Q2 2026 Alnylam Pharmaceuticals Inc Earnings Call

July 30, 2026

Operator: At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q2 Earnings Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by 1 on your telephone keypad. If you would like to withdraw your question, please press star 1 again. Thank you. I would now like to turn the conference over to the company. You may begin.

Operator: At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q2 Earnings Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by one on your telephone keypad. If you would like to withdraw your question, please press star one again. Thank you. I would now like to turn the conference over to the company. You may begin.

This time I would like to welcome everyone to the AL Milo and pharmaceuticals Q2 earnings conference call Alliance have been placed on you to prevent any background noise. After the speaker's remarks, there will be a question and answer session and if you would like to ask a question during this time, seemed to press star followed by the number 1 on your telephone keypad. If you would like to admire your question, please press star 1 again, thank you. I would now like to turn the conference over to the company. You may begin.

Good morning. I'm Josh broadsky vice president of investor relations at Elm island. With me today are Yvonne Green Street Chief Executive Officer, Jeff poulton Chief Financial Officer to get, angular Chief, commercial officer and push go guard, Chief research and development officer.

Speaker #1: Thank you for standing by. My name is Prilla, and I will be your conference operator today. At this time, I would like to welcome everyone to the ALNYLAM Pharmaceuticals Q2 earnings conference call.

Josh Brodsky: Good morning. I'm Josh Brodsky, vice president of investor relations at Alnylam. With me today are Yvonne Greenstreet, chief executive officer, Jeff Poulton, chief financial officer, Tolga Tanguler, chief commercial officer, and Pushkal Garg, chief research and development officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investors page of our website, investors.alnylam.com/events. During today's call, as outlined on slide two, Yvonne will offer introductory remarks and provide some general context. Jeff will review our financials and guidance. Tolga will provide an update on our global commercial progress, Pushkal will discuss our TTR franchise, our confidence in TRITON-CM, and upcoming pipeline milestones before we open the call for your questions.

Josh Brodsky: Good morning. I'm Josh Brodsky, Vice President of Investor Relations at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer, Jeff Poulton, Chief Financial Officer, Tolga Tanguler, Chief Commercial Officer, and Pushkal Garg, Chief Research and Development 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.

For those of you participating via conference call the accompanying slides can be accessed by going to the event section of the investors page of our website investors. Alma.com events.

Speaker #1: All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press the star key, followed by the number 1 on your telephone keypad.

During today's call as outlined on slide 2 Ivonne will offer introductory remarks and provide some general context. Jeff will review our financials and guidance

Speaker #1: If you would like to withdraw your question, please press the star 1 again. Thank you. I would now like to turn the conference over to the company.

Togo will provide an update on our global commercial progress. And push Global will discuss our TTR franchise, our confident, and Triton cm, and upcoming pipeline Milestones, before we open the call for your questions.

Speaker #1: You may begin.

Speaker #2: Good morning. I'm Josh Brodsky, Vice President of Investor Relations at ALNYLAM. With me today are Yvonne Greenstreet, Chief Executive Officer, Jeff Poulton, Chief Financial Officer, Tolga Tanguler, Chief Commercial Officer, and Pushkal Garg, Chief Research and Development Officer.

Josh Brodsky: During today's call, as outlined on slide two, Yvonne will offer introductory remarks and provide some general context. Jeff will review our financials and guidance. Tolga will provide an update on our global commercial progress, Pushkal will discuss our TTR franchise, our confidence in TRITON-CM, and upcoming pipeline milestones before we open the call for your questions.

I would like to remind you that this call will contain remarks concerning al num's future, expectations plans and Prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision.

Speaker #2: For those of you participating via conference call, the accompanying slides can be accessed by going to the event section of the Investors page of our website, investors.alnylam.com/events.

Josh Brodsky: I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision. 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 obligations to update such statements. With that, I'll now turn the call over to Yvonne. Yvonne?

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.

Speaker #2: During today's call, as outlined on slide 2, Yvonne will offer introductory remarks and provide some general context. Jeff will review our financials and guidance.

We disclaim any obligations to update such statements and with that. I'll now turn the call over to Ivan Ivan.

Josh Brodsky: 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 obligations 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.

Speaker #2: Tolga will provide an update on our global commercial progress, and Pushkal will discuss our TTR franchise, our confidence in Triton CM, and upcoming pipeline milestones.

Speaker #2: Before we open the call for your questions. I would like to remind you that this call will contain remarks concerning ALNYLAM's future expectations plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision.

Yvonne Greenstreet: Thanks, Josh, thank you everyone for joining the call today. During the Q2, we demonstrated strong performance across all aspects of the business. Notably, it marks the first time AMVUTRA revenues exceeded $1 billion in a single quarter, representing an annual run rate of more than $4 billion just 15 months into the ATTR cardiomyopathy launch. A testament to both the commercial opportunity and Alnylam's execution. As we reflect on the launch, several insights reinforce our confidence in the durability of AMVUTRA growth over the years ahead. First, this has been an impressive launch by industry benchmarks when looking across market share, access, and revenue generation. Second, the fundamentals of our TTR business are strong, they include AMVUTRA's compelling clinical profile and label. The strong access that we established at launch, which continues to improve, and our robust and expanding provider network.

June, the 2nd quarter, we demonstrated strong performance across all aspects of the business. Notably it marks the first time and future revenues exceeded 1 billion dollars in a single quarter representing an annual run rate of more than 4 billion dollars, just 15 months into the attr cardium market. This is a testament to both the commercial opportunity and our nm's execution.

Speaker #2: 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" that are most recent periodic report available on our website, and on file with the SEC.

As we reflect on the launch.

Several insights reinforce our confidence in the durability of amuta growth over the years ahead.

First.

This has been an impressive launch by industry benchmarks when looking across market share access and revenue generation.

Speaker #2: We disclaim any obligations to update such statements. And with that, I'll now turn the call over to Yvonne. Yvonne?

Second, the fundamentals of our TTR business is strong.

Speaker #3: Thanks, Josh. And thank you, everyone, for joining the call today. During the second quarter, we demonstrated strong performance across all aspects of the business.

And they include and virtuous compelling clinical profile, and label.

Yvonne Greenstreet: As we reflect on the launch, several insights reinforce our confidence in the durability of AMVUTTRA growth over the years ahead. First, this has been an impressive launch by industry benchmarks when looking across market share, access, and revenue generation. Second, the fundamentals of our TTR business are strong, they include AMVUTTRA's compelling clinical profile and label. The strong access that we established at launch, which continues to improve, and our robust and expanding provider network.

The strong access that we established at launch, which continues to improve and our robust and expanding provider Network.

Speaker #3: Notably, it marks the first time Amvutra revenues exceeded $1 billion in a single quarter, representing an annual run rate of more than $4 billion just 15 months into the ATTR cardiomyopathy launch, a testament to both the commercial opportunity and our ALNYLAM's execution.

Third.

Patient demand from vutra, continues to grow robustly, particularly in the first line setting, which has been our Focus as we aspire to Market leadership, given and boost with clinical differentiation and desirability as a foundational therapy for newly diagnosed patients

Speaker #3: As we reflect on the launch, several insights reinforce our confidence in the durability of Amvutra's growth over the years ahead. First, this has been an impressive launch by industry benchmarks when looking across market share, access, and revenue generation.

Yvonne Greenstreet: Third, patient demand for AMVUTRA continues to grow robustly, particularly in the first-line setting, which has been our focus as we aspire to market leadership given AMVUTRA's clinical differentiation and desirability as a foundational therapy for newly diagnosed patients. Tolga will discuss how we are now further investing in broadening our AMVUTRA prescriber base and supporting overall category growth, the latter of which has been accelerating. Finally, our geographic expansion strategy continues to gain momentum, and today we're pleased to announce our collaboration with B1, through which they will have exclusive commercialization and distribution rights for AMVUTRA in mainland China and Macau, subject to AMVUTRA receiving marketing authorization. Together with B1, we aim to help advance awareness and support diagnosis of ATTR amyloidosis and, if approved, bring the strength of TTR silencing with AMVUTRA to patients in these underserved regions.

Yvonne Greenstreet: Third, patient demand for AMVUTTRA continues to grow robustly, particularly in the first-line setting, which has been our focus as we aspire to market leadership given AMVUTTRA's clinical differentiation and desirability as a foundational therapy for newly diagnosed patients. Tolga will discuss how we are now further investing in broadening our AMVUTTRA prescriber base and supporting overall category growth, the latter of which has been accelerating. Finally, our geographic expansion strategy continues to gain momentum, and today we're pleased to announce our collaboration with B1, through which they will have exclusive commercialization and distribution rights for AMVUTRA in mainland China and Macau, subject to AMVUTRA receiving marketing authorization. Together with B1, we aim to help advance awareness and support diagnosis of ATTR amyloidosis and, if approved, bring the strength of TTR silencing with AMVUTRA to patients in these underserved regions.

Togo will discuss how we are now further investing in broadening our and foudre prescriber base and supporting overall category growth. The Lasher of which has been accelerating

Speaker #3: Second, the fundamentals of our TTR business are strong. And they include Amvutra's compelling clinical profile and label, the strong access that we established at launch, which continues to improve, and our robust and expanding provider network.

finally our Geographic expansion strategy continues to gain momentum and today we are pleased to announce our collaboration with B1 through which they will have exclusive commercialization and distribution rights for ambra in Mainline China and Macau subject to and future receiving marketing authorization.

Speaker #3: Third, patient demand for Amvutra continues to grow robustly, particularly in the first-line setting, which has been our focus as we aspire to market leadership, given Amvutra's clinical differentiation and desirability as a foundational therapy for newly diagnosed patients.

Together with B1, we aim to help Advance awareness and support diagnosis of ATR amloid. Doses. And if approved bring the strength of TTR silencing with AMV to patients in these underserved regions,

Speaker #3: Tolga will discuss how we are now further investing in broadening our Amvutra prescriber base and supporting overall category growth, the lasher of which has been accelerating.

As Jeff will describe shortly. We are luring our 2026 Revenue guidance. Today to reflect a better understanding with hindsight of the first few quarters of our us launch.

Speaker #3: Finally, our geographic expansion strategy continues to gain momentum. And today, we are pleased to announce our collaboration with B1, through which they will have exclusive commercialization and distribution rights for Amvutra in mainland China and Macau, subject to Amvutra receiving marketing authorization.

Specifically that early second line demand growth in 2025 benefited, significantly from pent-up demand for a new therapy that has since normalized.

Yvonne Greenstreet: As Jeff will describe shortly, we are lowering our 2026 revenue guidance today to reflect a better understanding with hindsight of the first few quarters of our US launch. Specifically, that early second-line demand growth in 2025 benefited significantly from pent-up demand for a new therapy that has since normalized. With that learning and our strong 2026 second-quarter performance, our confidence in AMVUTRA's growth trajectory has never been stronger. First-line new patient starts are now responsible for about 80% of category growth in this accelerating market, and we believe we're making great progress in establishing AMVUTRA as a foundational therapy. I will now turn to recent developments in the competitive landscape, specifically the negative outcome of the CARDIO-TTRansform study of eplontersen.

With that learning and our strong 2026 second quarter performance, our confidence in Hombres, growth trajectory has never been stronger.

Speaker #3: Together with B1, we aim to help advance awareness and support diagnosis of ATTR amyloidosis and, if approved, bring the strength of TTR silencing with Amvuttra to patients in these underserved regions.

In this accelerating market and we believe we're making great progress in establishing a vutra as a foundational therapy.

Speaker #3: As Jeff will describe shortly, we are luring our 2026 revenue guidance today, to reflect a better understanding with hindsight of the first few quarters of our US launch.

I will now turn to recent developments of the competitive. Landscape specifically, the negative outcome of the cardio transform study of ippon. Tersa

Speaker #3: Specifically, that early second-line demand growth in 2025 benefited significantly from pent-up demand for a new therapy, that has since normalized. With that learning, and our strong 2026 second-quarter performance, our confidence in Amvutra's growth trajectory has never been stronger.

We recognize investor interest in understanding any potential implications of that studies failure for our probability of success. In Triton, CM our phase 3 cardiovascular outcomes trial of new crease rep.

Let me be clear.

Yvonne Greenstreet: We recognize investor interest in understanding any potential implications of that study's failure for our probability of success in TRITON-CM, our phase III cardiovascular outcomes trial of nucresiran. Let me be clear. This outcome does not alter our conviction in the TRITON-CM study. As Pushkal will share in greater detail, our strong confidence is grounded in the established clinical evidence for RNAi therapeutics in TTR and the track record of our clinical organization. At the same time, we have a variety of options at our disposal to potentially adapt the study and position it for optimal success. We will carefully review the full eplontersen dataset when it becomes available and adapt our study plan if appropriate. We have successfully navigated complex TTR development before and believe we are exceptionally well-positioned to do so again with inclisiran.

This outcome does not alter our conviction in the Tricom CM study. And, as push gold was sharing greater detail. Our strong confidence is grounded in the established clinical evidence for rnai Therapeutics in PTR and the track record of our clinical organization.

Speaker #3: First-line new patient starts and now responsible for about 80% of category growth in this accelerating market. And we believe we're making great progress in establishing Amvutra as a foundational therapy.

At the same time, we have a variety of options at our disposal to potentially adapt the study and position it for optimal success.

We will carefully review the full e-pilen certain data set, when it becomes available and adapt our study plan if appropriate.

Speaker #3: I will now turn to recent developments in the competitive landscape, specifically the negative outcome of a CardioTransform study of eplontersen. We recognize investor interest in understanding any potential implications of that study's failure for our probability of success in TRIDENT-CM.

We have successfully navigated complex TTR development before and believe we exceptionally well positioned to do so again with Mr.

Speaker #3: Our Phase III cardiovascular outcomes trial of Nucrisrap, let me be clear, this outcome does not alter our conviction in the Triton CM study. And as Pushkal was sharing greater detail, our strong confidence is grounded in the established clinical evidence for RNAi therapeutics in TTR and the track record of our clinical organization.

Additionally, in the quarter, we were pleased to announce a series of strategic AI collaborations across the Enterprise including with inceptive to expand the next Frontier. In the discovery of RNA Therapeutics and a collaboration where police announced today was a large Health Care system in California aimed at supporting early identification of attr cardiac in routine care.

This Builds on our previously announced Partnerships with vizar and kamoto health.

Yvonne Greenstreet: Additionally, in the quarter, we were pleased to announce a series of strategic AI collaborations across the enterprise, including with Inceptive, to expand the next frontier in the discovery of RNAi therapeutics, and a collaboration we're pleased to announce today with a large healthcare system in California aimed at supporting early identification of ATTR cardiomyopathy in routine care. This builds on our previously announced partnerships with Viz.ai and Komodo Health. Altogether, this cohesive AI strategy from discovery and evidence generation to disease identification, clinical practice, and commercial execution reflects our long-term conviction that AI will fundamentally reshape how medicines are discovered, developed, and ultimately delivered to patients. Finally, we also continue to progress our deep pipeline of investigational medicines, initiating a phase II trial of ALN-6400 in von Willebrand disease and a phase II trial of mivelsiran in Down syndrome-associated Alzheimer's disease.

Speaker #3: At the same time, we have a variety of options at our disposal to potentially adapt the study and position it for optimal success. We will carefully review the full Eplon Thurson dataset when it becomes available, and adapt our study plan if appropriate.

Altogether this cohesive AI strategy from Discovery and evidence generation to disease identification, clinical practice and Commercial execution, reflects our long-term conviction, that AI will fundamentally reshape, our medicine that discovered developed and ultimately delivered to patients.

Speaker #3: We have successfully navigated complex TTR development before, and believe we are exceptionally well positioned to do so again with Nucrisrap. Additionally, in the quarter, we were pleased to announce a series of strategic AI collaborations across the enterprise, including with Inceptive, to expand the next frontier in the discovery of RNAi therapeutics.

Speaker #3: And a collaboration we're pleased to announce today with a large healthcare system in California, aimed at supporting early identification of ATTR cardiomyopathy in routine care.

Finally, we also continue to progress our deep pipeline of investigational medicines initiating, a phase 2, trial as aln 6400 in voneida Brens disease and a phase 2 trial of myver in Down syndrome Associated Alzheimer's disease. So we look forward to a series of clinical data readouts to the back office of this year including presentation of initial Phase 1 results as a on httt O2 in patients with Huntington's disease at EHD and in October

Speaker #3: This builds on our previously announced partnerships with VizAI and Komodo Health. Altogether, this cohesive AI strategy from discovery and evidence generation to disease identification, clinical practice, and commercial execution reflects our long-term conviction that AI will fundamentally reshape how medicines are discovered, developed, and ultimately delivered to patients.

all of this progress bills are momentum towards accelerating Innovation and scaling our impact as we look to deliver on our 5-year Vision on 92030

Yvonne Greenstreet: We look forward to a series of clinical data readouts in the back half of this year, including presentation of initial phase I results of ALN-HTT02 in patients with Huntington's disease at EHDN in October. All of this progress builds on our momentum towards accelerating innovation and scaling our impact as we look to deliver on our five-year vision, Alnylam 2030. Our strategy is anchored around three pillars. The first pillar is to establish global leadership in TTR while continuing to build a durable franchise. The momentum we have built in ATTR cardiomyopathy to date, along with recent developments in the competitive landscape, including the CARDIO-TTRansform phase III top-line results, and the delay in expected US generic entries for tafamidis until mid-2031, further reinforce the strength of our position and the significant opportunity ahead to establish AMVUTRA as a foundational therapy and realize our TTR leadership ambitions.

