Executive Summary / Key Takeaways

• Alnylam Pharmaceuticals is rapidly solidifying its position as a leader in RNAi therapeutics, driven by the exceptional launch of AMVUTTRA for ATTR cardiomyopathy (ATTR-CM) and a robust, expanding pipeline.
• The company reported strong Q3 2025 financial results, with total net product revenues reaching $851 million, a 103% year-over-year increase, and TTR franchise revenues growing 135% year-over-year to $724 million, largely fueled by AMVUTTRA's ATTR-CM uptake.
• Alnylam has significantly increased its full-year 2025 total net product revenue guidance to $2.95 billion - $3.05 billion, reflecting confidence in AMVUTTRA's market penetration and the overall TTR franchise growth.
• The company's proprietary RNAi technology offers a differentiated mechanism of action, providing rapid and sustained gene knockdown, which is a key competitive advantage in addressing severe genetic diseases.
• While facing competitive pressures from both stabilizers and other RNA-targeted therapies, Alnylam's strategic focus on innovation, global commercial infrastructure, and disciplined capital allocation positions it for sustainable non-GAAP operating profitability in 2025 and long-term value creation.

Alnylam's RNAi Foundation: A Decade of Innovation and Market Emergence

Alnylam Pharmaceuticals, founded in 2002, has pioneered the development and commercialization of therapeutics based on ribonucleic acid interference (RNAi), a naturally occurring biological pathway for sequence-specific gene silencing. This foundational technology, which prevents disease-causing proteins from being made, represents a revolutionary approach with the potential to transform patient care across a broad range of diseases. The company's strategic journey has been marked by a relentless focus on building a strong intellectual property portfolio, forging key collaborations, and establishing a global commercial footprint.

Early strategic collaborations, such as the 2013 agreement with The Medicines Company (MDCO) (later acquired by Novartis (NVS)) for inclisiran (Leqvio) and the 2014 alliance with Sanofi (SNY), were pivotal in expanding Alnylam's reach and validating its platform. The approval of ONPATTRO in August 2018 marked Alnylam's first commercial product, laying the groundwork for its multi-product vision. The "Alnylam P5x25" strategy, launched in early 2021, articulated an ambitious goal: to transition into a top-tier biotech company by the end of 2025, characterized by transformative medicines, sustainable innovation, and exceptional financial performance. This strategic roadmap has guided the company's aggressive pipeline expansion and commercial execution, culminating in a landmark 2025.

Technological Edge: The Power of RNAi

Alnylam's core technological differentiator lies in its RNAi therapeutics, specifically small interfering RNA (siRNA) molecules. These siRNAs function upstream of conventional medicines by potently silencing messenger RNA (mRNA) that encode for proteins implicated in disease, thereby preventing their production. This mechanism offers a high degree of specificity and the potential for profound, durable disease modification. The company utilizes N-acetylgalactosamine (GalNAc) conjugate or lipid nanoparticle (LNP) approaches for hepatic delivery, and is advancing alternative conjugate approaches for central nervous system (CNS) and ocular delivery, as well as for heart, skeletal muscle, and adipose tissue.

The tangible benefits of this technology are evident in its marketed products and pipeline. For instance, AMVUTTRA, an RNAi therapeutic, has demonstrated rapid knockdown of transthyretin (TTR), the disease-causing protein in ATTR amyloidosis. In the HELIOS-B study, vutrisiran (AMVUTTRA) achieved a 37% relative risk reduction in the composite of all-cause mortality or first cardiovascular event through 48 months in the overall population, and a 42% reduction in the monotherapy group. Furthermore, it was associated with a 37% to 49% reduction in gastrointestinal adverse events compared to placebo, addressing a significant burden for ATTR-CM patients. The quarterly subcutaneous administration of AMVUTTRA also offers convenience and verified adherence, which resonates well with physicians.

Alnylam's R&D engine is continuously pushing the boundaries of RNAi. Nucresiran (formerly ALN-TTRsc04), a next-generation TTR silencer, is designed to offer even greater TTR knockdown (over 90% reduction sustained through Day 180 in Phase 1) with biannual subcutaneous dosing, potentially offering superior efficacy and convenience. The ZENITH Phase 3 cardiovascular outcomes trial for zilebesiran, an investigational RNAi therapeutic for hypertension, aims to reduce major adverse cardiovascular events by targeting angiotensinogen upstream of the RAS cascade, potentially offering continuous blood pressure control and improved adherence with biannual dosing. Earlier-stage programs like ALN-6400 for bleeding disorders (targeting plasminogen to stabilize clots without increasing thrombosis risk) and ALN-5288 for Alzheimer's disease (targeting MAPT/tau) further underscore the breadth and ambition of Alnylam's technological roadmap. These innovations contribute to Alnylam's competitive moat by offering potentially best-in-class profiles, driving higher average selling prices (ASPs), and securing long-term market positioning.

