Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Analysis

Alnylam Reports Strong Growth and Positive Pipeline Progress in Q3 2024

In Q3 2024, Alnylam achieved $420 million in product revenue, a 34% increase year-over-year, driven by robust demand in their TTR and rare franchises. Collaborations' revenue fell significantly to $57 million due to last year's upfront payments. Royalty revenue surged to $23 million, benefitting from Novartis' LEQVIO sales. Despite a projected Q4 decline in gross margin, total cash reserves rose to $2.8 billion. For 2024, Alnylam expects net product revenues between $1.575 billion and $1.65 billion, alongside collaboration and royalty revenues of $575 million to $650 million, as they prepare for a potential product launch in ATTR cardiomyopathy.

Strong Revenue Growth and Key Highlights

In Q3 2024, Alnylam Pharmaceuticals achieved an impressive 34% year-over-year growth in global net product revenue, reaching $420 million. This growth stemmed mainly from the success of its TTR (transthyretin) and rare franchises, both growing at 34%. The company is witnessing a consistent uptick in patient numbers, showcasing ongoing strong demand for its therapies. Notably, they are nearing the treatment milestone of 5,000 patients with their TTR medications, ONPATTRO and AMVUTTRA, highlighting the market's growing acceptance and need for these innovations【4:0†source】.

Revenue Dynamics and Collaboration Income

Alnylam reported a net revenue from collaborations for the quarter at $57 million, which reflects a significant decrease of $370 million compared to last year. This notable change results from a one-time $310 million upfront payment from Roche recognized in Q3 2023, as well as a $65 million milestone from the mivelsiran program. Additionally, royalty revenues surged to $23 million, marking more than a 100% increase from the prior year, primarily due to the rise in LEQVIO sales【4:0†source】.

Gross Margin and Operating Costs

The gross margin for product sales improved to 80%, up from 75% a year earlier. This improvement is largely attributed to reduced costs associated with manufacturing commitments that were canceled last year. However, expectations for Q4 suggest margins may decline due to increased royalty rates on AMVUTTRA sales. On the expense side, non-GAAP R&D costs rose 12%, and SG&A expenses grew by 19%, reflecting strategic investments for market competitiveness and clinical activities【4:0†source】.

Future Financial Guidance

Alnylam reiterated its 2024 financial guidance. The company expects combined net product revenues for its four commercial products to fall between $1.575 billion and $1.65 billion, and collaboration and royalty revenue to range from $575 million to $650 million. Furthermore, they anticipate total non-GAAP R&D and SG&A expenses will be between $1.775 billion and $1.875 billion【4:0†source】.

Pipeline Progress and New Clinical Trials

The pipeline continues to gather momentum with new initiatives, especially in the neurological space. Alnylam's exciting developments include the completion of regulatory filings for vutrisiran, targeting ATTR cardiomyopathy, and promising early results from ongoing trials for mivelsiran in Alzheimer’s disease. The HELIOS-B study highlighted vutrisiran's potential, reporting over 30% reduction in all-cause mortality, positioning Alnylam favorably for the corresponding regulatory approvals【4:0†source】【4:19†source】.

Increasing Investment in Future Growth

Alnylam is firmly focused on expanding its clinical pipeline, pledging to file proprietary INDs for nine programs by the end of 2025. This commitment reflects their goal of doubling the clinical pipeline, thereby enhancing their potential for sustained growth. As part of their strategy, clinical development activities were outlined, deducing robust and sustained responses in safety and efficacy from their various trials【4:0†source】【4:9†source】.

Navigating Competitive Landscape

With the increasing market competition, particularly following the entrance of alternative therapies, Alnylam is poised to leverage the favorable data from their studies as a competitive edge. The anticipation surrounding the launch of AMVUTTRA for cardiomyopathy signifies a crucial point in Alnylam's growth story, with expectations for strong market penetration due to the emerging clinical efficacy and improved patient access【4:0†source】【4:14†source】.

Conclusion and Strategic Outlook

Overall, Alnylam's Q3 results illuminate a period of robust growth, strategic pipeline advancements, and proactive management of expenses and revenue streams. The company's unwavering dedication to innovation and addressing profound unmet patient needs establishes it as a formidable player in the biotech landscape, with much to look forward to in the wake of upcoming product launches and regulatory approvals【4:0†source】【4:19†source】.

Earnings Call Transcript 2024-Q3

[Operator]

Good day, everyone, and welcome to today's Alnylam Pharmaceuticals' Q3 2024 Earnings Conference Call. [Operator Instructions] Please note this call is being recorded. [Operator Instructions]

It is now my pleasure to turn the conference over to the company.