In our strategy is anchored around 3 pillars. The first pillar is to establish Global Leadership and TTR, while continuing to build a durable franchise

Speaker #3: Finally, we also continue to progress our deep pipeline of investigational medicines, initiating a Phase II trial of ALN6400 in von Wiedebren's disease, and a Phase II trial of Myvalsaran in Down syndrome-associated Alzheimer's disease, and we look forward to a series of clinical data readouts in the back half of this year.

Speaker #3: Including presentation of initial Phase I results of ALNHTT02 in patients with Huntington's disease at EHDN in October. All of this progress builds our momentum towards accelerating innovation and scaling our impact as we look to deliver on our five-year vision ALNYLAM 2030.

The momentum we have built in ATR cardiopathy to date along with recent developments in the competitive landscape including the cardio transform phase 3, Topline results and the delay and expected us generic entry for tammis until mid 2031. Further reinforced the strength of our position and the significant opportunity ahead to establish ambra as a foundational therapy and realize our TTR leadership ambitions.

The second pillar is growing through sustainable Innovation where we aim to deliver therapies that not only slow the progression of disease to prevent halt or reverse it. And the third pillar is scaling with discipline and Agility to enable durable profitable growth.

Speaker #3: And our strategy is anchored around three pillars. The first pillar is to establish global leadership in TTR while continuing to build a durable franchise.

Yvonne Greenstreet: The second pillar is growing through sustainable innovation, where we aim to deliver therapies that not only slow the progression of disease, but prevent, halt, or reverse it. The third pillar is scaling with discipline and agility to enable durable, profitable growth. Alnylam 2030 represents our commitment to becoming the leading science-driven, fully integrated global biopharmaceutical company, and to maximize the full potential of RNAi therapeutics for patients. With that, let me now turn the call over to Jeff for a review of our Q2 financial results and 2026 guidance. Jeff?

Speaker #3: The momentum we have built in along with recent developments in the competitive landscape, including the cardiotransform Phase III top-line generic entry for tafamides until mid-2031, further reinforce the strength of our position and the significant opportunity ahead to establish Amvutra as a foundational therapy and realize our TTR leadership ambitions.

Our Madame 20130 represents our commitment to becoming the leading surance driven, fully integrated Global bar pharmaceutical company and to maximize the full potential of RNA Therapeutics for patients with that. Let me now turn the call over to Jeff for a review of our second quarter Financial results and 2026 guidance, Jeff.

Thanks, Ivon. Good morning everyone. This morning, I'll be presenting a summary of online, second quarter 2026. Financial results in discussing updates to our full year guidance.

Let's begin with the summary of our p&l results for the second quarter.

Speaker #3: The second pillar is growing through sustainable innovation, where we aim to deliver therapies that not only slow the progression of disease, but prevent, halt, or reverse it.

Jeff Poulton: Thanks, Yvonne, and good morning, everyone. This morning I will be presenting a summary of Alnylam Q2 2026 financial results and discussing updates to our full year guidance. Let us begin with a summary of our P&L results for Q2. Total global net product revenues were approximately $1.2 billion, representing 74% growth versus Q2 last year, driven by the continued uptake of AMVUTRA in ATTR cardiomyopathy. Q2 of 2026 marks the first time we achieved more than $1 billion of TTR revenue. These results reflect a substantial improvement in quarter-on-quarter growth compared with growth in Q1 this year, consistent with the phasing expectations we discussed on our year-end and Q1 earnings calls earlier this year. Tolga will share more details on our TTR performance in the quarter.

Speaker #3: And the third pillar is scaling with discipline and agility to enable durable, profitable growth. ALNYLAM 2030 represents our commitment to becoming the leading science-driven, fully integrated, global biopharmaceutical company and to maximize the full potential of RNAi therapeutics for patients.

Speaker #3: With that, let me now turn the call over to Jeff for a review of our second-quarter financial results and 2026 guidance. Jeff?

Total global net product revenues, were approximately. 1.2 billion representing 74% growth versus Q2 last year, driven by the continued uptake of bamboo tra and attr cardiomyopathy second quarter of 2026 marks. The first time, we achieved more than 1 billion of TTR Revenue these results, reflect a substantial Improvement in quarter on quarter growth. Compared with growth in q1 this year, consistent with the phasing expectations. We discussed on our year end and q1 earnings calls earlier. This year all go will share more details on our TTR performance in the quarter.

Speaker #4: Thanks, Yvonne. Good morning, everyone. This morning, I'll be presenting a summary of ALNYLAM's second quarter 2026 financial results and discussing updates to our full-year guidance.

Speaker #4: Let's begin with the summary of our P&L results for the second quarter. Total global net product revenues were approximately $1.2 billion, representing 74% growth versus Q2 last year, driven by the continued uptake of AMVUTTRA and ATTR cardiomyopathy.

For 23, decrease compared with the same period last year due to lower Revenue. Recognized from our regeneron collaboration partially offset by increased revenue from our row collaboration driven by higher reimbursable development, activities related to the Zenith phase 3, clinical trial, asabe San

Jeff Poulton: In Q2, collaboration revenue was $47 million or a 23% decrease compared with the same period last year due to lower revenue recognized from our Regeneron collaboration, partially offset by increased revenue from our Roche collaboration, driven by higher reimbursable development activities related to the ZENITH phase III clinical trial of zilebesiran. Royalty revenue for Q2 increased 79% to $72 million, driven by higher Leqvio sales by Novartis. Gross margin on product sales was 75%, or 4% lower than Q2 last year. The decrease in margin was primarily driven by increased royalties on AMVUTRA as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi.

Royalty revenue for the second quarter increased 79% to 72 million driven by higher lepto sales by Novartis.

Speaker #4: The second quarter of 2026 marks the first time we achieved more than $1 billion of TTR revenue. These results reflect a substantial improvement in quarter-on-quarter growth compared with growth in Q1 this year, consistent with the phasing expectations we discussed on our year-end and Q1 earnings calls earlier this year.

Gross margin on product sales was 75% or 4% lower than Q2 last year. The decrease in margin was primarily driven by increased royalties on in bootstrap as higher revenues in 2026 resulted. In an increase in the average royalty rate payable to Santa Fe

Speaker #4: Tolga will share more details on our TTR performance in the quarter. In Q2, collaboration revenue was $47 million, or a 23% decrease compared with the same period last year due to lower revenue recognized from our Regeneron collaboration.

Our non-gaap R&D expenses of 377 million increased 38% compared to last year. Primarily driven by costs associated with our 3 ongoing phase 3 clinical studies

including the Zenith phase 3, cardiovascular outcomes trial for zeran and the Triton cm and PN studies for an increase around.

Speaker #4: Partially offset by increased revenue from our Roche collaboration driven by a higher reimbursable development activities related to the Zenith Phase III clinical trial of Zolbesaran.

Jeff Poulton: Our non-GAAP R&D expenses of $377 million increased 38% compared to last year, primarily driven by costs associated with our three ongoing phase III clinical studies, including the ZENITH phase III cardiovascular outcomes trial for zilebesiran and the TRITON-CM and PN studies for nucresiran. Beyond the pivotal studies, we also continue to increase investment to support important programs for bleeding disorders, Huntington's disease, and CAA. Non-GAAP SG&A expenses of $297 million increased 14% compared to last year, driven primarily by investments in support of the AMVUTRA ATTR cardiomyopathy launch in the US and in key international markets. We achieved non-GAAP operating income of $318 million, more than triple the amount we achieved last year, driven primarily by the strong top-line results that I previously highlighted. Finally, we ended the Q2 with cash equivalents, and marketable securities of $3.3 billion, compared with $2.9 billion as of year-end 2025.

Beyond the pivotal studies. We also continue to increase investment to support important programs for bleeding disorders, Huntington's disease and CIA.

Speaker #4: Royalty revenue for the second quarter increased $79% to $72 million, driven by higher Lectio sales by Novartis. Gross margin on product sales was $75%, or 4% lower than Q2 last year.

Non-gaap as GNA expenses of 297 million increased 14% compared to last year, driven, primarily, by investments in support of the ambua, attr, cardiomyopathy launched in the US and key International markets.

Speaker #4: 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 to Sanofi.

We achieved non-gaap operating income of 318 million. More than triple the amount we achieved last year, driven primarily by the strong Topline results. They had previously highlighted

Speaker #4: Our non-GAAP R&D expenses of $377 million increased 38% compared to last year. Primarily driven by costs associated with our three ongoing Phase III clinical studies, including the Zenith Phase III cardiovascular outcomes trial for Zolbesaran, and the Triton CM and TN studies for Nucrisaran.

Finally, we ended the second quarter with cash cash equivalents and marketable securities of 3.3 billion compared with 2.9 billion as of year end 2025.

The primary driver of the increase in cash year to date is our strong operating performance.

Now, turning to our full year, 2026 guidance.

Speaker #4: Beyond the pivotal studies, we also continue to increase investment to support important programs for bleeding disorders, Huntington's disease, and CAA. Non-GAAP SG&A expenses of $297 million increased 14% compared to last year, driven primarily by investments in support of the Amvutra ATTR cardiomyopathy launch in the US and in key international markets.

Jeff Poulton: The primary driver of the increase in cash year to date is our strong operating performance. Now turning to our full year 2026 guidance. As Yvonne noted, we are revising our total net product revenue guidance to $4.7 to $5.1 billion, driven fully by an update of our TTR revenue guidance to $4.2 to $4.5 billion, representing a $200 million reduction from our original TTR guidance at the midpoint and still reflects a robust 75% growth year-over-year. Guiding the market's expectations appropriately is important. We didn't get it right with our original guidance. We own that. Revised guidance we are sharing today reflects a better understanding of the evolution of second-line demand as our launch has progressed. Let me provide some additional color on the basis for this revision.

As is on noted we are revising. Our total net product Revenue, guidance to 4.7 to 5.1 billion driven fully by an update of our TTR, Revenue guidance, 4.2 to 4.5 billion representing a hundred million dollar reduction from our original TTR guidance at the midpoint and still reflects a robust 75% growth year-over-year.

Speaker #4: We achieved non-GAAP operating income of $318 million, more than triple the amount we achieved last year, driven primarily by the strong top-line results that I previously highlighted.

In the markets, expectations appropriately is important and we didn't get it right with our original guidance. We own that revised guidance. We are sharing today, reflects a better understanding of the evolution of second line demand as our launch is progressed.

Speaker #4: Finally, we ended the second quarter with cash, cash equivalents, and marketable securities of $3.3 billion, compared with $2.9 billion as of year-end 2025. The primary driver of the increase in cash year-to-date is our strong operating performance.

Speaker #4: Now turning to our full-year 2026 guidance. As Yvonne noted, we are revising our total net product revenue guidance to $4.7 to $5.1 billion, driven fully by an update of our TTR revenue guidance to $4.2 to $4.5 billion, representing a $200 million reduction from our original TTR guidance at the midpoint, and still reflects a robust 75% growth year-over-year.

Let me provide some additional color on the basis for this revision. Overall, the Umbro cardiomyopathy launch continues to perform ahead of analogs. And importantly, we are pleased with uptake in the first line portion of the market which has been and Remains the primary focus of our commercial efforts, given the importance of this segment to driving long-term growth

Jeff Poulton: Overall, the AMVUTRA cardiomyopathy launch continues to perform ahead of analogs. Importantly, we are pleased with the uptake in the first-line portion of the market, which has been and remains the primary focus of our commercial efforts, given the importance of this segment to driving long-term growth. When AMVUTRA was launched in April 2025, the compelling HELIOS-B data and our team's success in establishing access enabled physicians to rapidly transition existing patients who were progressing on stabilizers onto AMVUTRA. As a result, second-line demand volumes remained consistently robust throughout 2025, which informed our original 2026 guidance. As the launch progressed into 2026, and with the benefit of hindsight, it is now clear that a greater-than-understood proportion of early second-line volume growth was driven by pent-up demand from patients who were waiting for a new treatment option.

When in was launched in April 2025, the compelling, Helio speed data and our team success in establishing access enabled positions to rapidly transition existing patients who are progressing on stabilizers on ambra as a result. Second line demand volumes remain consistently robust throughout 2025 which informed our original 2026 guidance.

Speaker #4: Guiding the market's expectations appropriately is important, and we didn't get it right with our original guidance. We own that. Revised guidance we are sharing today reflects a better understanding of the evolution of second-line demand as our launch has progressed.

Speaker #4: Let me provide some additional color on the basis for this revision. Overall, the Amvutra cardiomyopathy launch continues to perform ahead of analogs and, importantly, we are pleased with uptake in the first-line portion of the market, which has been and remains the primary focus of our commercial efforts, given the importance of this segment to driving long-term growth.

However, as the launch progressed into 2026 and with the benefit of hindsight, it is now clear that a greater than understood proportion of early second line. Volume growth was driven by pen up demand from patients who are waiting for a new treatment option.

Consistent with the trend we highlighted in our q1 2026 earnings, call growth. In second line volumes began to moderate in early 2026 to what we now recognize as a normalized level.

This normalization of second line, demand is the driver of the hundred million dollar reduction, in tpr guidance that we are announcing today.

Speaker #4: When Amvutra was launched in April 2025, the compelling HelioSpeed data and our team's success in establishing access enabled physicians to rapidly transition existing patients who were progressing unstabilizers onto Amvutra.

Jeff Poulton: Consistent with the trend we highlighted in our Q1 2026 earnings call, growth in second-line volumes began to moderate in early 2026 to what we now recognize as a normalized level. This normalization of second-line demand is the driver of the $200 million reduction in TTR guidance that we are announcing today. Tolga will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in three key elements: The strength of our current market fundamentals, positive impact we expect from new investments we're making based on early launch learnings, and lastly, the favorable competitive developments that Yvonne mentioned in her opening remarks. Back to updating our guidance.

Ogle will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in 3. Key elements, the strength of our current market fundamentals.

Speaker #4: As a result, second-line demand volumes remain consistently robust throughout 2025, which informed our original 2026 guidance. However, as the launch progressed into 2026, and with the benefit of hindsight, it is now clear that a greater-than-understood proportion of early second-line volume growth was driven by pent-up demand from patients who were waiting for a new treatment option.

Positive impact. We expect from new Investments for making based on early launch learnings, and, lastly, the favorable competitive developments that Ivon mentioned in her opening remarks.

Now, back to updating our guidance.

Speaker #4: Consistent with the trend we highlighted in our Q1 2026 earnings call, growth in second-line volumes began to moderate in early 2026 to what we now recognize as a normalized level.

Speaker #4: This normalization of second-line demand is the driver of the $200 million reduction in TTR guidance that we are announcing today. Tolga will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in three key elements.

Jeff Poulton: We are also updating our guidance for collaboration and royalty revenues to a revised range of $575 to 625 million, representing a $150 million increase at the midpoint of the range, driven primarily by strong performance of Leqvio and the resulting royalties from Novartis, as well as higher cost reimbursement from Roche favorably impacting collaboration revenue driven by the pace of enrollment in our ZENITH phase III study with zilebesiran. The remainder of our non-GAAP financial guidance remains unchanged. Let me now turn it over to Tolga to provide more color on our commercial performance in Q2. Tolga?

We are also updating our guidance for collaboration and royalty revenues to revised range of 575 to 625 million. Representing a 150 million dollar increase at the midpoint of the range driven primarily by strong performance of Leo, and the resulting royalties from nardis as well as higher cost reimbursement from row favorably. Impacting collaboration Revenue driven by the pace of enrollment and our Zenith phase 3 study was Elvis Ram, remainder of our non-gaap financial guidance remains unchanged. Let me now turn it over to Tolga to provide more color on our commercial performance. In the second quarter, toga

And good morning.

Speaker #4: The strength of our current market fundamentals, positive impact we expect from new investments we're making based on early-launch learnings, and lastly, the favorable competitive developments that Yvonne mentioned in her opening remarks.

I'm pleased to share our continued progress in bringing online's therapies to patients globally.

Speaker #4: Now back to updating our guidance. We are also updating our guidance for collaboration and royalty revenues to a revised range of $575 to $625 million, representing a 150 million increase at the midpoint of the range driven primarily by strong performance of Lectio and the resulting royalties from Novartis, as well as higher cost reimbursement from Roche, favorably impacting collaboration revenue driven by the pace of enrollment in our Zenith Phase III study with Zolbesaran.

Is delivering a category-defining ATR, attr-cm launched and is on track toward delivering on our online 2030 ambitions.

As Ivonne and Jeff mentioned.

We have gained valuable insights as the launch has progressed.

Tolga Tanguler: Thanks, Jeff, and good morning. I'm pleased to share our continued progress in bringing Alnylam's therapies to patients globally. AMVUTRA is delivering a category-defining ATTR-CM launch and is on track toward delivering on our Alnylam 2030 ambitions. As Yvonne and Jeff mentioned, we have gained valuable insights as the launch has progressed. These learnings have sharpened our understanding of demand dynamics while also reinforcing our confidence in the fundamental drivers of sustainable growth. Overall, we remain highly confident in our path to achieving TTR leadership. The momentum of the business, coupled with an increasingly favorable competitive landscape, reinforce our conviction in achieving our long-term ambitions. Q2 marked another quarter of strong commercial execution and growth. Specifically, we delivered $1.17 billion in combined net product revenues, up 74% year over year and 13% over Q1 2026.

These learnings have sharpened our understanding of demand Dynamics, while also reinforcing our confidence in the fundamental drivers of sustainable growth.

Overall, we remain highly confident in our path to achieving teach our leadership.

Speaker #4: The remainder of our non-GAAP financial guidance remains unchanged. Let me now turn it over to Tolga to provide more color on our commercial performance in the second quarter.

The momentum of the business coupled with an increasingly favorable competitive landscape. Reinforced our conviction in achieving our long-term ambitions.

