Alnylam Pharmaceuticals (ALNY) Q3 2026 earnings call transcript

Good morning. I'm Josh Brodsky, Vice President of Investor Relations at El Nylum. With me today are Yvonne Greenstreet, Chief Executive Officer, Tolga Tangular, Chief Commercialization Officer, Pushgal Garg, Chief Research and Development 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. elnylum. com-slash-events.

I'd like to remind you that this call will contain remarks concerning El Nylum's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important risks and uncertainties, including those discussed under the heading risk factors in our most recent periodic report available on our website and on file with the SEC.

We disclaim any obligation to update such statements. With that, I'll now turn the call over to Yvonne. Yvonne.

Thanks, Josh, and thank you everyone for joining the call today. I'm going to begin by putting the call into context and discussing why our commercial portfolio and pipeline give us confidence in our Nylum's growth. Togor will then review our commercial performance and the work underway to expand and vutra adoption and support patient access. For this call, we'll walk through our decision to further expand, try to on CM enrollment, and important progress across our pipeline.

And finally, Jeff will review our Q3 financial results and our outlook for the fourth quarter and full year before we go to Q&A. I want to start by why we remain confident in the opportunity ahead of our Nylum. And vutra has demonstrated significant benefits for patients with ATTR cardiomopathy, including reductions in mortality and cardiovascular events with quarterly dosing.

We believe that this profile and I'm vutra's unique mechanism of action, position it to become a foundational treatment in a market where many patients remain untreated and many physicians are still gaining experience with the medicine.

Now moving on to the quarter, our third quarter product revenues grew 52% year over year to approximately $1.3 billion, led by continued and vutra uptake, establishing a strong foundation for our TTR franchise. We generate a total TTR revenues of $1.15 billion during the third quarter, representing nearly 60% growth year over year. We have deep conviction in the commercial initiatives and investments we authorized earlier this year and have now fully implemented.

Given the magnitude of the opportunity in front of us, we believe these are the right actions to broaden and vutra's prescriber base, deepen physician engagement and over time, drive adoption at scale. That said, we're not yet satisfied with the underlying demand growth we have observed and this is reflected in the four-year outlook that Jeff will discuss shortly.

As Toga will describe in more detail, our Salesforce expansion is increasing physician engagement but that engagement takes time to translate into additional patient starts. We have more work to do and accelerating that translation is a clear priority for us. With what we believe is the best in class clinical profile, demonstrated by continued evidence generation from PDSB and vutra continues to offer a significant opportunity to expand physician adoption and reach more patients in a growing ATTR market.

And at the same time, the performance of our TTR franchise is funding the future drivers of our 9Ms growth. We're investing in and advancing the next wave of medicines as we build a more diversified multi-franchise business.

Within the TTR category, the increase around gives us the opportunity to build on and vutra success with deeper TTR lowering and twice yearly dosing. We have a high level of conviction and a positive trait on CM Outcome and today we announce further expansion of enrollment in the study to approximately 2,250 patients. This expansion optimizes the increase around chances for success and strengthens our long-term TTR position.

Bush goal will go into more detail, but importantly, this expansion does not change our expected ATTR multi-launch timing of 2030, subject to positive study results and regulatory approval. Beyond TTR, the early brazosiran results we recently reported in Huntington's disease are particularly encouraging. The target engagement and safety findings to date support our preparations to initiate a pivotal study in 2027 pending regulatory alignment.

Longer term, our 9M2030 vision continues to guide our priorities and investments for the next half of the decade. Our 9M2030 represents our aspiration to become the leading science-driven, fully integrated global bar pharmaceutical company and to maximise the full potential of RNAi therapeutics for patients. It also means driving commercial execution with laser-like focus and urgency while continuing to invest in the science that can sustain our 9M2030 growth over time.

We have a substantial opportunity in front of us, and our responsibility is to turn it into results for patients and shareholders. With that, let me now turn the call over to Tolga, who will take you through our commercial progress, including our efforts to expand the prescriber base and reach more patients. Tolga?

Thanks, Simon. And good morning. We delivered significant year-over-year growth in the third quarter and continued to bring our therapies to more patients around the world. Today, I will discuss what drove our revenue, where underlying demand has room to grow, and the plans we have in place to capture the opportunity ahead.

In the third quarter, we generated $1.29 billion in combined net product revenues, an increase of 52% year-over-year and 10% compared with the second quarter, including the impact of foreign exchange.

