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]