Speaker #4: Tolga?

Speaker #1: Thanks, Jeff. And good morning. I'm pleased to share our continued progress in bringing ALNYLAM therapies to patients globally. Amvutra is delivering a category-defining ATR CM launch and is on track toward delivering on our ALNYLAM 2030 ambitions.

Q2 marked another quarter of strong commercial execution and growth.

Specifically, we delivered 1.17 billion dollars in combined. Net product, revenues up 74% year-over-year and 13% over q1 2026.

Speaker #1: As Yvonne and Jeff mentioned, we have gained valuable insights as the launch has progressed. These learnings have sharpened our understanding of demand dynamics, while also reinforcing our confidence in the fundamental drivers of sustainable growth.

In just 5 quarters. Since RCM launch, we have generated over 4 billion dollars in total revenue reflecting both a strong base.

And a clear growth trajectory.

Speaker #1: Overall, we remain highly confident in our path to achieving TTR leadership. The momentum of the business, coupled with an increasingly favorable competitive landscape, reinforced our conviction in achieving our long-term ambitions.

Tolga Tanguler: In just 5 quarters since our CM launch, we have generated over $4 billion in total revenue, reflecting both a strong base and a clear growth trajectory. Our rare disease portfolio also continues to deliver meaningful impact for patients and consistent performance for our business. In Q2, we generated $142 million in rare disease net revenue, up 11% year over year. Turning to our TTR franchise. Global TTR net revenues reached $1.03 billion in Q2, increasing 13% versus Q1 and 89% year over year, reflecting the continued strength of the launch and the robust execution of our global teams. In the US, TTR revenues increased 15% versus Q1 and 114% year over year, reflecting robust underlying demand with reported revenue partially held back by changes in inventory days on hand during Q2. Access remained broad, pull-through was strong, and adherence continued to exceed 90%.

Our rare disease portfolio, also continues to deliver meaningful impact for patients, and consistent performance for our business. In Q2, we generated 1402 million in rare disease, net revenue up 11% year-over-year.

Speaker #1: Q2, marked another quarter of strong commercial execution and growth. Specifically, we delivered $1.17 billion in combined net product revenues up 74% year-over-year and 13% over Q1 2026.

Is reached 1.03 billion in the second quarter.

Increasing 13% versus q1 and 89% year-over-year, reflecting the continued strength of the launch and the robust execution of our Global teams.

Speaker #1: In just five quarters since our CM launch, we have generated over $4 billion in total revenue, reflecting both a strong base and a clear growth trajectory.

In the US TTR revenues increased 15% versus q1 and 114% year-over-year reflecting robust underlying demand.

Speaker #1: Our rare disease portfolio also continues to deliver meaningful impact for patients, and consistent performance for our business. In Q2, we generated $142 million in rare disease net revenue, up 11% year-over-year.

With reported Revenue, partially held back by changes, in inventory days on hand during Q2.

Access remain brought pull through or strong and adherence continue to exceed. 90%.

Speaker #1: Turning to our TTR franchise. Global TTR net revenues reached $1.03 billion in the second quarter, increasing 13% versus Q1 and 89% year-over-year. Reflecting the continued strength of the launch and the robust execution of our global teams.

Outside the US TTR, revenues increased 7% versus q1 and 31% year-over-year.

in Japan, the UK and Germany along with strong pul neuropathy performance across our International markets drove, Q2 growth,

despite price related to ongoing, CM launches in several countries,

Tolga Tanguler: Outside the US, TTR revenues increased 7% versus Q1 and 31% year over year. Continued ATTR-CM uptake in Japan, the UK, and Germany, along with strong polyneuropathy performance across our international markets, drove Q2 growth despite pricing headwinds related to ongoing CM launches in several countries. Double-clicking on our Q2 TTR performance in the US, underlying demand was exceptionally strong, increasing by $129 million in the quarter, more than doubling the demand growth achieved in Q1. A portion of that demand was offset by inventory dynamics, which reduced reported growth by $21 million, and to a lesser extent, by the continued and anticipated modest reduction in net price. As a reminder, our Q1 US TTR growth was more modest and was impacted by several seasonal phasing dynamics, and we are therefore pleased by the robust re-acceleration in demand in Q2 and the continued strength of the business.

Speaker #1: In the US, TTR revenues increased 15% versus Q1 and $114% year-over-year, reflecting robust underlying demand with reported revenue partially held back by changes in inventory days on hand during Q2.

Double clicking on our Q2 TTR performance in the US.

Underlying demand was exceptionally strong increasing by 129 million in the quarter, more than doubling, the demand growth achieving q1.

Speaker #1: Access remained broad, pull-through was strong, and adherence continued to exceed 90%. Outside the US, TTR revenues increased 7% versus Q1 and 31% year-over-year, continued ATTR CM uptake in Japan, the UK, and Germany, along with strong polyneuropathy performance across our international markets drove Q2 growth.

A portion of that demand was offset by inventory Dynamics, which reduced reported growth by 21 million and 2. A lesser extent by the continued and anticipated modest reduction in net price.

As a reminder, our q1 us TTR growth was more modest and was impacted by several seasonal, phasing Dynamics.

And we are therefore pleased by the robust re acceleration and demanding Q2 and the continuing strength of the business.

Speaker #1: Despite pricing headwinds related to ongoing CM launches in several countries, double-clicking on our Q2 TTR performance in the U.S., underlying demand was exceptionally strong.

I would trust differentiated clinical profile. Under pins are confidence in the long-term growth opportunity.

Speaker #1: Increasing by 129 million in the quarter, more than doubling the demand growth achieving Q1. A portion of that demand was offset by inventory dynamics, which reduced reported growth by 21 million.

We believe that our mutra stands apart as a personal choice on attributes, that matter to Physicians and patients.

It is the first and only product approved in the US.

For both attr-cm and hereditary ATP.

It works Upstream at the source.

Tolga Tanguler: AMVUTTRA's differentiated clinical profile underpins our confidence in the long-term growth opportunity. We believe that AMVUTTRA stands apart as a first-line choice on attributes that matter to physicians and patients. It is the first and only product approved in the US for both ATTR-CM and hereditary ATTR-PN. It works upstream at the source, delivering rapid, deep, and sustained knockdown of the disease-causing protein. In the pivotal HELIOS-B study, AMVUTTRA met 10 out of 10 endpoints and demonstrated robust treatment effects in the primary endpoint of all-cause mortality and recurring CV events, and secondary endpoints of functional capacity and health-related quality of life. Across all of these endpoints, consistent treatment effects with or without background stabilizers were observed.

Speaker #1: And to a lesser extent, by the continued and anticipated modest reduction in net price. As a reminder, our Q1 US TTR growth was more modest and was impacted by several seasonal phasing dynamics, and we are therefore pleased by the robust re-acceleration in demand in Q2 and the continued strength of the business.

Delivering rapid deep and sustained knockdown of the disease causing protein.

In the pivotal Helios B, study a Ultra Met 10 out of 10 end points and demonstrated robust.

Treatment effects in the primary endpoint of all, cause mortality and recurring CV events.

And secondary end points of functional capacity and health related, quality of life.

Speaker #1: Amvutra's differentiated clinical profile underpins our confidence in the long-term growth opportunity. We believe that Amvutra stands apart as a first-line choice on attributes that matter to physicians and patients.

Across all of these end points. Consistent treatment effects with or without background stabilizers were observed.

With the convenience of 1's, quarterly Healthcare provided Administration and real world data that suggests greater than 90% adherence.

Speaker #1: It is the first and only product approved in the US for both ATTR-CM and hereditary ATTR-PN. It works upstream at the source, delivering rapid, deep, and sustained knockdown of the disease-causing protein.

We believe our mutra is uniquely positioned to address the needs of the growing attr-cm patient population.

Tolga Tanguler: Combined with the convenience of once quarterly healthcare provided administration and real-world data that suggests greater than 90% adherence, we believe AMVUTTRA is uniquely positioned to address the needs of the growing ATTR-CM patient population. The first 5 quarters of launch have provided valuable insights that are informing where we increase investment and how we position the business for its next phase of growth. During the initial quarters following approval, many of our high-volume early adopters transitioned a substantial number of stabilizer-treated progressing patients to AMVUTTRA. While those transitions continue, we are now seeing that portion of demand volume growth normalize toward a more sustainable underlying rate, and we continue to capture leadership share of second-line starts. Today, approximately 80% of new treatment initiations are first-line starts. Establishing AMVUTTRA as first-line treatment choice has been our priority since launch, and we continue to strengthen our competitive position.

Speaker #1: In the pivotal Helios B study, Amvutra met 10 out of 10 endpoints and demonstrated robust treatment effects in the primary endpoint of all-cause mortality and recurring CV events, and secondary endpoints of functional capacity and health-related quality of life.

The first 5 quarters of launch have provided valuable insights, that are informing where we increase investment and how we position the business for its next phase of growth.

During the initial quarters following approval, many of our high volume early. Adopters transitioned a substantial number of stabilizer treated progressing, patients to ambra.

Speaker #1: Across all of these endpoints, consistent treatment effects with or without background stabilizers were observed. Combined with the convenience of once-quarterly healthcare-provided administration, and real-world data that suggests greater than 90% adherence, we believe Amvutra is uniquely positioned to address the needs of the growing ATTR CM patient population.

While those transitions continue, we are now seeing that portion of demand volume growth, normalized toward a more sustainable underlying rate and we continue to capture leadership share of second line start.

Today, Approximately 80% of new treatment, initiations are first-line starts.

Establishing a mutra. As first line, treatment Choice has been our priority since launch and we continue to strengthen our competitive position.

Speaker #1: The first five quarters of launch have provided valuable insights that are informing where we increase investment and how we position the business for its next phase of growth.

What's more while our strategy has never depended on competitor's outcomes.

Speaker #1: During the initial quarters following approval, many of our high-volume early adopters transitioned a substantial number of stabilizer-treated progressing patients to Amvutra. While those transitions continue, we are now seeing that portion of demand volume growth normalize toward a more sustainable underlying rate, and we continue to capture leadership share of second-line starts.

2. Favorable developments in the external landscape have cleared the path for us to be even more competitive in the first 9 setting.

first, we now anticipate the families us loss of exclusivity in 2031,

Tolga Tanguler: What's more, while our strategy has never depended on competitors' outcomes, two favorable developments in the external landscape have cleared a path for us to be even more competitive in the first-line setting. First, we now anticipate tafamidis US loss of exclusivity in 2031. AMVUTTRA is already challenging this 7-year incumbent for leadership share of new patient starts, and we see a significant opportunity to continue strengthening that position years ahead of genericization of the stabilizer class. Second, based on the CARDIO-TTRansform study top-line results, we now anticipate one fewer branded ATTR-CM competitor in both the first-line and stabilizer progressor segments. Category growth continues to accelerate, and our competitive first-line share, coupled with this clear competitive path to greater first-line penetration, aligns well with where we see the largest opportunity.

Am mutra is already challenging the 7-year incumbent for leadership, share of new patient starts and we see a significant opportunity to continue strengthening that position years ahead of generalization of the stabilizer class.

Speaker #1: Today, approximately 80% of new treatment initiations are first-line starts. Establishing Amvutra as first-line treatment choice has been our priority since launch, and we continue to strengthen our competitive position.

Second based on the cardio. T transforms study Topline results. We now anticipate 1 fewer branded atrs attr-cm competitor in both the first line and stabilizer, progressor segments.

Speaker #1: What's more, while our strategy has never depended on competitors' outcomes, two favorable developments in the external landscape have cleared the path for us to be even more competitive in the first-line setting.

Finally category growth continues to accelerate and our competitive first line, share coupled with this clear competitive path to Greater first-time penetration aligns well, with where we see the largest opportunity.

Speaker #1: First, we now anticipate Tefamidus US loss of exclusivity in 2031. Amvutra is already challenging the seven-year incumbent for leadership share of new patient starts, and we see a significant opportunity to continue strengthening that position years ahead of generalization of the stabilizer class.

With an estimated 80% of patients, still untreated and additional Physicians and Health Systems, initiating treatment of attr-cm. We expect the robust growth in first line starts to continue.

Speaker #1: Second, based on the cardio TT transform study top-line results, we now anticipate one fewer branded ATTR CM competitor in both the first-line and stabilizer progressor segments.

Tolga Tanguler: With an estimated 80% of patients still untreated and additional physicians and health systems initiating treatment of ATTR-CM, we expect the robust growth in first-line starts to continue. We're helping to drive that category growth. More specifically, we're accelerating our investments in diagnosis-enabling initiatives, investments to identify patients earlier, to expand the treatable population, and ultimately, to improve patient outcomes. Taken together, these insights provide great confidence in our ability to expand leadership across both ATTR-CM and hereditary ATTR-PN and deliver on our 2030 ambitions of TTR leadership and a 25% revenue CAGR during the period. As we shared today, our differentiated profile has translated into exceptional launch momentum, and that experience has sharpened our understanding of what will drive the next phase of growth.

And we're helping to drive that category growth more specifically. We're accelerating our investments in diagnosis enabling initiatives Investments, to identify patients earlier, the expanded treatable population and ultimately to improve patient outcomes.

Taken together these insights provide, great confidence, in our ability to expand leadership across both.

Speaker #1: Finally, category growth continues to accelerate, and our competitive first-line share, coupled with this cleared competitive path to greater first-line penetration, aligns well with where we see the largest opportunity.

Attrc and hereditary trpn and deliver on our 2030, Ambitions of TTR leadership and a 25% Revenue tagger During the period.

Speaker #1: With an estimated 80% of patients still untreated and additional physicians and health systems initiating treatment of ATTR CM, we expect the robust growth in first-line starts to continue.

As we share today our differentiated profile has translated into exceptional launch momentum. And that experience has sharpened. Our understanding of what will drive the next phase of growth.

Speaker #1: And we're helping to drive that category growth. More specifically, we're accelerating our investments in diagnosis-enabling initiatives, investments to identify patients earlier, to expand the treatable population, and ultimately to improve patient outcomes.

First after 5 quarters, in the markets, I would just compelling profile and our Focus efforts have driven broad coverage and efficient patient access with no meaningful reimbursement, headwinds

we believe this strong access foundation will continue to support physician confidence and patient adoption as we expand the franchise second,

Speaker #1: Taken together, these insights provide great confidence in our ability to expand leadership across both ATTR CM and hereditary ATTR PN, and deliver on our 2030 ambitions of TTR leadership and a 25% revenue CAGR during the period.

Tolga Tanguler: First, after five quarters in the market, AMVUTTRA's compelling profile and our focused efforts have driven broad coverage and efficient patient access with no meaningful reimbursement headwinds. We believe this strong access foundation will continue to support physician confidence and patient adoption as we expand the franchise. Second, we continue to deepen adoption among physicians who have already incorporated AMVUTTRA into their practice. Among prescribers using AMVUTTRA, it now represents more than 50% of new patient starts, underscoring the strong physician preference that develops with experience. From ATTR-CM launch through the end of Q2, we have added over 1,700 new prescribers. Third, and perhaps most importantly, we have significant opportunity to expand the breadth of prescribers who have experience with AMVUTTRA, which we estimated about a third of the growing pool of TTR prescribers.

We continue to deepen adoption among Physicians who have already Incorporated our mutra into their practice.

Among prescribers using Amite.

Speaker #1: As we share today, our differentiated profile has translated into exceptional launch momentum and that experience has sharpened our understanding of what will drive the next phase of growth.

It now represents more than 50% of new patient starts under underscoring. The strong physician preference that develops with experience.

And from attr-cm launched through the end of Q2, we have added over 1700 new prescribers.

Speaker #1: First, after five quarters in the market, Amvutra's compelling profile and our focus efforts have driven broad coverage and efficient patient access, with no meaningful reimbursement headwinds.

So third. And perhaps, most importantly, we have significant opportunity, to expand the breadth of prescribers who have experienced with alvra, which we estimated about a third of the growing pool of TTR prescribers.

Speaker #1: We believe the strong access foundation will continue to support physician confidence and patient adoption as we expand the franchise. Second, we continue to deepen adoption among physicians who have already incorporated Amvutra into their practice.

What we know we know that experience drives preference. There are many more Physicians including many, who are new to the category who have not yet prescribed alvra.

To capture that opportunity.

Speaker #1: Among prescribers using Amvutra, it now represents more than 50% of new patient starts, underscoring the strong physician preference that develops with experience. And from the ATTR-CM launch through the end of Q2, we have added over 1,700 new prescribers.

We are intensifying our focus and increasing our investment in customer-facing activities, to expand the breadth of prescribing.

Tolga Tanguler: While we know that experience drives preference, there are many more physicians, including many who are new to the category, who have not yet prescribed AMVUTTRA. To capture that opportunity, we are intensifying our focus and increasing our investment in customer-facing activities to expand the breadth of prescribing. We are already seeing early progress from these efforts with accelerated growth in new AMVUTTRA prescribers during Q2. We believe we are in the early stages of that expansion opportunity. While we are still early in the commercialization journey, we believe AMVUTTRA is well-positioned to capture the significant opportunity ahead as we bring this differentiated therapy to more patients living with ATTR-CM. With that, I will now turn it over to Pushkal.

We are already seeing early progress from these efforts with accelerated growth in new and water prescribers. During the second quarter.

We believe we are in the early stages of that expansion opportunity.

while we're still in the

Speaker #1: Third, and perhaps most importantly, we have significant opportunity to expand the breadth of prescribers who have experience with Amvutra which we estimated at about a third of the growing pool of TTR prescribers.

