Alnylam Pharmaceuticals Inc.

Company Overview

Business Model: Alnylam Pharmaceuticals, Inc. is a global commercial-stage biopharmaceutical company focused on developing and commercializing novel therapeutics based on ribonucleic acid interference (RNAi). This technology silences messenger RNA (mRNA) to prevent the production of disease-causing proteins. The company's primary revenue generation mechanisms include net product sales of its five approved RNAi-based medicines and collaboration revenues from strategic partnerships.

Market Position: Alnylam Pharmaceuticals, Inc. is a leader in RNAi therapeutics, having developed five first-in-class RNAi-based medicines: ONPATTRO (patisiran), AMVUTTRA (vutrisiran), GIVLAARI (givosiran), OXLUMO (lumasiran), and Leqvio (inclisiran). The company targets genetically validated genes and utilizes proprietary delivery technologies such as N-acetylgalactosamine (GalNAc) conjugate and lipid nanoparticle (LNP) for hepatic delivery, and hexadecyl (C16) moiety for central nervous system (CNS) and ocular delivery. Its Alnylam P5x25 strategy aims for the company to be a top-tier biotech company by the end of 2025, with five marketed products and over 20 clinical programs as of the end of 2024.

Recent Strategic Developments:

• AMVUTTRA for ATTR Amyloidosis with Cardiomyopathy: Positive topline results from the HELIOS-B clinical trial were reported in June 2024, showing a 28% reduction in the composite of all-cause mortality and recurrent cardiovascular events in the overall population. An sNDA was filed with the FDA on October 9, 2024, using a Priority Review Voucher, with an action date of March 23, 2025.
• Zilebesiran for Hypertension: Positive topline results from the KARDIA-2 clinical trial were reported in March 2024. A Phase 3 cardiovascular outcomes trial is expected to initiate in the second half of 2025, following the initiation of the KARDIA-3 Phase 2 clinical trial in April 2024. This program is being co-developed and co-commercialized with F. Hoffmann-La Roche Ltd. and Genentech, Inc. (collectively, Roche).
• Nucresiran for ATTR Amyloidosis: Positive Phase 1 study results in healthy volunteers in November 2024 showed single doses of 300 mg or higher resulted in mean reductions of serum TTR greater than 90% from baseline at Day 15, sustained through at least Day 180. A Phase 3 clinical trial in ATTR amyloidosis with cardiomyopathy is expected to initiate in the first half of 2025.
• Mivelsiran for Alzheimer’s Disease and Cerebral Amyloid Angiopathy: Positive initial results from the multiple dose portion of the Phase 1 clinical trial in early-onset AD were announced in October 2024. A Phase 2 clinical trial in AD is expected to initiate in the second half of 2025, and the cAPPRicorn-1 Phase 2 clinical trial in CAA began dosing in July 2024. Regeneron Pharmaceuticals, Inc. opted out of further co-development in May 2024, granting Alnylam Pharmaceuticals, Inc. full global development and commercialization rights.
• Cemdisiran for Complement-Mediated Diseases: In June 2024, Alnylam Pharmaceuticals, Inc. granted Regeneron Pharmaceuticals, Inc. global rights to develop, manufacture, and commercialize cemdisiran as monotherapy and in combination with anti-C5 antibodies.
• Fitusiran for Hemophilia: An NDA was filed with the FDA by Genzyme Corporation, a Sanofi Company, with a target action date of March 28, 2025.
• Strategic Financing Collaboration with The Blackstone Group Inc.: Blackstone agreed to provide up to $2.00 billion in financing, including $1.00 billion for 50% of royalties and 75% of commercial milestones from Leqvio sales, and up to $750.0 million in a first lien senior secured term loan. Blackstone also committed up to $150.0 million for vutrisiran and zilebesiran development.

