Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY) Q3 2023 Earnings Conference Call November 2, 2023 8:30 AM ET Company Participants Christine Lindenboom - Senior Vice President-Investor Relations and Corporate Communication Yvonne Greenstreet - Chief Executive Officer Tolga Tanguler - Chief Commercial Officer Pushkal Garg - Chief Medical Officer and EVP, Development & Medical Affairs Jeff Poulton - Chief Financial Officer Conference Call Participants Ritu Baral - TD Cowen Paul Matteis - Stifel Lisa Munro - RBC El ...

Nathan (USA) Diagnosed with AHP Third Quarter 2023 Financial Results November 2, 2023 1 © 2023 Alnylam Pharmaceuticals, Inc. Agenda Welcome ...

PART I. FINANCIAL INFORMATION [Financial Statements (Unaudited)](index=6&type=section&id=ITEM%201%2E%20FINANCIAL%20STATEMENTS%20%28Unaudited%29) Alnylam reported a **$147.8 million net income** in Q3 2023, a significant turnaround from a prior year loss, with total assets increasing to **$3.84 billion** and a narrowed nine-month net loss [Condensed Consolidated Balance Sheets](index=6&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) The balance sheet highlights an increase in total assets to **$3.84 billion** by September 30, 2023, while the total stockholders' deficit slightly widened Condensed Consolidated Balance Sheet Highlights (In thousands) | Account | Sep 30, 2023 | Dec 31, 2022 | | :--- | :--- | :--- | | **Assets** | | | | Cash and cash equivalents | $1,033,024 | $866,394 | | Total current assets | $2,985,452 | $2,692,247 | | **Total assets** | **$3,839,073** | **$3,546,359** | | **Liabilities & Stockholders' Deficit** | | | | Total current liabilities | $949,785 | $767,915 | | Convertible debt | $1,019,809 | $1,016,942 | | Liability related to the sale of future royalties | $1,355,009 | $1,292,204 | | **Total liabilities** | **$4,004,939** | **$3,704,582** | | **Total stockholders' deficit** | **($165,866)** | **($158,223)** | [Condensed Consolidated Statements of Operations and Comprehensive Income (Loss)](index=7&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations%20and%20Comprehensive%20Income%20%28Loss%29) The statement of operations shows a **$147.8 million net income** for Q3 2023, a significant improvement from a **$405.9 million net loss** in Q3 2022 Statement of Operations Summary (In thousands, except per share amounts) | Metric | Q3 2023 | Q3 2022 | 9 Months 2023 | 9 Months 2022 | | :--- | :--- | :--- | :--- | :--- | | Total revenues | $750,530 | $264,306 | $1,388,574 | $702,383 | | Net product revenues | $313,153 | $232,267 | $895,186 | $632,654 | | Net revenues from collaborations | $427,472 | $29,297 | $469,778 | $64,267 | | Total operating costs and expenses | $536,663 | $522,346 | $1,554,345 | $1,298,841 | | Income (loss) from operations | $213,867 | ($258,040) | ($165,771) | ($596,458) | | **Net income (loss)** | **$147,753** | **($405,920)** | **($302,372)** | **($923,663)** | | Net income (loss) per share - diluted | $1.15 | ($3.32) | ($2.43) | ($7.62) | [Condensed Consolidated Statements of Cash Flows](index=10&type=section&id=Condensed%20Consolidated%20Statements%20of%20Cash%20Flows) Operating activities generated **$134.0 million** in cash for the nine months ended September 30, 2023, a significant improvement from cash usage in the prior year Cash Flow Summary for the Nine Months Ended September 30 (In thousands) | Activity | 2023 | 2022 | | :--- | :--- | :--- | | Net cash provided by (used in) operating activities | $133,951 | ($409,296) | | Net cash (used in) provided by investing activities | ($95,694) | $309,265 | | Net cash provided by financing activities | $132,903 | $362,316 | | **Net increase in cash, cash equivalents and restricted cash** | **$166,654** | **$253,236** | [Notes to Condensed Consolidated Financial Statements](index=11&type=section&id=Notes%20to%20Condensed%20Consolidated%20Financial%20Statements) The notes detail the company's strategic goals, product revenue breakdown, key collaboration agreements, and ongoing patent litigation - The company's strategy, **Alnylam P5x25**, aims to transition it to a top-tier biotech company by the end of **2025** by delivering transformative medicines for rare and prevalent diseases[27](index=27&type=chunk) Net Product Revenues by Product (In thousands) | Product | Q3 2023 | Q3 2022 | 9 Months 2023 | 9 Months 2022 | | :--- | :--- | :--- | :--- | :--- | | ONPATTRO | $81,589 | $144,950 | $275,540 | $435,387 | | AMVUTTRA | $148,680 | $25,229 | $382,584 | $25,229 | | GIVLAARI | $54,148 | $45,659 | $159,953 | $126,086 | | OXLUMO | $28,736 | $16,429 | $77,109 | $45,952 | | **Total** | **$313,153** | **$232,267** | **$895,186** | **$632,654** | - In July 2023, Alnylam entered into a strategic collaboration with Roche for the joint development of zilebesiran, an investigational treatment for hypertension. The agreement included a **$310.0 million upfront payment** to Alnylam, which was recognized as revenue in Q3 2023[43](index=43&type=chunk)[45](index=45&type=chunk)[48](index=48&type=chunk) - Under the collaboration with Regeneron, Alnylam earned a **$100.0 million milestone** in Q3 2023 for achieving certain criteria in the early clinical development of its CNS program, ALN-APP. A **cumulative catch-up adjustment of $65.0 million** was recognized in net revenues from collaborations[49](index=49&type=chunk) - The company is involved in ongoing patent infringement lawsuits filed in March 2022 against **Pfizer/BioNTech** and **Moderna**, seeking damages related to the use of Alnylam's biodegradable cationic lipid technology in their respective **mRNA COVID-19 vaccines**[102](index=102&type=chunk)[103](index=103&type=chunk)[232](index=232&type=chunk) [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=29&type=section&id=ITEM%202%2E%20MANAGEMENT%27S%20DISCUSSION%20AND%20ANALYSIS%20OF%20FINANCIAL%20CONDITION%20AND%20RESULTS%20OF%20OPERATIONS) Management highlights **significant Q3 2023 revenue growth** from AMVUTTRA and the Roche collaboration, leading to net income and a strong cash position to fund the 'Alnylam P5x25' strategy [Overview](index=29&type=section&id=Overview) Alnylam, a commercial-stage biopharmaceutical company, focuses on RNAi therapeutics with five marketed products and aims for top-tier biotech status by **2025** - Alnylam is a commercial-stage biopharmaceutical company focused on **RNAi therapeutics**, with **five marketed products**: ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO, and the partnered product Leqvio (inclisiran)[107](index=107&type=chunk) - The company's '**Alnylam P5x25**' strategy aims to transition it into a top-tier biotech company by the end of **2025** through sustainable innovation and strong financial performance[107](index=107&type=chunk) - In October 2023, the FDA issued a **Complete Response Letter (CRL)** for the supplemental New Drug Application (sNDA) for **patisiran (ONPATTRO)** for the treatment of **ATTR amyloidosis with cardiomyopathy**, stating that clinical meaningfulness was not established[107](index=107&type=chunk) [Results of Operations](index=34&type=section&id=Results%20of%20Operations) Total revenues surged by **184%** in Q3 2023, primarily driven by collaboration revenue and strong AMVUTTRA sales, while operating costs increased moderately Revenue Breakdown (In thousands) | Revenue Source | Q3 2023 | Q3 2022 | % Change | | :--- | :--- | :--- | :--- | | Net product revenues | $313,153 | $232,267 | 35% | | Net revenues from collaborations | $427,472 | $29,297 | >500% | | Royalty revenue | $9,905 | $2,742 | 261% | | **Total revenues** | **$750,530** | **$264,306** | **184%** | - The substantial increase in collaboration revenue for Q3 2023 was primarily due to recognizing **$310.0 million** from the new Roche agreement and a **$65.0 million cumulative catch-up adjustment** from a milestone achieved under the Regeneron collaboration[132](index=132&type=chunk) - Net product revenue growth was driven by the strong launch of **AMVUTTRA**, which saw sales increase by **489% YoY** in Q3 2023. This was partially offset by a **44% YoY decline** in **ONPATTRO** revenue, largely due to patients switching to AMVUTTRA[129](index=129&type=chunk)[130](index=130&type=chunk) Operating Costs and Expenses (In thousands) | Expense Category | Q3 2023 | Q3 2022 | % Change | | :--- | :--- | :--- | :--- | | Cost of goods sold | $79,473 | $36,507 | 118% | | Research and development | $253,179 | $245,371 | 3% | | Selling, general and administrative | $199,175 | $235,859 | (16)% | | **Total operating costs and expenses** | **$536,663** | **$522,346** | **3%** | - Cost of goods sold as a percentage of net product revenues increased from **15.7%** in Q3 2022 to **25.4%** in Q3 2023, primarily due to an inventory impairment for **ONPATTRO** following the negative regulatory decision for its **cardiomyopathy indication**[134](index=134&type=chunk)[135](index=135&type=chunk) [Liquidity and Capital Resources](index=39&type=section&id=Liquidity%20and%20Capital%20Resources) Net cash from operating activities significantly improved to **$134.0 million** for the first nine months of 2023, supported by strong cash reserves - Net cash provided by operating activities for the first nine months of 