While we're, while we're still early in the commercialization journey, we believe our mutra is well, positioned to capture the significant opportunity ahead. As we bring this differentiated therapy to more patients, living with attr-cm

with that, I will now turn it over to pushkov.

Speaker #1: While we now know that experience drives preference, there are many more physicians including many who are new to the category who have not yet prescribed Amvutra.

Thank you, toga. And good morning, everyone. Uh, at toga just highlighted, we believe in bra has a remarkable clinical profile that supports it being the first line treatment of choice.

Speaker #1: To capture that opportunity, we are intensifying our focus and increasing our investment in customer-facing activities to expand the breadth of prescribing. We are already seeing early progress from these efforts.

For patients with attr cardiomyopathy. These key attributes are highlighted here with data from The Landmark Helio speed study.

Speaker #1: With accelerated growth in new Amvutra prescribers during the second quarter, we believe we are in the early stages of that expansion opportunity. While we're still in the while we're still early in the commercialization journey, we believe Amvutra is well positioned to capture the significant opportunity ahead as we bring this differentiated therapy to more patients living with ATTR CM.

Pushkal Garg: Thank you, Tolga, and good morning, everyone. As Tolga just highlighted, we believe AMVUTTRA has a remarkable clinical profile that supports it being the first-line treatment of choice for patients with ATTR cardiomyopathy. These key attributes are highlighted here with data from the landmark HELIOS-B study. First and foremost, we have seen substantial benefits with regard to improving clinical outcomes, both all-cause mortality and cardiovascular events, with reductions of nearly 40% over 48 months across these two endpoints. Second, the treatment effects are largest when we intervene early. You can see that in the forest plot on the bottom left, where patients with lower BNP, greater walking ability, and younger age have had even greater reductions in the composite endpoint of 47%, 42%, and 45% respectively.

First and foremost, we've seen substantial benefits with regard to improving clinical outcomes both all cause mortality and cardiovascular events with reductions of nearly 40% over 48 months across these 2 end points.

Second, the treatment effects are largest when we intervene early.

Speaker #1: With that, I will now turn it over to Pushkal.

Speaker #2: Thank you, Tolga. And good morning, everyone. As Tolga just highlighted, we believe Amvuttra has a remarkable clinical profile that supports it being the first-line treatment of choice for patients with ATTR cardiomyopathy.

You can see that in the forest plot on the bottom left. Where patients with lower BNP greater walking ability and younger age have had even greater reductions in the composite endpoint of 47% 42% and 45%. Respectively, and importantly, in data recently presented at ESC, heart failure and shown on the lower. Right quadrant, we see that the treatment effect is preserved irrespective of background medications, including TTR, stabilizers these attributes along with the quarterly dosing that supports adherence. In our view, represents an ideal profile for First Line agent for patients, with attr cardiomyopathy,

Speaker #2: These key attributes are highlighted here with data from the landmark Helios B study. First and foremost, we've seen substantial benefits with regard to improving clinical outcomes.

Pushkal Garg: Importantly, in data recently presented at ESC Heart Failure and shown on the lower right quadrant, we see that the treatment effect is preserved irrespective of background medications, including TTR stabilizers. These attributes, along with the quarterly dosing that supports adherence, in our view, represents an ideal profile for a first-line agent for patients with ATTR cardiomyopathy. Now, the strength of these HELIOS-B results, along with our many learnings from our deep experience in TTR amyloidosis, provide us with staunch conviction in the value of nucresiran, our next-generation investigational RNAi TTR silencer, which we believe has the potential for even greater improved efficacy by a greater knockdown, over 95%, with just two doses per year. As you are aware, we continue to advance nucresiran in the TRITON phase III program. TRITON-CM is a randomized, double-blind, event-driven outcome study of nucresiran versus placebo.

Speaker #2: Both all-cause mortality and cardiovascular events with reductions of nearly 40% over 48 months across these two endpoints. Second, the treatment effects are largest when we intervene early.

Speaker #2: You can see that in the forest plot on the bottom left, where patients with lower BNP, greater walking ability, and younger age have had even greater reductions in the composite endpoint of 47%, 42%, and 45% respectively.

Now, the strength of these Helios be results along with our many learnings from our deep experience in TTR ammo. Doses, provide us with staunch conviction in the value of newer in our next Generation investigational, RNA, ITR silencer which we believe has the potential for even greater improved efficacy by a greater knockdown over 95% with Just 2 doses per year.

As you're aware, we continue to advance decreased ran in the Triton phase 3 Program.

Triton cm is a randomized. Double blind. Event-driven outcome study of newest Rand versus placebo.

Speaker #2: And importantly, in data recently presented at ESC heart failure and shown on the lower right quadrant, we see that the treatment effect is preserved irrespective of background medications, including TTR stabilizers.

Speaker #2: These attributes, along with the quarterly dosing that supports adherence in our view, represents an ideal profile for first-line agent for patients with ATTR cardiomyopathy.

We announced last quarter that we utilized a pre-specified option in our protocol to expand enrollment by about by approximately 500 patients to 1715 total further mitigating the potential risk of low event rates while maintaining or potentially even accelerating timelines for this important study.

Speaker #2: Now, the strength of these Helios B results, along with our many learnings from our deep experience in TTR amyloidosis, provide us with staunch conviction in the value of Nucrisorin, our next-generation investigational RNAi TTR silencer, which we believe has the potential for even greater improved efficacy by a greater knockdown over 95% with just two doses per year.

Pushkal Garg: We announced last quarter that we utilized a pre-specified option in our protocol to expand enrollment by approximately 500 patients to 1,715 total, further mitigating the potential risk of low event rates while maintaining or potentially even accelerating timelines for this important study. Given recent competitor data and given that many patients in TRITON-CM will be on a background stabilizer, we understand that there have been many questions raised about the feasibility of delivering positive results from this clinical trial. While we still have more to learn about the eplontersen results, we believe they're likely attributable to a combination of molecule and study-specific issues. As we compare what we know about nucresiran with what's been reported about eplontersen, I want to assure you that we remain highly confident in nucresiran and TRITON-CM.

Now, given recent competitor data and given that many patients in Triton CM will be on a background stabilizer. We understand that there have been many questions raised about the feasibility of delivering positive results from this clinical trial.

Speaker #2: As you're aware, we continue to advance Nucrisorin in the Triton phase three program. Triton CM is a randomized, double-blind event-driven outcome study of Nucrisorin versus placebo.

While we still have more to learn about the EP tears and results, we believe they're likely attributable to a combination of molecule and study specific issues. And as we compare what we know about increased Iran with what's been reported about Upland turenne, I want to assure you that we remain highly confident in increased Iran and tritonia.

Speaker #2: We announced last quarter that we utilized a pre-specified option in our protocol to expand enrollment by about by approximately 500 patients, to 1,715 total, further mitigating the potential risk of low event rates while maintaining or potentially even accelerating timelines for this important study.

I'll explain more in a moment, but first, let me share. What we what we'll be looking for in the upcoming data, presentations of the cardio transform results at ESC to better understand the reasons, why the study did not meet its primary endpoint.

Speaker #2: Now, given recent competitor data and given that many patients in Triton CM will be on a background stabilizer, we understand that there have been many questions raised about the feasibility of delivering positive results from this clinical trial.

First. We'll be interested to learn more about the population and Baseline characteristics of the cardio transform study, particularly in the 2 key, subgroups of monotherapy and the patients on background stabilizers.

Pushkal Garg: I'll explain more in a moment. First, let me share what we'll be looking for in the upcoming data presentations of the CARDIO-TTRansform results at ESC to better understand the reasons why the study did not meet its primary endpoint. First, we'll be interested to learn more about the population and baseline characteristics of the CARDIO-TTRansform study, particularly in the two key subgroups of monotherapy and in the patients on background stabilizers. As I noted, in HELIOS-B, we saw that treatment effects with AMVUTRA were greatest in early patients. A drug signal may be obscured if many advanced patients were enrolled. We already know from published data that the CARDIO-TTRansform study enrolled 17% NYHA Class 3 patients, nearly double that in HELIOS-B, patients with higher NAC stage and patients with higher BNPs.

As I noted in Helios B, we saw that treatment effects within buitre were greatest in early patients.

And so a drug signal may be obscured. If many Advanced patients were enrolled

Speaker #2: While we still have more to learn about the Eplin-Turson results, we believe they're likely attributable to a combination of molecule and study-specific issues. And as we compare what we know about Nucrisorin with what's been reported about Eplin-Turson, I want to assure you that we remain highly confident in Nucrisorin and Triton CM.

We already know from published data that the cardio transform study enrolled 17% nyha. Class 3 patients, nearly double that in Helios B, patients with higher Knack stage in patients with higher bnps.

Speaker #2: I'll explain more in a moment, but first, let me share what we'll be looking for in the upcoming data presentations of the cardiotransformer results at ESC to better understand the reasons why the study did not meet its primary endpoint.

Importantly, as I'll explain further in a moment, We Believe deep rapid knockdown of TTR is critical to improving outcomes in attr cardiomyopathy.

Speaker #2: First, we'll be interested to learn more about the population of baseline characteristics of the cardiotransformer study. Particularly in the two key subgroups of monotherapy and in the patients on background stabilizers.

Graphs in the primary manuscript for the EPL tears and PN study indicated. It took longer to get to Peak knock down than mutra but the depth and variability of knockdown are also important so we'll be looking for those details.

Pushkal Garg: Importantly, as I'll explain further in a moment, we believe deep rapid knockdown of TTR is critical to improving outcomes in ATTR cardiomyopathy. Graphs in the primary manuscript for the eplontersen PN study indicated it took longer to get to peak knockdown than AMVUTRA. The depth and variability of knockdown are also important. We'll be looking for those details. Safety will be important given what we know about ASOs in the past and the frailty of the ATTR cardiomyopathy population. Did patients stay on drug, and were there any competing risks that impacted study outcomes? We'll also want to look at study execution and completeness of follow-up. Finally, we'll want to take a much deeper look at the outcomes data. For example, how do the individual components of their primary endpoint, CV mortality and CV events, look?

Speaker #2: As I noted in Helios B, we saw that treatment effects with Amvutra were greatest in early patients. And so a drug signal may be obscured if many advanced patients were enrolled.

Safety will be important given what we know about Asos in the past and the Frailty of the attr cardiomyopathy population. The patients stay on drug. And were there any competing risks that impacted study outcomes?

We also want to look at study execution and completeness of follow-up.

And finally, we'll want to take a much deeper. Look at the outcomes data.

Speaker #2: We already know from published data that the cardiotransformer study enrolled 17% NYHA class III patients, nearly double that in Helios B, patients with higher NAC stage and patients with higher BNPs.

How did the individual components of their primary endpoint CV? Mortality and CV events. Look,

And what about all cause mortality? Which is part of our primary end point.

Speaker #2: Importantly, as I'll explain further in a moment, we believe deep rapid knockdown of TTR is critical to improving outcomes in ATTR cardiomyopathy. Graphs in the primary manuscript for the Eplin-Turson PN study indicated it took longer to get to peak knockdown than Amvutra, but the depth and variability of knockdown are also important.

How did these acrew over time and did the results vary in particular, subgroups particularly by disease severity?

Bottom line is, there are a lot of details not yet known about the failure of cardio transform. However, however we are in an ideal position to learn from it.

Pushkal Garg: What about all-cause mortality, which is part of our primary endpoint? How did these accrue over time, and did the results vary in particular subgroups, particularly by disease severity? Bottom line is there are a lot of details not yet known about the failure of CARDIO-TTRansform. However, we are in an ideal position to learn from it. With enrollment ongoing and a projected launch for nucresiran in 2030 for ATTR cardiomyopathy, we have plenty of time to digest this information, thoroughly consider our options, and implement appropriate changes to TRITON-CM, assuming any are even warranted. Let me return now to why we remain confident in TRITON-CM following the CARDIO-TTRansform top-line release. The reasons come down to three key factors: the specific attributes of our molecule, nucresiran, key design elements of the TRITON-CM study, and the track record of our team here at Alnylam. Starting with the molecule.

Speaker #2: So we'll be looking for those details. Safety will be important given what we know about ASOs in the past and the frailty of the ATTR cardiomyopathy population.

With enrollment ongoing in a projected launch for an increase in in 2030 for attr cardiomyopathy. We have plenty of time to digest. This information thoroughly consider our options and Implement appropriate changes to Triton CM assuming any or even warranted.

Speaker #2: Did patients stay on drug, and were there any competing risks that impacted study outcomes? We'll also want to look at study execution and completeness of follow-up.

Let me return now to why we remain confident. In Triton, CM following the cardio transform Topline release release.

Speaker #2: And finally, we'll want to take a much deeper look at the outcomes data. For example, how did the individual components of their primary endpoint, CV mortality, and CV events look?

The reasons come down to 3, key factors the specific attributes of our molecule and increase around key design. Elements of the Triton CM study and the track record of our team here at Al Nylo.

Speaker #2: And what about all-cause mortality, which is part of our primary endpoint? How did these accrue over time and did the results vary in particular subgroups, particularly by disease severity?

Starting with the molecule, first, rnai Therapeutics are fundamentally different than anti-sense. All of the nucleotides.

Speaker #2: Bottom line is, there are a lot of details, not yet known, about the failure of cardiotransformer. However, we are in an ideal position to learn from it.

In our hands rni, has been able to deliver rapid deep and durable TTR knockdown, which we believe has implications on treating the course of disease.

Speaker #2: With enrollment ongoing and a projected launch for Nucrisorin in 2030 for ATTR cardiomyopathy, we have plenty of time to digest this information, thoroughly consider our options, and implement appropriate changes to Triton CM, assuming any are even warranted.

There are now several recent examples of Asos and rnai, silencing the same. Genetic Target with very different profiles.

We've also seen that the safety profiles of these 2 approaches differ as well.

Pushkal Garg: First, RNAi therapeutics are fundamentally different than antisense oligonucleotides. In our hands, RNAi has been able to deliver rapid, deep, and durable TTR knockdown, which we believe has implications on treating the course of disease. There are now several recent examples of ASOs and RNAis silencing the same genetic target with very different profiles. We've also seen that the safety profiles of these two approaches differ as well. Second, nucresiran's depth of TTR knockdown is expected to be best in class based on preliminary phase I results showing over 95% TTR knockdown with much tighter intrapatient variability. I'll explain why we believe that will result in strong efficacy in a moment. Finally, we have data from two prior studies evaluating RNAi in ATTR cardiomyopathy patients, APOLLO-B and HELIOS-B, both of which generated data supporting a combination benefit.

Speaker #1: Let me return now to why we remain confident in Triton CM following the cardiotransformer top-line release. The reasons come down to three key factors.

Second ends depth of TTR knockdown is expected to be Best in Class based on preliminary Phase 1 results showing over 95% TTR knockdown with much tighter interpatient variability.

I'll explain why we believe that will result in strong efficacy in a moment.

Speaker #1: The specific attributes of our molecule, Nucrisorin, key design elements of the Triton CM study, and the track record of our team here at ALNYLAM.

Speaker #1: Starting with the molecule, first, RNAi therapeutics are fundamentally different than antisense oligonucleotides. In our hands, RNAi has been able to deliver rapid, deep, and durable TTR knockdown, which we believe has implications on treating the course of disease.

And finally we have data from 2 prior studies, evaluating rnai and attr cardiomyopathy patients Apollo B and Helio speed. Both of which generated data supporting a combination benefit.

You've seen the Helios B data and label, which shows a clear benefit of rnai mediated TTR, silencing in a population that included, heavy stabilizer, use, and consistent effects in combination and monotherapy.

Speaker #1: There are now several recent examples of ASOs and RNAi's silencing the same genetic target with very different profiles. We've also seen that the safety profiles of these two approaches differ as well.

But I as I'll show you in a moment, we saw the same effect with the Tyron as well.

Moving to the study.

Speaker #1: Second, Nucrisorin's depth of TTR knockdown is expected to be best in class based on preliminary phase one results showing over 95% TTR knockdown, with much tighter interpatient variability.

Pushkal Garg: You've seen the HELIOS-B data and label, which shows a clear benefit of RNAi-mediated TTR silencing in a population that included heavy stabilizer use and consistent effects in combination in monotherapies. As I'll show you in a moment, we saw the same effect with patisiran as well. Moving to the study. TRITON-CM, now with 1,750 patients, will be the largest study conducted in ATTR-CM, which will allow us to accrue more outcome events. Further to that point, we designed TRITON-CM as an event-driven study. Given the evolving treatment landscape, patients with somewhat milder disease on baseline on average, and other dynamics, we determined that a time-based primary endpoint was not ideal. Instead, we'll continue the study until we have enough endpoint events to ensure sufficient study power.

Triton CM. Now, with 1750 patients, will be the largest study conducted in attr-cm which will allow us to crew more outcome events.

Speaker #1: I'll explain why we believe that will result in strong efficacy in a moment. And finally, we have data from two prior studies evaluating RNAi and ATTR cardiomyopathy patients: Apollo B and Helios B.

And further to that point. We design, Triton CM as an event-driven study, given the evolving treatment landscape patients with somewhat milder disease on Baseline, on average, and other Dynamics. We determine that a time-based. Primary endpoint was not ideal. Instead we'll continue to study until we have enough. Endpoint events to ensure sufficient study power.

Speaker #1: Both of which generated data supporting a combination label, which shows a clear benefit of RNAi-mediated TTR silencing in a population that included heavy stabilizer use and consistent effects in combination in monotherapy.

Third. We've used our insights to Define entry criteria that enriched for patients, who are most likely to benefit based on our prior learnings.

And finally, we have an outstanding experience team here at El nilo,

Speaker #1: But as I'll show you in a moment, we saw the same effect with Patisorin as well. Moving to the study. Triton CM, now with 1,750 patients, will be the largest study conducted in ATTR CM.