Commercial Momentum and Financial Strength

Alnylam's commercial performance in Q3 2025 was exceptional, showcasing the strength of its TTR franchise and the successful U.S. launch of AMVUTTRA for ATTR-CM. Total net product revenues for the quarter reached $851 million, marking a robust 103% year-over-year growth. The TTR franchise, comprising AMVUTTRA and ONPATTRO, was the primary growth engine, delivering $724 million in global net revenues, a 135% increase from Q3 2024. In the U.S., TTR revenues surged to $543 million, representing a 194% year-over-year increase, largely driven by the AMVUTTRA ATTR-CM launch, which saw its revenue approximately double from Q2 2025 to an estimated $300 million.

The rare disease portfolio, including GIVLAARI and OXLUMO, also demonstrated steady performance, achieving $127 million in sales in Q3 2025, up 14% year-over-year. This growth was primarily driven by increasing patient demand for both medicines. Collaboration revenue saw a significant boost in Q3 2025, reaching $352 million, primarily due to a $300 million milestone payment from Roche following the initiation of the ZENITH Phase 3 trial for zilebesiran. Royalty revenue also doubled year-over-year to $46 million, fueled by the successful global sales of Leqvio by Novartis.

Despite increased sales, the gross margin on product sales decreased to 77% in Q3 2025 from 80% in Q3 2024. This was primarily due to higher royalties payable on AMVUTTRA as increased revenues pushed the product into higher royalty tiers. Operating expenses also grew, with non-GAAP R&D expenses increasing 23% to $310 million and non-GAAP SG&A expenses rising 35% to $263 million, reflecting significant investments in late-stage clinical trials (zilebesiran, nucresiran) and the AMVUTTRA ATTR-CM launch. Despite these investments, Alnylam achieved a non-GAAP operating income of $476 million in Q3 2025, a substantial increase from the prior year, and reported adjusted net income of $396 million, achieving a key profitability goal set in 2021.

As of September 30, 2025, Alnylam maintained a strong liquidity position with $2.72 billion in cash, cash equivalents, and marketable securities. The company strategically refinanced its debt in September 2025, issuing $661.30 million in new 0% convertible senior notes due 2028 and repurchasing $637.80 million of its 2027 convertible notes for approximately $1.11 billion. A new $500 million revolving credit facility further enhances its financial flexibility. Management believes current resources are sufficient to cover operating needs for at least the next 12 months.

Competitive Landscape and Strategic Positioning

Alnylam operates in an intensely competitive biopharmaceutical market, facing both direct and indirect rivals. Its primary direct competitors in RNAi therapeutics and genetic medicines include Ionis Pharmaceuticals (IONS), Regeneron Pharmaceuticals (REGN), and Novartis.

Alnylam's RNAi technology offers a distinct advantage over Ionis's antisense technology by potentially providing greater precision in gene silencing and more effective disease modification in rare disorders. This technological edge translates into stronger customer loyalty for specialized treatments, supporting recurring revenue and potentially superior margins through pricing power. While Ionis has a broader pipeline of partnered assets and a longer history in RNA-targeted therapies, Alnylam's R&D agility in RNAi-specific pipelines allows for potentially faster market entry in shared segments. Financially, Alnylam has demonstrated strong revenue growth from its product launches and partnerships, with solid cash flow generation supporting R&D. However, its profitability margins may lag Ionis due to higher R&D expenditures relative to Ionis's more diversified revenue streams.

Against Regeneron, Alnylam's RNAi therapeutics offer targeted gene silencing with potentially greater specificity in rare diseases compared to Regeneron's broader antibody-based approaches. Alnylam's strategy of deep investment in RNAi R&D and collaborations (including with Regeneron itself) positions it strongly in niche genetic markets. While Regeneron excels in scalable biologics with wider applications and possesses greater operational scale and market reach, Alnylam's proprietary RNAi technology provides a differentiator for long-term disease modification. Financially, Alnylam's growth trends from pipeline advancements and partnerships are strong, but it may trail Regeneron in overall profitability and efficiency due to Regeneron's diversified revenue and robust cash reserves.