This performance reflects continued execution across our portfolio, led by the TTR franchise, and complemented by our rare disease therapies. And turning to our TTR franchise, global net product revenues reached $1.15 billion in the third quarter, increasing 12% compared with Q2 and 59% year-over-year.

In the US, TTR revenues increased 12% sequentially and 69% year-over-year. This approximate $100 million in US quarter-over quarter revenue growth was driven primarily by an $81 million increase in demand, along with an inventory benefit of $17 million.

Net price during Q3 modestly increased from Q2 and benefited from approximately $10 million in one-time gross-tonet adjustments. Jeff will cover these items in more detail. Outside the US, TTR revenues increased 10% sequentially and 28% year-over-year. Year-over-year growth was primarily driven by ATTR CM uptake in Japan and Germany, partially offset by the impact of CM launch price reductions.

We're excited by the speed with which we are obtaining access in new markets across Europe, with favorable pricing, recognizing the value of Amutra over stabilizers.

XUS markets have contributed significantly to TTR families' growth over time, and there is significant opportunity here to support our TTR global leadership ambitions.

Taken together, these results reflect sustained global growth across the TTR franchise. Looking beyond quarterly revenue, we continue to see encouraging indicators of expansion across the US TTR market and the Amutra prescriber base.

Total ATTR CM prescriptions grew nearly 40% year-over-year in the third quarter. While the rate of growth can vary quarter-to-quarter, category growth continues to be robust and sustained.

What's more, approximately 80% of prevalent ATTR CM patients remain untreated, underscoring the substantial long-term potential to bring therapy to many more patients.

Since the Amutra CM launch in the United States, more than 2,000 new unique prescribers have prescribed Amutra. This metric is particularly encouraging, given what we know about prescribing behavior among physicians with Amutra experience.

As we highlighted on our Q2 earnings call, we've seen that utilization deepens with experience. Put a simply trial, begins preference, and only with approximately a third of all active prescribers having prescribed Amutra to date, we see a significant opportunity to drive broader adoption and deepen utilization.

This was a key factor behind our decision to expand our customer-facing teams to broaden our reach and engage more prescribers. Now, with that expression in place, we have indeed increased the reach and volume of HCP customer engagements.

While these increased engagements have not yet translated into increased demand growth, we are encouraged by the breadth and depth of HCP engagement, positive message resonance, and continued growth in the Amutra prescribing base with utilization balanced across both centers of excellence and community settings.

That said, we recognize there is more work to do to drive demand growth. Just 18 months into its ATTR CM launch, Amutra already represents approximately 24% of all total TTR category, including CM and PM, through the end of the third quarter.

As launch matures, we will report on total prescriptions or TRX, which captures both new patient starts and ongoing treatments.

Importantly, our share of new to brand prescriptions or NBRX, we previously reported, has stayed stable at north of 30%. And is helping build a growing base of patients who contribute to recurring prescriptions over time.

TRX provides a more comprehensive view of our commercial momentum and the sustain utilization of Amutra as our patient base grows. Notably, we achieved 24% TRX share with only about a third of category prescribers, having tried Amutra to date.

Continued TRX share growth will be driven by deeper utilization among existing prescribers and an expanding breadth of riders, including new to category writers who collectively drive significant category prescription growth and further supported by the strong patient adherence associated with Amutra's quarterly administration.

On access, I would like to address two items. First, the proposed CMS rule change that if finalized as proposed would substantially reduce Medicare reimbursement for Part B medicines acquired through the 340B drug discount program.

The terms of the final rule are not yet known. A final rule is expected imminently and if implemented would become effective January 1st, 2027, though we do not we do anticipate legal challenges from hospital groups.

If the rule is finalized as proposed, we believe that affected health systems may reassess their procurement pathways and or their side of care strategies, protecting patient choice and access to our products will remain our priority. We have multiple options available to mitigate potential risks to patients to access from any final rule, reducing reimbursement, including contracting to make discounts available to 340B covered entities and supporting patients in finding alternative sites of care if needed.

We will remain closely engaged with health systems as the rulemaking process progresses and will be prepared to respond as greater clarity emerges.

Importantly, Amutra has broad and favorable access with approximately 99% of covered lives, having access and approximately 90% of patients able to receive treatment within approximately 10 miles of where they live.

Beyond the potential 340B reimbursement changes, we continue to see the normal evolution of payer policies as 2027 negotiations have progressed. As part of that evolution, effective October 1st, UnitedHealth implemented a more restrictive first line Amutra policy in the Medicare Advantage portion of the market.

Importantly, this is not expected to impact existing patients and there is an exception process that allows appropriate new patients to access Amutra first line.

