiran is a leading program in our effort to expand our RNAi platform to target organ systems beyond the liver and address the high unmet need that exists for neurologic diseases. Mivelsiran is a C16 conjugated RNAi therapeutic targeting amyloid beta precursor protein or APP and is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy or CAA. APP is the upstream precursor of all amyloid beta peptides that form the amyloid deposits characteristic of these two diseases. We believe that by lowering APP production, we can reduce the substrate for new amyloid deposition, potentially enable natural clearance and slow, halt, or even improve the clinical manifestations of these devastating diseases. Today, we are sharing initial interim data from the first multiple dose cohort from the Phase 1 study of mivelsiran in early onset Alzheimer’s disease patients. In the chart here in the dotted line, you can see the rapid, robust, and sustained target engagement we achieved with a single 50-milligram dose during the single-dose part of the study as measured by the target engagement biomarker soluble APP beta. After a single dose on day zero, mean reductions of approximately 75% in soluble APP beta were seen at month 1 with sustained reduction of approximately 50% still apparent at month 6 and a slow return towards baseline thereafter. In pink, you can see the initial interim data from the multiple dose portion of the study where patients were administered 50 milligrams at month zero and 6 and then followed through month 7 or 30 days after that second dose. You can see that APP beta follows a very similar trajectory to the patients after the single dose of 50 milligrams through the first 6 months. But then after the second 50-milligram dose at month 6, we see further reductions of APP beta at month 7, with patients achieving above 90% lowering of APP beta. So these are very encouraging data as they indicate we can achieve sustained robust lowering of APP with relatively low doses. Importantly, mivelsiran has been generally well tolerated in both the single and multiple dose parts of the study. No new safety signals have been identified in Phase 1 and no significant abnormalities have been seen on CSF safety labs such as total protein and CSF white cell count or on the exploratory biomarker neurofilament light chain. Given these encouraging results, we continue to aggressively advance this program through clinical development. Specifically, we have continued dose escalation in the single ascending dose portion of the study to fully explore the safety and pharmacology profile of mivelsiran. We've now also initiated multiple ascending dose cohort in the study to explore additional dose regimens. As we announced earlier this year, we've begun a Phase 2 study in CAA, the second leading cause of hemorrhagic stroke and for which there is no existing disease-modifying treatment. In parallel, we're defining next steps for a Phase 2 study in Alzheimer’s disease and will provide updates in due course. Moving to another exciting pipeline update. We moved our third CNS program into the clinic with initiation of a Phase 1 study of ALN-HTT02, which targets the disease-causing Huntington protein in patients with Huntington's disease. In Q3, we shared nonclinical data supporting the broad CNS distribution as well as the tolerability of deep and sustained lowering of HTT in nonhuman primates after single and repeated intrathecal administration of ALN-HTT02. We look forward to sharing updates on this exciting program in the future as we seek to address this progressive and fatal neurodegenerative disease. As we've discussed, our potential upcoming launch in ATTR cardiomyopathy, assuming regulatory approval and near-term achievement of sustainable profitability, are going to give us a strong foundation to continue investing in the promise of RNAi therapeutics to treat a broad variety of diseases with critical unmet needs. But as we've also discussed, we continue to be disciplined about resource allocation in this key phase of growth. As part of that ongoing commitment to optimize our efforts, we've announced today a decision to stop clinical development of ALN-KHK, an investigational RNAi therapeutic targeting ketohexokinase for the treatment of type 2 diabetes mellitus. This decision furthers our efforts to allocate clinical, managerial and financial resources carefully to bring transformative medicines to patients, including our other programs in the metabolic space, which is an exciting one for RNAi therapeutics. We continue to explore multiple targets for metabolic disorders and look forward to sharing updates in the future. So in sum, we've made great progress in advancing our pipeline and platform with much more to come. As a reminder, we're working towards filing proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNS, muscle, and adipose. If we include partnered programs, we anticipate the potential for 15 new INDs by the end of 2025, representing a near doubling of our clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2024 financial results and discussing our full year guidance. Starting with a summary of our P&L results for Q3 2024 compared with the same period in 2023. Total product revenue for the quarter was $420 million or 34% growth versus 2023, with both our TTR and rare franchises reporting strong growth of 34%, primarily driven by continued strong demand, as Tolga previously highlighted. Net revenue from collaborations for the quarter was $57 million, representing a $370 million decrease when compared with last year. The decrease was primarily driven by the recognition in Q3 2023 of the $310 million upfront payment from Roche as well as the $65 million in revenue recognized from a $100 million milestone earned for achieving certain criteria during early clinical development for mivelsiran. Royalty revenue for the quarter was $23 million or more than double what was recognized in the third quarter of 2023. The increase was driven by higher Leqvio sales as Novartis continues to grow demand for Leqvio worldwide. Gross margin on product sales was 80% for the quarter compared with 75% in the third quarter of 2023. The improvement in margin is primarily due to higher costs in 2023 associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses did not occur this year, offset by an increased rate of royalties payable on net sales of AMVUTTRA. I expect our gross margin on product sales will be lower in Q4, driven by a higher royalty rate payable on sales of AMVUTTRA. Our non-GAAP R&D expenses increased 12% in the third quarter compared to the same period last year, primarily due to increased costs associated with our preclinical activities as we progress our 225 strategy to expand our clinical pipeline by the end of 2025 as well as clinical activities, which mainly grew with expenses associated with zilebesiran KARDIA-3 Phase 2 clinical study and increased personnel costs. Our non-GAAP SG&A expenses increased 19% in the third quarter compared to the same period in 2023, primarily due to higher costs associated with marketing investments to promote our TTR therapies and preparations for the potential launch of AMVUTTRA for cardiomyopathy, along with increased personnel costs. Our non-GAAP operating loss for the quarter was $31 million, representing more than a $300 million decrease compared with Q3 2023, primarily driven by the recognition of collaboration revenue related to our Roche agreement and achievement of a mivelsiran milestone last year, as previously highlighted. We ended the quarter with cash, cash equivalents and marketable securities of $2.8 billion compared with $2.4 billion as of December 31, 2023, with the increase primarily due to 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 financial guidance for 2024. Today, we are reiterating our 2024 guidance that was updated on our Q2 earnings call. We anticipate combined net product revenues for our four commercial products will be within a range of $1.575 billion and $1.65 billion. Our collaboration and royalty revenue guidance range is $575 million to $650 million. And lastly, our guidance for combined non-GAAP R&D and SG&A expenses remains a range of between $1.775 billion and $1.875 billion. Let me now turn from financials and discuss some key goals and upcoming milestones for late 2024. We announced that we'll present additional findings from the ongoing Phase I study of ALN-TTRsc04 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions in November. We plan to share our Phase 3 development plan for ALN-TTRsc04 in the first quarter of 2025. We also intend to initiate a Phase 2 study for mivelsiran in patients with Alzheimer's disease at or around year-end. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions. 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. We will take our first question from Ellie Merle with UBS. Your line is open.