Geographic Footprint: Alnylam Pharmaceuticals, Inc. has global commercial operations, with its primary operational regions including the U.S. and Europe, where its four commercialized products (ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO) are primarily marketed. Leqvio, commercialized by Novartis AG, is registered in over 100 countries as of January 2025. The company also has a presence in Japan, Brazil, Canada, UK, Argentina, Australia, Switzerland, Israel, Taiwan, Oman, Qatar, and other countries for its approved products, with regulatory filings pending or planned in Colombia, Mexico, South Korea, and Kuwait. Its corporate headquarters and primary research facilities are in Cambridge, Massachusetts, U.S., with an international headquarters in Zug, Switzerland, and additional offices in Maidenhead, UK, Amsterdam, Netherlands, and Tokyo, Japan.

Financial Performance

Revenue Analysis

Profitability Metrics:

• Gross Margin: 85.6%
• Operating Margin: -7.9%
• Net Margin: -12.4%

Investment in Growth:

• R&D Expenditure: $1,126.2 million (50.1% of revenue)
• Capital Expenditures: $34.3 million
• Strategic Investments:
  • Roche Collaboration: $92.7 million in R&D expenses incurred by Alnylam Pharmaceuticals, Inc.
  • Regeneron Pharmaceuticals, Inc. Collaboration: $71.7 million in R&D expenses incurred by Alnylam Pharmaceuticals, Inc.
  • Blackstone Life Sciences funding for vutrisiran and zilebesiran clinical development: $12.3 million received in 2024, with total funding of $70.0 million for vutrisiran and $26.0 million for zilebesiran Phase 2 as of December 31, 2024. Blackstone Life Sciences has the right to fund up to an additional $54.0 million for zilebesiran Phase 3.

Business Segment Analysis

Alnylam Pharmaceuticals, Inc. operates in a single segment focused on RNAi therapeutics. The following details are provided for its key commercialized products.

ONPATTRO (patisiran)

Financial Performance:

• Revenue: $252.9 million (-29% YoY)
• Key Growth Drivers: Sales decreased due to patient switches to AMVUTTRA (vutrisiran).
  • U.S. Revenue: $74.8 million (-23% YoY)
  • Europe Revenue: $134.2 million (-36% YoY)
  • Rest of World Revenue: $43.9 million (-4% YoY)

Product Portfolio:

• Intravenously administered RNAi therapeutic targeting transthyretin (TTR) protein production in the liver.
• Approved in the U.S. for polyneuropathy of hATTR amyloidosis in adults; in the EU for hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy; in Japan for TTR-type familial amyloidosis with polyneuropathy; and in multiple additional countries.
• Received regulatory approval from the Brazilian Health Regulatory Agency (ANVISA) for ATTR amyloidosis with cardiomyopathy in February 2025.
• Alnylam Pharmaceuticals, Inc. does not plan to pursue label expansions for ONPATTRO in other regions.

Market Dynamics:

• Competes in the hATTR amyloidosis with polyneuropathy market.
• Faces competition from AMVUTTRA (vutrisiran), WAINUA (eplontersen), VYNDAQEL/VYNDAMAX (tafamidis), and TEGSEDI (inotersen).

AMVUTTRA (vutrisiran)

Financial Performance:

• Revenue: $970.5 million (+74% YoY)
• Key Growth Drivers: Strong sales growth across all regions, driven by its approval for hATTR amyloidosis with polyneuropathy and anticipation of a cardiomyopathy indication.
  • U.S. Revenue: $630.6 million (+53% YoY)
  • Europe Revenue: $235.4 million (+232% YoY)
  • Rest of World Revenue: $104.4 million (+38% YoY)

Product Portfolio:

• Subcutaneously administered RNAi therapeutic targeting TTR, utilizing Enhanced Stabilization Chemistry-Plus (ESC+) delivery, designed for quarterly administration.
• Approved in the U.S. for hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with polyneuropathy in adults; in the EU and UK for hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy; in Japan for TTR-type familial amyloidosis with polyneuropathy; and in multiple additional countries.
• In June 2024, positive topline results from the HELIOS-B clinical trial in patients with ATTR amyloidosis with cardiomyopathy were reported, showing a 28% reduction in the composite of all-cause mortality and recurrent cardiovascular events in the overall population.
• An sNDA was filed with the FDA on October 9, 2024, using a Priority Review Voucher, with an action date of March 23, 2025. Regulatory reviews are ongoing by the European Medicines Agency (EMA), ANVISA, the Japanese Health Authority (PMDA), and the Colombian Health Authority (INVIMA).