[Christine Lindenboom, executive]

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 on 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'd like to turn the call over to Yvonne. Yvonne?

[Yvonne Greenstreet, executive]

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 4 marketed products. We made great progress with our TTR franchise, sharing additional results on 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 I 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 I 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 achievement by year-end 2025 of our Alnylam P5x25 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?

[Tolga Tanguler, executive]

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 continued 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 continued 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 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 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 the TTR franchise growth decreased by minus 9% compared to the second quarter of 2024, yet our quarter-over-quarter patient demand remained strong with plus 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 are 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 end points in a population reflective of today's patients.

We have a track record of success in polyneuropathy and experienced operating in a competitive environment. And our dedicated focus on ATTR will be instrumental as we scale for a successful launch, building on Alnylam's flagship franchise and ushering a new phase of growth.

Now moving to our rare franchise and 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; a 79% increase in our rest of world market 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. 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 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?

[Pushkal Garg, executive]

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 RNA mechanism of action. We then saw a 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 I study of mivelsiran in patients with early onset Alzheimer's disease. As you recall, mivelsiran 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.

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 that are characteristic of these 2 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 I 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 0, 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 months 0 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 I 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 a multiple ascending dose cohort in the study to explore additional dose regimens. As we announced earlier this year, we have begun a Phase II 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 we'll 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 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 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 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?

[Jeffrey Poulton, executive]

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 progressed 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 II 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 4 commercial products will be within a range of $1.575 billion and $1.65 billion. Our collaboration and royalty revenue guidance ranges $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 III development plan for ALN-TTRsc04 in the first quarter of 2025.

We also intend to initiate a Phase II 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?

[Christine Lindenboom, executive]

Thank you, Jeff. Operator, we will now open the call for questions. For those dialed in, we would like to ask you to limit yourself to 1 question each and then get back in the queue if you have any additional questions.

[Operator]

[Operator Instructions] And we'll take our first question from Ellie Merle with UBS.

[Eliana Merle, analyst]

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?

[Pushkal Garg, executive]

Yes. Thanks, Ellie. As Jeff highlighted, we've talked about, 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 2 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.

So we're making good progress. And for competitive reasons, we're probably not going to say a lot more at this point.

[Yvonne Greenstreet, executive]

Thanks, Pushkal. That's great. 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.

[Operator]

We'll take our next question from Gena Wang with Barclays.

[Huidong Wang, analyst]

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 knocking down in nonhuman primate brains instead of most of others showing rodent brains. So I know everyone is using 50% as a benchmark. Is that something you are looking for? What else you will be looking for regarding the Phase I data?

[Pushkal Garg, executive]

Yes. 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. 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.

So 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 I highlighted in the slide, was well tolerated both in rodent and nonhuman 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 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 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, we'll be looking at changes in mutant Huntington's level -- mutant Huntington levels. And we'll also have in that, as we go forward, clinical imaging and biomarker measures, measures such as NFL, et cetera, that can be very useful in looking at progression in this disease.

The study is in active start-up mode in the U.K., 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 3 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.

[Operator]

We'll take our next question from David Lebowitz with Citi.

[David Lebowitz, analyst]

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 the 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?

[Tolga Tanguler, executive]

Yes. Look, I mean now we have 9 months under our belt with another competitor in the marketplace in the United States. And what you will see in our -- both our quarter-over-quarter growth in the U.S. which is 8% up, as well as our year-over-year growth that is 37% up, is a good indicator of actually not only how this category still there's a significant unmet need, but how we've been able to actually compete versus a competitor.

And we believe the fact that our route of administration is quarterly with 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 at 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 put, established very clear guardrails to make sure that we are promoting compliantly and making sure that the launch is ahead of us, not -- 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 polyneuropathy hereditary indication.

[Yvonne Greenstreet, executive]

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 AMVUTTRA. So we're very excited about the future.

[Operator]

We'll take our next question from Paul Matteis with Stifel.

[Paul Matteis, analyst]

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 that they want to prescribe AMVUTTRA 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 phenotype population at this point before getting an expanded label?

[Tolga Tanguler, executive]

Yes. Paul, that's a great question. And you clearly grasped some of the complications in 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 indication is hereditary, that you would actually go through 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.

[Operator]

We'll take our next question from Ritu Baral with TD Cowen.

[Ritu Baral, analyst]

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 -- 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 AMVUTTRA?

[Yvonne Greenstreet, executive]

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

[Tolga Tanguler, executive]

So Ritu, as we shared at the TTR Day, what payers care, as 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 -- what we're so far seeing is payers understanding, acknowledging that this remains a rare, albeit growing disease, and the fact that 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 polyneuropathy indication, how we've been able to get seamless access to our patients, and a great majority of them not having any co-pay burden and about 30% of them end up having about $2,000 or less co-pay 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 PDUFA date, which is not set yet.