We've been focused on TTR drug development for well over 15 years. Delivering, 2 approved products. We've amassed tremendous experience across study design, execution and Analysis to maximize the probability of success of a trial in this area.

Pushkal Garg: Third, we've used our insights to define entry criteria that enrich for patients who are most likely to benefit based on our prior learnings. Finally, we have an outstanding, experienced team here at Alnylam. We've been focused on TTR drug development for well over 15 years, delivering two approved products. We've amassed tremendous experience across study design, execution, and analysis to maximize the probability of success of a trial in this area. Part of this experience and history of conducting TTR trials is our vast database of deep patient-level insights that we can leverage to optimize study design and conduct. To that last point, we have a track record of meticulous execution to ensure study success. This was most recently exemplified by how we optimized the endpoint structure and analytic plan for HELIOS-B to deliver remarkable results, resulting in the strong label that Tolga highlighted earlier.

Speaker #1: Which will allow us to accrue more outcome events. And further to that point, we designed Triton CM as an event-driven study. Given the evolving treatment landscape, patients with somewhat milder disease on baseline on average, and other dynamics, we determined that a time-based primary endpoint was not ideal.

Part of this experience in history of conducting TTR, trials is our vast database of deep patient level insights that we can leverage to optimize study design and conduct.

And to that last point, we have a track record of meticulous expert execution to ensure study success.

Speaker #1: Instead, we'll continue the study until we have enough endpoint events to ensure sufficient study power. Third, we've used our insights to define entry criteria that enrich for patients who are most likely to benefit based on our prior learnings.

this was most recently exemplified by how we optimize the endpoint structure and analytic plan for Helios B to deliver remarkable results resulting in a strong label, the toga highlighted earlier,

Before I move on, I'd like to underscore a few of the points. I just made by sharing some clinical data that support the additive benefits of rnai mediated silencing on top of a stabilizer.

Speaker #1: And finally, we have an outstanding experienced team here at ALNYLAM. We've been focused on TTR drug development for well over 15 years, delivering two approved products, we've amassed tremendous experience across study design, execution, analysis, to maximize the probability of success of a trial in this area.

As you'll recall, The Helio speech study, demonstrated an approximately 41% reduction in the risk of all, cause mortality up to 42 months, when Mutual was given to patients on a stabilizer at Baseline.

Pushkal Garg: Before I move on, I'd like to underscore a few of the points I just made by sharing some clinical data that support the additive benefits of RNAi-mediated silencing on top of a stabilizer. As you'll recall, the HELIOS-B study demonstrated an approximately 41% reduction in the risk of all-cause mortality up to 42 months when AMVUTTRA was given to patients on a stabilizer at baseline, highlighting both the residual unmet need in these stabilizer-treated patients as well as the additive benefit of vutrisiran. What you may not know is that we saw a nearly identical effect in APOLLO-B. As shown here with just 24 months of follow-up in a comparable population in that study, we saw an estimated 44% reduction in all-cause mortality.

Speaker #1: Part of this experience and history of conducting TTR trials is our vast database of deep patient-level insights that we can leverage to optimize study design and conduct.

Highlighting both the residual unmet need in these stabilizer treated patients, as well as the additive benefit of Utrecht strand.

Speaker #1: And to that last point, we have a track record of meticulous execution to ensure study success. This was most recently exemplified by how we optimized the endpoint structure and analytic plan for Helios B to deliver remarkable results, resulting in a strong label, the Tolga highlighted earlier.

But what you may not know is that we saw a nearly identical effect in Apollo b. As shown here, with just 24 months of follow-up. In a comparable population in that study, we saw an estimated 44% reduction on cause mortality.

Since we have data from 2 different molecules in 2, different studies showing comparable improvements in outcomes, which provides the strongest evidence of a combo effect.

Speaker #1: Before I move on, I'd like to underscore a few of the points I just made by sharing some clinical data that support the additive benefits of RNAi-mediated silencing on top of a stabilizer.

Speaker #1: As you'll recall, the Helios B study demonstrated an approximately 41% reduction in the risk of all-cause mortality up to 42 months when Amvutra was given to patients on a stabilizer at baseline.

Deep knockdown.

Pushkal Garg: We have data from two different molecules in two different studies showing comparable improvements in outcomes, which provides the strongest evidence of a combo effect. We believe these clinical data result from the knockdown profile of these two medicines. There are many ways to look at TTR knockdown, but what we believe matters is the speed and depth of knockdown, and particularly getting as many patients as possible to deep knockdown. Here we show TTR knockdown from our polyneuropathy studies, which had the richest sampling of TTR levels. Both show median knockdown of approximately 90% at steady state. Now, we don't know exactly what level of knockdown is critical for efficacy in cardiomyopathy, but we have robust data in hereditary ATTR, where we have more sensitive endpoints that suggest on a population basis achieving 80% knockdown or greater is associated with halting of polyneuropathy.

Here we show TTR knockdown from our poly neuropathy studies which had the richest sampling of TTR levels.

Both show Media knockdown of approximately, 90% of steady state.

Speaker #1: Highlighting both the residual unmet need in these stabilizer-treated patients as well as the additive benefit of Vutrisorin. But what you may not know is that we saw a nearly identical effect in Apollo B.

Now we don't know exactly what level of knockdown is critical for effort. Efficacy in cardiomyopathy but we have robust data and hereditary attr where we have more sensitive endpoints.

Speaker #1: As shown here with just 24 months of follow-up in a comparable population in that study, we saw an estimated 44% reduction in all-cause mortality.

That suggests on a population basis achieving 80% knockdown or greater is associated with halting of polyurethane.

Speaker #1: Hence, we have data from two different molecules in two different studies showing comparable improvements in outcomes, which provides the strongest evidence of a combo effect.

And based on our depth speed and variability of knockdowns, the large majority of patients about 802 to 84% of Utrecht. Rated patients reached that Threshold at steady state.

So how does this compare to other molecules?

Speaker #1: We believe these clinical data result from the knockdown profile of these two medicines. There are many ways to look at TTR knockdown, but what we believe matters is the speed and depth of knockdown, and particularly getting as many patients as possible to deep knockdown.

Here, we've plotted the same data as on the prior slide for retracement. Now shown as bar graphs, you see 91% median knockdown with about 82% of patients achieving that 80% threshold of deep knockdown.

Pushkal Garg: Based on our depth, speed and variability of knockdown, the large majority of patients, about 82% to 84% of vutrisiran-treated patients reached that threshold at steady state. How does this compare to other molecules? Here we've plotted the same data as on the prior slide for vutrisiran, now shown as bar graphs. You see 91% median knockdown with about 82% of patients achieving that 80% threshold of deep knockdown. How does that compare to the data reported for eplontersen? Our team used published data from the eplontersen PN study, which showed median knockdown of 84% at steady state, as well as available data on variability to model the expected proportion of patients who will reach that same 80% knockdown threshold. Our model estimates that only about 67% of eplon-treated patients would reach that same deep level of knockdown.

Speaker #1: Here we show TTR knockdown from our polyneuropathy studies, which had the richest sampling of TTR levels. Both show median knockdown of approximately 90% at study state.

So, how does that compare to the data reported for e-pilen turenne?

Speaker #1: Now, we don't know exactly what level of knockdown is critical for efficacy in cardiomyopathy, but we have robust data and hereditary ATTR, where we have more sensitive endpoints.

Our team used published data from the eplant, PN study, which showed median knockdown of 84% at steady state as well as available data on variability, to model, the expected proportion of patients who will reach that same 80% knockdown threshold.

Speaker #1: That suggests on a population basis, achieving 80% knockdown or greater is associated with halting of polyneuropathy. And based on our depth, speed, and variability of knockdown, the large majority of patients about 82 to 84% of Vutrisorin-treated patients reach that threshold at study state.

Our model estimates that only about 67% of e-pilen treated patients were reached that same deep level of knockdown.

Or set another way 1. Third of patients, may not reach the thresholds of knockdown. We've seen to be associated with strong efficacy.

Nearly double that calculated for good treatment.

Speaker #1: So how does this compare to other molecules? Here we've plotted the same data as on the prior slide for Vutrisorin, now shown as bar graphs.

Speaker #1: You see 91% median knockdown, with about 82% of patients achieving that 80% threshold of deep knockdown. So, how does that compare to the data reported for eplontersen?

These are estimates and should be interpreted with appropriate caution that they highlight that the TTR knockdown data and cardio transform will be critical to review. And in insufficient knockdown is 1 plausible contributor.

To the failure of that study.

Pushkal Garg: Said another way, one-third of patients may not reach the threshold of knockdown we've seen to be associated with strong efficacy, nearly double that calculated for vutrisiran. These are estimates and should be interpreted with appropriate caution, but they highlight that the TTR knockdown data in CARDIO-TTRansform will be critical to review. An insufficient knockdown is one plausible contributor to the failure of that study. We ran the same modeling exercise for nucresiran using the same dose and regimen that we are using in the TRITON-CM and PN studies. The good news is that by these same metrics, nucresiran has the potential to be even better than vutrisiran's high mark. With median knockdown of 95% and low variability, over 99% of patients treated with nucresiran are expected to surpass this deep knockdown threshold.

We ran the same modeling exercise for a new crease run using the same dose and regimen that we are using in the Triton cm and PN studies.

Speaker #1: Our team used published data from the Eplantirsin PN study, which showed median knockdown of 84% at study state as well as available data on variability to model the expected proportion of patients who will reach that same 80% knockdown threshold.

And the good news is that by these same metrics you increase your end as the potential to be even better than V's. Hi Mark.

With median knockdown of 95% and low variability over 99% of patients.

Speaker #1: Our model estimates that only about 67% of Eplan-treated patients would reach that same deep level of knockdown. Or said another way, one-third of patients may not reach the thresholds of knockdown we've seen to be associated with strong efficacy.

Choose new increase in are expected to surpass this deep knockdown threshold.

so, in some

Speaker #1: That's nearly double what was calculated for vutrisorin. These are estimates and should be interpreted with appropriate caution. However, they highlight that the TTR knockdown data in CardioTransformer will be critical to review, and insufficient knockdown is one plausible contributor to the failure of that study.

We don't believe that the Topline results shared a few weeks ago, negate the hypothesis and rationale of using a silent surf for AT&T Crescent attr-cm patients, who are already on a stabilizer, more likely as we see it, they may demonstrate that the type and depth of silencing along with aspects of the study design are what really matter.

Pushkal Garg: In sum, we don't believe that the top-line results shared a few weeks ago negate the hypothesis and rationale of using a silencer for ATTR-CM patients who are already on a stabilizer. More likely, as we see it, they may demonstrate that the type and depth of silencing, along with aspects of the study design, are what really matter. With that, I'd like to remind you that we're progressing a broad pipeline of medicines beyond TTR with over 25 clinical programs spanning multiple therapeutic areas across rare specialty and prevalent indications. This robust pipeline represents a tremendous opportunity to improve patient health and create value in the years ahead. To that end, we look forward to a lot of pipeline momentum in the next few years. This year, in 2026, we continue to execute on our three ongoing pivotal studies, including two cardiovascular outcomes trials.

Speaker #1: We ran the same modeling exercise for Nucrisorin using the same dose and regimen that we are using in the Triton CM and PN studies.

That I'd like to remind you that we're progressing a broad pipeline of medicines Beyond TTR, with over 25. Clinical programs, spending multiple therapeutic areas across rare specialty and prevalent indications

Speaker #1: And the good news is that by these same metrics, Nucrisorin has the potential to be even better than Vutrisorin's high mark. With median knockdown of 95% and low variability over 99% of patients, truth Nucrisorin are expected to surpass this deep knockdown threshold.

This robust pipeline represents a tremendous opportunity to improve patient health and create value in the years ahead.

Speaker #1: So in sum, we don't believe that the top-line results shared a few weeks ago negate the hypothesis and rationale of using a silencer for ATTR CM patients who are already on a stabilizer.

To that end. We look forward to a lot of pipeline momentum in the next few years, this year in 2026, we continue to execute on our 3 on pivotal studies, including 2 cardiac outcomes trial. We also anticipate 4 c. Key data readouts in the second half, which will outline on the next slide.

Speaker #1: More likely, as we see it, they may demonstrate that the type and depth of silencing along with aspects of the study design are what really matter.

And looking ahead, we anticipate many more data readouts and pivotal trial starts in 27 and 28. Additionally in 2028, we anticipate the launch of an increase around in hatr poly, neuropathy assuming positive phase 3 data and Regulatory approval.

Speaker #2: That I'd like to remind you that we're progressing a broad pipeline of medicines beyond TTR with over 25 clinical programs, spanning multiple therapeutic areas across rare specialty and prevalent indications.

Pushkal Garg: We also anticipate four key data readouts in H2, which I will outline on the next slide. Looking ahead, we anticipate many more data readouts and pivotal trial starts in 2027 and 2028. Additionally, in 2028, we anticipate the launch of nucresiran in hATTR polyneuropathy, assuming positive phase III data and regulatory approval. Of course, we will continue to build the pipeline through the filing of three to four new INDs each year as we scale to meet our Alnylam 2030 ambitions. Coming back to 2026 and our pipeline goals for the remainder of the year, we are looking forward to four important data readouts from three key programs. For ALN-6400, we plan to share healthy volunteer data from the ongoing phase I study, as well as initial results from the phase II study in patients with hereditary hemorrhagic telangiectasia.

And of course we'll continue to build the pipeline to the filing of 3 to 4 new Endz each year as we scale to meet our to align them 2030 ambitions.

Coming back to 26 and our pipeline goals for the remainder of the Year, we're looking forward to 4 important data readouts from 3 Key Programs.

Speaker #2: This robust pipeline represents a tremendous opportunity to improve patient health and create value in the years ahead. To that end, we look forward to a lot of pipeline momentum in the next few years.

For alien 6400, we plan to share healthy volunteer data from the ongoing Phase 1 Study as well as initial results in the phase 2 study in patients with hereditary haemorrhagic Talent. Asia.

Speaker #2: This year in 2026, we continue to execute on our three ongoing pivotal studies, including two cardiovascular outcomes trials. We also anticipate four key data readouts in the second half, which I'll outline on the next slide.

Speaker #2: And looking ahead, we anticipate many more data readouts and pivotal trial starts in 2027 and 2028. Additionally, in 2028, we anticipate the launch of Nucrisorin in HATTR polyneuropathy, assuming positive phase three data and regulatory approval.

We also expect to initiate Phase 1 data, from both Al and http2, our Huntington disease, program, and aln 2232 and development for obesity and weight management with that. Let me turn it back to Josh to coordinate, our Q&A session Josh. Thank you, push. Go. Operator will now open the call for questions to those dialed in. We'd like to ask you to limit yourself to 1 question, each and then get back in the queue if you have additional questions.

Pushkal Garg: We also expect to initiate phase I data from both ALN-HTT02, our Huntington's disease program, and ALN-2232 in development for obesity and weight management. With that, let me turn it back to Josh to coordinate our Q&A session. Josh?

Speaker #2: And of course, we'll continue to build the pipeline through the filing of three to four new INDs each year as we scale to meet our ALNYLAM 2030 ambitions.

Speaker #2: Coming back to 2026 and our pipeline goals for the remainder of the year, we're looking forward to four important data readouts from three key programs.

Thank you. We will now begin to question and answer session. And again, if you would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. And if you would like to withdraw your question, please press star 1 again.

Josh Brodsky: Thank you, Pushkal. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

Speaker #2: For ALN6400, we plan to share healthy volunteer data from the ongoing phase one study, as well as initial results from the phase two study in patients with hereditary hemorrhagic telangiectasia, we also expect to initiate phase one data from both ALNHD202, our Huntington disease program, and ALN2232, and development for obesity and weight management.

With that. Your first question comes from the line of policies with people. Please go ahead.

Operator: Thank you. We will now begin the question-and-answer session. Again, if you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, please press star one again. With that, your first question comes from the line of Paul Matteis with Stifel. Please go ahead.

Speaker #2: With that, let me turn it back to Josh to coordinate our Q&A session. Josh?

Speaker #3: Thank you, Pushkal. Operator, we'll now open the call for questions. To those dialed in, we'd like to ask you to limit yourself to one question each, and then get back in the queue if you have additional questions.

Paul Matteis: Great. Good morning. Thanks so much for taking my question. I appreciate it. I wanted to just talk about the change in guidance. By our math, under the new guide, you're growing around 50-ish% at the midpoint in H2 2024. For 2030, I think you still guided to this 25% CAGR. Given this drop-off versus your original expectations and when you gave this long-term guidance, I was wondering if you could talk a little bit more about the next sort of 12-to-24-month outlook and your confidence that you can keep the growth rate on track, likely above that 25% number for a while, and still meet your long-term goals. Thank you.

Speaker #4: Thank you. We will now begin the question and answer session. And again, if you would like to ask a question, please press the star one on your telephone keypad to raise your hand and join the queue.

Like the change in in guidance. Um, you know, by our math under the new guide, you're growing around, 50-ish percent at the midpoint in the second half of this year, and for 2030, I think you still guided to this 25% tagger, given this drop off versus your original expectations. And when you gave this long-term guidance, I was wondering if you could talk a little bit more about the next sort of 12, to 24 month Outlook, and your confidence that you can keep the growth rate on track, likely above that. 25% number for a while, uh, and still meet your long-term goals. Thank you.

Speaker #4: And if you would like to withdraw your question, please press star one again. With that, your first question comes from the line of Paul Matisse with People.

Speaker #4: Please go ahead.