Market Dynamics:

• Competes in the hATTR amyloidosis with polyneuropathy market and, if approved, will compete in the ATTR amyloidosis with cardiomyopathy market.
• Current competitors for hATTR amyloidosis with polyneuropathy include ONPATTRO, WAINUA (eplontersen), VYNDAQEL/VYNDAMAX (tafamidis), and TEGSEDI (inotersen).
• Potential competitors for ATTR amyloidosis with cardiomyopathy include VYNDAQEL/VYNDAMAX (tafamidis) and ATTRUBY (acoramidis).

GIVLAARI (givosiran)

Financial Performance:

• Revenue: $255.9 million (+17% YoY)
• Key Growth Drivers: Increased patient numbers in the U.S., Europe, and Rest of World.
  • U.S. Revenue: $165.4 million (+16% YoY)
  • Europe Revenue: $65.9 million (+15% YoY)
  • Rest of World Revenue: $24.6 million (+24% YoY)

Product Portfolio:

• First GalNAc-conjugate RNA therapeutic approved for acute hepatic porphyria (AHP).
• Approved in the U.S. for adults with AHP; in the EU for adults and adolescents aged 12 years and older; and in several other countries including Brazil, Canada, Japan, UK, Argentina, Australia, Switzerland, Israel, and Taiwan.
• Regulatory filings are pending or planned in Colombia, Mexico, South Korea, and Kuwait.

Market Dynamics:

• GIVLAARI is the only approved prophylactic treatment for AHP in the U.S. and EU.
• Competes with Recordati S.p.A's PANHEMATIN (U.S.) and NORMOSANG (EU) for acute attacks.

OXLUMO (lumasiran)

Financial Performance:

• Revenue: $167.1 million (+52% YoY)
• Key Growth Drivers: Significant growth across all regions due to increased patient uptake.
  • U.S. Revenue: $62.8 million (+64% YoY)
  • Europe Revenue: $80.8 million (+35% YoY)
  • Rest of World Revenue: $23.5 million (+102% YoY)

Product Portfolio:

• First approved pharmaceutical therapy for primary hyperoxaluria type 1 (PH1).
• Approved in the U.S. for PH1 to lower urinary and plasma oxalate levels in pediatric and adult patients; in the EU and UK for PH1 in all age groups.
• Additional marketing authorizations in Argentina, Australia, Brazil, UK, Switzerland, Canada, Israel, Taiwan, Oman, and Qatar.
• Regulatory filings are pending or planned for 2025 and beyond.

Market Dynamics:

• Competes with RIFVLOZA (nedosiran, Novo Nordisk), approved in September 2023 and launched in the U.S. in early 2024 for PH1 in children 9+ and adults with preserved kidney function.
• Investigational drugs in clinical development include those from Biocodex, Inc. (with M8 Pharmaceuticals, Inc.) and YolTech Therapeutics (China only).

Capital Allocation Strategy

Shareholder Returns:

• Share Repurchases: Not disclosed.
• Dividend Payments: Not disclosed.
• Future Capital Return Commitments: Not disclosed.

Balance Sheet Position:

• Cash and Equivalents: $966.4 million
• Total Debt: $2,472.0 million (includes $1,024.6 million in convertible debt and $1,447.4 million in liability related to the sale of future royalties)
• Net Cash Position: -$1,505.6 million (Net Debt)
• Debt Maturity Profile: Convertible Senior Notes of $1.04 billion aggregate principal amount mature on September 15, 2027. They bear 1% interest per year, payable semi-annually. Alnylam Pharmaceuticals, Inc. may redeem Notes on or after September 20, 2025, if the common stock price is >=130% of the conversion price for 20 of 30 trading days.

Cash Flow Generation:

• Operating Cash Flow: -$8.3 million
• Free Cash Flow: -$42.6 million (Operating Cash Flow - Capital Expenditures)
• Cash Conversion Metrics: Inventory decreased by $10.6 million from $89.1 million in 2023 to $78.5 million in 2024. Accounts receivable increased by $77.5 million from $327.8 million in 2023 to $405.3 million in 2024.

