阿尔尼拉姆 (ALNY) 2026年第三季度业绩电话会：TTR指引及TRITON-CM拓展

核心要点

• Alnylam Pharmaceuticals 2026年第三季度全球产品净收入约为13亿美元，同比增长52%，这主要得益于AMVUTTRA在转铁蛋白淀粉样变性（ATTR）心肌病领域的持续普及。
• TTR系列产品收入达11.5亿美元，同比增长59%，环比增长12%。美国市场的环比增长包括8100万美元的需求增加、1700万美元的库存拉动以及约1000万美元的一次性毛净价调整。
• 管理层预计2026年全年TTR产品销售额将处于42亿至45亿美元业绩指引区间的低端。管理层并未假设扩充后的销售团队会在2026年带来实质性的收入贡献。
• 截至季度末，AMVUTTRA约占TTR类总处方量（TRx）的24%。其新患者处方（NBRx）份额保持在30%以上，自上市以来，已有超过2000名不同的美国处方医生使用过该疗法。
• Alnylam将把nucresiran的III期TRITON-CM临床试验规模扩大500名患者，达到约2250名。管理层表示，由于事件发生率下降，此举旨在保持统计效力，在结果积极且获得监管批准的前提下，并不改变预计在2030年左右上市的时间表。
• 截至第三季度末，该公司拥有的现金、现金等价物和可交易证券共计36亿美元。22亿美元的GAAP净利润中包含约19亿美元的非现金所得税收益。

关键财务数据

业务与运营表现

AMVUTTRA仍是主要增长引擎。美国TTR收入较第二季度增加约1亿美元，其中包括8100万美元的需求增加，以及库存天数从19天增至21天带来的1700万美元收益。净价也受益于约1000万美元与医疗补助（Medicaid）相关的一次性毛净价调整。

在美国以外市场，TTR的增长主要受到日本和德国对ATTR-CM疗法接受度提高的推动，但部分被产品上市相关的降价所抵消。管理层还提及欧洲市场的准入状况正在改善。

全美ATTR-CM处方药市场总体同比增长近40%。AMVUTTRA占TTR类总处方量（TRx）的约24%，而其新处方（NBRx）份额保持在30%以上。然而，管理层表示，该领域仅有约三分之一的开方医生尝试过AMVUTTRA。

扩充后的面对客户团队扩大了对医生的覆盖和接触，但转化为新患者开始用药的过程比预期更长。管理层将这一滞后部分归因于社区医生经验不足、固有的处方习惯，以及买购与结算流程（buy-and-bill）、预先授权（prior authorization）和治疗地点协调等行政壁垒。

AMVUTTRA在承保人群中的覆盖率约为99%。在约2000家第三方诊所和居家治疗方案的支持下，约90%的患者可以在距离住处约10英里范围内接受治疗。

在TTR以外的管线中，brazosiran用于治疗亨廷顿舞蹈症的I期中期临床数据显示，单次给药后，在两种检测方法下，脑脊液中突变亨廷顿蛋白的平均最大降幅达60%至64%，个体最大降幅达83%。公司报告称在分析的五个队列中均未发现剂量依赖性安全性信号，并计划在获得监管部门一致意见后，于2027年启动关键的安慰剂对照研究。

管理层业绩指引

Alnylam重申了其2026年42亿至45亿美元的TTR产品销售额指引范围，但预计实际结果将处于区间低端。达到42亿美元将代表近70%的同比增长，即约17亿美元的增量收入。

由于医生接触度的提升未能像预期那样快速转化为需求，管理层假设销售团队的扩充不会对2026年营业收入产生实质性贡献。公司同样预计2026年第四季度的需求增长不会加速。

预计第四季度报告的增长将面临库存和美国净价格的不利影响，因为第三季度的库存增加和一次性毛净价收益并不代表基础需求。该展望还纳入了在340B最终法规出台前医院订购可能出现的波动，以及联合健康（UnitedHealth）在Medicare Advantage中实施更严格的一线用药政策后新患者开始用药的延迟。