Hey, guys. Thanks for taking the question. Just in terms of your earlier-stage pipeline, can you elaborate a bit on some of the work that you've done to improve the ability to deliver RNAi to adipose tissue and muscle? And how are you thinking about what makes the most sense as initial targets or diseases in these tissues? And any specific advantages to your approach versus other modalities? Thanks.

Yes. Thanks, Ellie. As Jeff highlighted, we've talked about how we are very excited about the emerging profile of RNAi therapeutics. What we're seeing is that these therapies appear to be well tolerated, and we can get sustained knockdown of a disease-causing protein that allows for infrequent administration. We're guided by human genetics in terms of the diseases that we pursue, which can allow us to validate both efficacy and safety using population genetics as well as preclinical work. So adipose and muscle are two of the areas that we've highlighted in our 225 strategy as new tissues to pursue. We highlighted a little bit at R&D Day earlier in the year some of the approaches that we're taking, and we remain on track to progress those. We will be talking about an R&D Day early next year, and we'll give the specific timing of that. And that's probably the best time for us to provide a more substantive update on those programs. But we're making good progress. For competitive reasons, we're probably not going to say much more at this point.

Thanks, Pushkal. That's great. And I think it's one of the opportunities of our platform really is to continue delivering ongoing innovation as we start to make progress in some of these extrahepatic issues. Thank you, Ellie. Next question.

Thank you. We'll take our next question from Gena Wang with Barclays. Your line is open.

Thank you for taking my questions. I wanted to ask one question regarding the ALN-HTT02. It seems like very impressive data in nonhuman primates. I believe this is one of very few showing actual knockdown in nonhuman primate brains instead of most showing rodent brain. So I know everyone is using 50% as a benchmark. Is that something you are looking for? What else will you be looking for regarding the Phase 1 data?