We therefore do not expect an impact to existing patients, though these additional requirements could create some delays for new patients going forward.

Our patient support services and field reimbursement teams have significant experience supporting patients' access where step therapy is in place.

As we have done in the commercial portion of our business, we remain focused on navigating these changes and protecting patient access to Amutra.

Taken together, we remain confident in the underlying fundamentals of the TTR franchise and encouraged by the continued growth and expanding reach of Amutra. We also recognize the work ahead and we remain focused on execution, expanding patient reach and actively navigating the evolving access environment.

With that, I will now turn the call over to Pushka.

Thanks, Toga, and good morning, everyone. Today, I'll cover why we remain confident in Triton CM, the rationale behind the enrollment expansion of our reference this morning and the progress we're making beyond TTR, particularly with Brazil, Saran, and Hunt Against Disease.

On Island is well positioned to build durable leadership in TTR. As we've discussed, we believe Amutra has a differentiated clinical profile that supports its being the first line treatment of choice for patients with ATTR CM. Amutra's demonstrated substantial improvement in clinical outcomes, function, and quality of life, and its treatment effect is preserved irrespective of background medications, including TTR stabilizers, and has a quarterly dosing profile that supports high adherence.

We're poised to extend our leadership beyond Ambutra with Neutra and our next-generation investigational TTR silencer, which we believe has the potential for even greater efficacy by a deeper knockdown, over 95% with just two doses per year. As you know, Neutra is continuing to advance for both a hereditary ATTR polyneuropathy and ATTR cardamopathy in the Phase III Triton studies.

Recent data from the Cardiotransform study have reinforced our confidence in the Triton CM study, but as I'll explain, we intend to increase the sample size by 500 patients to further enhance the probability of success.

Now, as we've previously shared, we believe three factors may have contributed to the failure of Eplon-Terson to meet its primary endpoint in the Cardiotransform study. One, Eplon-Ferson is an ASO that achieved much less TTR knockdown than Vittrisa-Ran. At under 70%, it seems this was not enough to drive enough of a clinical benefit. Two, patient selection matters. It stands to reason that patients earlier in their disease course will benefit most from a silencing approach, and we saw that in Helios B. The enrollment in Cardiotransform of more advanced patients may have further impaired the ability of Eplon-Terson to deliver significant clinical benefit.

And third, their endpoint was not optimized for success. Cardiotransform focused on cardiovascular mortality in their primary composite endpoint, which fails to capture the multi-system nature of ATTR cardiomyopathy.

The key learnings I just outlined are things we've understood from our own clinical trials over the years, and which we incorporated into the original design of Triton-CM. From the outset, we've enriched our study for patients with early disease who are anticipated to have the largest treatment effect. In addition, our study is an event-driven study with an endpoint of all cosmortality and recurrent CV events. As noted, we believe ACM is a more sensitive endpoint in this disease than CV mortality and an event-driven study is much more robust than a time-bound endpoint.

That said, we have taken this opportunity to evaluate Triton-CM in the context of the data from Cardiotransform in order to maximize the probability of study success.

An important learning that was reinforced in Cardiotransform is that the care of patients with ATTR-CM is very rapidly evolving. With earlier diagnosis and treatment, and greater use of background therapies such as SGLT2 inhibitors. While we remain confident in increased transpotential to deliver a strong treatment effect in the setting, these secular trends do tend to reduce event rates, which can compromise study power.

As such, we are announcing today that we are amending the protocol to further increase the sample size by 500 patients to a total of 2,250 patients to address the potential risk of lower than expected event rates. This larger sample size will ensure adequate study power under quite conservative estimates of event rates. In this expanded population, we will further enrich for early patients who are anticipated to have the largest treatment effect with the use of anti-probienp inclusion criteria.

Importantly, we do not expect this expansion to change our expected launch timeline of approximately 2030 given the speed of enrollment and the ability with more patients to accrue more events. And finally, as we've previously said, we will continue to monitor the ongoing study and consider refinements to the study analysis plan down the road, if warranted.

Moving on, Al Nilum is progressing a broad pipeline of medicines beyond TTR with over 25 clinical programs spanning multiple therapeutic areas, representing a significant opportunity to improve patient health and create value in the years ahead. Today, I'd like to focus on our program in Huntington's disease, which we've announced we're advancing to a pivotal trial pending regulatory alignment.