Alnylam不会在1月份的摩根大通（JPMorgan）医疗健康大会上提供2027年产品收入指引。管理层计划在2月中旬随2026年第四季度及全年业绩一同发布该指引，届时医疗系统对预期340B变动的应对措施将更加清晰。

风险与关注焦点

• 需求转化率：医生接触面扩大的成果尚未按管理层预期的速度转化为患者开始用药。
• 340B报销制度改革：如果拟议的CMS规定最终确定，受影响的医疗系统可能会改变采购渠道或给药地点。这可能会影响毛净价扣除额、净价、订购模式及销量。
• Medicare Advantage准入：联合健康自10月1日起生效了一项更为严格的一线用药政策。预计现有患者不会受到影响，但附加要求可能会推迟新患者获药。
• 第三季度收入质量：美国市场的环比增长包含了1700万美元的库存拉动和约1000万美元的一次性毛净价调整，管理层将这两项均排除在基础需求之外。
• 临床事件发生率较低：早期诊断以及SGLT2抑制剂等背景疗法的使用增加可能会降低ATTR-CM试验中的事件发生率，从而潜在地影响统计效力。
• 毛利率压力：随着AMVUTTRA销售额的增加，支付给赛诺菲的平均特许权使用费率上升，导致产品毛利率有所下降。

分析师问答集锦

为何扩大TRITON-CM临床试验规模？管理层表示，治疗假说和nucresiran的预期治疗效果没有改变。增加500名患者旨在保守的事件发生率假设下保持充足的统计效力。试验招募将利用NT-proBNP标准进一步增加早期患者的比例，预计上市时间仍保持在2030年左右。

为何更大的销售团队未能加速需求增长？管理层表示，新开方医生通常接诊的心肌病患者较少，需要反复沟通以克服临床熟悉度不够和行政方面的顾虑。有AMVUTTRA使用经验的医生往往会深化使用，这验证了公司的策略，但转化过程所需的时间比计划更长。

340B改革将如何影响财务模型？若继续留在传统340B渠道并签订附加合同，可能会增加毛净价扣除额并降低净价。若转为按批发采购成本（WAC）采购或转向其他给药地点，则可能提高净价。管理层表示，对销量的影响仍存在不确定性。

Alnylam对其长期增长目标是否仍充满信心？管理层表示，对截至2030年实现25%以上总收入复合年增长率目标的信心，来自于接受治疗的美国ATTR-CM患者群体的预期增长、实现获取美国该类别约三分之一TRx处方的目标，以及海外市场的持续拓展。这些仍属于公司的努力目标，而非必然结果。

财报电话会议完整文字记录

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完整财报电话会议逐字稿

管理层陈述

Operator

Hello, everyone. Thank you for joining us, and welcome to the Alnylam Pharmaceuticals Q3 Earnings Conference Call. [Operator Instructions] Now I hand the conference over to the company. Please go ahead.

Joshua Brodsky

Good morning. I'm Josh Brodsky, Vice President of Investor Relations at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercialization Officer; Pushkal 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.alnylam.com/events.

I'd 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. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important risks and uncertainties and 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?