2023 was **$134.0 million**, a significant improvement from the **$409.3 million used** in the same period of 2022. This was primarily due to the **$310.0 million upfront payment** from Roche and stronger cash receipts from product sales[145](index=145&type=chunk)[146](index=146&type=chunk) - Management believes that its cash, cash equivalents, and marketable securities of **$2.41 billion** as of September 30, 2023, along with expected revenues, will be sufficient to fund operations for at least the next **12 months**[150](index=150&type=chunk)[179](index=179&type=chunk) [Quantitative and Qualitative Disclosures About Market Risk](index=40&type=section&id=ITEM%203%2E%20QUANTITATIVE%20AND%20QUALITATIVE%20DISCLOSURES%20ABOUT%20MARKET%20RISK) The company states that there have been no significant changes to its financial market risks, primarily related to interest rates, since the end of 2022 - There have been **no significant changes** to the company's financial market risk exposures, mainly **interest rate risk**, as of September 30, 2023, compared to December 31, 2022[151](index=151&type=chunk) [Controls and Procedures](index=40&type=section&id=ITEM%204%2E%20CONTROLS%20AND%20PROCEDURES) Management, including the CEO and CFO, evaluated the company's disclosure controls and procedures as of September 30, 2023, and concluded they were effective at a reasonable assurance level - The CEO and CFO concluded that the company's disclosure controls and procedures were **effective** as of September 30, 2023[152](index=152&type=chunk) - No changes in internal control over financial reporting occurred during the quarter that have materially affected, or are reasonably likely to materially affect, internal controls[153](index=153&type=chunk) PART II. OTHER INFORMATION [Legal Proceedings](index=41&type=section&id=ITEM%201%2E%20LEGAL%20PROCEEDINGS) The company refers to Note 13 of its financial statements for a discussion of material pending legal proceedings, primarily patent infringement lawsuits against Pfizer/BioNTech and Moderna - For details on material legal proceedings, the report refers to Note 13 of the financial statements, which discusses patent infringement lawsuits against **Pfizer** and **Moderna**[155](index=155&type=chunk) [Risk Factors](index=41&type=section&id=ITEM%201A%2E%20RISK%20FACTORS) The company faces significant risks including commercialization challenges, a history of losses, dependence on collaborators, regulatory hurdles, intense competition, and ongoing patent litigation - The commercial success of approved products is not guaranteed, and the company may be unable to expand indications, as exemplified by the FDA's **Complete Response Letter (CRL)** for patisiran's sNDA for **cardiomyopathy** in October 2023[169](index=169&type=chunk) - The company has a history of significant operating losses, with an accumulated deficit of **$6.87 billion** as of September 30, 2023, and may not achieve or maintain profitability[170](index=170&type=chunk) - Alnylam is dependent on strategic alliances with companies like **Roche**, **Novartis**, and **Regeneron** for development, commercialization, and funding, and the failure of these partners to perform could harm the business[182](index=182&type=chunk)[184](index=184&type=chunk) - The company faces **intense competition** from large pharmaceutical companies and other firms developing **RNAi**, **antisense** (e.g., Ionis), and other novel drug technologies, which could render its products obsolete or noncompetitive[237](index=237&type=chunk)[239](index=239&type=chunk) - Alnylam is involved in significant intellectual property litigation, including lawsuits against **Pfizer** and **Moderna** for patent infringement related to **mRNA COVID-19 vaccines**, which could incur substantial costs and divert management attention[232](index=232&type=chunk) - The **Inflation Reduction Act of 2022 (IRA)** introduces Medicare price negotiation, which could impact future revenues. The company decided not to pursue a Phase 3 trial for vutrisiran in Stargardt Disease to avoid losing the single-orphan exemption for **AMVUTTRA** from these negotiations[217](index=217&type=chunk) [Other Information](index=78&type=section&id=ITEM%205%2E%20OTHER%20INFORMATION) During Q3 2023, two directors adopted Rule 10b5-1 trading plans for the potential sale of company common stock, setting pre-determined conditions for share sales - Director **Michael W. Bonney** established a Rule 10b5-1 trading plan on August 10, 2023, to sell up to **30,000 shares** of common stock between November 2023 and December 2024, subject to price conditions[252](index=252&type=chunk) - Director **David E.I. Pyott** established a Rule 10b5-1 trading plan on August 11, 2023, to sell up to **32,450 shares** of common stock between November 2023 and November 2024, subject to price conditions[253](index=253&type=chunk) [Exhibits](index=79&type=section&id=ITEM%206%2E%20EXHIBITS) This section lists the exhibits filed with the Form 10-Q, including the Collaboration and License Agreement with Roche and Genentech, and officer certifications - Key exhibits filed include the Collaboration and License Agreement with **F. Hoffmann-La Roche Ltd.