Huntington's disease is a progressive, fatal neurodegenerative disease. Symptoms typically appear in midlife during prime working and family years, affect motor cognitive and emotional health with patients' average lifespan shortened to approximately 10 to 30 years from diagnosis. We estimate there are more than 100,000 symptomatic patients globally with many more individuals who may be pre-symptomatic or undiagnosed. Huntington is a well-known genetically validated target for Huntington's disease, which is caused by an expanded CAG repeat in the first exon of the Huntington gene. Individuals who inherit an allele with 40 or more repeats are expected to develop Huntington's disease during their lifetime. The mutant gene can give rise to more than one protein species, a longer full-length mutant hunting protein, and a shorter mutant HTT1A isoform.

Both full-length HTT and HTT1A are implicated as toxicity drivers. However, many approaches to date have failed to address the shorter HTT1A isoform.

At the EHDN conference in Poland this past week, we announced interim results from a phase one study of bersoceran in patients with Huntington's disease. Encouragingly, we saw robust dose-dependent reductions in CSF mutant Huntington after a single dose. Across two assays, we saw mean maximum reductions of CSF mutant Huntington's of 60 to 64 percent, with individual reductions up to 83 percent. Across the five cohorts included in this analysis, no dose-dependent safety signals have been observed to date with few serious adverse events reported thus far. Importantly, we haven't observed any dose-dependent increases in CNS inflammatory signals, white blood cells, or total protein to date. Likewise, we have not seen increases in neurofilament light chain in the CSF or evidence of ventricular enlargement, despite the high degree of HTT lowering we've been able to achieve.

This is in contrast to other programs and an encouraging signal of safety and tolerability. These results give us confidence to advance bersoceran through two complementary studies in parallel. The ongoing phase 1B, open-label extension, allows all participants to receive bersoceran every six months. This will enable us to continue characterizing the long-term safety of sustained HTT lowering and to explore potential efficacy trends over time. At the same time, pending regulatory alignment we're investing in a large placebo-controlled pivotal study which we plan to initiate in 2027.

This study is intended to provide a definitive test of whether bersoceran can slow Huntington's disease progression and will be the first placebo-controlled test of the HTT 1A lowering hypothesis. For more about bersoceran, the recent data and the overall opportunity, I encourage you to watch the replay of the RNA roundtable we hosted earlier this week available on our website.

Wrapping up, we have a few remaining pipeline goals to deliver for 2026. We plan to share phase 1 healthy volunteer data for ALIN6400 and bleeding disorders at the ASH annual meeting in December. We expect to share the phase 2 HHT results for ALIN6400 as well as the phase 1 data for ALIN2232 and obesity on our 24 and full-year results call in February. We look forward to providing these updates and continuing to advance our pipeline as we execute toward our ALNILUM 2030 goals.

Let me now turn the call over to Jeff for a review of our third quarter financial results and 2026 outlook. Jeff.

Thanks, push call and good morning, everyone. I'll be presenting the summary of ALNILUM's third quarter 2026 financial results and discussing our outlook for the balance of the year. Let's begin with a summary of our P&L results for the third quarter. Total global net product revenues were approximately 1.3 billion, 52 percent growth versus Q3 last year, driven by the continued third quarter USTTR revenue grew approximately 100 million compared with Q2. The key drivers of growth being an $81 million increase in demand and a $17 million inventory benefit, driven by an increase of inventory in the distribution channel from 19 to 21 days. Additionally, net price for Q3 was modestly higher than Q2 and was favorably impacted by a one-time Medicaid related gross to net adjustment of approximately 10 million.

The inventory and gross to net items supported revenue in Q3 but are not measures of underlying demand and for Q4 we anticipate that both inventory and price in the US will be headwinds to reported growth. The third quarter collaboration revenue was 71 million or an 80 percent decrease compared with the same period last year. The decrease was primarily driven by the $300 million one-time milestone recognized from Roche in Q3 2025 for dosing the first patient in the Z and phase three trial. Royalty revenue for the third quarter was 95 million, more than doubled out of the third quarter last year, driven by higher Latino sales. Gross margin on product sales was 72 percent for the third quarter, representing a 5 percent decrease compared with Q3 last year.

The decrease in margin was primarily driven by increased royalties on Ibutra as higher revenues in 2026 resulted in an increase in the average royalty rate payable of Sanofi. Our non-GAP R&D expenses of 376 million increased 21 percent compared to last year, primarily driven by costs associated with our three ongoing phase three clinical studies, including the zenith phase three cardiovascular outcome trial for Zalb Seran and the Triton CM and PN studies for new creaser ant. Non-GAP SGA expenses of 296 million increased 13 percent compared to last year, driven primarily by investments in support of the Ibutra, TTR, cardiomyopathy launch in the U. S. and in key international markets. We achieved non-GAP operating income of 425 million represents an 11 percent decrease compared to last year, driven primarily by lower gross collaboration revenue that I explained earlier.