Yvonne Greenstreet

Thanks, Josh, and thank you, everyone, for joining the call today. I'm going to begin by putting the quarter into context and discussing why our commercial portfolio and pipeline give us confidence in our items growth. Tolga will then review our commercial performance and the work underway to expand Anvita adoption and support patient access. Pushkal will walk through our decision to further expand Triton 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 Alnylam. And vutri has demonstrated significant benefits for patients with ATTR cardiomyopathy including reductions in mortality and cardiovascular events with quarterly dosing. We believe that this profile and Amfuta'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 Amvutra uptake, establishing a strong foundation for our TTR franchise. We generated 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 Amvutra's prescriber base, deepen physician engagement and over time, drive adoption at scale. That said, we are not yet satisfied with the underlying demand growth we have observed, and this is reflected in the full year outlook that Jeff will discuss shortly. As Tolga will describe in more detail, our sales force 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 a best-in-class clinical profile demonstrated by continued evidence generation from Helios-B and vutri 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 Niles Group. We're investing in and advancing the next wave of medicines as we build a more diversified, multi-franchise business. Within the TTR category, ucrisiran gives us the opportunity to build on Arbutus success with deeper TTR lowering and twice yearly dosing. We have a high level of conviction and a positive trite on CM con. And today, we announced further expansion of enrollment in the study to approximately 2,250 patients. This expansion optimizes the crises chances for success and strengthens our long-term TTR position.

Pushkal will go into more detail. But importantly, this expansion does not change our expected ATTR Mid-month launch timing of 2030, subject to positive study results and regulatory approval. Beyond TTR, the early brazotiran 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. In longer term, are our Alnylam 2030 vision continues to guide our priorities and investments for the next half of the decade.

Our Alnylam 2030 represents our aspiration to become the leading science driven fully integrated global biopharmaceutical company and to maximize 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 Alnylam 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?

Tolga Tanguler

Thanks, Yvonne, and good morning. We delivered significant year-over-year growth in the third quarter and continue 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.

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 U.S., TTR revenues increased 12% sequentially and 69% year-over-year. This approximate $100 million in U.S. 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 onetime gross to net adjustments. Jeff will cover these items in more detail.

Outside the U.S. 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 AMVUTTRA over stabilizers. Ex U.S. markets have contributed significantly to tafamidis 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 U.S. TTR market and the AMVUTTRA prescriber base. Total ATTR-CM subscriptions 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 ATTRCI patients remain untreated, underscoring the substantial long-term potential to bring therapy to many more patients.

Since our ultra launch in the United States, more than 2,000 new unique prescribers have prescribed Amtrak. This metric is particularly encouraging, given what we know about prescribing behavior among physicians with our ultra experience. As we highlighted on our Q2 earnings call, we've seen that utilization deepens with experience. put a simple trial begins preference and only with approximately 1/3 of all active prescribers having prescribed AMVUTTRA to date, we see a significant opportunity to drive broader adoption and deeper 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 expansion 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 AMVUTTRA 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, AMVUTTRA already represents approximately 24% of all prescriptions in the 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 sustained utilization of AMVUTTRA as our patient base grows. Notably, we achieved 24% TRx share with only about 1/3 of category prescribers having tried AMVUTTRA 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 AMVUTTRA'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 reduced Medicare reimbursement for Part B medicines acquired through the 340B drug discount program. The terms of the final rule are not yet know. A final rule is expected imminently, and if implemented, would become effective January 1, 2027. Though 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 site 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 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 rule-making process progresses and will be prepared to respond as greater clarity emerges. Importantly, AMVUTTRA 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 1, UnitedHealth implemented a more restrictive first-line motor policy in the Medicare Advantage portion of the market. Importantly, this is unexpected to impact existing patients, and there is an exception process that allows appropriate new patients to access AMVUTTRA first line. We, therefore, do not expect any 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 AMVUTTRA. Taken together, we remain confident in the underlying fundamentals of the TTR franchise and encouraged by the continued growth and expanding reach of AMVUTTRA. 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 Pushkal.

Pushkal Garg

Thanks, Tolga, and good morning, everyone. Today, I'll cover why we remain confident in Triton CM, the rationale behind the enrollment expansion of reference this morning and the progress we're making beyond TTR, particularly with razosiran in Huntington's disease. Alnylam is well positioned to build durable leadership in TTR. As we've discussed, we believe AMVUTTRA has a differentiated clinical profile that supports it being the first-line treatment of choice for patients with ATTR-CM.

