Financial Data and Key Metrics Changes - Total global net product revenues for 2025 were nearly $3 billion, representing an 81% growth compared to 2024, driven by a more than doubling of revenue in the TTR franchise [25][26] - The company achieved GAAP profitability for the full year 2025 and expects to sustain profitability going forward [7][29] - Non-GAAP operating income for 2025 was $850 million, a $755 million increase compared to the previous year [28] Business Line Data and Key Metrics Changes - The TTR franchise generated $858 million in net revenues in Q4 2025, up 151% year-over-year [12] - The rare disease portfolio generated $136 million in net revenue in Q4, up 26% year-over-year [11] - GIVLAARI and OXLUMO together became a $500 million franchise in 2025, reflecting continued growth more than five years post-launch [11] Market Data and Key Metrics Changes - U.S. net revenues for the TTR franchise grew 20% compared to Q3 2025 and 222% compared to Q4 2024 [12] - International revenues grew 13% quarter-over-quarter and 47% year-over-year, indicating strong global momentum [14] - The company anticipates launching AMVUTTRA for ATTR cardiomyopathy in additional international markets throughout 2026 [14] Company Strategy and Development Direction - The company has set new five-year goals, Alnylam 2030, focusing on achieving global TTR leadership, sustainable innovation, and disciplined growth [8][9] - Plans include launching nucresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy, with an aim for over 25% revenue CAGR through 2030 [10] - The company expects to invest approximately 30% of revenues in non-GAAP R&D to accelerate organic innovation and selectively access external innovation [9] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the size and growth of the ATTR-CM category, noting that the majority of patients remain untreated [15] - The early momentum of AMVUTTRA is encouraging, with strong customer demand and broad access expected to drive future growth [17] - Management highlighted the importance of improving diagnosis and treatment rates to expand the category further [18] Other Important Information - The company ended 2025 with cash, cash equivalents, and marketable securities of $2.9 billion, an increase from $2.7 billion at the end of 2024 [29] - Collaboration revenue for 2025 was $553 million, an 8% growth compared to 2024, including a significant milestone payment [26] Q&A Session Summary Question: Insights on new patient additions and first-line mix for patisiran versus tafamidis - Management expressed satisfaction with the AMVUTTRA launch and noted strong fundamentals supporting continued growth [41][43] Question: Addressing choppiness in scripts and pricing dynamics - Management indicated confidence in access and pricing, with a mid-single-digit net price decline expected in 2026 [49][61] Question: Seasonality effects in Q4 and potential tailwinds for Q1 2026 - Management acknowledged typical industry seasonality but emphasized that underlying momentum remains strong [53][54] Question: Gross to net pattern over 2026 - Management confirmed a gradual mid-single-digit net price decrease expected throughout the year [59][61] Question: External innovation strategy and potential partnerships - Management highlighted a focus on complementary technologies that enhance the existing portfolio and pipeline [66][98] Question: Impact of nucresiran on operating margins - Management anticipates significant positive margin impacts post-2030 if nucresiran demonstrates a best-in-class profile [70][71] Question: Updates on the Huntington's program and trial initiation - Management is optimistic about the Huntington's program and plans to accelerate it responsibly based on initial data [78][79] Question: Prioritization of ACVR1C asset in obesity pipeline - Management explained the prioritization based on preclinical data indicating ACVR1C's potential for greater efficacy compared to other targets [86][87]