We had GAP net income of 2.2 billion during the quarter, which includes a non-cash benefit from income taxes of approximately 1.9 billion due to the release of the island's U. S. valuation allowance on the majority of its net operating losses and other deferred tax assets underpinned by the company achieving sustainable profitability.

Finally, we ended the third quarter with cash, cash equivalents and marketable securities of 3.6 billion compared to 2.9 billion as of year end 2025. Primary driver of the increase in cash year to date is our strong operating performance and continued profitability.

Now turning to our full year outlook. Today we are reiterating our 2026 guidance as presented during our last earnings call and as summarized on our guidance slide. For TTR product sales based on performance to date and our expectations for Q4, we expect to land at the low end of our 4.2 billion to 4.5 billion dollar range. As we think about the evolution of our assumptions underlying the guide, there are two main drivers to highlight.

First, while we remain confident in our commercial strategy and transcribing behaviors take time to change, our expanded efforts to grow the prescriber base are gaining traction but are not yet translating into demand at the pace that we anticipated. We are moving expeditiously to execute the strategy in our laser focused on driving new starts.

With that said, we believe it is prudent to assume no material top line contribution from our field expansion in our 2026 outlook. Second, there are two additional factors impacting our expectation for fourth quarter demand.

First, our outlook reflects a prudent view of potential fourth quarter ordering behavior as hospital customers await the final 340B rule. While the proposed rule would not become effective until January 1st, 2027, our interactions with health systems over the last few months suggest that it could create Q4 ordering volatility as providers assess the implications for their economics and site of care choices.

Second, our outlook also reflects an expected impact from more restrictive first line in butra access in the Medicare Advantage portion of the market following a policy change at United Health that was implemented October 1st. All that said, achieving 4.2 billion in total TTR revenues would represent nearly 70 percent growth versus last year or 1.7 billion in growth on a dollar basis.

As we look beyond 2026, we remain confident in the underlying opportunity for our TTR franchise. At the same time as I mentioned a moment ago, we expect the final 340B rule in the coming weeks and for this rule to formally go into effect on January 1st. This would provide only a limited window between the effective date and the JP Morgan Conference to observe how health systems are responding under the new framework. We will therefore not be providing 2027 product revenue guidance at JP Morgan as in past years and instead expect to do so in conjunction with our fourth quarter and full year 2026 results in mid-February. That additional time will allow us to incorporate a more informed view of any changes in ordering patterns and site of care behavior as we guide the year ahead.

We will continue to provide preliminary fourth quarter and full year 2026 revenue at JP Morgan in January as has been our normal practice. Let me now turn it back to Josh to coordinate our Q&A session. Josh.

Thank you, Jeff. We're now going to open the call for Q&A. To those of you dialed in, only ask you to limit yourself to one question each and then get back in the queue if you have additional questions. Operator, please open the call for Q&A.

Thanks, Costas. Maybe a couple points there. Maybe just to reiterate, as we kind of look at what we expect New Crease Rant to do, nothing has changed in terms of expectations around the therapeutic hypothesis or the expectation around the added efficacy that we'll get on top of a stabilizer nor its effect as a monotherapy. We've shown some of our clinical trial simulations that let feed into that and our understanding of the biology.

Second, I think as I've tried to highlight, our belief is also that you have to get in early to treat these patients most effectively. Our study is designed to do that. We've already highlighted why we think it all caused mortality endpoint is particularly relevant in this disease, as well as an event-driven endpoint. The key elements of the study design, we believe in strongly. I think the change that we made today is, again, look at evolution in event rates in the background as this patient population is better and better treated and earlier diagnosed. In that context, there's no changes to the assumptions around the effect of the drug. It's really just about making sure we have adequate events and adequate power to demonstrate the efficacy of the drug.

That's why we've added these 500 patients. As I've noted in prior calls, we're in an active enrollment period. We think that we can accrue these patients quite quickly and we continue to further enrich for patients who are going to have the greatest benefit. That's the study. As it relates to analytic changes, this is an event-driven study. As we say, we project this to launch in 2030. We have several years to look and follow the patient population, event rates, et cetera, over the course of the study in a blinded fashion. As we've done in the past, if there are any tweaks or adjustments to the analytic plan, those can be made at a later date. Again, we are very vigilant and diligent on this study.