AMVUTTRA demonstrates substantial improvement in clinical outcomes, function and quality of life and his 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 AMVUTTRA with nucrisiran, 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, nucrisirin is continuing to advance for both a hereditary ATTR polyneuropathy in ATTR cardiomyopathy in the Phase III TRITON studies.

Recent data from the cardio transform 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 ipontersen to meet its primary endpoint in the cardiotransform study. One, Apple Person is an ASO that achieved much less TTR knockdown than vutrisiran 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 eplentersen to deliver significant clinical benefit.

And third, their endpoint was not optimized for success. Cardio transform focused on cardiovascular mortality in their primary composite endpoint, which fails to capture the multisystem 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-cause mortality and recurrent CV events.

As noted, we believe ACM is a more sensitive endpoint in this disease than CV mortality in 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 cardio transform in order to maximize the probability of study success. An important learning that was reinforced in cardio transform 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 nucrisirant's potential to deliver a strong treatment effect in this 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-proBNP 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, Alnylam 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, effect motor, cognitive and emotional health with patients average life span 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 presymptomatic 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 huntingtin protein and a shorter mutant HTT1a isoform.

Both full-length HTT and HTT 1A 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 I study of brazosiran 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 huntingtin of 60% to 64% with individual reductions up to 83%.

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 brezosiran through two complementary studies in parallel. The ongoing Phase Ib open-label extension allows all participants to receive brazosiran 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 brazosiran can slow Huntington's disease progression and will be the first placebo-controlled test of the HTT 1a lowering hypothesis. For more about brazosiran, the recent data and the overall opportunity, I encourage you to watch the replay of the RNAi 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 I healthy volunteer data for ALN-6400 and bleeding disorders at the ASH Annual Meeting in December. We expect to show the Phase II HHT results for ALN-6400 as well as the Phase I data for ALN-2232 in obesity on our Q4 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 Alnylam 2030 goals.

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

Jeffrey Poulton

Thanks, Pushkal, and good morning, everyone. I'll be presenting a summary of Alnylam'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% growth versus Q3 last year, driven by the continued uptake of AMVUTTRA and ATTR cardiomyopathy.

As Tolga previously mentioned, third quarter U.S. TTR 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 onetime Medicaid-related gross to net adjustment of approximately $10 million.

The inventory and gross to net items reported revenue in Q3 and but are not measures of underlying demand. And for Q4, we anticipate that both inventory and price in the U.S. will be headwinds to reported growth. In the third quarter, collaboration revenue was $71 million, or an 80% decrease compared with the same period last year. The decrease was primarily driven by the $300 million onetime milestone recognized from Roche in Q3 2025 for dosing the first patient in the ZENITH Phase III trial. Royalty revenues for the third quarter was $95 million, more than double that of the third quarter last year, driven by higher Lucio sales.

Gross margin on product sales was 72% for the third quarter representing a 5% decrease compared with Q3 last year. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2026 resulted in an increase in the average royalty rate payable at Sanofi. Our non-GAAP R&D expenses of $376 million increased 21% compared to last year, primarily driven by costs associated with our three ongoing Phase III clinical studies including the ZENITH Phase III cardiovascular outcome trial for zalbisiran and the TRITON CPN studies for necrisiran.

Non-GAAP SG&A expenses of $296 million increased 13% compared to last year driven primarily by investments in supportive of the AMVUTTRA TTR cardiomyopathy launch in the U.S. and in key international markets. We achieved non-GAAP operating income of $425 million represents an 11% decrease compared to last year, driven primarily by lower Roche collaboration revenue that I explained earlier. We had GAAP net income of $2.2 billion during the quarter, which includes a noncash benefit from income taxes of approximately $1.9 billion due to the release of Alnylam'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. The 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 is summarized on our guidance slide. For TTR product sales, based on performance to date and our expectations for Q4 and we expect to land at the low end of our $4.2 billion to $4.5 billion 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 trends prescribing 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 and are 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 expectations 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 1, 2027, our interactions with health systems over the last few months suggests that it could create Q4 ordering volatility as providers assess the implications for their economics and site of care choices.