Operational Excellence

Production & Service Model: Alnylam Pharmaceuticals, Inc. manufactures limited drug substance for IND-enabling studies and clinical trials, and patisiran formulated bulk drug product at its own facilities. For preclinical, clinical, and commercial supply of drug substance, drug product, and finished goods, the company primarily relies on third-party contract manufacturing organizations (CMOs).

Supply Chain Architecture: Key Suppliers & Partners:

• Active Pharmaceutical Ingredient (API) Manufacturer: Agilent Technologies, Inc. is the sole manufacturer of API for ONPATTRO, AMVUTTRA, and GIVLAARI.
• Contract Manufacturing Organizations (CMOs): Utilized for most drug substance and all drug product requirements.

Facility Network:

• Corporate Headquarters & Primary Research: 675 West Kendall Street, Cambridge, Massachusetts (295,000 sq ft, lease expires January 2034).
• Office & Additional Research: 300 Third Street, Cambridge, Massachusetts (129,000 sq ft, lease expires January 2034).
• Office Space: 101 Main Street, Cambridge, Massachusetts (37,000 sq ft, lease expires June 2026).
• GMP Manufacturing (Patisiran formulated bulk drug product): 665 Concord Avenue, Cambridge, Massachusetts (15,000 sq ft, lease expires September 2027).
• GMP Manufacturing (Drug substance for clinical programs, future commercial): 20 Commerce Way, Norton, Massachusetts (200,000 sq ft, owned). Began GMP operations in December 2020.
• International Headquarters: Grafenauweg 2 & 4, 6300 Zug, Switzerland (15,800 sq ft, lease expires May 2029).
• Other Offices: Maidenhead, Berkshire, UK (21,500 sq ft), Amsterdam, Netherlands (12,500 sq ft), Tokyo, Japan (12,700 sq ft), and other small offices globally.

Operational Metrics:

• Cost of goods sold as a percentage of net product revenues decreased to 18.6% in 2024 from 21.6% in 2023, primarily due to the non-recurrence of 2023 charges for cancelled manufacturing commitments and ONPATTRO inventory impairment.

Market Access & Customer Relationships

Go-to-Market Strategy: Distribution Channels:

• Direct Sales: Alnylam Pharmaceuticals, Inc. has established global commercial operations to directly commercialize ONPATTRO, AMVUTTRA, GIVLAARI, and OXLUMO in major markets.
• Channel Partners: Relies on third parties for certain product candidates in specific geographies.

Customer Portfolio: Enterprise Customers:

• Distributor A: Represented 29% of consolidated total gross revenues in 2024 and 16% of consolidated gross accounts receivable as of December 31, 2024.
• Regeneron Pharmaceuticals, Inc.: Represented 11% of consolidated total gross revenues in 2024.
• Novartis AG: Represented 23% of consolidated gross accounts receivable as of December 31, 2024.
• Customer Concentration: The company has significant revenue and accounts receivable concentration with a few key distributors and collaborators.

Geographic Revenue Distribution:

• United States: 56.7% of total net product revenue
• Europe: 31.4% of total net product revenue
• Rest of World: 11.9% of total net product revenue
• Growth Markets: Regulatory filings for GIVLAARI and OXLUMO are pending or planned in Colombia, Mexico, South Korea, and Kuwait. ONPATTRO received approval in Brazil for ATTR amyloidosis with cardiomyopathy in February 2025. AMVUTTRA is under regulatory review by ANVISA, PMDA, and INVIMA.

Competitive Intelligence

Market Structure & Dynamics

Industry Characteristics: The pharmaceutical market, particularly for RNAi therapeutics, is intensely competitive. It involves significant R&D investment, complex regulatory pathways, and a high failure rate for product candidates. The market is characterized by the development of novel, first-in-class medicines for rare and prevalent diseases.