It's very important and we're committed to ensuring its success. But that's really the rationale and the thinking here.

Thanks, Ellie. That's a great question. As I said, look, we're not satisfied with the pace of unfutured demand growth and we need to do better. That being said, we have to live with substantial growth since the launch. It's early days and we think we've got significant opportunity ahead of us and we've built a very strong foundation. And all the market fundamentals remain favorable. As we said on our Q3 call, really the key insight is that the third of prescriber who's used ambutra prefer it. They use ambutra, they get experience, they prefer it. And that's across centers of excellence and the community. And that's the reason why it expands at the field force to address the two thirds of prescribers who have yet to use ambutra to drive the next wave of growth in the launch.

And as we reflect on performance to date, we're pleased that reach and engagement are increasing. As Talga said, we've now got 2,000 active prescribers of ambutra. And that's a good metric. But converting into patient starts is taking longer than we'd hoped. And we believe this is because as we expand the prescriber base, many of the newer physicians, they've got fewer cardiomyopathy patients, they've got less understanding of the disease and more entrenched prescribing behaviors that take time and sustained effort to change. And so we're increasing the intensity of interactions to overcome any perceived barriers to ambutra. And really what we need to do is build familiarity to drive adoption. Those physicians who are familiar with ambutra prefer it.

So we're very confident that we've made the right investments. And this is a right strategy. And we're focused on driving execution with urgency. It's going to take a little bit of time. We don't expect acceleration of growth in Q4 2026. But we're absolutely laser-like focused on ensuring that we can translate the additional engagements that we have with physicians and convert that into increased patient demand.

Talga, maybe you can talk about some of the very specific things that we're hearing from prescribers.

Yeah, so you covered the sort of the clinical piece. Well, maybe I can focus on the non-clinical barriers that we see. There are perceived beliefs that always are going to be easy for us to navigate the buy-in bill. How am I going to manage the patient coordination if I need to refer down to a side of care outside of my office?

How is my staff going to be clearing the prior authorization? Now, when we look at these, actually, non-clinical barriers, the good news is, as Yvonne indicated, half of our patient base is coming from community centers. And early on, those community centers had very similar perceptions. Once they've actually experienced our services and once the patient experienced ambutra, we've been actually able to overcome that. Now, the enemy here is the time. And it does take number of frequent visits to make sure that we can actually bring those patients and physician offices along with that. But once that happens, we've actually seen all these barriers that I just highlighted as eased out. And then the experience obviously begins preference.

So again, as Yvonne indicated, we're pleased but not satisfied with the progress that we made. And we do believe that we have the right strategy to be able to open up those new accounts.

Thanks, Toka.

Hey, Paul, this is Jeff. Thanks for the question. Yeah, understand the question. We did lay out of a framework for how we're thinking about this. I think our focus right now is we're waiting for the rule to be finalized is really focused on on patient access and ensuring that the institutions, the 340B institutions and health systems that are treating these patients today, will continue to have an economically viable option to do that in the future. We laid out on the slide and Toka mentioned in the script a couple of options that we'll have to support that. One would be contracting with the health systems again to ensure that there's an economically viable path for them to treat these patients.

And then for health systems that determine that they want to move the patients outside the health system, we have alternate sites of care. And this is actually one of the things that I think we've done very well since the launch that would support that. Things like third-party infusion clinics, things like getting the patients treated at home. I think to your question, I think it's very difficult for us to predict the potential impact here. I think until we finalize the rule, and actually we get some experience next year when we see the choices that the health systems are going to make, there could be impacts on on growth to nets, either positive or negative based on the choices they make.

And there could be impact on volume, we don't know that yet. Our belief is that the choices that physicians are making today, in terms of how they treat their patients is primarily based on clinical decisions, and what's going to be the best care for their patients. We see that if you look across health systems today, these 340B institutions, we see different market share for ambutra across different health systems that reflects that. And I think even within an existing health system, if you look across different positions within that same health system, you see different utilization of ambutra. So we do think it's primarily going to be driven based on physician and patient choice on what they think is the best product for them going forward, given the progressive and fatal nature of this disease.

Thanks, Chef.

Yeah, I'll take this one. Thanks for the question. I think in terms of 340B in our business, it's a meaningful portion of our business. We're not going to get more explicit about it today, but that's why we're very focused on this and ensuring that we're coming up with solutions to ensure that the institutions that treat these patients have the ability to continue to do so. In an economically viable manner. The second part of the question, bypass. Oh, look, again, we listed options here in terms of options that we'll have to work with these institutions to ensure that they continue to have the ability to put patients on therapy, keep patients on therapy. And we talked about two options.