Speaker #5: Great. Good morning. Thanks so much for taking my question. I appreciate it. I wanted to just talk about the change in guidance. By our math, under the new guide, you're growing around 50-ish percent at the midpoint in the second half of this year.

Tolga Tanguler: Thanks for the question, Paul. Look, clearly, we're not pleased to be lowering guidance. As Jeff said, we own it. I think it's really important to emphasize that we believe that the fundamentals driving our opportunity are really strong, particularly market growth and our first-line momentum. It's difficult to know every single factor when you kick off a launch from the get-go, but we are very pleased with the outlook that we have in front of us, both in the near future, but also in the longer term in reaching our 2030 goals. Jeff, do you want to add some color?

Yvonne Greenstreet: Thanks for the question, Paul. Look, clearly, we're not pleased to be lowering guidance. As Jeff said, we own it. I think it's really important to emphasize that we believe that the fundamentals driving our opportunity are really strong, particularly market growth and our first-line momentum. It's difficult to know every single factor when you kick off a launch from the get-go, but we are very pleased with the outlook that we have in front of us, both in the near future, but also in the longer term in reaching our 2030 goals. Jeff, do you want to add some color?

Speaker #5: And for 2030, I think you still guided to this 25% CAGR. Given this drop-off versus your original expectations, and when you gave this long-term guidance, I was wondering if you could talk a little bit more about the next sort of 12 to 24-month outlook and your confidence that you can keep the growth rate on track, likely above that 25% number for a while, and still meet your long-term goals.

Speaker #5: Thank you.

Thanks for the question for clearly we're not pleased to be learning guidance as Jeff said, you know, we own it. But I, I, I think it's really important to to emphasize that that we believe that the fundamentals driving, um, our opportunity a, a really strong, particularly market growth and our first line momentum. And, you know, it's difficult to know every single Factor when you um, kick off a launch from the get-go. But but but we are very pleased with the Outlook that we have in front of us. Both in the um um near future but also in the longer term and reaching our 2030 goals. Jeff, do you want to add some color? I mean I'll just comment on on the second half of 26. And what the, what the, you know, revised guidance implies and then maybe Togo would like to make some comments on on longer term confidence in in the online 23rd guide. The follow the revised guidance that we've given for of, you know, 4.2 to 4.5 billion in terms of the midpoint of that just relative to the growth that we just put up in the second quarter, the mid

Speaker #6: Thanks for the question, Pushkal. Clearly, we're not pleased to be lowering guidance, as Jeff said. We own it. But I think it's really important to emphasize that we believe that the fundamentals driving our opportunity are really strong, particularly market growth in our first-line momentum.

Jeff Poulton: I mean, I'll just comment on H2 2026 and what the revised guidance implies, and then maybe Tolga would like to make some comments on longer-term confidence in the Alnylam 2023 guide. Paul, the revised guidance that we've given of $4.2 to 4.5 billion in terms of the midpoint of that, just relative to the growth that we just put up in Q2. To achieve the midpoint, we would need to deliver growth in Q3 and Q4 that's consistent with what we just put up in Q2. I think we do have confidence in that given some of the things that Tolga talked about, particularly strength in the first-line part of the market in terms of demand we saw in the quarter in the US. Tolga, any more comments on the confidence in the longer term?

Speaker #6: And it's difficult to know every single factor when you kick off a launch from the get-go. But we are very pleased with the outlook that we have in front of us, both in the near future, but also in the longer term.

Speaker #6: And reaching our 2030 goals. Jeff, do you want to add some color?

Speaker #7: I'll just comment on the second half of 2026 and what the revised guidance implies, and then maybe Tolga would like to make some comments on longer-term confidence in the Alnylam 2030 guide.

Speaker #7: Paul, the revised guidance that we've given of 4.2 to 4.5 billion in terms of the midpoint of that, just relative to the growth that we just put up in the second quarter, the midpoint to achieve the midpoint, we would need to deliver growth in Q3 and Q4 that's consistent with what we just put up in Q2.

Tolga Tanguler: Yeah, maybe I'll combine both Yvonne and Jeff's points, which is, first and foremost, we are competing in a highly untapped market. 80% of patients remain untreated. Within that category, in a short 15 months, we've already been able to actually build a very strong base for our business. What's exciting about that, frankly, to me is while we're obviously normalizing our second-line new business, our first-line business is really rapidly replacing that. If you think about the fact that 80% in this category comes in as new patients as first line, we really like how we're positioned with the existing prescriber basis. As I highlighted in my remarks, one of the areas where we still need to do some work, which I believe we'll be able to do, is continue to expand our prescriber basis.

Point to achieve, the midpoint we would need to deliver growth in Q3 and Q4, that's consistent with what? We just put up in Q2, and I think we do have confidence in that. Given some of the things that toga talked about particularly strength in the first line part of the market. In terms of demand, we saw on the quarter in the US, but Paul got any more comments on on the confidence and and the longer term. Yeah, maybe I'll combine both Ivonne and Jeff's points, which is first and foremost. We are competing in a, in a highly, uh, untapped Market. 80% of patients, remain on untreated. And within that category in a short 15 months, we've already been able to actually, uh, build a very strong base for our business. And once exciting about that, frankly to me, is while we're obviously normalizing, our second line, uh, Second Line, new business, our first-time business is really rapidly replacing that. And if you think about the fact that 80%, in this category comes in as new patients as first line we

Speaker #7: And I think we do have confidence in that, given some of the things that Tolga talked about, particularly strength in the first-line part of the market in terms of demand.

Speaker #7: We saw in the quarter in the US. But Tolga, any more comments on the confidence and the longer-term?

Speaker #3: Yeah, maybe I'll combine both Yvonne and Jeff's points, which is, first and foremost, we are competing in a highly untapped market. 80% of patients remain untreated.

Really like how we're positioned uh with with the existing prescriber basis. And and and as I highlighted in my remarks, 1 of the areas where we still need to do some work, which I believe will be able to do, is continue to expand, our prescriber bases, and that's where we're up. Really investing our efforts. And we we've already done that, so, given matching that with the, actually, the access that we've been able to secure and good adherence rates, uh, our ability to demonstrate 25% career, growth Euro,

Speaker #3: And within that category, in a short 15 months, we've already been able to actually build a very strong base for our business. And what's exciting about that, frankly, to me, is while we're obviously normalizing our second-line new business, our first-line business is really rapidly replacing that.

Over a year is definitely within within our reach. I think I can add. We're actually, you know, even more confident now with the results of the cardio transform study. I mean, there's likely to be 1 less.

Tolga Tanguler: That's where we're really investing our efforts, and we've already done that. Matching that with actually the access that we've been able to secure and good adherence rates, our ability to demonstrate 25% CAGR growth year over year is definitely within our reach. If I can add, we're actually even more confident now with the results of the CARDIO-TTRansform study. I mean, there's likely to be one less branded competitor on the market. Pushkal touched on all the reasons why our confidence in nucresiran and TRITON-CM is undiminished. I think if anything, actually, we're sort of more confident about our future outlook given these developments. Thank you very much for that question. Next question, please. It's from Salveen. Salveen?

Speaker #3: And if you think about the fact that 80% in this category comes in as new patients as first-line, we really like how we're positioned with the existing prescriber basis.

Um, branded competitor on the market. Um, and and, and push call structure all the reasons why our confidence in Ukraine and, and Triton cm is is undefined. So, I think if anything actually, we are, we're we're sort of more confident about our future outlook given these developments.

Thank you very much for that question. Next question, please.

Yvonne Greenstreet: If I can add, we're actually even more confident now with the results of the CARDIO-TTRansform study. I mean, there's likely to be one less branded competitor on the market. Pushkal touched on all the reasons why our confidence in nucresiran and TRITON-CM is undiminished. I think if anything, actually, we're sort of more confident about our future outlook given these developments. Thank you very much for that question. Next question, please. It's from Salveen. Salveen?

Is from saline Saline.

Speaker #3: And as I highlighted in my remarks, one of the areas where we still need to do some work—which I believe we'll be able to do—is to continue to expand our prescriber base.

Speaker #3: And that's where we're really investing our efforts. And we've already done that. So given matching that with actually the access that we've been able to secure and good adherence rates, our ability to demonstrate 25% CAGR growth year over year is definitely within our reach.

Thanks for taking our question. This is Tommy on for Saline. Um, curious on, if you're seeing a slower rate of second line patients, uh, tap progressors per year, given Trends in earlier diagnosis and potentially patients staying on tap for longer. And, um, also if you could maybe comment on, um, what how you expect the timing for your diagnosis and awareness efforts to start, you know, playing a key role in first line capture, thank you.

Speaker #6: And if I can add, we're actually even more confident now with the results of the cardio transform study. I mean, there's likely to be one less branded competitor on the market.

Tommie Reerink: Thanks for taking our question. This is Tommie Reerink for Salveen. Curious on if you're seeing a slower rate of second-line patients, TAF progressors per year, given trends in earlier diagnoses and potentially patients staying on TAF for longer. Also, if you could maybe comment on how you expect the timing for your diagnosis and awareness efforts to start playing a key role in first-line capture. Thank you.

Tommie Reerink: Thanks for taking our question. This is Tommie on for Salveen. Curious on if you're seeing a slower rate of second-line patients, TAF progressors per year, given trends in earlier diagnoses and potentially patients staying on TAF for longer. Also, if you could maybe comment on how you expect the timing for your diagnosis and awareness efforts to start playing a key role in first-line capture. Thank you.

Speaker #6: And Pushkal touched on all the reasons why our confidence in new Korean and Triton CM is undiminished. So I think if anything, actually, we're sort of more confident about our future outlook, given these developments.

Speaker #6: Thank you very much. My question. Next question, please. It's from Salveen. Salveen.

Pushkal Garg: Those are great questions. First for Tolga.

Yvonne Greenstreet: Those are great questions. First for Tolga.

That's a great question both photographer. Yeah, so uh it's a good question about the the early, early diagnosis and frankly, um, the when we started just like any launch with, when you have an orthogonal mechanism of action product, like we do, we knew that there was going to be, uh, a level of pent-up demand and it's certainly over time we've seen that being normalizing. So we're still seeing actually a healthy. Number of patients that are coming into the category. That's about 20% both switch and calm.

Tolga Tanguler: Yeah. It's a good question around the early diagnosis. Frankly, when we started, just like any launch when you have an orthogonal mechanism-of-action product like we do, we knew that there was going to be a level of pent-up demand. Certainly over time, we've seen that being normalizing. We're still seeing actually a healthy number of patients that are coming into the category. That's about 20%, both switch and combo. That will continue to be the same. What's even more important to me is this early diagnosis is actually going to hopefully help increase the category growth and accelerating that category growth. We've already seen that. It's gone up from the prior years since we launched, an acceleration of these new patients. In fact, those patients that are getting treated early is going to be a nice tailwind for us.

Number.

Speaker #4: Thanks for taking our question. This is Tommy on for Salveen. I'm curious on if you're seeing a slower rate of second-line patients tap progressors per year, given trends in earlier diagnosis and potentially patients staying on tap for longer.

Speaker #4: And also, if you could maybe comment on how you expect the timing for your diagnosis and awareness efforts to start playing a key role in first-line capture.

Speaker #4: Thank you.

Speaker #6: That's a great question, both for Tolga.

Speaker #3: Yeah. So it's a good question around the early diagnosis. Frankly, when we started, just like any launch, when you have an orthogonal mechanism of action product like we do, we knew that there was going to be a level of pent-up demand.

Those patients that are getting treated early is is going to be a nice Tailwind for us.

Thank you. Next question, please.

Your next question comes from the line of tazeen Ahmad with Bank of America. Please go ahead.

Speaker #3: And it certainly over time, we've seen that being normalizing. So we're still seeing actually a healthy number of patients that are coming into the category.

Hi, good morning. Thanks for taking my question. Um, I wanted to get a little bit more color about your comments about Frontline is now about 80% of new starts. Um,

can you just tell me what the split is?

Speaker #3: That's about 20%, both switch and combo. That will continue to be the same what's even more important to me is these early diagnoses is actually going to hopefully help increase the category growth and accelerating that category growth.

Pushkal Garg: Thank you. Next question, please.

Yvonne Greenstreet: Thank you. Next question, please.

Operator: Your next question comes from the line of Tazeen Ahmad with Bank of America. Please go ahead.

Tazeen Ahmad: Hi, good morning. Thanks for taking my question. I wanted to get a little bit more color about your comments about frontline is now about 80% of new starts. Can you just tell me what the split is for use in community physician practices versus centers of excellence? I guess a question that a lot of people are asking is if, for better or for worse right now, physicians are looking at stabilizers as being similar in efficacy to silencers, how do you kind of maintain that growth that you're seeing in frontline with needing to balance educating physicians, presumably community-based physicians, on the real differences between silencers and stabilizers? Thanks.

Speaker #3: We already seen that. It's gone up from the prior years into since we launched. And acceleration of these new patients. So in fact, those patients that are getting treated early is going to be a nice tailwind for us.

For Youth and Community. Um, physician practices versus centers of excellence and I guess the question that that a lot of people are asking is If For Better or For Worse. Right now Physicians are are looking at stabilizers as being similar and efficacy to silencers. How do you kind of maintain that that growth that you're seeing in front lines? Uh with needing to balance, educating Physicians, presumably Community Based Physicians on the real differences between silencers and stabilizers. Thanks

Speaker #6: Thank you. Next question, please.

Speaker #4: Your next question comes from the line of Tazeen Ahmad with Bank of America. Please go ahead.

Speaker #8: Hi, good morning. Thanks for taking my question. I wanted to get a little bit more color about your comments about front-line is now about 80% of new starts.

Speaker #8: Can you just tell me what the split is for you in community physician practices versus centers of excellence? And I guess the question that a lot of people are asking is if, for better or for worse right now, physicians are looking at stabilizers as being similar in efficacy to silencers, how do you kind of maintain that growth that you're seeing in front-line with needing to balance educating physicians, presumably, community-based physicians on the real differences between silencers and stabilizers?

Yeah, so I'll I'll say a few words. Maybe I'll go. Yeah, look, I mean, first of all most, uh, we we continue to compete for a category leadership, against the product that's been in the market for approximately 7 years and and obviously we remain ahead of the other recent entrance. Um, but more importantly, the how the business is evolving, beneath the overall share, I think is really really important early in the launch growth.

Tolga Tanguler: Yeah, I'll say a few words, maybe I'll.

Tolga Tanguler: Yeah, I'll say a few words, maybe I'll. Pushkal will.

Pushkal Garg: Scott will.

Tolga Tanguler: Yeah.

Pushkal Garg: Yeah. Come on.

Pushkal Garg: Come on.

Tolga Tanguler: Look, I mean, first and foremost, we continue to compete for category leadership against a product that's been in the market for approximately seven years. Obviously, we remain ahead of the other recent entrants. More importantly, how the business is evolving beneath the overall share, I think, is really, really important. Early in the launch, growth was more balanced between first and second-line patients. Today, as second-line demand, as we described, has moved toward a more sustainable rate, an increasing proportion of our growth is now coming from first-line patients, which represents the larger and the more durable opportunity. At the same time, I think this is really important, we are deepening adoption within existing accounts and rapidly expanding that prescriber base. We're essentially maintaining a strong overall share while improving the underlying composition of the business through a broader physician adoption.

Was more balanced between first and second line patients today at second line demand is we described his move toward a more sustainable rate and increasing proportion of our growth is not coming from first line patients, which represents the larger and the more durable opportunity.

Speaker #8: Thanks.

Speaker #3: Yeah. So I'll say a few words, maybe I'll yeah. Look, I mean, first and foremost, we continue to compete for category leadership against the product that's been in the market for approximately seven years.

Speaker #3: And obviously, we remain ahead of the other recent entrants. But more importantly, the how the business is evolving beneath the overall share, I think, is really, really important.

Speaker #3: Early in the launch, growth was more balanced between first and second-line patients. Today, a second-line demand, as we described, has moved toward a more sustainable rate.

At the same time, I think this is really important. We are deepening adoption within existing accounts and rapidly expanding That prescriber Base. Uh, so we're essentially maintaining a strong overall share while improving the underlying composition of the business through a broader physician adoption. Now, you brought up the point around the Coes and, and communicate experts, what's been really encouraging for us is as we established that early based business that business didn't just come from the Coes. We actually had a very healthy balance of coe's academic centers, as well as Community experts. What we need to continue to do is to actually expand out those Community expert centers and we know how to do that.

Tolga Tanguler: Now, you brought up the point around the COEs and community experts. What's been really encouraging for us is, as we established that early base business, that business didn't just come from the COEs. We actually had a very healthy balance of COEs, academic centers, as well as community experts. What we need to continue to do is to actually expand out those community expert centers. We know how to do that. Some of the challenges we faced with them early on was, Well, okay, I don't know what the differences are between the silencers and stabilizers. Now those physicians have actually adopted AMVUTTRA and all other stabilizers. We actually have a significantly higher market share.

Speaker #3: And increasing proportion of our growth is not coming from first-line patients, which represents the larger and the more durable opportunity. At the same time, I think this is really important.

Uh, some of the challenges we face with them early on was well, okay, I don't know what the differences are between the silences and stabilizers. Now those Physicians have actually adopted on mutra and all other stabilizers. We actually have a significantly higher market share.

Speaker #3: We are deepening adoption within existing accounts. And rapidly expanding that prescriber base. So we're essentially maintaining a strong overall share while improving the underlying composition of the business through a broader physician adoption.

Speaker #3: Now, you brought up the point around the COEs and community experts. What's been really encouraging for us is, as we establish that early-based business, that business didn't just come from the COEs.