Financial Data and Key Metrics Changes - Total global net product revenues for 2025 were nearly $3 billion, representing an 81% growth compared to 2024, driven by a more than doubling of revenue in the TTR franchise [25][26] - GAAP profitability was achieved for the full year 2025, with non-GAAP operating income of $850 million, a $755 million increase compared to last year [29] - Gross margin on product sales was 77% for the full year, a 4% decrease compared to 2024, primarily due to increased royalties on AMVUTTRA [27] Business Line Data and Key Metrics Changes - The TTR franchise generated $858 million in Q4, up 151% year-over-year, and $4.4-$4.7 billion in total TTR revenue guidance for 2026, representing an 83% growth at the midpoint [11][31] - The rare disease portfolio generated $136 million in Q4, up 26% year-over-year, with GIVLAARI and OXLUMO together becoming a $500 million franchise in 2025 [11][12] Market Data and Key Metrics Changes - U.S. TTR net revenues grew 20% compared to Q3 2025 and 222% compared to Q4 2024, while international revenues grew 13% quarter-over-quarter and 47% year-over-year [13][14] - The company anticipates a mid-single-digit net price decrease for AMVUTTRA in 2026, with international TTR revenue growth expected to be consistent with 2025 [31][32] Company Strategy and Development Direction - The company aims to achieve global TTR leadership and launch nucresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy as part of its Alnylam 2030 goals [8][9] - The strategy includes investing approximately 30% of revenues in non-GAAP R&D to accelerate organic innovation and selectively access external innovation [9][10] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the growth potential of the TTR franchise, citing strong fundamentals and early momentum from the AMVUTTRA launch [41][44] - The company is focused on building a durable growth foundation through education, awareness, and diagnosis enablement to expand the ATTR-CM category [18][19] Other Important Information - The company initiated three Phase 3 studies in 2025 and expanded its clinical pipeline with four proprietary CTAs [19][20] - The proprietary enzymatic ligation manufacturing platform, Syrelis, was launched to enhance capacity and reduce costs [7][22] Q&A Session Summary Question: Insights on new patient adds and first-line mix for patisiran versus tafamidis - Management highlighted strong AMVUTTRA launch fundamentals and improved first-line access, supporting confidence in 2026 guidance [40][43] Question: Addressing choppiness in scripts and pricing dynamics - Management noted strong access for patients and a mid-single-digit net price decline integrated into the outlook [47][49] Question: Seasonality impact on Q1 and potential tailwind - Management acknowledged typical industry seasonality but emphasized that underlying momentum remains strong [52][54] Question: Gross to net pattern expectations for 2026 - Management expects a gradual mid-single-digit net price decrease throughout the year, with access discussions largely completed [59][61] Question: External innovation strategy and potential partnerships - Management indicated a focus on complementary technologies that enhance internal innovation, with a high bar for external opportunities [66][68] Question: Impact of nucresiran on operating margin - Management expressed high conviction in nucresiran's potential to drive margins to the mid-40s post-2030 due to its best-in-class profile [70][71] Question: Insights on Huntington's program and trial initiation - Management is optimistic about the Huntington's program and aims to accelerate it responsibly based on target engagement data [78][79] Question: Prioritization of ACVR1C asset in obesity pipeline - Management prioritized ACVR1C due to its potential for more potent effects compared to other targets, with results expected by year-end [86][87]

Financial Data and Key Metrics Changes - Total global net product revenues for 2025 were nearly $3 billion, representing an 81% growth compared to 2024, driven by a more than doubling of revenue in the TTR franchise [24][25] - The company achieved GAAP profitability for the full year 2025 and expects to sustain profitability going forward [5][27] - Non-GAAP operating income for the full year was $850 million, a $755 million increase compared to the previous year [26] Business Line Data and Key Metrics Changes - The TTR franchise generated $858 million in net revenues in Q4 2025, up 151% year-over-year [11] - The rare disease portfolio generated $136 million in net revenue in Q4, reflecting a 26% increase compared to the same period last year [10] - GIVLAARI and OXLUMO together became a $500 million franchise in 2025, showing continued growth more than five years post-launch [10] Market Data and Key Metrics Changes - U.S. net revenues for the TTR franchise grew 20% compared to Q3 2025 and 222% compared to Q4 2024 [11] - International revenues grew 13% quarter-over-quarter and 47% year-over-year, indicating strong global momentum [12] - The company anticipates launching AMVUTTRA for ATTR cardiomyopathy in additional international markets throughout 2026 [12] Company Strategy and Development Direction - The company has set new five-year goals, Alnylam 2030, focusing on achieving global TTR leadership, sustainable innovation, and disciplined