Novartis, a global pharmaceutical giant, presents competition through its broad portfolio and extensive global reach. Alnylam's RNAi offerings provide a more targeted approach to genetic diseases, potentially with advantages in efficacy for conditions like amyloidosis, compared to Novartis's broader gene therapy platforms. Alnylam's focused R&D in RNAi differentiates it in niche markets, while Novartis's scale allows for greater market positioning through extensive distribution. Alnylam's strengths in proprietary technology could lead in therapeutic precision, but Novartis may excel in operational execution due to its vast resources. Financially, Alnylam demonstrates growth trends from its products and collaborations, with solid cash flow for R&D, but it might trail Novartis in profitability and efficiency due to Novartis's diversified revenue streams.

The overall ATTR market remains largely underserved, with approximately 80% of the global addressable population untreated. This presents a significant market growth opportunity that Alnylam is actively capitalizing on. Management believes that more treatment options, including those from competitors like Pfizer (PFE) (VYNDAQEL/VYNDAMAX) and BridgeBio (BBIO) (ATTRUBY) for ATTR-CM, and Ionis/AstraZeneca (AZN) (WAINUA) for hATTR-PN, are expanding disease awareness and ultimately accelerating category growth. Alnylam's strategy focuses on leveraging AMVUTTRA's differentiated profile—rapid TTR knockdown, significant cardiovascular outcome benefits, and convenient quarterly dosing—to secure a leading position, particularly as a first-line treatment. Initial uptake of AMVUTTRA in ATTR-CM has been balanced between newly diagnosed patients and those progressing on stabilizers, with a clear focus on increasing first-line presence.

Outlook and Key Risks

Alnylam's outlook for 2025 is highly optimistic, with the company significantly raising its total net product revenue guidance to a range of $2.95 billion to $3.05 billion, representing an 82% increase at the midpoint compared to 2024. This confidence is primarily driven by the strong U.S. launch of AMVUTTRA in ATTR-CM, with patient demand doubling quarter-over-quarter in Q3 2025. The company expects its TTR franchise to contribute $2.475 billion to $2.525 billion to this total, a 12% increase at the midpoint from prior guidance. International launches for AMVUTTRA ATTR-CM are anticipated across 2026, following local pricing and reimbursement reviews, with modest contributions expected from Germany and Japan in Q4 2025. Alnylam also reiterated its guidance for the rare disease franchise ($475 million to $525 million) and expects to achieve sustainable non-GAAP operating profitability in 2025.

Despite this positive outlook, several risks warrant investor attention. The company recently received a subpoena from the U.S. Attorney's Office regarding government price reporting for its commercial products, which could lead to significant expenses and divert management attention. Proposed cuts to CMS reimbursement for PYP scintigraphy could impact diagnosis rates for ATTR amyloidosis, although management has not observed immediate anxiety in health systems. The Inflation Reduction Act (IRA) may also impact drug pricing and reimbursement, potentially affecting Alnylam's net revenues. Furthermore, the evolving BIOSECURE ACT could restrict Alnylam's ability to engage with certain Chinese biotechnology companies, potentially disrupting its supply chain.

Alnylam's reliance on third-party contract manufacturing organizations (CMOs) for drug substance and all drug product requirements poses a risk, as any disruption could impede supply. The inherent uncertainties of clinical development, including potential delays or failures of pipeline candidates like nucresiran or zilebesiran, could impact future revenue streams. Competition from existing and emerging therapies, including other RNAi and antisense drugs, as well as traditional small molecules, could also pressure market share and pricing. Finally, the accounting method for convertible debt securities could affect reported earnings and financial condition, potentially reclassifying long-term liabilities as current and impacting working capital.

Conclusion

Alnylam Pharmaceuticals stands at a pivotal juncture, poised for sustained growth and profitability, largely propelled by its leadership in RNAi therapeutics and the successful expansion of its TTR franchise. The exceptional launch of AMVUTTRA for ATTR cardiomyopathy in the U.S., coupled with a robust and innovative pipeline targeting multibillion-dollar opportunities, underscores the company's ability to translate groundbreaking science into commercial success. While competitive dynamics and regulatory scrutiny present ongoing challenges, Alnylam's differentiated technology, strategic collaborations, and disciplined execution provide a strong foundation for long-term value creation. Investors should closely monitor the continued market penetration of AMVUTTRA, the progress of its late-stage pipeline, and the company's ability to effectively manage its operational and regulatory risks as it solidifies its position as a top-tier biotech.