Alnylam Pharmaceuticals, Inc.

Please stand by. Your program is about to begin. If you need assistance during your conference today, please press star zero. Good day, everyone, and welcome to today's Nylon 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. You may register to ask a question at any time by pressing the star and 1 on your telephone keypad. You may withdraw yourself from the queue by pressing star 2. 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 LNILAM. With me today are Yvonne Greenstreet, Chief Executive Officer, Tolga Tanguilar, Chief Commercial Officer, Krishkal Garg, Chief Financial Officer, and Jeff Fulton, 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.lnlm.com slash events. During today's call, as outlined in slide two, Yvonne will offer introductory remarks and provide some general context. we'll provide an update on our global commercial progress, which 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 L9'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 we're representing our views as of any subsequent date. We specifically explain any obligation to update such statements. With that, I'd like to turn this 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 TCR franchise, sharing additional results from the helios b study of retreat ram and filing regulatory submissions in the us 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 ambutra and our broader ttr portfolio will serve as our flagship franchise similar in potential impact to what ilia 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 CNF. We initiated a phase one study of ALN-HTTO2 in Huntington's disease, And we're pleased to announce today initial results from the multi-dose portion of the phase one study of Mibeltoran 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 achievement by year-end 2025 of our nylon pizza fifth by 25 goals. and are steadfast in our belief that we're on track to become a top tier biotech, developing and commercializing 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 Onpatro or Ambutro globally, and there is still a significant growth opportunity given that 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 Onpatra and Ambutra increased by 8% compared with the second quarter and a robust 37% year-over-year as momentum in new patient ads continues to drive strong growth. The US 37% year-over-year growth was primarily driven by the following. A 31% increase in demand, driven by the strength of ongoing Ambutra patient uptake, more than offsetting the decrease in patients on Ampatro who have switched to Ambutra. 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 growth to net adjustment. Now let me turn to our international market where the TTR franchise growth decreased by minus 9% compared to the second quarter of 2024, yet our quarter over quarter patient demand remains strong with plus 6% growth. The 9% quarter-on-quarter decrease was driven by a gross net adjustment in Portugal that was booked in Q3 and large orders of OnPatro in our partner markets in Q2, including Australia, where we built inventory as we launched OnPatro 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 Vutrisram in addressing ATTR cardiomyopathy pending regulatory approval. We're confident in our journey toward 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. And our dedicated focus on ATTR will be instrumental as we scale for a successful launch, building a Lionel's flagship franchise, and ushering a new phase of growth. Now, moving to our rare franchise and the performance of Givlari Noxdova, 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 Givlari, 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 US, primarily driven by growth in new patients on therapy, a 79% increase in our rest of world market, primarily driven by the timing of orders, in our partner market, primarily Brazil, and increased demand growth across European markets. For Oxumo, 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. A 54% increase in the U.S., primarily driven by strong patient demand growth, a 33% growth from our rest of world market, primarily driven by strong patient demand growth across both EU and our partner market. 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 Utrecht'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 RNA 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. And 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 one study of Mivelt-Saran in patients with early onset Alzheimer's disease. As you recall, Mivelseran is the 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. Mivelseran 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 that are 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 Mevel-Saran 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 single dose on day zero, mean reductions of approximately 75% in soluble APP beta were seen at month one, with sustained reduction of approximately 50% still apparent at month six, 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 six, and then followed through month seven, 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 six months. But then after the second 50 milligram dose at month six, we see further reductions of APP beta at month seven, 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, mevelserine 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 one, 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 mevelseran. We've now also initiated multiple ascending dose cohorts in the study to explore additional dose regimens. As we announced earlier this year, we've begun a phase two study in CAA, the second leading cause of hemorrhagic stroke, and for which there is no existing disease modifying treatment. And in parallel, we're defining next steps for a Phase II study in Alzheimer's disease and 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 I study of ALNHT02, 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-HTTO2. 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 our antitherapeutics 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 ALNKHK, an investigational RNAi therapeutic targeting ketohexakinase 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 nine programs by the end of 2025 against targets in the liver, CNS, muscle, and adipose. If we include partner 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 Pushkol 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 Mabelsaran. 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 LECVIO sales as Novartis continues to grow demand for LECVIO 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 OnPatro 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 Inbutra. I expect our gross margin on product sales will be lower in Q4 driven by a higher royalty rate payable on sales of Inbutra. 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 LBCR and Cardio 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 Ambutra 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 Mabel Saran 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 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 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 one study of ALN TTR SCO4 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions in November. We plan to share our phase three development plan for ALN TTR SCO4 in the first quarter of 2025. We also intend to initiate a phase two study for mevalceran 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. At this time, if you would like to ask a question, please press the star and one on your telephone keypad. You may remove yourself from the queue at any time by pressing star two. Once again, that is star and one to ask a question. We will pause for a moment to allow questions to queue. And we'll 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.