growth [6][9] - Plans include launching nucresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy, with aspirations to deliver RNAi to 10 tissue types and expand the pipeline to over 40 clinical programs by 2030 [7][8] - The company aims for over 25% revenue CAGR through 2030 and a non-GAAP operating margin of approximately 30% [9] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the size and growth of the ATTR-CM category, noting that the majority of patients remain untreated [14] - The early momentum of AMVUTTRA is encouraging, with strong customer demand and broad access expected to drive growth [16] - The company is focused on improving diagnosis and treatment rates to expand the category further [17] Other Important Information - The company initiated three Phase 3 studies in 2025 and expanded its clinical pipeline with four proprietary CTAs [18] - The proprietary enzymatic ligation manufacturing platform, Syrelis, was launched to enhance capacity and reduce costs [20] - The company ended 2025 with cash, cash equivalents, and marketable securities of $2.9 billion, an increase from $2.7 billion at the end of 2024 [27] Q&A Session Summary Question: Can you comment on new patient adds and the mix of first-line for patisiran versus tafamidis switches? - Management highlighted strong AMVUTTRA launch momentum and improved first-line access, supporting confidence in 2026 guidance [38][41] Question: Can you speak to the choppiness in scripts for the first quarter and pricing dynamics? - Management noted that the majority of patients have first-line access and expect a mid-single-digit net price decline in 2026, which is integrated into their outlook [44][47] Question: Have you seen any seasonality during the fourth quarter? - Management acknowledged typical industry seasonality but emphasized that underlying momentum remains strong [50][51] Question: What is the rationale for prioritizing the ACVR1C asset over others in your pipeline? - Management indicated that ACVR1C appears to be a more potent target based on preclinical work and emerging data [81][85] Question: How should we think about the impact of nucresiran on operating margins once available? - Management expects nucresiran to have a best-in-class profile, potentially driving margins to the mid-40s post-2030 [68][69]

© 2026 Alnylam Pharmaceuticals, Inc. 1 Agenda Fourth Quarter and Full Year 2025 Financial Results Welcome February 12, 2026 • Christine Akinc Chief Corporate Communications Officer Overview • Yvonne Greenstreet, M.D. Chief Executive Officer Commercial Highlights • Tolga Tanguler Chief Commercial Officer Pipeline • Pushkal Garg, M.D. Chief Research & Development Officer Financial Summary • Jeff Poulton Chief Financial Officer Q&A Session 2 Alnylam Forward-Looking Statements This presentation contains forward ...

Financial Performance - Total net product revenues reached $851 million in Q3 2025, representing a 103% year-over-year growth compared to Q3 2024[17, 24] - Total TTR net revenues were $724 million in Q3 2025, a 135% increase year-over-year[17, 31] - U S total TTR net revenues amounted to $543 million in Q3 2025, demonstrating a 194% year-over-year growth[17] - The company increased its 2025 total net product revenue guidance to a range of $2950 million to $3050 million, a 10% increase at the midpoint[17] - Non-GAAP operating income was $476 million, resulting in a 38% non-GAAP operating margin[65] Product Performance - Rare disease franchise revenues totaled $127 million in Q3 2025, a 14% increase year-over-year[28] - OXLUMO sales grew by 31% year-over-year, driven by a 15% increase in global patients on therapy[29] - AMVUTTRA's ATTR-CM launch contributed significantly to growth, with estimated ATTR-CM revenue of approximately $300 million in Q3 2025 in the U S [33, 34] Pipeline and Clinical Development - Phase 3 trial initiated for nucresiran in ATTR-CM, with topline results expected in 2028 and targeting launch around 2030[17, 47] - Phase 3 cardiovascular outcomes trial (CVOT) initiated for zilebesiran in high cardiovascular risk patients with uncontrolled hypertension, randomizing approximately 11,000 patients[17, 56] - HELIOS-B data showed a 37% risk reduction in time-to-first ACM and CV events with long-term vutrisiran treatment[43]