** and **Genentech, Inc.**, and officer certifications pursuant to the Securities Exchange Act of 1934[255](index=255&type=chunk)

Nathan (USA) Diagnosed with AHP Second Quarter 2023 Financial Results August 3, 2023 1 © 2023 Alnylam Pharmaceuticals, Inc. Agenda Welcome ...

Financial Data and Key Metrics Changes - Total product revenues for Q2 2023 were $306 million, representing a 43% year-over-year growth compared to Q2 2022 [27] - Gross margin on product sales was 75%, a 9% decrease compared to Q2 2022, primarily due to fees associated with canceling manufacturing commitments for ONPATTRO [28] - Non-GAAP operating loss for the quarter was $154 million, showing a $7 million improvement compared to Q2 2022 [30] Business Line Data and Key Metrics Changes - The TTR franchise achieved $224 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 46% growth year-over-year [10] - GIVLAARI and OXLUMO together delivered $82 million in combined product sales during Q2, representing a 37% growth compared to Q2 2022 [13] Market Data and Key Metrics Changes - In the US, combined sales of ONPATTRO and AMVUTTRA increased by 72% year-over-year, marking the fourth consecutive quarter of TTR growth exceeding 70% [11] - AMVUTTRA demand in Japan is particularly encouraging, with new patient growth driven by switches from tafamidis and patients naive to therapy [10] Company Strategy and Development Direction - The company entered into a strategic partnership with Roche for the development and commercialization of zilebesiran, aiming to disrupt the global treatment paradigm for hypertension [6] - The company is focused on achieving its Alnylam P5x25 goals, positioning itself as a top-tier biotech company developing transformative medicines for rare diseases [7] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the upcoming catalysts, including the initial data from the KARDIA Phase 2 program and the potential launch of ONPATTRO for ATTR amyloidosis with cardiomyopathy [7] - The management highlighted the importance of maintaining high ethical standards in business conduct, especially in interactions with healthcare providers and patients [6] Other Important Information - The US Attorney's Office for the District of Massachusetts concluded its case regarding the marketing and promotion of ONPATTRO with no action taken [6] - Akshay Vaishnaw transitioned to the role of Chief Innovation Officer, focusing on the future of the R&D engine [8] Q&A Session Summary Question: Any updated thoughts on the upcoming AdCom ONPATTRO and ATTR CM? - Management is actively preparing for the advisory committee and believes the focus will be on the clinical meaningfulness of changes in the six-minute walk test and KCCQ [35] Question: Clarification on the Roche deal for zilebesiran? - The deal includes $310 million upfront and $365 million in potential development milestones, with Roche covering 60% of development costs [40] Question: Consideration by the FDA regarding the PDUFA date for ONPATTRO? - Management anticipates the PDUFA date of October 8th and is working towards that, with no changes communicated by the FDA at this time [44] Question: Timing and reasoning behind Akshay's role change? - The transition to Chief Innovation Officer allows for a more focused role in driving R&D success, with no specific reason for the timing [51] Question: Details on the expanded access program for patisiran? - The program enrolled 200 patients rapidly, highlighting the significant demand for alternative therapies for patients experiencing progression [69]

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 ____________________________________________ FORM 10-Q ____________________________________________ ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 Title of Each Class Trading Symbol(s) Name of Each Exchange on Which Registered Common Stock, $0.01 par value per share ALNY The Nasdaq Stock Market LLC For the quarterly period ended June 30, 2023 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15( ...