Competitive Positioning Matrix:

Direct Competitors

Primary Competitors:

• RNAi/microRNA Therapeutic Companies: Arrowhead Pharmaceuticals, Inc. (and collaborators Takeda Pharmaceutical Company Ltd., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc, Amgen Inc.), Quark Pharmaceuticals, Inc., F. Hoffmann-La Roche Ltd., Silence Therapeutics plc (and collaborators AstraZeneca plc, Jiangsu Hansoh Pharmaceuticals Group Co., Ltd., Mallinckrodt plc), Arbutus Biopharma Corp., Sylentis, S.A.U., Novo Nordisk (and collaborators Aro Biotherapeutics, Boehringer Ingelheim, Eli Lilly and Company), and Alnylam Pharmaceuticals, Inc. collaborators Regeneron Pharmaceuticals, Inc., Sanofi, and Vir Biotechnology, Inc.
• Antisense Technology Companies: Ionis Pharmaceuticals, Inc. (with WAINUA (eplontersen) and other antisense drugs) and Akcea Therapeutics, Inc. (a wholly owned subsidiary of Ionis Pharmaceuticals, Inc.) with inotersen (TEGSEDI).
• Companies with Marketed/Developing Therapeutics for Same Diseases:
  • hATTR Amyloidosis with Polyneuropathy: WAINUA (eplontersen, Ionis Pharmaceuticals, Inc. and AstraZeneca plc), VYNDAQEL/VYNDAMAX (tafamidis, Pfizer Inc.), TEGSEDI (inotersen, Ionis Pharmaceuticals, Inc.). Investigational: nexiguran ziclumeran (Intellia Therapeutics, Inc. and Regeneron Pharmaceuticals, Inc.), AT0-2 (Attralus, Inc.).
  • ATTR Amyloidosis with Cardiomyopathy: VYNDAQEL/VYNDAMAX (tafamidis, Pfizer Inc.), ATTRUBY (acoramidis, BridgeBio Pharma, Inc.). Investigational: WAINUA (eplontersen, AstraZeneca plc and Ionis Pharmaceuticals, Inc.), nexiguran ziclumeran (Intellia Therapeutics, Inc. and Regeneron Pharmaceuticals, Inc.), ALXN2220 (Neurimmune AG and Alexion, AstraZeneca Rare Disease), coramitug (Novo Nordisk), AT0-2 (Attralus, Inc.).
  • Acute Hepatic Porphyria: PANHEMATIN (U.S.) and NORMOSANG (EU) from Recordati S.p.A.
  • Primary Hyperoxaluria: RIFVLOZA (nedosiran, Novo Nordisk). Investigational: Biocodex, Inc. (with M8 Pharmaceuticals, Inc.), YolTech Therapeutics.
  • Hypercholesterolemia: REPATHA (Amgen Inc.), PRALUENT (Sanofi S.A.), VASCEPA (Amarin Corporation), NEXLETOL (Esperion Therapeutics, Inc.), EVKEEZA (Regeneron Pharmaceuticals, Inc.). Investigational: lerodalcibep (LIB Therapeutics, LLC), drugs from Merck & Co., Inc., Jiangsu Hengrui Pharmaceuticals Co., Ltd., Arrowhead Pharmaceuticals, Inc., Verve Therapeutics, Inc.
  • Hemophilia: Factor VIII/IX replacement products, extended half-life products, bispecific antibodies, ROCTAVIAN (gene therapy, BioMarin Pharmaceutical Inc.).

Emerging Competitive Threats: New entrants and disruptive technologies, particularly in gene editing (e.g., CRISPR-based therapies for ATTR amyloidosis) and other novel modalities, pose potential long-term threats.

Competitive Response Strategy: Alnylam Pharmaceuticals, Inc. focuses on advancing its proprietary RNAi technology, expanding its product pipeline, pursuing label expansions for approved products (e.g., AMVUTTRA for cardiomyopathy), and forming strategic collaborations to broaden its reach and mitigate development risks. The company also emphasizes its differentiated delivery platforms and aims for less frequent dosing regimens.