Uh, when it comes to, oh well, I don't know how to buy and build this product particularly around the community expert. Centres, we know how to bring them along with that whether through building their own helping their their own practice or creating alternative sites of care for for their injections. So it's it is something we've done already and now we're essentially intensifying our efforts to make sure that actually that adoption curve continues to to go get deeper.

Tolga Tanguler: When it comes to, "Oh, well, I don't know how to buy and bill this product," particularly around the community expert centers, we know how to bring them along with that, whether through helping their own practice or creating alternative sites of care for their injections. It is something we've done already, and now we're essentially intensifying our efforts to make sure that actually that adoption curve continues to get deeper.

Speaker #3: We actually had a very healthy balance of COEs, academic centers, as well as community experts. What we need to continue to do is to actually expand out those community expert centers.

Speaker #3: And we know how to do that. Some of the challenges we faced with them early on were, well, okay, I don't know what the differences are between the silencers and stabilizers.

Speaker #3: Now those physicians have actually adopted Ambutra and all other stabilizers. We actually have a significantly higher market share. When it comes to, oh, well, I don't know how to buy and build this product, particularly around the community expert centers, we know how to bring them along with that, whether through building their own, helping their own practice, or creating alternative sites of care for their injections.

Pushkal Garg: Yeah. Tazeen, may I just add to what Tolga said in response to your question. Look, there's no head-to-head data, of course, we know between these different classes of medicines. As tried to highlight in the main presentation, we think we have actually an incredibly unique profile for AMVUTRA. It starts with the outcomes data, which we think are really quite remarkable. I've shown you substantial impact on outcomes. Importantly, the fact that we've seen now in two studies additive benefits on top of stabilizers, which suggests there is efficacy left that's not fully addressed by the stabilizers alone. It's indirect evidence, but we think it's very strong and reproducible evidence. We've also seen that starting this class of agents early, silencers, has the greatest treatment effect. Even approaching almost 45% reductions in mortality, which I think is quite remarkable.

Speaker #3: So it is something we've done already. And now we're essentially intensifying our efforts to make sure that actually that adoption curve continues to get deeper.

Speaker #2: Yeah. And Tazeen may just add to what Tolga said in response to your question. Look, there's no head-to-head data, of course, we know, between these different classes of medicines.

Yeah. And to the email, just add to what to say in response to your question. Look, there's no head-to-head data of course, we know between these different classes of medicines, but as tried to highlight in the main presentation, we think we have actually an incredibly unique profile, uh, for him buitre. Uh, it starts with the outcomes data which we think are really, uh, quite remarkable. I've shown you, uh, substantial impact on outcomes. And importantly, the fact that, uh, you know, we've seen now in 2 studies added a benefits on top of stabilizers would suggest, there is efficacy left. Uh, that's not fully addressed by the stabilizers alone. It's indirect evidence, but we think it's very strong and and reproducible evidence. We've also seen that starting these classes class of Agents early silencers has the greatest treatment effect. Um, and even, you know, approaching almost 45% reductions in mortality, which I think is quite remarkable. And we're seeing evidence of disease. Remodeling. When we look at echocardiographic parameters, we look at cardiac MRI Etc. So look our job. Uh, as toga is highlighted, is to continue to

Speaker #2: But as trying to highlight in the main presentation, we think we have actually an incredibly unique profile for Ambutra. It starts with the outcomes data, which we think are really quite remarkable.

Speaker #2: I've shown you substantial impact on outcomes. And importantly, the fact that we've seen now in two studies additive benefits on top of stabilizers, which suggests there is efficacy left that's not fully addressed by the stabilizers alone.

Pushkal Garg: We're seeing evidence of disease remodeling when we look at echocardiographic parameters, we look at cardiac MRI, et cetera. Look, our job, as Tolga has highlighted, is to continue to educate on those attributes, continue to generate evidence. You've seen at recent meetings more and more that we're putting out. To continue to educate. As Tolga's talked about expanding the prescriber base, an important aspect of it is educating these prescribers on the attributes of this class of medicines. We've seen that once they gain experience with it, that they find that it actually becomes a dominant part of their practice in terms of the prescribing. That's going to be our effort.

Educate, uh, on those attributes continue to generate evidence, you've seen at recent meetings, more and more that we're putting out, um, and to continue to educate. And so, as tolerance talked about expanding, uh, the prescriber base, an important aspect of this educating these prescribers on the attributes of of this class of medicines and we've seen, um, that once they gain experience with it, uh, that they find that it actually is is, you know, becomes a dominant part of their practice in terms of prescribing. So that's going to be our effort.

Very good. Thank you. Great question.

Speaker #2: It's indirect evidence, but we think it's very strong and reproducible evidence. We've also seen that starting these class of agents early, silencers has the greatest treatment effect.

Yeah, next question comes from the line of cost. Will yours with up in higher. Please go ahead.

Speaker #2: And even approaching almost 45% reductions in mortality, which I think is quite remarkable. And we're seeing evidence of disease remodeling when we look at echocardiographic parameters, we look at cardiac MRI, etc.

Speaker #2: So look, our job, as Tolga has highlighted, is to continue to educate on those attributes, continue to generate evidence. You've seen at recent meetings more and more that we're putting out.

Yvonne Greenstreet: Very good.

Tazeen Ahmad: Very good.

Yvonne Greenstreet: Thank you.

Operator: Thank you.

Josh Brodsky: Next question.

Operator: Your next question comes from the line of Kostas Biliouris with Oppenheimer. Please go ahead.

Will soon be genetic in Europe to what extent do you think the commercial Dynamics between ambra and a generic drug in Europe? Will reflect what may happen in the US Post 2031 when a family? This goes generic, thank you.

Speaker #2: And to continue to educate. And so as Tolga has talked about expanding the prescriber base, an important aspect of it is educating these prescribers on the attributes of this class of medicines and we've seen that once they gain experience with it, that they find that it actually is becomes a dominant part of their practice in terms of prescribing.

Kostas Biliouris: Thanks for taking our question. One on Europe. Given that Vyndaqel will soon be generic in Europe, to what extent do you think the commercial dynamics between AMVUTRA and a generic drug in Europe will reflect what may happen in the US post-2031 when tafamidis goes generic? Thank you.

Speaker #2: So that's going to be our effort.

Speaker #6: Very good.

Speaker #4: Thank you.

Speaker #6: Next question.

Speaker #4: Your next question comes from the line of Custis Villares with Oppenheimer. Please go ahead.

Yvonne Greenstreet: Thank you very much. Tolga?

Tolga Tanguler: Thank you, Kostas, for that question. First and foremost, I think we've always highlighted that the contribution of growth for Europe is going to be relatively modest, similar to the growth that we had last year. That had a lot to do with the fact that we were going to actually make the appropriate price adjustments in order to capture a larger cardiomyopathy volume. In terms of tafamidis, the 80 mg, the 4 pills a day option is going to be going generic. I believe 61 mg will continue to be available for a while. In respect to our ability to actually capture those reimbursements, since these are single-payer systems, these systems have already anticipated that genericization transition.

Speaker #5: Thanks for taking our question. One on Europe. Given that Vindacare will soon be generic in Europe, to what extent do you think the commercial dynamics between Ambutra and a generic drug in Europe will reflect what may happen in the US post-2031 when Tafamidis goes generic?

Thank you very much. It's all good. Um, so thank you, Costas, for that question. Uh, first and foremost, I think we've always highlighted that the the contribution of growth for Europe is going to be uh relatively modest similar to the growth that we had last year. And there's a lot to do with the fact that, you know, we were going to actually uh, make the appropriate uh, uh, price adjustments to in order to capture a larger cardiomyopathy volume. Now, in terms of, uh, teff the, the the 80 migram, the the 4 pills a day uh, option is going to be going generic, I believe 61 milligram will continue to be available for for a while. Now in respect to our ability to actually capture those reimbursements since these are uh, single-payer systems.

Speaker #5: Thank you.

Speaker #6: Thank you very much. Tolga?

Speaker #3: So, thank you, Custis, for that question. First and foremost, I think we've always highlighted that the contribution of growth for Europe is going to be relatively modest, similar to the growth that we had last year.

These systems have already anticipated that generalization, uh, transition. And what I'm pleased to say that we've actually in most cases been able to secure premium pricing, uh, versus teff family is and quite pleased with, uh, the ongoing negotiations. We have, whether it's, you know, Germany Spain, uh, Italy. Um and and Japan, we we highlighted the fact that we are

Speaker #3: And that's a lot to do with the fact that we were going to actually make appropriate price adjustments in order to capture a larger cardiomyopathy volume.

Tolga Tanguler: What I'm pleased to say that we've actually, in most cases, been able to secure premium pricing versus tafamidis, and quite pleased with the ongoing negotiations we have, whether it's Germany, Spain, Italy, and Japan. We highlighted the fact that we are competing very effectively, essentially exceeding all analogs, and a good uptake. While, again, because of the pricing changes, we're going to have a modest growth contribution, particularly in 2026, we see 2027 and beyond, the launches is going to have a meaningful impact on our overall business.

Speaker #3: Now, in terms of Tafamidis, the 80 milligram, the four pills a day, option is going to be going generic. I believe 61 milligram will continue to be available for a while.

Uh, competing very effectively, especially exceeding all analog, uh, and a good uptake. So, while again, because of the pricing changes, we're going to have a modest growth contribution, particularly in 26. We see 27 and Beyond, uh, the the the the launches is going to have a meaningful impact on our overall business.

Thank you.

Speaker #3: Now, in respect to our ability to actually capture those reimbursements, since these are single-payer systems, these systems have already anticipated that genericization transition. And what I'm pleased to say that we've actually, in most cases, been able to secure premium pricing versus Tafamidis and quite pleased with the ongoing negotiations we have whether it's Germany, Spain, Italy, and Japan.

Your next question comes from Ellie Merl with Barclays. Please go ahead.

Josh Brodsky: Thank you.

Kostas Biliouris: Thank you.

Operator: Your next question comes from Eliana Merle with Barclays. Please go ahead.

Operator: Your next question comes from Ellie Merle with Barclays. Please go ahead.

Speaker #3: We've highlighted the fact that we are competing very effectively essentially exceeding all analogs. And a good uptake. So while, again, because of the pricing changes, we're going to have a modest growth contribution, particularly in '26.

Eliana Merle: Hey, guys. Thanks for taking the question. Just curious if you could give us more color on what a steady-state level of second-line starts look like. I think you said 80% of starts in Q2 were from the first-line. Is 20% a steady state for second-line starts, or do you expect that to decline over time? I guess, what drives your confidence that the first-line starts will continue at this cadence going forward? Specifically, if you could give us more color on if we strip out the second-line starts, have you seen growth in first-line starts or a stable number of first-line starts each quarter? Thanks.

Ellie Merle: Hey, guys. Thanks for taking the question. Just curious if you could give us more color on what a steady-state level of second-line starts look like. I think you said 80% of starts in Q2 were from the first-line. Is 20% a steady state for second-line starts, or do you expect that to decline over time? I guess, what drives your confidence that the first-line starts will continue at this cadence going forward? Specifically, if you could give us more color on if we strip out the second-line starts, have you seen growth in first-line starts or a stable number of first-line starts each quarter? Thanks.

Hey guys, thanks for taking the question. Um just curious if you could give us more caller on what a steady state level of second line, starts look like, I think you said 80% of starts in 2q, were from the front lines. It was 20% of steady state for second line starts, or do you expect that to decline over time? Um and then I guess what drives your confidence that the front line starts, will continue at this Cadence going forward. Um, and specifically, if you could give us more caller on if we strip out the second line, start, have you seen growth in first line start or a stable number of First Time Stars each quarter. Thanks

Speaker #3: We see '27 and beyond the launches is going to have a meaningful impact on our overall business.

Speaker #6: Thank you.

Speaker #4: Your next question comes from Elie Merle with Barclays. Please go ahead.

Speaker #7: Hey, guys. Thanks for taking the question. Just curious if you could give us more color on what a steady state level of second-line starts look like.

Yeah, thank you for that question. I mean, just just, just to be clear when we talk about 80/20, uh, perspective. That's that's, uh, mainly driven by the overall category and and what we've seen essentially is not a market share loss on second lines, but the overall volume uh shift into a lesser uh, contribution of uh, the new brand.

Speaker #7: I think you said 80% of starts in Q2 were from the front line. So, is 20% a steady state for second-line starts, or do you expect that to decline over time?

Tolga Tanguler: Yeah. Thank you, Ellie, for that question. Just to be clear, when we talk about 80/20 perspective, that's mainly driven by the overall category. What we've seen essentially is not a market share loss on second-line, but the overall volume shift into a lesser contribution of the new brands from switches for the entire category. What I'm really pleased about is while we're continuing to maintain and having a nice gradual progression of our market share, that market share growth is actually being contributed by the first-line share. That's actually a very healthy sign of our business. In respect to the first-line contributions, as I alluded to earlier, those physicians that actually use all three products predominantly use AMVUTRA as their first-line choice. That's the analysis that we have.

Speaker #7: And then I guess, what drives your confidence that the front-line starts will continue at this cadence going forward? And specifically, if you could give us more color on if we strip out the second-line starts, have you seen growth in first-line starts or a stable number of first-line starts each quarter?

From from switches for, for the entire category, what I'm really pleased about is, while we're continuing to maintain. And, and, and having a nice gradual progression of our market share that market share growth is actually being contributed by the first time share, so that's actually a very healthy sign sign of our business. And in respect to um, the the first-line contributions as I as I alluded to earlier.

Speaker #7: Thanks.

Speaker #3: Yeah. Thank you, Elie, for that question. I mean, just to be clear, when we talk about 80/20 perspective, that's mainly driven by the overall category.

Speaker #3: And what we've seen essentially is not a market share loss on second lines, but the overall volume shift into a lesser contribution of the new brands from switches for the entire category.

Speaker #3: What I'm really pleased about is while we're continuing to maintain and having a nice gradual progression of our market share, that market share growth is actually being contributed by the first-line share.

Tolga Tanguler: Now the question is, how can we actually continue to expand the prescriber base so more physicians actually test and understand and experience AMVUTRA? Because experience begets preference. This is where we're really honing our efforts in. We've been able to expand that prescriber base at 1,500 new prescribers since the launch, and we believe we're going to be able to continue to do that. Again, the goal has always been actually on first-line, and this normalization is just a question, actually, frankly, not just the dynamic, but also the strategy.

Speaker #3: So that's actually a very healthy sign of our business. And in respect to the first-line contributions, as I alluded to earlier, those physicians that actually use all three products, predominantly use Ambutra as their first-line choice.

Those Physicians that actually use all 3 products predominantly used on with ra is their first time Choice. That's, that's the the the, the analysis that we have. So now the question is, how can we actually continue to expand the prescriber base? So more Physicians, actually test and understand and experience some Ultra because they experience begins preference. And this is, uh, where we're really pointing our efforts in. And, and we've been able to expand That prescriber Base, uh, at 1500, uh, new prescribers since the launch, and we believe we can, we're going to be able to continue to do that. And again, the goal has always been actually on the first line. And this is this normalization is just a a question actually, frankly, not just the dynamic but also the strategy

Okay. Thank you. Your next question comes from Luca EC with RBC. Go ahead.

Speaker #3: That's the analysis that we have. So now the question is, how can we actually continue to expand the prescriber base so more physicians actually test and understand and experience Ambutra?

Speaker #3: Because the experience begets preference. And this is where we're really honing our efforts in. And we've been able to expand that prescriber base at 1,500 new prescribers since the launch.

Operator: Thank you. Your next question comes from Luca Issi with RBC. Go ahead.

Luca Issi: Great. Thanks so much for taking my question. Maybe quick one for Tolga. Pretty clear that AstraZeneca did not show any additive effect between stabilizer and silencers in their trial based on the press release. Again, appreciated that's a different molecule. That's Pushkal nicely articulated. Are you seeing any impact commercially based on that data? Are you seeing payers forcing docs to pick one versus the other and no longer allowing patients to be on the combo? Any call there much appreciated. Super quickly, can you comment on the evolution of net price in the US for the rest of the year? Thanks so much.

Of net, net price in the US for the rest of the year. Thanks so much.

Speaker #3: And we believe we're going to be able to continue to do that. And again, the goal has always been actually on first line. And this normalization is just a question actually, frankly, not just the dynamic, but also the strategy.

Yeah. So that's a 3-party right? Yes. So maybe I'll I'll start. I mean, obviously pushka laid it out very clearly why we believe what we believe, uh, look in terms of, um, in terms of the payer pushback. Obviously, it's too early to say. But what I can tell you, is this, um,

Speaker #4: All right. Thank you. Your next question comes from Luca Issi with RBC. Go ahead.

Speaker #6: All great. Thanks so much for taking my question. Maybe quick one for Tolga. Pretty clear that AstraZeneca did not show any additive effect between stabilizer and silencers in their trial based on the press release.

Tolga Tanguler: That's a three-parter, I guess. Maybe I'll start. Obviously, Pushkal laid it out very clearly why we believe what we believe. Look, in terms of the payer pushback, obviously, it's too early to say, but what I can tell you is this. Oral access to AMVUTTRA remains very strong. Some Medicare Advantage policies that are already placed, that already puts limitation on combination use. In fee-for-service coverage always follows the label. Frankly, physicians continue to have pathways to pursue access when they believe a particular treatment approach is medically appropriate given the severity of this disease. What's also very important is CARDIO-TTRansform does not change AMVUTTRA's evidence or its label. It was a study of a different molecule. We would not expect payers to alter AMVUTTRA coverage based on those results.

Speaker #6: Again, appreciate that that's a different molecule. Let's push calls nicely articulated. But are you seeing any impact commercially based on that data? Are you seeing payers forcing docs to pick one versus the other and no longer allowing patients to be on the combo?