Financial Data and Key Metrics Changes - Alnylam reported total net product revenues of $672 million for Q2 2025, representing a 64% year-over-year growth [9][35] - The TTR franchise generated revenues of $544 million, reflecting a 77% increase year-over-year [7][35] - The company increased its total net product revenue guidance for 2025 from a range of $2.05 billion to $2.25 billion to a revised range of $2.65 billion to $2.8 billion, marking a $575 million or 27% increase at the midpoint [9][39] Business Line Data and Key Metrics Changes - The TTR franchise in the U.S. saw combined Q2 sales of ONPATTRO and Ambutra rise by 80% compared to Q1, driven primarily by the Ambutra launch [13][35] - The rare franchise, including GIVLAARI and OXLUMO, delivered $128 million in combined Q2 sales, up 24% year-over-year [12][35] - The U.S. TTR franchise grew 125% compared to 2024, primarily due to the ATTR Centimeters launch [14] Market Data and Key Metrics Changes - Approximately 1,400 cardiomyopathy patients were receiving Ambutra by the end of Q2, contributing an estimated $150 million in revenue [13][23] - International markets are expected to begin contributing to Ambutra sales in the second half of the year, with launches in Germany and Japan [8][26] - The U.S. TTR franchise achieved $383 million in Q2, representing an 80% quarter-over-quarter growth [15] Company Strategy and Development Direction - Alnylam is focusing on TTR leadership, growth through innovation, and strong financial performance as key strategic pillars [4][6] - The company aims to establish itself as a top-tier biotech firm by delivering sustainable innovation and value creation [5][10] - The launch of Ambutra is seen as a flagship commercial franchise with robust long-term growth potential [6][27] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the strong early launch performance of Ambutra and the potential for continued growth [9][39] - The company remains committed to advancing care through real-world evidence generation and the development of next-generation RNAi therapeutics [26][34] - Management highlighted the importance of disciplined execution and patient-centricity in driving long-term growth [27][39] Other Important Information - The FDA granted fast track designation to nucrisiran for ATTR Centimeters, which is expected to streamline the review process [9][31] - The gross margin on product sales was reported at 79%, down from 84% in the previous year, primarily due to increased royalties on Ambutra [37] Q&A Session Summary Question: Details on patient profiles for Ambutra - Management noted broad uptake across first-line patients and stabilizer progressors, with a healthy share of first-line patients emerging [45][46] Question: Thoughts on net price for Ambutra - The expectation is for a mid-single-digit reduction in net price for Ambutra in 2025 compared to 2024 [50][52] Question: Bolus effect in cardiomyopathy scripts - Management indicated solid commercial execution and emphasized that results are not just a flash in the pan, expecting continued sustainable growth [56][57] Question: Assumptions underpinning updated TTR franchise guidance - Management expects steady growth in both first-line and second-line patient flows, with a healthy trend in first-line use observed [65][70] Question: Criteria for stabilizer progressors - Clinical evidence suggests that one-third to half of patients on stabilizers progress, and physicians are using a variety of factors to determine eligibility for Ambutra [76][82] Question: Rate of new patient starts per quarter - Management is pleased with the initial uptake and expects both categories of patients to continue growing, though specific numbers will not be reported [91][94] Question: Payer requirements for Ambutra treatment - Broad coverage is reported across Medicare and commercial payers, with minimal step edits required for access [98][102]

Financial Performance - Total Q2 Net Product Revenues reached $672 million, a 64% increase year-over-year[17, 24] - Total TTR Net Revenues in Q2 were $544 million, representing a 77% year-over-year growth[17] - Rare Franchise Net Product Revenues in Q2 totaled $128 million, a 24% increase year-over-year[28] - Alnylam increased its 2025 Total Net Product Revenue Guidance to a range of $2650 million to $2800 million[17, 74] - The company's Q2 Non-GAAP Operating Income was $95 million[70] Commercial Highlights - U S ATTR-CM launch contributed approximately $150 million in revenue during Q2[33, 34] - There are approximately 1,400 ATTR-CM patients receiving AMVUTTRA as of June 30, 2025[17, 37, 45] - U S TTR franchise experienced 125% year-over-year growth in Q2[32] - GIVLAARI saw a 30% year-over-year growth, driven by an approximately 18% increase in global patients on therapy[29] - OXLUMO experienced a 15% year-over-year growth, driven by an approximately 16% increase in global patients on therapy[29] Pipeline Development - The TRITON-CM Phase 3 study for nucresiran in ATTR-CM has been initiated, with a targeted launch around 2030[17, 60] - Phase 1 multidose results for mivelsiran in Alzheimer's Disease were announced[17] - A Phase 1 study for ALN-4324 in Type 2 Diabetes was initiated[17]