And second, our outlook also reflects an expected impact from more restrictive first-line and Butra access in the Medicare Advantage portion of the market following a policy change in UnitedHealth that was implemented on October 1. All that said, achieving $4.2 billion in total TTR revenues would represent nearly 70% 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 1. This would provide only a limited window between the effective date and the JPMorgan conference to observe how health systems are responding under the new framework. We will, therefore, not be provided in 2027 product revenue guidance at JPMorgan 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 JPMorgan in January as has been our normal practice. Let me now turn it back to Josh to coordinate our Q&A session. Josh?

Joshua Brodsky

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. .

Operator

[Operator Instructions] Your first question comes from the line of Costas Volaris with Oppenheimer. .

分析师问答

Konstantinos Biliouris

Congrats on all the progress. many updates here. Maybe I'll ask a question on Titan changes. Some people were expecting more changes than the one you made. Can you maybe talk a little bit about potential other changes that you may have consider, for example, changing the primary endpoint by adding different components to the composite. And the second part of the question, should we expect more changes or this is perhaps the final version of the design?

Pushkal Garg

Thanks, Kostas. Maybe a couple of points there. Maybe just to reiterate, as we kind of look at what we expect nuclisiran to do, nothing has changed in terms of our 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. And we've shown some of our clinical trial simulations that 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. And we've already, we think highlight why we think an all-cause mortality endpoint is particularly relevant in this disease as well as an event-driven endpoint. So the key elements of the study design, we believe in strongly. I think the change that we made today is as we, again, look at evolution in event rates in the background as this patient population is better and better treated and an earlier diagnosed.

And so 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. And so that's why we've added these 500 patients. As I've noted in prior calls, we're in an active enrollment period. And so 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. So I think that's the study. Now as it relates to analytic changes, this is an event-driven study. As we say, we project this to launch in 2030. So we have several years to kind of look and follow the patient population, event rates, et cetera, over the course of the study in a blinded fashion.

And 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. And so 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.

Operator

Your next question comes from the line of Eli Merrell with Barclays.

Eliana Merle

And just to elaborate a little bit on what you're seeing in some of the ATTR-CM commercial dynamics. You said that the expanded field force has increased physician engagement, but that hasn't turned into capacitor demand growth yet. Can you elaborate a bit on that dynamic and why you think that is translating and maybe what hurdles might be affecting this? And strategies you can use to sort of grow this going forward? Is this mainly a lag issue? And I guess what feedback are you getting from some of these prescriber growth efforts?

Yvonne Greenstreet

Thanks, Eddie. That's a great question. As I said, look, we're not satisfied with the pace of future demand growth, and we need to do better. That being said, we have delivered substantial growth since the launch. It's early days, and we think we 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 the 1/3 of prescriber who's used AMVUTTRA.

They use AMVUTTRA, they get experience, they prefer it. And that's across centers of excellence and the community. And that's the reason why we expanded the field force to address the 2/3 of prescribers who have yet to use AMVUTTRA 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 Tolga said, we've now got 2,000 active prescribers of AMVUTTRA. And that's a good metric. The converting into patient starts is taking longer than we'd hoped. And we believe this is because of the expand the prescriber base. Many of the newer physicians, they've got a few automopathy 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 are increasing the intensity interactions to overcome any perceived barriers to Anvita.

And really, what we need to do is build familiarity to drive adoption. There's physicians who are familiar with Anvita prefer it. So we're very confident that we've made the right investments, and this is the 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. Tolga, maybe you can talk about some of the very specific things that we're hearing from prescribers.

Tolga Tanguler

Yes. So you covered the sort of the clinical piece, while maybe I can focus on the nonclinical barriers that we see. There are perceived beliefs that always is going to be easy for us to navigate the buy and build. How am I going to manage the patient coordination if I need to refer them to a site of care outside of my office. How is my staff going to be clearing the prior authorization.