[Ritu Baral, analyst]

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

[Tolga Tanguler, executive]

You mean carpal tunnel or spinal stenosis?

[Ritu Baral, analyst]

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

[Tolga Tanguler, executive]

Yes. Look, I mean, I think TTR is a systemic disease, and that's why you have multicenters that actually treats -- multidisciplinary physicians that actually treat this disease. Now this doesn't also, of course, exist in every -- every academic -- even every academic center. But in most centers, you have a good collaboration between the cardiologists and neurologists, and in some cases even orthopedic surgeon.

But because the disease has been involved -- 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.

[Yvonne Greenstreet, executive]

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 -- the 2 questions. Let's take the next question.

[Operator]

We'll take our next question from Salveen Richter with Goldman Sachs.

[Tommie Reerink, analyst]

This is Tommie on for Salveen. So you talked about how there is this initial focus on the frontline for cardiomyopathy. But wondering if -- what's your thoughts on if there could be a bolus of fast progressors in the second half of next year who are aware and kind of want something new?

[Tolga Tanguler, executive]

Yes. I mean at our TTR day, we delayered the strategy. And the reason why we 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 dialytic 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 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 tafamidis 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 AMVUTTRA will be well positioned to become a first-line standard of care therapy. Assuming approval, of course.

[Operator]

We'll take our next question from Jessica Fye with JPMorgan.

[Jessica Fye, analyst]

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 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?

[Yvonne Greenstreet, executive]

Yes. Like everybody, obviously, we're interested in seeing the acoramidis label, assuming approval. I mean we feel very confident about the data that we've generated with HELIOS-B. And we're looking forward actually to moving through the regulatory process in both the U.S. and in Europe and using our priority review voucher assuming a potential approval early next year.

So we feel really good about where we are. And I think we also have to wait to see exactly what gets delivered with respect to acoramidis.

[Pushkal Garg, executive]

Yes. The only thing I would add is, obviously, to comment on their label would be speculative. But from a broader market dynamic perspective, we believe acoramidis will be a twice daily stabilizer. And how that market dynamic will shape, I think we'll have to do -- a lot to do with our [ own sort of ] mechanism of action and how we would be able to compete in the patient population that are still, again, is the first-line agent or those patients that are progressing on a stabilizer.

[Operator]

We'll take our next question from Gary Nachman with Raymond James.

[Gary Nachman, analyst]

So as we anticipate the launches of vutri and ATTR-CM 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.

[Yvonne Greenstreet, executive]

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

[Jeffrey Poulton, executive]

Yes. I mean I would say we upgraded our guidance this year at Q2 on OpEx, right? And that reflected confidence that we had in the HELIOS-B results and sort of playing to win. And so 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 more broadly even then just in the U.S. as we move towards the second half of the year 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.

[Yvonne Greenstreet, executive]

Yes. No, what's been great is that we've actually built a very strong foundation actually in TTR polyneuropathy. 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 that...

[Tolga Tanguler, executive]

I mean the only thing I would add is, from an organizational focus perspective, we have establish 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 of -- on the demand side of our international business, it's been up at 6% quarter-over-quarter.

Now that's been done in a market where there is significant price sensitivity, where we have a PN product that's priced for the narrower indication. And we've been able to become a market leader at 80% versus tafamidis 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 HELIOS-B data as a tailwind.

[Operator]

We'll take our next question from Kostas Biliouris with BMO Capital.

[Konstantinos Biliouris, analyst]

[Technical Difficulty] outside of the 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 potentially support even additional growth in addition to your internal efforts.

[Yvonne Greenstreet, executive]

Yes, 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 one of the most exciting pipelines in the industry. And Pushkal 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 AMVUTTRA launch. And so we're really focused on driving both our internal pipeline as well as continuing to optimize the platform.

What we think about BD, we're also very open to considering opportunities that really enable our platform and help us continue to access all the other tissues, and Pushkal described some of these. And so really that's our focus at the moment.

Clearly, we obviously 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? I think it's our last question.

[Operator]

We'll take our last question from Tazeen Ahmad with Bank of America.

[Tazeen Ahmad, analyst]

Great. 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, 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 time lines as to extended time period, at least initially, to hold true here? Or do you expect that to already have been smoothed out from your PN launch?

[Tolga Tanguler, executive]

Yes. Thank you, Tazeen. 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 time lines and the respective engagements that we will have. And we should be able to provide additional context as we get closer to the launch.

[Yvonne Greenstreet, executive]

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.

[Operator]

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