Yeah, thanks, Ellie. Jeff Eileid, we've talked about, you know, we are very excited about the emerging profile of RNAi therapeutics, right? 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. And 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 actually are, we'll 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 give a more substantive, update on those programs. But we're making good progress. And for competitive reasons, we're probably not going to say a lot more at this point.

Thanks, Pushkar. 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 tissues. Thank you, Eddie. Next question.

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

Thank you for taking my questions. I wanted to ask one question regarding the Htt02. It seems like very impressive data in non-human primates. I believe this is one of very few showing actual knocking down in non-human primates' brains instead of most of others showing rodent brains. So I know everyone's using 50% as a benchmark. Is that something you are looking for? What else you would be looking for regarding the phase one data.

Yeah, thanks, Gina. 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. And what we're seeing here is that Many of the insights that we learned from our APP program in terms of being able to have sustained knockdown of a disease-causing gene and appears to be well tolerated in preclinical studies is very encouraging. You know, so this, you know, 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 non-human primate species. And then the targeting approach we're taking is quite unique. We're going after an upstream portion of the gene, which includes the exon 1 fragment. And, you know, there's been an emerging amount of data in the literature that suggests that beyond targeting the full-length mutant protein, that targeting the exon 1 fragment may also help. in progression of this otherwise, you know, very, very rapidly progressive and fatal disease. So we think we may have an opportunity for unique efficacy with this molecule. So we're moving forward in our single ascending dose study. These are in patients with symptomatic disease. We'll be looking at safety and tolerability. PK, PD will be looking at changes in mutant Huntington's level. mutant Huntington levels, and we'll also have in that, as we go forward, clinical and imaging and biomarker measures, measures such as NFL, et cetera, that can be very useful in looking at progression of this disease. The study is in active startup mode in the UK, Canada, and then in the United States, we also have a green light to proceed. I'll note that we do have a dose cap in the United States. And so we still have a green light to proceed in all three territories, and we're moving forward, so I'm very excited that we'll be able to do that. And we'll work with the FDA going forward if and when we need to sort of lift that dose cap. It may give us enough coverage as it is to cover the doses that we're interested in, but we'll work with the FDA in terms of lifting that dose cap over time. And so we're very excited about this program.

Next question. Thank you. We'll take our next question from David Leibowitz 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? And 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 nine months under our belt with another competitor in the marketplace in the United States, and what you will see in our quarter growth in the U.S., which is 8% up, As well as our year over year growth that is 34 37% up is a good indicator of actually not only how this category this category still there's a significant omit needs, but how we've been able to actually compete versus a competitor. And we believe the fact that our you know route of administration is is quarterly. with a number of optionalities in terms of where those patients actually can receive their treatment. The fact that our patients remain on treatment due to this quarterly dosing and our patient services, as well as obviously what you'll see in our platform that the ability to provide rapid knockdown as quickly as within the first dose at 60% and up to 88% after the second dose are important differentiators, and we believe this is really getting good traction, both with patients as well as physicians. In terms of the cardiologists, the second part of your question, look, we've established very clear guardrails to make sure that we are promoting compliantly and making sure that the launch is ahead of us. We're not in the launch phase. And when there is questions around Helios B, we appropriately address that and triage that with our medical affairs colleagues. But in terms of the number of patients that are coming in with that indication, that would not be something that we would allow as an organization. But overall, again, I'm very pleased with the performance of Q3. And we are seeing, we're continuing to see good, robust demand in our pulmonary hereditary indications.

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

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

Great. Thanks so much. I wanted to ask one more follow-up question just on recent prescribing dynamics and TTR in light of the heliospeed 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 that they want to prescribe and butcher right now, what are the prior auth requirements that you see? Do they need to have a neurologist offer corroboration of a polyneuropathy diagnosis? Like, are there kind of significant impediments in place that really confine this drug to that true mixed-venom type population at this point before getting an expanded label? Thank you.

Yeah, Paul, that's a great question. And you clearly grasp some of the complications and how the patients are actually getting diagnosed. So if you're in a cardiomyopathy, if you're suspected of having a cardiomyopathy, physicians, especially in the United States, tend to go through scintigraphy. and if the patient actually is determined to have the condition as suspected, they would then be quickly put on the treatment. Now, in polyneuropathy, not only because of our indications hereditary that you would actually go to a genetic testing to validate that, and then you would also have an additional neurological workup to make sure that that patient actually has the neurological manifestations of the disease. and then you would be put on the treatment. Now, in terms of the access challenges, nearly all of our patients actually end up getting good sustained access regardless of what source of reimbursement channel they have. So that's really not the challenge. It mostly is the challenge on the diagnostic pathway, polyneuropathy hereditary being the last stage of that pathway rather than the first stage what we see in cardiomyopathy.