Speaker #6: And they call it they're much appreciated. And then super quickly, can you comment on the evolution of net price in the US for the rest of the year?

Speaker #6: Thanks so much.

Speaker #3: Yeah. So that's a three-parter, I guess. So maybe I'll start. I mean, obviously, push call laid it out very clearly why we believe what we believe.

Speaker #3: Look, in terms of the payer pushback, obviously, it's too early to say, but what I can tell you is this. Overall access to Ambutra remains very strong.

Overall access on which remains very strong. Uh, some Medicare Advantage policies that are already placed. That already puts limitation on combination use uh and and in C4 service coverage, always follows the label. And and frankly, Physicians continue to have Pathways to pursue accent access. When they believe a particular treatment approach is medically appropriate, given given the severity of of the of this disease. What's also very important is cardio. Transform does not change Arbitrage, evidence or its labor. It was a study of a different molecule. We would not expect payers to offer, you know, alter emitra coverage based on those results our priority remains ensuring appropriate pain. Patients can access on utra where they whether they're initiating first line therapy or switching from another treatment. So we're not seeing uh any push back again. Given the fact that actually the policies are already in place and yet when the physician wants uh to have access they they obtain a

Speaker #3: Some Medicare Advantage policies that are already placed, that already puts limitation on combination use. And in fee-for-service coverage, always follows the label. And frankly, physicians continue to have pathways to pursue access when they believe a particular treatment approach is medically appropriate given the severity of this disease.

uh, if if they provide the right appropriate, uh, materials

Tolga Tanguler: Our priority remains ensuring appropriate patients can access AMVUTTRA, whether they're initiating first-line therapy or switching from another treatment. We're not seeing any pushback, again, given the fact that actually the policies are already in place, and yet when a physician wants to have access, they obtain it if they provide the right appropriate materials.

Speaker #3: What's also very important is cardiotransformer does not change Ambutra's evidence or its label. It was a study of a different molecule. We would not expect payers to after alter Ambutra coverage based on those results.

Yvonne Greenstreet: Yeah, no, thanks for that. Look, I think there are many examples of drugs in similar classes where one drug fails and the other succeeds, and we really believe what we have here are two distinct molecules with different mechanisms, as well as different profiles and a different study. Really our job is to get out there, as Tolga was saying, and educate physicians on the compelling benefits that we see for AMVUTTRA. The focus on first-line, because we believe this should be a foundational therapy, as well as explaining the benefits that we've seen in two separate studies, as Pushkal has explained, with respect to combination use.

Speaker #3: Our priority remains ensuring appropriate patients can access Ambutra. Whether they're initiating first-line therapy or switching from another treatment. So we're not seeing any pushback.

Speaker #3: Again, given the fact that the policies are already in place, when the physician wants to have access, they obtain it if they provide the right, appropriate materials.

Yeah, no thanks for that look. I think that there are many examples of drugs um you know in similar classes where 1 drug fails and the other succeeds and we really believe what we have here are 2 distinct molecules with different mechanisms as well as you know, different profiles and a different study. And really our job is to get out there as Togo saying and and educate Physicians on the compelling benefits that we see for a vutra, the focus on first line because we believe this should be a foundational therapy as well as explaining the benefits that we've seen in in 2 separate studies of social as explained with respect to combination use. So it was 1 question on net price in terms of what we expect and I you know I think the the slide that toga showed that showed the first half Dynamic showed the modest quarter to quarter decreases in that price. We expect that that will continue for the second half and if we were to show you that on a year-over-year basis, the way we had guided was mid single digit, net price, decrease year-over-year. I we're still on track for that Luka.

Speaker #6: Yeah. And thanks for that. Look, I think there are many examples of drugs in similar classes where one drug fails and the other succeeds.

Jeff Poulton: There was one question on net price in terms of what we expect, and I think the slide that Tolga showed that showed the H1 dynamics showed the modest quarter-to-quarter decreases in net price. We expect that will continue for the H2. If we were to show you that on a year-over-year basis, the way we had guided was mid-single digit net price decrease year-over-year. We're still on track for that, Luca.

Thank you. The next question comes from. Jessica fee with JP Morgan. Please go ahead.

Speaker #6: And we really believe what we have here are two distinct molecules with different mechanisms. As well as different profiles and a different study. And really, our job is to get out there as Tolga was saying and educate physicians on the compelling benefits that we see for Ambutra.

Speaker #6: The focus on first-line because we believe this should be a foundational therapy, as well as explaining the benefits that we've seen in two separate studies as push calls explained, with respect to combination use.

Hey guys. Good morning. Thanks for taking my question. Um, question for push gal. Um, recognizing that this is hypothetical, can you elaborate on some of those potential changes available to you with Triton cm to maximize its probability of success?

Operator: Thank you. The next question comes from Jessica Fye with JPMorgan. Please go ahead.

Speaker #6: So it was one question on net price in terms of what we expect. And I think the slide that Tolga showed that showed the first half dynamic showed the modest quarter-to-quarter decreases in net price.

Jessica Fye [Managing Director, Equity Research Analyst: Hey, guys. Good morning. Thanks for taking my question. Question for Pushkal. Recognizing that this is hypothetical, can you elaborate on some of those potential changes available to you with TRITON-CM to maximize its probability of success? Then maybe as a follow-up to that, are there potentially other paths to approval for nucresiran in ATTR-CM beyond TRITON-CM? For example, would it be feasible to run a non-inferiority trial against AMVUTTRA? Thank you.

Jessica Fye: Hey, guys. Good morning. Thanks for taking my question. Question for Pushkal. Recognizing that this is hypothetical, can you elaborate on some of those potential changes available to you with TRITON-CM to maximize its probability of success? Then maybe as a follow-up to that, are there potentially other paths to approval for nucresiran in ATTR-CM beyond TRITON-CM? For example, would it be feasible to run a non-inferiority trial against AMVUTTRA? Thank you.

And then maybe as a follow-up to that are there potentially other paths to approval for new, krisanne in attr-cm Beyond Triton CM. For example, would it be feasible to run a non-inferiority trial against ambra? Thank you.

Speaker #6: We expect that'll continue for the second half. And if we were to show you that on a year-over-year basis, the way we had guided was mid-single-digit net price decrease year over year.

Speaker #6: We're still on track for that, Luca.

Speaker #4: Thank you. The next question comes from Jessica Fire with JP Morgan. Please go ahead.

Speaker #5: Hey, guys. Good morning. Thanks for taking my question. Question for push call. Recognizing that this is hypothetical, can you elaborate on some of those potential changes available to you with Triton CM to maximize its probability of success?

Pushkal Garg: Yeah. Thanks, Jess, for your question. Look, again, we feel really good about what we have on our hands, both in terms of the molecule nucresiran for all the reasons I talked about and the study that we have. Again, I want to reinforce, we may not need to do anything different from what we already have ongoing. That said, we do have options at our disposal. We'll look at the data and we'll consider. I think they broadly fall into a couple of buckets. One is whether we modify enrollment in certain subpopulations, for instance, and enrich in certain ways for those. Again, we've done that already in the context of study, but we could potentially further do that based on information that we see.

Speaker #5: And then maybe as a follow-up to that, are there potentially other paths to approval for Nucrisoran in ATTRCM beyond Triton CM? For example, would it be feasible to run a non-inferiority trial against Ambutra?

Speaker #5: Thank you.

Speaker #6: Yeah. Thanks, Jess, for your question. Look, again, we feel really good about what we have in our hands both in terms of the molecule Nucrisoran for all the reasons I talked about and the study that we have.

Yeah. Thanks, Jess for your question. Look, uh, again, we feel really good about what we have in our hands both in terms of the molecule increased ran for all the reasons I talked about and the uh, and, and the study that we have. So again, I want to reinforce, we may not need to do anything different from what we already have ongoing. Uh, that said, uh, we do have options at our disposal. We'll look at the data and we'll consider. I think they broadly fall into a couple of buckets. 1 is whether we uh, modify enrollment in certain subpopulations, for instance, and enriched in certain ways for those. Again, we've done that already in the context of study, but we could potentially further do that based on information that we see, the other thing would be to make modifications around the analytic plan. In terms of how we think about various end points, uh, the hierarchy Etc. Um, and so they're largely in those 2, big buckets. I mean to the second part of your question, you know, is there a possibility that if we wanted to we could do additional studies? Yeah. Certainly those things are are potential. Um,

Pushkal Garg: The other thing would be to make modifications around the analytic plan in terms of how we think about various endpoints, the hierarchy, et cetera. They're largely in those two big buckets. To the second part of your question, is there a possibility that if we wanted to, we could do additional studies? Yes, certainly those things are potential. I'm not going to speculate, though, further on what those might look like. I think broadly speaking, I think there's a variety of options that are at hand. Again, we're playing the long game here. I think our commitment is to deliver a successful study. We've done that in the past. We think nucresiran has the opportunity to be an amazing medicine for patients, and we're committed to delivering a positive study for that. We will consider all the potential options at hand.

Speaker #6: So again, I want to reinforce, we may not need to do anything different from what we already have ongoing. That said, we do have options at our disposal.

Speaker #6: We'll look at the data and we'll consider. I think they broadly fall into a couple of buckets. One is whether we modify enrollment in certain subpopulations, for instance.

Speaker #6: And enrich in certain ways for those. Again, we've done that already in the context of the study, but we could potentially further do that based on information that we see.

I'm not going to speculate though further on what those might look like. But I think, broadly speaking, I think there's a variety of options that are, you know, that are and again, we're playing the long game here. I think our commitment is to deliver, uh, a successful study. We've done that in the past. We we uh, we think new creature are in has the opportunity to be an amazing medicine for patients. And we're committed to delivering a positive study for that. And so we will consider all the potential options at hand. I, as I said, they fall into several key buckets. Um, and we'll, we'll kind of consider all those opportunities and see if anything at all is warranted.

Speaker #6: The other thing would be to make modifications around the analytic plan in terms of how we think about various endpoints. The hierarchy, etc. And so they're largely in those two big buckets.

Thank you. The next question comes from Whitney Young. We had kind of coordinated. Please go ahead.

Speaker #6: I mean, to the second part of your question, is there a possibility that if we wanted to, we could do additional studies? Yes, certainly those things are potential.

Pushkal Garg: As I said, they fall into several key buckets, and we'll consider all those opportunities and see if anything at all is warranted.

Speaker #6: I'm not going to speculate, though, further on what those might look like. But I think broadly speaking, I think there's a variety of options that are again, we're playing the long game here.

Operator: Thank you. The next question comes from Whitney Ijem with Canaccord Genuity. Please go ahead.

Speaker #6: I think our commitment is to deliver. A successful study. We've done that in the past. We think Nucrisoran has the opportunity to be an amazing medicine for patients, and we're committed to delivering a positive study for that.

Sorry if I missed it. But can you remind us on how you any updated thinking? I guess around the total us, uh, patient population or or Pam for attr-cm and where you are with diagnosis rate, currently and then just as a point of comparison, ahead of the 6400 uh, Phase 2 Data later this year. What what are the comparable numbers for, uh, hht, uh, us Pam? In terms of patient numbers and diagnosis, right? Thanks

Whitney Ijem: Hey, guys. Thanks very much for taking my question. Sorry if I missed it, can you remind us on any updated thinking, I guess, around the total US patient population or TAM for ATTR-CM and where you are with diagnosis rate currently? As a point of comparison ahead of the 6400 phase II data later this year, what are the comparable numbers for HHT US TAM in terms of patient numbers and diagnosis rates? Thanks.

Speaker #6: And so we will consider all the potential options at hand. As I said, they fall into several key buckets. And we'll kind of consider all those opportunities and see if anything at all is warranted.

Speaker #4: Thank you. The next question comes from Whitney Eason with Connecticut Community. Please go ahead.

Tolga Tanguler: For TTR, what I can tell you is in our latest estimates, if you go back to our TTR webinar we've highlighted, we estimate around 200,000 patients and about 80% of those remain untreated. What to me is sort of a good confirmatory data set is the fact that you're seeing around 40% year-over-year growth of the category with a single option on the table. That has actually accelerated since we launched, that remains very robust. We believe more competitors, more awareness, more education, frankly, some of those initiatives that we've just actually laid will continue to help accelerate those patients getting diagnosed. As you all know, we have excellent data that demonstrates those patients that are treated earlier end up actually getting more benefits from AMVUTTRA. We're very actually excited about that.

Speaker #5: Hey, guys. Thanks very much for taking my question. Just sorry if I missed it, but can you remind us on how any updated thinking, I guess, around the total US patient population or TAM for ATTRCM and where you are with diagnosis rate currently?

Speaker #5: And then just as a point of comparison, ahead of the 6400 phase two data later this year, what are the comparable numbers for HHT US TAM in terms of patient numbers and diagnosis rates?

Speaker #5: Thanks.

Speaker #3: So for TTR, what I can tell you is in our last estimates, if you go back to our TTR webinar, we've highlighted we estimate around 200,000 patients and about 80% of those remain untreated.

So for TTR, what I can tell you is uh in our last estimate if you go back to our TTR webinar we've highlighted the we estimate around 200,000 patients, and about uh 80% of those remain uh untreated uh what to me is uh sort of a good confirmatory data set. Is the fact that you're seeing around 40% year-over-year, growth of the category with a single, uh, option on the table that is actually accelerated since since we launched. So, and that remains very robust. So we believe, uh, more competitors, more awareness, more education, a and frankly, some of those initiatives that we've just actually uh, laid uh, will continue to help accelerate the those patients getting, um, diagnosed and and as you all know, we have excellent data that demonstrates, those patients that are treated earlier end up actually getting more benefits from Amal. So we're very actually excited about that.

Speaker #3: What to me is sort of a good confirmatory data set is the fact that you're seeing around 40% year-over-year growth of the category with a single option on the table.

Again, our position on first line, uh, gives us the confidence that we can actually continue to be the the leading, uh, uh, leading, um, you know, option on the table in this growing uh category.

Yeah, and with regard to uh, hereditary haemorrhagic tangipa.

um,

Speaker #3: That is actually accelerated since we launched. And that remains very robust. So we believe more competitors, more awareness, more education, and frankly, some of those initiatives that we've just actually laid will continue to help accelerate those patients getting diagnosed.

Tolga Tanguler: Again, our position on first-line gives us the confidence that we can actually continue to be the leading option on the table in this growing category.

Pushkal Garg: Yeah. With regard to hereditary hemorrhagic telangiectasia, there really are no approved treatments for this disease. It's actually the second most common rare bleeding disorder that's out there. I think globally there's about one and a half million patients with this disease. I think when we think about the addressable population in the United States, I think again, those estimates vary. I think there's a number of these patients who don't actually get the medical attention, we think there's probably about

Speaker #3: And as you all know, we have excellent data that demonstrates those patients that are treated earlier end up actually getting more benefits from Ambutra.

Speaker #3: So we're very actually excited about that. And again, our position on first line gives us the confidence that we can actually continue to be the leading option on the table in this growing category.

There are you know there really are. No approved treatments for this disease. It's actually the second most common uh rare bleeding disorder. That's out there. I think globally there's about 1 and a half million patients, with this disease. I think, when we think about the addressable population, the United States, I think, again, those estimates vary, I think there's a number of these patients who don't actually get to medical attention, but we think there's probably about 70,000 or so patients in the United States. Uh, who may be addressable with this condition but again, that epidemiology will firm up again. As we've seen with rare diseases where there aren't treatments, once there are effective treatments more and more come to attention. So that's probably a ballpark, though, for you.

Thank you, thank you. That's

And that can get your question and answer session, I will hand it back to the company for closing remarks.

Pushkal Garg: 70,000 or so patients in the US who may be addressable with this condition. Again, that epidemiology will firm up. Again, as we've seen with rare diseases where there aren't treatments, once there are effective treatments, more and more come to attention. That's probably a ballpark though for you.

Speaker #6: Yeah. And with regard to hereditary hemorrhagic cholangiectasia, there really are no approved treatments for this disease. It's actually the second most common rare bleeding disorder that's out there.

Thank you sir. Um to close, we continue to build momentum across our business as we execute against our, our strategy and advanced towards our 2030 goals. And um I'd like to thank everyone who's joined us today. Thank you.

Speaker #6: I think globally, there's about one and a half million patients with this disease. I think when we think about the addressable population in the United States, I think again, those estimates vary.

Josh Brodsky: Thank you.

Whitney Ijem: Thank you.

Josh Brodsky: Thank you. That concludes our question and answer session, and we'll hand it back to the company for closing remarks.

Operator: Thank you. That concludes our question and answer session, and we'll hand it back to the company for closing remarks.

Thank you for presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining you may now. Disconnect

Speaker #6: I think there's a number of these patients who don't actually get to medical attention. But we think there's probably about 70,000 or so patients in the United States who may be addressable with this condition.

Yvonne Greenstreet: Thank you. To close, we continue to build momentum across our business as we execute against our strategy and advance towards our 2030 goals. I'd like to thank everyone who's joined us today. Thank you.

Speaker #6: But again, that epidemiology will firm up, as we've seen with rare diseases—where there aren't treatments—once there are effective treatments, more and more come to attention.

Operator: Thank you, presenters. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.

Speaker #6: So that's probably a ballpark, though, for you.

Speaker #5: Thank you.

Speaker #4: Thank you, Jess. And that concludes our question and answer session. I will hand it back to the company for closing remarks.

Speaker #1: Thank you. So to close, we continue to build momentum across our business as we execute against our strategy and advance toward our 2030 goals.

Speaker #1: And I'd like to thank everyone who's joined us today. Thank you.

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