Financial Data and Key Metrics Changes - Total product revenues for Q1 2023 were $276 million, representing a 48% increase compared to Q1 2022, primarily driven by growth in TTR product revenues from the AMVUTTRA launch [36][37] - Net revenue from collaborations was approximately $36 million, a 41% increase year-over-year, attributed to increased activities with Regeneron [36] - Gross margin on product sales was 85%, a 2% decrease from Q1 2022, mainly due to increased royalties on AMVUTTRA sales [37] - Non-GAAP operating loss for Q1 2023 was $110 million, showing a $7 million improvement compared to Q1 2022 [38] Business Line Data and Key Metrics Changes - The TTR franchise achieved $204 million in global net product revenues, a 49% growth compared to Q1 2022, with U.S. market growth at 75% [10][12] - Ultra-rare products GIVLAARI and OXLUMO generated $72 million in combined product sales, reflecting a 45% increase year-over-year [13] - AMVUTTRA's launch contributed significantly to the TTR franchise, with over 3,160 patients on treatment worldwide, marking a 6% quarterly growth [10][11] Market Data and Key Metrics Changes - In international markets, total TTR product sales increased 9% compared to the previous quarter, driven by strong demand in Japan [12] - The U.S. market saw a 5% increase in combined sales of ONPATTRO and AMVUTTRA, with a 7% increase in demand [11] Company Strategy and Development Direction - The company aims to expand its TTR franchise and address more common disease areas beyond rare diseases [8] - Alnylam is focused on sustainable innovation through new platform enhancements and genetically validated targets to drive pipeline expansion [9] - The company is committed to advancing its clinical-stage product candidates for ATTR amyloidosis and exploring new therapeutic areas such as hypertension with zilebesiran [30][34] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the ongoing growth trajectory of AMVUTTRA and the overall TTR franchise, highlighting strong patient uptake and prescriber expansion [11][65] - The company anticipates continued strong performance from its pipeline, particularly with upcoming data presentations and clinical milestones [40] Other Important Information - The FDA has accepted the supplemental New Drug Application for patisiran for cardiomyopathy, with a PDUFA date set for October 8 [31] - The company has received regulatory approval to begin Part B of the ALN-APP Phase 1 study in Canada, while a partial clinical hold is in place in the U.S. [27][28] Q&A Session Summary Question: Can you talk about the upcoming 18-month data from APOLLO-B? - Management confirmed that the data will include ongoing follow-up and key secondary endpoints, with high retention rates in the study [44][46] Question: What is the market share impact of AMVUTTRA on ONPATTRO? - Management indicated a healthy switch rate from ONPATTRO to AMVUTTRA while also adding new patients, suggesting a positive growth trajectory for the TTR franchise [49][51] Question: Can you discuss the timelines for the CAA program? - Management highlighted the potential for ALN-APP in both Alzheimer's and CAA, with ongoing studies to establish safety and efficacy [53][55] Question: What are the expectations for zilebesiran in hypertension? - Management expressed excitement about zilebesiran's potential, with ongoing Phase 2 studies expected to provide pivotal data for future registrational programs [57][62]

Financial Performance - Alnylam reported a 48% increase in net product revenues in Q1 2023 compared to Q1 2022, reaching $276 million [63] - Total revenues increased by 50% to $319 million in Q1 2023 compared to $213 million in Q1 2022 [63] - The company's cash and investments stood at $2071 million as of March 31, 2023 [63] - Alnylam reiterates its full-year 2023 net product revenue guidance of $1200 million to $1285 million, representing a 34% to 44% growth compared to 2022 [64] Commercial Highlights - Global TTR net product revenue grew by 49% year-over-year [13] - U S TTR QoQ growth of +5% primarily driven by demand growth +7% due to strong AMVUTTRA demand more than offsetting decrease in ONPATTRO demand [14] - ROW QoQ growth +9% primarily due to AMVUTTRA launch demand in Japan & Germany, ONPATTRO demand in markets where AMVUTTRA not yet available, and timing of orders in partner markets [14] - Total Ultra Rare global Q1 2023 net product revenues were $72 million [15] - Ultra Rare YoY % Growth: GIVLAARI 36%, OXLUMO 66%, Total Ultra Rare 45% [16] Pipeline Development - ALN-APP Phase 1 study in Early-Onset Alzheimer's Disease (EOAD) showed that single doses of ALN-APP were well tolerated to date [28] - ALN-APP Phase 1 Study in EOAD – Interim Results showed Robust and Sustained Reduction in sAPP and sAPP in CSF at the Highest Dose Tested [29] - Topline Phase 1 data for ALN-TTRsc04, an investigational RNAi therapeutic for potential treatment of ATTR Amyloidosis, is expected in late 2023 [53] - Zilebesiran demonstrated >90% mean serum AGT reduction for 6 months after single dose of zilebesiran 800mg [56]