Financial Performance - Alnylam's combined net product revenues reached $469 million, a 28% year-over-year (YoY) increase compared to Q1 2024[15, 25] - The U S TTR franchise primarily drove this growth, experiencing a 45% YoY increase[15] - The company is on track to meet its 2025 financial guidance, projecting combined net product revenues between $2050 million and $2250 million[15] - Non-GAAP operating income was $75 million, resulting in a 13% non-GAAP operating margin[70] Franchise Performance - The Rare Franchise achieved $109 million in global net product revenues in Q1 2025, representing an 8% YoY growth[28] - GIVLAARI sales increased by 15% YoY, driven by a ~15% increase in global patients on therapy[29] - The TTR Franchise experienced a robust 36% growth, primarily driven by U S performance, reaching $359 million in global net product revenues[30, 31] - U S TTR growth was 45% YoY, driven by demand (+32%), inventory (+6%), and gross-to-net adjustments (+7%)[32] AMVUTTRA Launch and Pipeline - AMVUTTRA captured approximately 70% of new hATTR-PN patient starts in the U S in Q1 2025[32, 35] - Alnylam is optimizing access pathways for AMVUTTRA in ATTR-CM at ~170 priority health systems, covering ~80% of Rx volume[39] - Regulatory approvals for AMVUTTRA have been granted in the U S and Brazil, with a positive CHMP opinion in the European Union[56]

Financial Data and Key Metrics Changes - In Q1 2025, Alnylam Pharmaceuticals reported total product revenues of $469 million, representing a 28% year-over-year growth, driven by a 36% increase in the TTR franchise revenues [8][40] - Collaboration revenue decreased by 16% to $99 million compared to the previous year, primarily due to a milestone achieved in Q1 2024 [41] - Non-GAAP operating profit for the quarter was $75 million, reflecting a $73 million improvement year-over-year [43] Business Line Data and Key Metrics Changes - The TTR franchise generated $359 million in global net revenues, a 36% increase compared to Q1 2024, with U.S. sales growing by 45% year-over-year [15][16] - The rare disease franchise, including GIVLAARI and OXLUMO, delivered $109 million in combined product sales, representing an 8% growth year-over-year [14] Market Data and Key Metrics Changes - In the U.S., the TTR franchise saw a 32% increase in demand driven by ongoing ONPATTRO patient uptake, with Ambutra capturing approximately 70% of new patient starts in Q1 2025 [16][19] - Internationally, the TTR franchise grew by 24% compared to Q1 2024, primarily due to increased demand for Ambutra [17] Company Strategy and Development Direction - Alnylam aims to become the global leader in TTR, focusing on broad access, driving awareness, and supporting treatment initiation for patients [7][10] - The company is committed to achieving sustainable non-GAAP profitability in 2025 and emphasizes a disciplined approach to capital allocation [9][11] Management's Comments on Operating Environment and Future Outlook - Management acknowledged uncertainties related to potential policy changes, including tariffs and FDA personnel reorganization, but expressed confidence in Alnylam's positioning to mitigate impacts [9][45] - The management reiterated guidance for continued growth and a strong launch in ATTR cardiomyopathy, projecting a robust 36% year-over-year growth in TTR franchise revenues [27][39] Other Important Information - Alnylam received FDA approval for Ambutra as the first and only silencer approved in the U.S. for ATTR Centimeters, with a successful launch underway [20][30] - The company is advancing its pipeline with several pivotal studies planned, including TRITON Centimeters and TRITON PN [47] Q&A Session Summary Question: Initial patients starting treatment and prescriber base - Management noted a broad uptake among both experienced and new prescribers, indicating strong early momentum in the cardiomyopathy launch [51][53] Question: Revenue benchmarks for ATTR cardiomyopathy - Management clarified that the revenue contribution from ATTR cardiomyopathy was not included in Q1 results, as the approval came late in the quarter [57][62] Question: Commercial strategies to capture market share - Management highlighted the unique mechanism of action of Ambutra and its potential as a first-line treatment, which is driving physician interest [64][66] Question: Use of Quick Start program and formulary access - Management reported limited use of the Quick Start program, with most patients paying zero copay, and confirmed no price difference between indications [70][72] Question: Impact of TrueBee on Ambutra's launch - Management indicated no headwinds from TrueBee's launch, emphasizing the growing and unsatisfied market for ATTR treatments [76][78] Question: Metrics on health systems and patient initiation - Management confirmed that over half of the 170 priority health systems have Ambutra on formulary, with many already initiating treatments [97][99]