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

Hi, guys. Thanks for taking the question. I wanted to ask just how, Tolga and maybe Jeff, how you are thinking about payer discussions now, even ahead of potential label expansion, what are the levers Well, what are the topics that you're discussing, and how are you viewing the potential for volume-based discounts upon potential label expansion and increasing number of patients on Hootra?

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 is, they should be, is the value proposition, which is really driven by the clinical outcome. And as we have demonstrated in the Helios B, the product really does provide an incredible and important differentiator in terms of CV outcome in today's patient population. So that's what we're so far seeing is payers understanding, acknowledging that this remains a rare, albeit growing disease, and the fact that, you know, the Helios B results, outcomes, are compelling. In terms of how we're going to be able to navigate the access landscape has a lot to do with our patient access philosophy. I think what we've been able to demonstrate within the pole neuropathy indication, how we've been able to get seamless access to our patients and a big majority of them not having any copay burden and about 30% of them end up having about $2,000 or less copay burden. And part of our patient access philosophy has to do with value-based agreements and appropriate rebates. This is an area where obviously we're going to be disclosing more. We understand and appreciate why there is interest in this. But we will actually communicate that as we get more closer to our producer date, which is not set yet.

Got it. And if I may ask a very quick follow-up, guys, just on Paul's question. To follow up to Paul's, so I'm going to squeeze this in. How is the cardiologist and neurologist's understanding of compressive neuropathies factor into Paul's question?

Oh, you mean carpal tunnel or spinal stenosis?

Carpal tunnel, spinal stenosis, yeah, in that pathway.

Yeah. Look, I mean, I think TTR is a systemic disease. And that's why you have multi-centers that actually treat multidisciplinary physicians that actually treat this disease. Now, this doesn't also, of course, exist in every market, every academic, even every academic center. But in most centers, you have a good collaboration between a cardiologist and a neurologist, and in some cases, even orthopedic surgeons. But because the disease has been evolved, the genesis of the disease evolved by the cardiologists, The first stop tends to be the cardiologist where they actually do the scintigraphy and do the preliminary diagnosis. And if there is not suspicion of additional manifestations of disease, they tend to go with the only approved product that's available today. And we believe that's obviously going to change over time.

I think it's a great question actually, Ritu, because these red flag, Symptoms, I think, are going to be an important part of physician education and awareness going forward. So thanks for the question. There are two questions. Let's take the next question.

Thank you. We'll take our next question from Salveen Richer with Goldman Sachs. Your line is open. Thanks for taking our question.

This is Tommy on for Salveen. So you talked about how there's this initial focus on the front line for cardiomyopathy, but wondering if, what's your thoughts on if there could be a bolus of past progressors in the second half of next year who are aware and kind of want something new? Thank you.

Yeah, I mean, at our TTR day, we belayered the strategy. And the reason why we, you know, explained that strategy has a lot to do with what the data suggests, and where today's patients are. So as we highlighted, this is a fast-progressing and severe disease. So our understanding is the treaters are really focusing in to make sure that they, as soon as they diagnose these patients, they want to diagnose them early, and they want to hit hard, hit hard with a product that we believe is going to be providing data with today's patient population where the subgroup patients where a portion of them are on the only stabilizers that is available or with GLP-1 or they're on diuretic intensification. Those are the patients that they are currently seeing. And if you look at the dynamic of the market, we see ever larger number of patients that are coming into the category. So you want to be able to establish yourself as a first-line product because of the data and because of the fast progress about the nature of the disease, so those patients actually can get treated. Now, in terms of, you know, patients that might be progressing on a stabilizer, of course, I'm sure physicians will start identifying those patients if they haven't already done so and will probably eventually either, depending on the access limitations or challenges that they may have, either put them, switch them on those patients, or use a combination therapy. Now, it's important to highlight that until tefamidase will become generic, there is no switch behavior that's been established in this category. Therefore, we do believe that will take some time to establish. And obviously, we will be doing our part to make sure that those patients are identified, those patients that are progressing, are well-identified. But I think it's important to highlight that given the number of patients that are coming into the category and the dynamic and the data that we have, we believe Amutra will be well-positioned to become a first-line standard of care therapy.