Yeah. Thanks, Gena. I'm glad you highlighted the Huntington’s program because it's one that we're particularly excited about. This now represents our third CNS program that we're moving into the clinic. Many of the insights we learned from our APP program in terms of being able to have sustained knockdown of a disease-causing gene and appearing well tolerated in preclinical studies is very encouraging. We believe we will have something that will allow sustained knockdown as well as hopefully be well tolerated in the clinic as we've seen with our APP program to date. The nonclinical findings were actually quite benign in the preclinical studies that we saw, as we highlighted in the slide. It was well tolerated both in rodent and nonhuman primate species. The targeting approach we're taking is quite unique. We're going after an upstream portion of the gene, including the exon 1 fragment. An emerging amount of data in the literature suggests that beyond targeting the full-length mutant protein, targeting the exon 1 fragment may also help in the progression of this rapidly progressive and fatal disease. We think we may have an opportunity for unique efficacy with this molecule. We are moving forward in our single ascending dose study in patients with symptomatic disease. We'll be looking at safety and tolerability, pharmacokinetics, pharmacodynamics, changes in mutant Huntington levels, as well as clinical and imaging and biomarker measures, such as neurofilament light chain, which can be very useful in looking at progression in this disease. The study is in active start-up mode in the U.K., Canada. In the United States, we also have a green light to proceed. I'll note that we do have a dose cap in the U.S. So we still have a green light to proceed in all three territories, and we're moving forward. I'm very excited that we'll be able to do that. We'll work with the FDA going forward if and when we need to lift that dose cap.

Okay. Next question.

Thank you. We'll take our next question from David Lebowitz with Citi. Your line is open.

Thank you very much for taking my question. In terms of polyneuropathy at this point in time, how would you say the impact of a second silencer has been on the market and your overall trajectory? Additionally, I know that plenty of your prescribers for polyneuropathy are cardiologists. Have you noticed an inflection in the number of questions coming regarding the ATTR cardiomyopathy data?

Hi, Dave. Yeah. Look, I mean, now we have 9 months under our belt with another competitor in the marketplace in the United States. What you will see in our quarter-over-quarter growth in the U.S., which is up 8%, as well as our year-over-year growth that is up 37%, is a good indicator of not only how this category still has a significant unmet need, but how we've been able to compete against a competitor. We believe the fact that our route of administration is quarterly, with several options regarding where those patients can receive their treatment, contributes strongly. Patients remain on treatment due to this quarterly dosing and our patient services, as well as the ability to provide rapid knockdown as quickly as with the first dose at 60% and up to 88% after the second dose are important differentiators. We believe this is really gaining good traction among patients and physicians. Regarding the cardiologists, for the second part of your question, we've established very clear guidelines to ensure compliance in our promotion and that the launch is ahead of us. We're not yet in the launch phase. When there are inquiries about HELIOS-B, we appropriately address them and coordinate with our medical affairs colleagues. However, the number of patients coming in with that indication is something we manage as an organization. Overall, again, I'm very pleased with our Q3 performance, and we are continuing to see strong demand in our polyneuropathy hereditary indication.

That's terrific, Tolga. I think it illustrates that we've built a really high-performing commercial engine, and we have a compelling profile for AMVUTTRA. So we're very excited about the future. Thank you. Next question.

Thank you. We'll take our next question from Paul Matteis with Stifel. Your line is open.

Hi. Great. Thanks so much. I wanted to ask one more follow-up question just on recent prescribing dynamics in TTR in light of the HELIOS-B data. And Tolga, I totally understand where you're coming from, right, that you guys promote solely in polyneuropathy. But just as it relates to a cardiologist, if they want to prescribe AMVUTTRA right now, what are the prior authorization requirements that you see? Do they need to have a neurologist corroborate the polyneuropathy diagnosis? Are there significant impediments in place that could limit this drug to that true mixed phenotype population at this point before getting an expanded label? Thank you.

Yeah, Paul, that's a great question. You clearly grasp some of the complications involved in diagnosing patients. If a cardiologist suspects cardiomyopathy, physicians, especially in the United States, tend to perform scintigraphy. If the patient is confirmed to have the condition as suspected, they would then quickly begin treatment. In the case of polyneuropathy, since our indication is hereditary, genetic testing is conducted to validate that. An additional neurological assessment is also performed to ensure the patient presents neurological manifestations of the disease before their treatment begins. Regarding access challenges, nearly all of our patients actually end up receiving good sustained access, regardless of their reimbursement source. So that's really not the challenge. It's primarily an issue with the diagnostic pathway, as polyneuropathy hereditary is the final stage of that pathway rather than the first stage as we observe in cardiomyopathy.