Financial Data and Key Metrics Changes - In Q1 2025, Alnylam Pharmaceuticals reported total product revenues of $469 million, representing a 28% year-over-year growth, driven by a 36% increase in the TTR franchise revenues [6][37] - Collaboration revenue decreased by 16% to $99 million compared to the previous year, primarily due to a milestone achieved in Q1 2024 [38] - Gross margin on product sales remained at 85%, consistent with Q1 2024, but is expected to decrease for the remainder of the year due to escalating royalty rates [39][41] Business Line Data and Key Metrics Changes - The TTR franchise generated $359 million in global net revenues, a 36% increase year-over-year, with U.S. sales growing by 45% [14][15] - The rare disease franchise, including GIVLAARI and OXLUMO, delivered $109 million in combined product sales, reflecting an 8% growth year-over-year [13] - The TTR franchise's growth was primarily driven by increased demand for ONPATTRO and Ambutra, with a 32% increase in demand noted [15][16] Market Data and Key Metrics Changes - In the U.S., Ambutra captured approximately 70% of new patient starts in the first quarter of 2025, indicating strong market leadership despite new competition [18] - Internationally, the TTR franchise grew by 24% compared to the first quarter of 2024, driven by robust patient uptake [16] - The company noted that about 80% of the global addressable population remains untreated, presenting significant growth opportunities [19] Company Strategy and Development Direction - Alnylam aims to become the global leader in TTR, focusing on broad access, driving awareness, and supporting treatment initiation for patients [5][9] - The company is committed to achieving sustainable non-GAAP profitability in 2025 while continuing to advance its high-value pipeline [7][10] - Alnylam's strategy includes leveraging its innovative pipeline with multiple multibillion-dollar opportunities and maintaining strong financial performance through disciplined capital allocation [9][10] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the company's positioning despite uncertainties related to potential policy changes, tariffs, and FDA reorganizations [7][8] - The management highlighted the strong early progress in the launch of Ambutra for ATTR cardiomyopathy and reiterated guidance for continued growth [6][37] - The company remains optimistic about achieving its 2025 goals, which include expanding access to its therapies and enhancing patient outcomes [10][26] Other Important Information - Alnylam received FDA approval for Ambutra as the first and only silencer approved in the U.S. for ATTR cardiomyopathy, with positive opinions from regulatory bodies in Brazil and the EU [20][29] - The company is advancing its pipeline with new clinical programs targeting various diseases, including a Phase I study for ALN434 targeting Type 2 diabetes [34][35] Q&A Session Summary Question: What is the profile of prescribers for Ambutra? - Management noted a broad uptake among both experienced prescribers and new doctors, indicating strong initial engagement with the product [48][51] Question: How does the revenue from ATTR cardiomyopathy compare to previous products? - Management clarified that the revenue from ATTR cardiomyopathy did not contribute to Q1 results, as the approval came late in the quarter [55][60] Question: What strategies are being employed to compete with tafamidis? - Management emphasized the unique mechanism of action of Ambutra and its compelling clinical data, which positions it as a first-line treatment option [62][64] Question: What are the dynamics of reimbursement for Ambutra? - Management explained that Ambutra has a single price across indications and highlighted the effectiveness of their patient support programs in facilitating access [68][70] Question: What are the expectations for formulary inclusion? - Management aims to complete formulary inclusion for all priority health systems by year-end, with encouraging early results already seen [81][82] Question: How is the early uptake of Ambutra characterized? - Management indicated that early uptake includes both switch patients and new patients, reflecting a strong initial market response [100][102]