Thanks for that. Assuming approval, of course. Yes, of course. Thank you for answering that question.

Next question. Thank you. We'll take our next question from Jessica Tsai with JP Morgan. 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 acaramidus label with their PDUFA coming up? And I guess stepping back, do you see any of the potential label scenarios for that product as relevant to your expectations for your own launch in TTR cardiomyopathy? Thank you.

Yeah, I know, like, like everybody, obviously, we're interested in, you know, seeing the accurate the acronym is label, assuming approval, I mean, we feel very confident about the data that we've generated with EDSB. And, you know, we're looking forward actually to moving through, you know, the regulatory process in both the US and in Europe, and, you know, using our priority review voucher, assuming potential approval early next year. So we feel really good about where we are. And I think we'll just have to wait to see exactly what gets delivered with respect to Acromedas.

The only thing I would add is obviously, you know, to comment on their label would be speculative. But from a broader market dynamic perspective, we believe Acromedas will be a twice daily stabilizer. And how that market dynamic will shape, I think, will have to do a lot to do with our orthogonal mechanism of action and how we would be able to compete in the patient population that are still, you know, again, is a first-line agent or those patients that are 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. So as we anticipate the launches of VUTRI and ATTRCM next year in both the U.S. and then the 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 also pricing? Thanks.

That's a great question. Thanks. 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 potential arbitrage.

Yeah, I would say we upgraded our guidance this year at Q2 on OpEx, right, and that reflected confidence that we had in the results and sort of playing to win. you'll see in the second half of the year this year an increase in investment. And the commercial team has made very good progress in starting to prepare for the launch, particularly in the U.S. with the hiring that's been done. So with a lot of that happening in the second half of the year, that's obviously going to create growth for next year. And we'll continue to invest, you know, more broadly even than just in the U.S. as we move towards the second half of the year and launches in Europe. I don't have specific guidance, but I would expect that certainly double-digit growth in terms of SG&A But we'll provide our annual guidance for 25 on our year-end call in February.

Yeah, and what's been great is that we've actually built a very strong foundation, actually, in TCR public neuropathy. And so, really, it's been more of a sort of incremental growth to make sure that we're absolutely well-positioned to be successful in the CM indication. But, Tolga, anything else?

I mean, the only thing I would add is, from an organizational-focused perspective, we have a established an end-to-end organization, which has actually demonstrated excellent results, not only in TTR, but also in rare. So our TTR organization, not only in Europe, but also in Japan, has been demonstrating really robust growth numbers. I mean, we've just posted a 31% year-over-year growth. If you look at the performance on the demand side of our international business, has been up at 6% quarter over quarter. Now that's been done in a market where there's significant price sensitivity, where we have a PN product that's priced for the narrow indication, and we've been able to become a market leader at 80% versus Tefamilis in that specific PN indication where we also compete with them in that indication. So we actually are quite pleased with the structure that we've established. And as Jeff indicated, we're going to play to win and make sure that we are providing the right access options in those markets. And so far, we've been able to compete well, and we believe we'll be able to do that with the Heliospeed data as a tailwind. Great.

Thank you, Tolga. Next question.

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

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

Yeah, no, that's a great question. Look, we're very privileged, actually, to have kind of an incredibly rich pipeline. I mean, we think it's, you know, one of the most exciting pipelines in the industry. And Pushkar touched on the fact that we'll be doubling the pipeline by the end of 25. So we've got a lot of really, really interesting opportunities in the company. And clearly, we're also going to make sure that we focus on a successful Avutra launch. And so we're really focused on driving both our internal pipeline as well as continuing to optimize the platform. When we think about BDs, We're also very open to considering, you know, opportunities that really enable our platform and help us, you know, continue to access, you know, all the other tissues and Prashkar described some of these. And so really, that's our focus at the moment. Clearly, we, you know, we obviously, you know, pay a lot of attention to what's happening in the innovation landscape around us. But really, we have We're in a very privileged position to have an awful lot that we can progress within the company. We're excited to move all of that forward. Next question. Thank you.

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 the last one is for Toga going back to the launch. In terms of expectations, For the early part of any rare disease launch, I think companies talk about the time it's going to take from the time the script is written to the time that the script is dispensed to the patient. But since this is going to be the second indication for your product, do you expect those traditional, sometimes conservative timelines as to extended time periods, at least initially, to hold true here? Or do you expect that to already have been smoothed out from your PM launch? Thanks.

Yeah, thank you. We recognize that this is an area where we do need to provide some additional color and we will do that closer to our launch timelines and the respective engagements that we will have. And we should be able to provide additional context as we get closer to 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've delivered robust national 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.