And we'll take our next question from Ritu Baral with TD Cowen. Your line is open.

Hi, guys. Thanks for taking the question. I wanted to ask how Tolga and maybe Jeff are thinking about payer discussions now even ahead of potential label expansion. What are the levers and topics you're discussing? How do you see potential for volume-based discounts after potential label expansion and with the increasing number of patients on AMVUTTRA?

That's a great question, Ritu. I think it's actually for Tolga.

Yeah. So Ritu, as we shared at the TTR Day, what payers care about is the value proposition, which is really driven by clinical outcomes. As we have demonstrated in HELIOS-B, the product provides an important differentiator in terms of cardiovascular outcomes in today's patient population. So far, payers are acknowledging that this remains a rare, albeit growing disease and the compelling outcomes from HELIOS-B are being recognized. The success of our strategy to navigate the access landscape is attributed to our patient access philosophy. We've demonstrated within the polyneuropathy indication how we've enabled seamless access for our patients, a majority of whom encounter no co-pay burden, and around 30% have a co-pay burden of approximately $2,000 or less. Part of our patient access philosophy involves value-based agreements and appropriate rebates. This is an area where, obviously, we will disclose more information. We understand the interest in this; however, we'll communicate that as we approach our PDUFA date, which is not set yet.

Got it. And let me ask a very quick follow-up, guys, just on Paul's question. It's a follow-up to Paul's. So how does the cardiologists' and neurologists' understanding of compressive neuropathies factor into Paul's question?

You mean carpal tunnel syndrome or spinal stenosis? Yeah, in that.

I mean, yeah. Look, I think TTR is a systemic disease, and that's why you have multidisciplinary physicians that actually treat this disease. This doesn’t exist in every market or academic center. However, most centers have a good collaboration between cardiologists and neurologists, and in some cases, even orthopedic surgeons. As the disease has evolved, it tends to be the cardiologists who first diagnose the condition, where they conduct scintigraphy and make a preliminary diagnosis. If there isn't suspicion of additional disease manifestations, they typically prescribe the only approved product available today. We believe this will change over time.

I think it's a great question because these red flag symptoms are going to be an essential aspect of physician education and awareness going forward. So thank you for the two questions. Let's take the next one.

Thank you. We'll take our next question from Salveen Richter with Goldman Sachs. Your line is open.

Thanks for taking our question. This is Tommy on for Salveen. So you talked about how there is this initial focus on frontline for cardiomyopathy. But wondering what your thoughts are on a potential bolus of path progressors in the second half of next year who are aware and want something new?

Yeah. I mean at our TTR Day, we outlined the strategy. The reason for explaining it is deeply linked to what the data suggests and where today's patients are. As we've highlighted, this is a rapidly progressive and severe disease. Our understanding is that treaters are focusing on diagnosing patients early and want to treat them immediately with products we believe will provide effective data for today’s population. A portion of patients are currently on stabilizers available or on GLP-1 or diuretic intensification. These are the patients they are currently seeing. If you look at the market dynamics, we see an ever-increasing number of patients coming into the category. Thus, establishing ourselves as a first-line product due to the rapid nature of the disease progression and robust data is essential for these patients to get treated. Regarding patients progressing on a stabilizer, physicians may start to identify those and either switch them to our therapy or use a combination therapy, depending on the access limitations they might face. Until tafamidis becomes generic, we anticipate no established switch behavior within this category. We believe it will take time to establish this. We are doing our part to ensure that those progressing are identified, but highlighting the influx of patients and dynamics in the market, we believe AMVUTTRA will be well-positioned to become a first-line standard of care therapy.

Thanks, Tolga.

Thank you. We'll take our next question from Jessica Fye with JPMorgan. Your line is open.

Hey, guys. Good morning. Thanks for taking my question. I got another one on TTR. Is there anything that you're going to be watching for in the acoramidis label with their PDUFA coming up? And stepping back, do you see any potential label scenarios for that product as relevant to your expectations for your own launch in TTR cardiomyopathy? Thank you.

Yeah. Look, like everybody, obviously, we're interested in seeing the acoramidis label, assuming approval. We feel very confident about the data generated with HELIOS-B. We're looking forward to moving through the regulatory process in both the U.S. and Europe, utilizing our priority review voucher to potentially gain early approval next year. We're very pleased with our positioning. We’ll have to wait to see what gets delivered with respect to acoramidis.