One would be contracting, and the second would be enabling alternate sites of care. Ultimately, the health systems themselves are then going to have to make choices about how they purchase the product. And if they want to keep the patients within their existing system, they'll likely have two options. One would be continuing in the 340B channel. Now, the economics of that are going to change, but we think we have the ability to ensure that it stays in economically viable path for them. And then the second option would be if they want non 340B purchasing, they could shift to WAC purchasing, which is also likely to be an economically viable path for them. If they choose not to continue to treat the patients within their health system, they also have options to move the patients outside of the system in terms of where they get access to the medicine.

And that would be third-party infusion clinics, again, which we've done a very good job establishing 2,000 third-party clinics, 90% of patients within 10 miles of one of those clinics, or to treat the patient in the home. So those are the options, I think, that are going to be at play here. And again, I think the good news is that those will if the systems want to continue to treat patients and add patients, they'll be able to do that.

Thanks, Jeff. And we're actively engaging with health systems so that we're ready to respond when the proposal is finalized and infinite. So thank you.

Thanks, Whitney. Maybe just to put a little context, there's been really no change in our overall timelines for either of those studies. They're still reading out. The studies are progressing well. They're on schedule, et cetera. They just are coming in at the end of the year, consistent with our goals. And so the next time for us to report those publicly will be at our Q4 year end call. And so that's really what you're hearing there. So now in terms of the content for ALIN-2232, that's our ACBR 1C program for obesity and weight management, that's going to be our first adipose targeting program. And so we're looking forward to hopefully showing that we can, as we proceed along our goals to expand delivery to many tissues by 2030, that we can actually deliver safely and deeply into adipose tissue with good durability.

And we'll be looking for primarily knocked down in safety data, but we will have some data in terms of biometrics, in terms of weight and visceral fat, et cetera. We again, particularly see this as an agent that can reduce visceral fat while maintaining muscle mass. For ALIN-6400, we'll have some phase one data later this year at ASH. But we have this in the phase two program in HHT. And we expect to have some initial proof of concept data and safety data, so efficacy and safety data that we'll present early next year. So those are the key highlights of the data that are coming out.

Thanks, Prischel. We've progressed with our pipeline.

Yeah, thanks for the question. The Brazil Strand program is one that we're really, really excited about. And it really highlights the potential that we believe we have with our R&I platform to make a deep and meaningful impact on really some of the most devastating diseases, Huntington's disease being one of them. So the data that we announced to show that we really now have a differentiated approach to knockdown, that we can deliver deep knockdown. We believe, based on our preclinical and clinical data, that we're getting good by distribution, that we can target not just the full length, but also the shorter HGT-1A-I with good safety and tolerability to date. So as I noted, we're going to move forward into phase three program.

The key things that we're looking for, we are continuing to do dose escalation in our phase one. So we, again, want to maintain and ensure deep knockdown throughout the brain, including the deeper structures in the CAUT-8. We want to ensure good durability and good tolerability. So we're continuing to do some further dose exploration in the phase one.

As I noted, those patients will transition into an open label extension. As we get a little bit more, we firm up the doses and go through the regulatory process. We'll kick off that phase three study that I noted in my prepared remarks. This will be an NDA program. All of our R&I therapeutics are captured that way. As far as your last question, which is around a TFR-based approach, we are very excited about what we have at hand. We think efficacy and safety are the most important things. And we don't see the current intrathecal approach at all a barrier in this disease, with this infrequent administration that we anticipate. But we are continuing to progress brain-shuttle that can deliver peripherally.

And so those activities are underway, and we'll update on that as well in the not-so-distant future.

I do. That's like eight questions. No, but I get the gist of what you're asking. Look, I think maybe two main elements I think that are in there. One is, how are we adjusting for severity? I think the heliospeed data, the cardiac transform data all indicate that if you can get into these patients early before they have, presumably, we hypothesize a lot of built-up amyloid in the heart, which then becomes harder to modify and is going to lead to ongoing cardiovascular events.

But this, getting in earlier before that accumulates is where we're seeing the largest treatment effects. And we're seeing very substantial treatment effects. And those earlier populations, we were seeing upwards of 40% reduction in cardiovascular event rates. And I think if you looked at the fact that it didn't in its primary endpoint, in that subgroup of patients with earlier disease, you were seeing a greater benefit. And that earlier disease population is often defined by NAC stage, which really is heavily weighted based on NT-ProBNP. And so our study has entry criteria for NT-ProBNP that can ensure we enroll patients who are likely to have underlying disease and likely experience events, but are not so advanced. And we've believed somewhat earlier in the disease course, consistent with the principles I just laid out.