Now when we look at these actual nonclinical barriers, the good news is, as Yvonne indicated, half of our actual 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 experience on mute, we've been actually able to overcome that.

Now the enemy here is the time. And it does take a 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 is eased out than the experience, obviously, biggest 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.

Operator

Your next question comes from the line of Paul Matteis with Stifel. .

Paul Matteis

I appreciate it. I know that there's probably some reluctance on speculating on the 340B rule change until it's finalized. But as you guys contemplate the impact right now, is this impact, if it does go through in its current iteration, confined to a hit to net price or do you also think that it could actually disrupt demand, both on the new start side or even on the actual existing patient side and drive patient switches is the reimbursement paradigm becomes more complicated or less attractive at the 340B institutions?

Jeffrey Poulton

Paul, this is Jeff. Thanks for the question. Yes, I understand the question, we did lay out 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 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 Tolga 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 they 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 gross 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 AMVUTTRA 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 AMVUTTRA. 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.

Operator

Your next question comes from the line of Salveen Richter with Goldman Sachs.

Salveen Richter

So as we think about your 2027 outlook for the TTR franchise, it seems like there's a couple of moving parts, one being the demand growth via your commercial investments, but then also 340B reform. If it does pass at the proposed discount, recognizing you don't understand the likely impact here. Can you just help us kind of frame this around quantifying both your 340B exposure fee-for-service. But then also, are you allowed to bypass 340B with your own discounts, even if a covered entity?

Jeffrey Poulton

Yes, 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 look, Yes. 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 an economically viable path for them. And then the second option would be if they want non-340B purchasing that could shift to WACC 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.

Yvonne Greenstreet

Thanks, Jeff, and we're actively engaging with health systems so that we're ready to respond when the proposal is finalized and infant.

Operator

Your next question comes from the line of Whitney Ijem with Canaccord Genuity.

Unknown Analyst

I'm just going to ask a pipeline on timing. I guess, can you talk about what drove the delay of the HHT obesity data, which is now expected instead with fourth quarter earnings as opposed to before in year-end this year. And I guess remind us of what each data set will include and in particular, if that's changed with the delay .

Pushkal Garg

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 in our Q4 year-end call. And so that's really what you're hearing there.

So now in terms of the content for ALN2232, that's our ACVR1c 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 as we sort of 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 knockdown 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 ALN6400 we'll have some Phase I data later this year at ASH, but we have this in the Phase II program in HHT. And we expect to have some initial proof-of-concept data and safety data. So efficacy and safety data that will present early next year. So those are the key highlights of the data that are coming out.

Yvonne Greenstreet

Good progress with our pipeline.

Operator

Your next question comes from the line of June Lee with UBS. .

Unknown Analyst

Really enjoyed your webinar on the Huntington's program. What are some key events in the space you're looking for to help you guide clinical development? And remind us, would it be a BLA or NDA. And a quick follow-up. Do you have any thoughts on developing a transparent receptor conjugated sRNA for CNS indications based on the evolving competitive landscape?

Pushkal Garg

Yes. 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 RNAi 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 show that we really now have a differentiated approach to knock down 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 HTT-1a isoform and that we've been able to do so with good safety and tolerability to date. So as I noted, we're going to move forward into a Phase III program. The key things that we're looking for we are continuing to do dose escalation in our Phase I.

So we, again, want to maintain and ensure deep knockdown throughout the brain, including the deeper structures in the code. We want to ensure good durability and good tolerability. So we're continuing to do some further dose exploration in the Phase I. As I've 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 III study that I noted in my prepared remarks.

This will be an NDA program. All of our RNAi 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 as at all a barrier in this disease with this infrequent administration that we anticipate. But we are continuing to progress internally as part of our research efforts to explore ways to have a 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.

Operator

Your next question comes from the line of Ritu Baral with Cowen.