Product Development and Market Performance - The company has five marketed RNAi therapeutics and over ten clinical programs, with four products in the Genetic Medicines strategic area: ONPATTRO, AMVUTTRA, GIVLAARI, and OXLUMO[98] - Leqvio, the company's fifth product, has received marketing authorization in over 75 countries, including the U.S. and EU, for treating hypercholesterolemia and mixed dyslipidemia[100] - The company is advancing multiple late-stage investigational programs, including patisiran and vutrisiran for ATTR amyloidosis with cardiomyopathy, and fitusiran for hemophilia[99] - The company reported positive interim data from the Phase 1 study of zilebesiran, an investigational RNAi therapeutic for hypertension, with Phase 2 studies expected to yield results in mid-2023 and at year-end 2023[99] - Alnylam continues to advance patisiran for ATTR amyloidosis, submitting 18-month data from the APOLLO-B Phase 3 study to the U.S. FDA[109] - The U.S. launch of AMVUTTRA contributed significantly to revenue growth, with total revenues from AMVUTTRA reaching $101,768,000, as it was launched in Q3 2022[119] - The company plans to continue advancing its product candidates into later-stage development and expand its global commercial infrastructure[132] Financial Performance - As of March 31, 2023, the company reported an accumulated deficit of $6.74 billion, primarily due to research and development costs and general administrative expenses[100] - Total revenues for Q1 2023 reached $319.3 million, a 50% increase from $213.3 million in Q1 2022[115] - Net product revenues for Q1 2023 were $276.3 million, up 48% from $186.9 million in Q1 2022[117] - Global net product revenues for ONPATTRO and AMVUTTRA in Q1 2023 were $102.5 million and $101.8 million, respectively[109] - Global net product revenues for GIVLAARI and OXLUMO in Q1 2023 were $47.9 million and $24.2 million, respectively[109] - Net revenues from collaborations in Q1 2023 were $36.5 million, a 41% increase from $25.9 million in Q1 2022[117] - Royalty revenue in Q1 2023 surged to $6.5 million, a 1,371% increase from $442,000 in Q1 2022[117] - The net loss for Q1 2023 was $174.1 million, a decrease of 28% from a net loss of $240.3 million in Q1 2022[115] Research and Development Expenses - The company anticipates continued operating losses as it invests in research and development, clinical trials, and commercialization efforts, although it expects 2019 to be the peak operating loss year[100] - Research and development expenses rose by 36% to $230,569,000, primarily due to increased clinical research and headcount to support the R&D pipeline[129] - Selling, general and administrative expenses increased by 19% to $183,659,000, attributed to higher compensation and strategic investments for the global launch of AMVUTTRA[132] Cash Flow and Financing - The company issued $1.04 billion in Convertible Senior Notes in September 2022, with proceeds used to repay borrowings and for general corporate purposes[103] - Interest expense decreased by 32% to $28,955,000 compared to $42,362,000 in the same period last year[135] - Interest income increased by 1,743% to $18,655,000 from $1,012,000 year-over-year[135] - Net cash used in operating activities decreased to $(166,475,000) from $(171,193,000) year-over-year[136] - Net cash used in investing activities decreased to $(76,217,000) from $(147,419,000) year-over-year[138] - Net cash provided by financing activities increased to $46,371,000 from $34,956,000 year-over-year[139] - The company expects its cash and marketable securities will be sufficient for at least the next 12 months[142] Strategic Alliances and Compliance - The company has formed alliances with leading pharmaceutical companies, including Regeneron and Novartis, to support development and commercialization