So that's really the primary factor. There are other entry criteria in terms of history of events, et cetera. But I think that really we believe is an important driver in terms of stratifying a population, identifying the high risk and most appropriate to treat patients. So that's that. And in terms of the underlying event rates, you know, I'm not going to get into any of the details of that. But I guess what I would like to assure you is that we've always been quite conservative in terms of our underlying trial assumptions. And again, the main thing is a secular trend towards these patients experiencing lower cardiovascular event rates because they're being diagnosed earlier, and they're being treated more aggressively, particularly with SGLT2 inhibitors.

And so we've taken that into account. And that's, you know, so we believe that with these 500 patients, 22, 250 patients that were now well positioned and well powered, even under conservative assumptions of event rates. And so we'll follow those patients going forward.

Thank you, Pascal.

Yeah, thanks for the question, David. It's Jeff. I mean, I think there are two potential implications. One would be the price. And if you look at the slide that we have in the deck on 340B and you look at the potential provider responses, because ultimately it's really going to be dictated by the choices that they make. But if the providers stay in the traditional 340B purchasing channel, that would put that would increase gross to nets, you know, move net price down, because we would be providing a discount below the current statutory 340B rate.

However, if health systems move to WAC purchasing, that moves out of the 340B channel, and that's positive to net price. And lastly, on that slide, if they move the patients out of the health system out of the 340B health system to an alternate side of care, that would also be positive from a net price perspective for us. I can't tell you exactly the choices they're going to make or what that's ultimately going to mean, but that gives you a sense of direction.

And there was a prior question about impact on volume. Again, I can't predict that at this point, either. We do think that physicians and patients are making choices based on what's the best product for their care and progressive fatal disease. So we're going to wait and see how things play out with the rules. We understand it and then get some experience with it in January before we provide more color on our year on call in February.

Thanks, Jeff.

Yeah, no, thank you. Because that's really an online sort of 2030 question and just kind of stepping back a little bit. I just wanted to say that I think we're making kind of really good progress just nine months into the year across across all the dimensions of online 2030. You're the unfortunate launch is still early. We see significant opportunity ahead and we're investing against that to broaden the prescriber base. We're advancing a new crease round. As Pushkal described, we have a lot of conviction in the study that we're progressing with Triton CM to extend the franchise. And we're building a pipeline which is progressing very well to live a new medicines beyond TTR.

With respect to the 25% CAGA, I think our confidence is really underpinned by the strong foundation we've built and by the continued market growth that we see and robust market share. You know, expect that to be in the US, you know, treated ATTR cardiomyopathy population. We think that's going to grow and reach about 75,000 patients by 2030. And in the US, we're really looking to get a third of the category TRX. And if we achieve, if we get there, we'll achieve our ambitions. And we're ready there with MBRX. With TRX, we're now at 24% as we share today. We're making meaningful progress. So I'm kind of in summary, if we can capture a third of the market in the US with our current pricing assumptions and continue to grow, we haven't talked very much about XUS, it can continue to grow XES.

We believe we're well positioned and of course, you know, we're going to be navigating near-term demand as well as the evolving payer environment.

So I believe that is our last question. So I just like to close by thanking everyone for joining us today. And, you know, I'd like to return to the patients that we have the opportunity to reach and the key priorities that will take us there. So the first thing that we need to do is convert the AMVUTRA opportunity into more patient starts. We've had an exceptional first 18 months in ATTR cardiomyopathy, but it's early. So we need to act, continue to act with a laser-like focus abroad on the prescriber base. And we're going to continue to invest behind AMVUTRA as a foundational therapy in this great market. And of course, the second is we need to build and sustain our leadership in TTR and try to on CM is central to that ambition.

The expansion we announced today is intended to make an already well-designed study, as Pushkar described, even more robust without changing our expected timing. And then the third is advancing our pipeline. And you've heard the progress that we've made with. Reserves around to give us the opportunity to bring our science to new groups of patients. And we're very excited about moving forward in this regard. So together, these priorities drive our long-term 2030 ambition. And I'd like to finish by just thanking our employees, the physicians, the investigators we work with and the patients and families who place their trust in what we do. Thank you for joining us today. This concludes today's call. Thank you for attending.

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