Risk Assessment Framework

Strategic & Market Risks

Market Dynamics:

• Competition: Intense competition from other RNAi/microRNA therapeutic companies, antisense technology companies, and companies developing therapeutics for the same diseases. This could lead to reduced market share or pricing pressure.
• Technology Disruption: Risk of obsolescence if new technologies or treatment modalities emerge that are more effective, safer, or cost-efficient.
• Customer Concentration: Significant revenue and accounts receivable concentration with a few key distributors and collaborators (e.g., Distributor A, Regeneron Pharmaceuticals, Inc., Novartis AG), posing a risk if these relationships are disrupted or performance declines.

Operational & Execution Risks

Supply Chain Vulnerabilities:

• Supplier Dependency: Reliance on Agilent Technologies, Inc. as the sole manufacturer of active pharmaceutical ingredient for ONPATTRO, AMVUTTRA, and GIVLAARI creates a single-source risk.
• Contract Manufacturing Dependence: Dependence on third-party CMOs for most drug substance and all drug product requirements introduces risks related to manufacturing capacity, quality control, and timely supply.

Financial & Regulatory Risks

Market & Financial Risks:

• Operating Losses: Alnylam Pharmaceuticals, Inc. has experienced significant operating losses since inception, with an accumulated deficit of $7.29 billion as of December 31, 2024. While aiming for self-sustainability by the end of 2025, future profitability is not guaranteed.
• Foreign Exchange: Exposure to fluctuations in Japanese yen, Euro, and British pound against the U.S. Dollar, which can impact reported financial results.
• Credit & Liquidity: Future capital requirements are uncertain, and while current cash is deemed sufficient for 12 months, unforeseen needs could arise. The company has $1.04 billion in convertible notes maturing in September 2027 and a $1.45 billion liability related to the sale of future royalties.
• Blackstone Royalties Agreement: If Blackstone Royalties does not receive $1.00 billion in Leqvio royalties by December 31, 2029, its interest increases to 55% (Alnylam Pharmaceuticals, Inc.'s decreases to 45%) starting January 1, 2030, impacting future royalty streams.

Regulatory & Compliance Risks:

• Drug Approval Process: High historical failure rate for product candidates and lengthy, complex regulatory approval processes (e.g., FDA, EMA). The FDA issued a Complete Response Letter (CRL) for patisiran for ATTR amyloidosis with cardiomyopathy in October 2023.
• Orphan Drug Exemption Loss: An FDA approval for vutrisiran for Stargardt Disease would cause Alnylam Pharmaceuticals, Inc. to lose the orphan exemption for AMVUTTRA from Medicare price negotiation, though the company announced in October 2022 it would not pursue this indication.
• Pricing and Reimbursement: Sales depend on favorable reimbursement from third-party payors. The Inflation Reduction Act of 2022 (IRA) introduces rebates for Medicare Part B and D drugs whose net price increases exceed inflation and allows Centers for Medicare and Medicaid Services (CMS) to negotiate prices for high-expenditure single-source drugs, potentially impacting future revenues.
• Healthcare Fraud and Abuse: Subject to federal and state anti-kickback, false claims, and other fraud and abuse laws, as well as the U.S. Foreign Corrupt Practices Act of 1977 (FCPA) and European privacy laws (GDPR, UK GDPR), with potential for significant penalties for non-compliance.
• BIOSECURE ACT: Proposed legislation (H.R. 7085, S.3558) could prohibit U.S. federal agencies from contracting with "biotechnology companies of concern," potentially restricting Alnylam Pharmaceuticals, Inc.'s ability to purchase services/products from certain Chinese companies.

Geopolitical & External Risks

Geopolitical Exposure:

• Trade Relations: Impact of trade tensions and policy changes, such as Florida's drug importation proposal from Canada authorized January 5, 2024.
• Sanctions & Export Controls: Compliance requirements and business limitations due to international sanctions and export controls.