Ritu Baral

Another question for Pushkal on Triton. Pushkal, how will you be further amending reducing the severity of patients enrolled in Triton. And can you talk to how you might enrich them just beyond proBNP? And can you talk about the impact on powering of the 500 -- of the new 500 patients that you're going to be rolling and how much of a lower event rate are you calculating for in that powering?

Pushkal Garg

Actually, that's like eight questions. Now 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 HELIOS SPEED data, the cardio 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.

With this getting it earlier before that accumulates is where we're seeing the largest treatment effects. And we're seeing very substantial treatment effects in those earlier populations we were seeing upwards of 40% reduction in cardiovascular event rates. So and I think if you looked at the subgroup analysis of cardio transform despite the lower knockdown that, that drug was happening despite the fact that it doesn't din 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, a, are likely to have underlying disease and are likely experience events, but are not so advanced and we believe 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 appropriate to treat most appropriate to treat patients. So that's that.

And in terms of the underlying event rates, 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 so we believe that with these 500 patients, 2,250 patients that we're now well positioned and well powered even under conservative assumptions of event rates. And so we'll follow those patients going forward.

Operator

Your next question comes from the line of David Lebowitz with BMO Capital Markets.

David Lebowitz

Appreciating that you don't know details on 340B. As we look at our models and try to at least back into what potential impacts could be. What parts of the model should we consider looking at on both the top and bottom line side that could be impacted by the new regulation?

Jeffrey Poulton

Yes. Thanks for the question, Dave. 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 provider stay in the traditional 340B purchasing channel, that would increase gross to net, 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 site 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 in a 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-end call in February.

Operator

Your last question comes from the line of Luca Issi with RBC Capital Markets.

Luca Issi

I appreciate you're not going to guide 2027 today and I appreciate you're not going to guide Egypt and Morgan as well. Can I maybe check your temperature on how you're thinking more broadly about your guided 25% plus total revenue CAGR throughout year-end. Obviously, that guide was put forward before you recognize the second-line bolus before you recognize the 340B CMS proposal before this restricted Medicare Advantage change in policy by United. So should we think that, that 25% plus total revenue CAGR throughout 2030 is at this point a little bit on the optimistic side? Or do you still stand by that number? Again, any color there, much appreciated.

Yvonne Greenstreet

Yes. No, thank you because that's really in our Alnylam sort of 2030 question and just kind of stepping back a little bit. I just want to say that I think we're making kind of really good progress, just nine months into the year across all the dimensions of online 2030. The AMVUTTRA launch is still early. We see significant opportunity ahead, and we're investing against that to broaden the prescriber base. We're advancing nucrisiran.

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 deliver new medicines beyond TTR. With respect to the 25% CAGR, 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, we expect that to be in the U.S. treated ATTR cardiomyopathy population.

We think that's going to grow and reach about 75,000 patients by 2030. And in the U.S., we're really looking to get 1/3 of the category TRx. And if we get there, we'll achieve our ambitions, and we're already there with NBRx. With TRx, we're now at 24% as we shared today, we're making meaningful progress. So kind of in summary, if we can capture 1/3 of the market in the U.S. with our current pricing assumptions and continue to grow, we haven't talked very much about ex U.S., it can continue to grow XES, we believe we're well positioned. And of course, 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 look, I'd just like to close by thanking everyone for joining us today. And 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 AMVUTTRA opportunity into more patient starts. We've had an exceptional first 18 months in ATTR cardiomyopathy, but it's early. So we need to continue to act with a laser-like focus to broaden the prescriber base, and we're going to continue to invest behind AMVUTTRA as a foundational therapy in this growing market.

And of course, the second is we need to build and sustain our leadership in TTR and Triton CM is central to that ambition and the expansion we announced today is intended to make an already well-designed study, as Pushkal described, even more robust, without changing our expected launch timing. And then the third is advancing our pipeline. And you've heard the progress that we've made with Bassian 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 of 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.

Operator

This concludes today's call. Thank you for attending. You may now disconnect.