Yeah. The only thing I would add is that, while any comments on their label would be speculative, from a broader market dynamic perspective, we believe acoramidis will act as a twice-daily stabilizer. How this market dynamic shapes will heavily depend on our orthogonal mechanism of action and how we can compete with patients still seeking first-line agents or those progressing on a stabilizer.

Terrific. Thank you. Next question, please.

Thank you. We'll take our next question from Gary Nachman with Raymond James. Your line is open.

Thanks. Good morning. As we anticipate the launches of vutriseran and ATTR-CM next year in both the U.S. and EU, how should we think about spending levels in SG&A relative to this year for all the commercial activities you'll be doing, just order of magnitude? And then remind us of the infrastructure you have in Europe and how you think of the CM opportunity there relative to the U.S. in terms of both accessing patients and pricing?

That's a great question. Thank you. I think Jeff will take the first part of it, and then Tolga will follow up with his plans for making sure that we kind of execute on our plans for a potential AMVUTTRA launch.

I would say we upgraded our guidance this year at Q2 on OpEx, which reflected the confidence we had in the HELIOS-B results and this competitive attitude we are taking. You will see in the second half of the year an increase in investment. The commercial team has made good progress in preparing for the launch, particularly in the U.S., with staffing. Much of this hiring occurs in the second half and will naturally lead to growth next year. We will continue to broaden our investments beyond just the U.S. as we move towards launches in Europe. I don't have specific guidance, but I would expect double-digit growth in terms of SG&A. We will provide annual guidance for '25 on our year-end call in February.

We've built a very strong foundation in TTR polyneuropathy. Thus, the growth has been more of an incremental nature to position ourselves well for the CM indication. But Tolga, any other insights to add?

The only thing I would add is, from an organizational perspective, we have established an end-to-end organization that has demonstrated exceptional results, not just in TTR but also in rare. Our TTR organization in Europe and Japan is exhibiting impressive growth numbers. We've posted a 31% year-over-year growth. If you look at our international demand performance, it has seen 6% quarter-over-quarter growth. This has been achieved in a market that has significant price sensitivity, with our PN product priced for a narrower indication. We've been able to become a market leader at 80% versus tafamidis in that specific PN indication. We are quite pleased with the organizational structure established and, as Jeff indicated, we intend to “play to win” and ensure that we provide the right access options in those markets. So far, we've been competing effectively, and we believe that with the HELIOS-B data, we have a tailwind moving forward.

Great. Thank you, Tolga. Next question.

Thank you. We'll take our next question from Kostas Biliouris with BMO Capital. Your line is open.

Good morning, everyone. Thanks for the question. Outside of your pipeline, acknowledging that your pipeline is large and very robust and can drive growth, I'm wondering whether you can comment on potential BD activities that could support even additional growth in addition to your internal efforts? Thank you.

That's a great question. Look, we're very privileged to have an incredibly rich pipeline. We believe it’s one of the most exciting pipelines in the industry. Pushkal touched on the idea that we will be doubling our pipeline by the end of '25, meaning we have many truly interesting opportunities in the company. We're ensuring adequate focus on achieving a successful AMVUTTRA launch. We continue to monitor the innovation landscape and remain open to considering opportunities that enhance our platform and allow access to other tissues, as Pushkal described. That remains our main focus for now. We're in a privileged position with a lot we can progress within the company, and we're excited to advance all our efforts.

Next question. I think this is our last question.

We'll take our last question from Tazeen Ahmad with Bank of America. Your line is open.

Great. Thank you for squeezing me in. Maybe this last one is for Tolga, going back to the launch. In terms of expectations for the early part of any rare disease launch, companies discuss the time it takes from when the script is written to when the script is dispensed to the patient. However, since this will be the second indication for your product, do you expect the traditional timelines usually described to hold true, or will they have been smoothed out following your PN launch?

Thank you, Tazeen. We recognize that this is an area where we do need to provide additional color, and we will do that closer to our launch timelines along with the respective engagements we will have. We should be able to provide additional context as we approach the launch.

Thank you, Tolga. And look, thank you to everyone for joining us on the call. We feel very pleased with the third quarter of 2024. It was one of continued progress. We delivered robust financial growth as well as advancements in our pipeline. So thank you, everybody, and have a great day.

That concludes today's teleconference. Thank you for your participation. You may now disconnect.