Innovation & Technology Leadership

Research & Development Focus: Core Technology Areas:

• RNAi Therapeutics: Core focus on silencing messenger RNA (mRNA) to prevent protein production implicated in disease.
• Delivery Technologies:
  • N-acetylgalactosamine (GalNAc) conjugate: For hepatic delivery (e.g., GIVLAARI, OXLUMO, Leqvio, AMVUTTRA).
  • Enhanced Stabilization Chemistry-Plus (ESC+) GalNAc-conjugates: Improves specificity and therapeutic index up to six-fold (e.g., zilebesiran, elebsiran).
  • Lipid Nanoparticle (LNP): For hepatic delivery (e.g., ONPATTRO).
  • Hexadecyl (C16) moiety: For central nervous system (CNS) and ocular delivery (e.g., mivelsiran, ALN-HTT02).
  • IKARIA platform: Aims for bi-annual or annual dosing, with nucresiran Phase 1 showing rapid TTR knockdown sustained for six months after a single dose.
• Extrahepatic Delivery: Advancing approaches for heart, skeletal muscle, and adipose tissue delivery.
• GEMINI technology: Combines conjugate siRNAs for simultaneous silencing of two transcripts.
• Novel Target Sourcing: Collaborations with UK BioBank and Our Future Health.

Innovation Pipeline:

• Over 20 clinical programs as of the end of 2024.
• Late-stage investigational programs: Zilebesiran (hypertension), Nucresiran (ATTR amyloidosis), Mivelsiran (Alzheimer’s disease, cerebral amyloid angiopathy), Fitusiran (hemophilia), Cemdisiran (complement-mediated diseases), Elebsiran (chronic Hepatitis B and D Virus infection), ALN-HTT02 (Huntington’s Disease).
• Early-stage and preclinical programs: Plans to file four or more new investigational new drug applications (INDs) or CTAs from its organic product engine in 2025.

Intellectual Property Portfolio:

• Patent Strategy: Holds a portfolio of patents and patent applications covering siRNAs, chemical modifications, compositions, delivery technologies, and development candidates/marketed products.
  • ONPATTRO: U.S. patents expire between 2025 and 2032. EU patents expire between 2029 and 2033. FDA Orphan Drug Exclusivity (ODE) until August 10, 2025. EMA marketing exclusivity and ODE until August 26, 2028.
  • AMVUTTRA: U.S. patents expire between 2028 and 2036. EU patents expire between 2032 and 2036. FDA New Chemical Entity (NCE) exclusivity until June 13, 2027. EMA marketing exclusivity and ODE until September 15, 2032.
  • GIVLAARI: U.S. patents expire between 2025 and 2034. EU patent expires 2033. FDA ODE until November 20, 2026. EMA marketing exclusivity and ODE until March 2, 2030.
  • OXLUMO: U.S. patents expire between 2028 and 2035. EU patent expires 2034. FDA NCE exclusivity until November 23, 2025, and ODE until November 23, 2027. EMA marketing exclusivity and ODE until November 19, 2030.
• Licensing Programs: Engages in cross-licensing agreements (e.g., with Ionis Pharmaceuticals, Inc., Dicerna Pharmaceuticals, Inc.) and grants licenses to other companies for RNAi therapeutics.
• IP Litigation: Involved in patent infringement lawsuits against Pfizer Inc. and Moderna, Inc. related to mRNA COVID-19 vaccines, and a lawsuit filed by The Board of Regents of the University of Texas System alleging infringement by ONPATTRO. Acuitas Therapeutics Inc. filed a declaratory judgment action seeking co-inventorship on certain patents.

Technology Partnerships:

• PeptiDream, Inc.: Collaboration to discover and develop peptide-siRNA conjugates for extrahepatic delivery.
• Regeneron Pharmaceuticals, Inc.: Global, strategic collaboration for RNAi therapeutics for eye, CNS, and select liver targets.
• F. Hoffmann-La Roche Ltd. and Genentech, Inc. (collectively, Roche): Collaboration for joint development and commercialization of zilebesiran.
• Genzyme Corporation, a Sanofi Company (Sanofi): Strategic alliance for fitusiran and exclusive TTR License for ONPATTRO and AMVUTTRA.
• Novartis AG: Exclusive, worldwide license for RNAi therapeutics targeting PCSK9 (inclisiran/Leqvio).