efforts[100] - The company maintains a focus on enhancing its global compliance program to align with its strategic objectives and mitigate risks[99] Market Trends and Expectations - The company expects net product revenues to continue increasing in 2023 as new patients are added to commercial products and products are launched in additional markets[119] - The company anticipates variability in net revenues from collaborations and royalties in 2023 due to timing and achievement of milestones[123] - Total net product revenues decreased by 25% in the U.S. for ONPATTRO, reflecting a shift in patient demand to AMVUTTRA[119] - There have been no significant changes to financial market risks related to interest rates since December 31, 2022[143]

Financial Data and Key Metrics Changes - Alnylam achieved full year 2022 net product revenues of $894 million, representing year-over-year growth of 35% or 43% at constant exchange rates, with a 13% increase from Q3 to Q4 [7][34] - Total product revenues for 2022 were $894 million, reflecting a 35% increase compared to 2021, with growth contributions from all four commercial products [34] - Non-GAAP operating loss for 2022 was $554 million, approximately flat compared to 2021, with expectations to reduce this loss in 2023 [37][40] Business Line Data and Key Metrics Changes - The TTR franchise achieved $191 million in global net product revenues in Q4, a 12% increase from Q3 and a 38% increase from Q4 2021 [12][13] - GIVLAARI generated $47 million in global net product revenues in Q4, representing a 3% increase compared to Q3 and a 16% increase year-over-year [19] - OXLUMO achieved $24 million in global net product revenues in Q4, a 45% increase compared to Q3 [20] Market Data and Key Metrics Changes - In the U.S., combined sales of ONPATTRO and AMVUTTRA increased 12% versus Q3, driven by a 19% increase in demand growth [14][15] - The U.S. market for AMVUTTRA saw a 72% growth compared to Q4 2021, with over 2,975 patients on treatment worldwide by the end of 2022 [13][15] - International sales of ONPATTRO and AMVUTTRA also increased 12% versus Q3, primarily due to initial launches in Germany and Japan [14][18] Company Strategy and Development Direction - Alnylam aims to expand its ATTR franchise and become a global leader in delivering impactful medicines, while also addressing more common disease areas [10] - The company is focusing on sustainable innovation through new platform enhancements and finding new genetically validated targets [10] - Alnylam plans to advance TTRsc04, a new investigational RNAi therapeutic, which may offer a transformative profile with potential for annual dosing [30] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the upcoming FDA review and potential approval of patisiran for cardiomyopathy, with a PDUFA date set for October 8, 2023 [24][39] - The company anticipates combined net product revenues for 2023 to be between $1.2 billion and $1.285 billion, reflecting a growth range of 34% to 44% [39][40] - Management highlighted the strong initial commercial performance of AMVUTTRA and its potential to expand the market opportunity for the TTR franchise [21][22] Other Important Information - Alnylam ended 2022 with cash, cash equivalents, and marketable securities of $2.2 billion, down from $2.4 billion at the end of 2021 [38] - The company plans to submit an sNDA in Brazil for patisiran in early 2023, focusing efforts on regions with positive results from ongoing studies [25] Q&A Session Summary Question: Advisory committee meeting topics - Management indicated no specific areas to address for the advisory committee meeting, as no review issues have been identified [44][45] Question: Learnings from AMVUTTRA dosing - Management stated that the quarterly regimen of AMVUTTRA has been effective, and the decision not to pursue a six-month regimen was strategic [48][49] Question: Top line data from ALN-APP study - Management confirmed that the top line data will focus on safety, tolerability, and target engagement, with results expected in early 2023 [52][54] Question: HELIOS-B study design rationale - Management explained that the all-cause mortality endpoint maximizes event capture and provides a clinically meaningful effect [57][59] Question: Impact of J-Code on AMVUTTRA launch - Management noted that the J-Code received would not significantly change the trajectory of the launch, as access strategies were already in place [82][84]