Leadership & Governance

Executive Leadership Team

Leadership Continuity: Not explicitly detailed, but the company is highly dependent on senior management and scientific, clinical, sales, and medical staff.

Board Composition: The Board of Directors oversees cybersecurity risk management, and the Nominating and Corporate Governance Committee assists in this oversight. The Audit Committee coordinates oversight of disclosure controls and procedures.

Human Capital Strategy

Workforce Composition:

• Total Employees: Approximately 2,230 full-time employees as of December 31, 2024.
• Geographic Distribution: 1,760 employees in the U.S. and 470 employees outside the U.S.
• Skill Mix: Not explicitly detailed, but the company is highly dependent on scientific, clinical, sales, and medical staff.

Talent Management: Acquisition & Retention:

• Hiring Strategy: Added approximately 200 new full-time employees in 2024 and expects to add more in 2025.
• Employee Value Proposition: Offers a total rewards package including base salary, cash target bonus, comprehensive benefits, and equity compensation. Annual cash bonus targets are based on grade level, and equity compensation is based on grade level, geography, and performance.

Regulatory Environment & Compliance

Regulatory Framework: Industry-Specific Regulations:

• U.S. Regulatory Considerations: Regulated by the FDA under the Federal Food, Drug, and Cosmetic Act (FDCA). Requires nonclinical testing, IND submission, IRB approval, clinical trials (Phase 1, 2, 3), NDA submission, cGMP inspection, and FDA review/approval. Subject to the Pediatric Research Equity Act of 2023 (PREA).
• EU Regulatory Considerations: Clinical trials comply with Regulation (EU) No 536/2014 (Clinical Trials Regulation) and ICH guidelines on GCP. Marketing authorization requires Common Technical Document, often via the Centralized procedure for biotech and orphan medicinal products.
• Orphan Drug Designation: Patisiran, vutrisiran, nucresiran (ATTR amyloidosis), givosiran (AHP), lumasiran (PH1), and inclisiran (homozygous familial hypercholesterolemia) received orphan drug designation in the U.S. and/or EU, providing market exclusivity (7 years in U.S., 10 years in EU).
• Rare Pediatric Disease Designation and Priority Review Voucher (PRV): Alnylam Pharmaceuticals, Inc. received a PRV upon lumasiran approval (November 2020) and used it for vutrisiran sNDA for ATTR amyloidosis with cardiomyopathy.
• Manufacturing: Medicinal products manufactured/imported in the EU by holders of manufacturing authorization, with facilities subject to cGMP inspections.

Trade & Export Controls:

• Export Restrictions: Subject to trade restrictions and export controls.
• Sanctions Compliance: Compliance with sanctions requirements.

Legal Proceedings:

• Patent Infringement Lawsuits: Involved in ongoing patent infringement lawsuits against Pfizer Inc. and Moderna, Inc. related to mRNA COVID-19 vaccines. Also facing a lawsuit from The Board of Regents of the University of Texas System alleging infringement by ONPATTRO, and a declaratory judgment action from Acuitas Therapeutics Inc. seeking co-inventorship on certain patents.

Tax Strategy & Considerations

Tax Profile:

• Effective Tax Rate: 26.3% (2024), -1.5% (2023), -0.4% (2022). The U.S. federal statutory rate was 21.0% for all years.
• Geographic Tax Planning: Foreign income of $194.6 million in 2024 was primarily from Switzerland, driven by AMVUTTRA sales growth. A $108.0 million valuation allowance on certain Switzerland deferred tax assets was released in 2024 due to expected future profitability.
• Tax Reform Impact: The Bermuda corporate income tax (15% effective January 1, 2025) led to a full valuation allowance on Bermuda intangible assets, which were transferred to Switzerland in 2024. The Inflation Reduction Act of 2022 (IRA) may require rebates for Medicare Part B and D drugs and allows CMS to negotiate prices, potentially impacting tax liabilities.

Insurance & Risk Transfer

Risk Management Framework:

• Insurance Coverage: Maintains product liability insurance and insurance for cybersecurity incidents.
• Risk Transfer Mechanisms: Not explicitly detailed beyond insurance.