Rapirosiran

− Achieved Second Quarter 2023 Global Net Product Revenues of $306 Million, Representing 43% Year-Over-Year Growth Compared to Q2 2022 – −Submitted 18-Month APOLLO-B Data to the U.S. Food and Drug Administration as Amendment to Supplemental New Drug Application for Patisiran – −Presented Updated Positive Interim Results from Phase 1 Study of ALN-APP in Patients with Early-Onset Alzheimer’s Disease – −Entered into Global Strategic Collaboration with Roche for Co-Development and Co-Commercialization of Zilebesiran – −U.S. Attorney’s Office for District of Massachusetts Concluded and Closed Investigation Regarding Marketing and Promotion of ONPATTRO, with no Action Taken – −Akshay Vaishnaw, M.D., Ph.D., Named Alnylam’s First Chief Innovation Officer – − Reiterated 2023 Financial Guidance, Including Combined Net Product Revenues of $1,200 Million to $1,285 Million – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the second quarter ended June 30, 2023 and reviewed recent business highlights. “The second quarter of 2023 was a very productive one at Alnylam, with commercial execution delivering 43% year-over-year growth in net product revenues, supported by the strong ongoing launch of AMVUTTRA,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “We also had some very important data readouts in the quarter and recent period, including updated interim results from the Phase 1 trial of ALN-APP in patients with early onset Alzheimer’s disease, as well as positive 18-month results from the APOLLO-B Phase 3 study of patisiran, that we believe reaffirm the potential of patisiran in ATTR amyloidosis with cardiomyopathy. Furthermore, we entered into an exciting new partnership with Roche for the development and commercialization of zilebesiran. This progress underscores our commitment to executing across all areas of the business in order to meet our Alnylam P5x25 goals of becoming a top-tier biotech company delivering sustained innovation and exceptional financial results.” Second Quarter 2023 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO® (patisiran) & AMVUTTRA® (vutrisiran) Achieved global net product revenues for ONPATTRO and AMVUTTRA for the second quarter of $91 million and $132 million, respectively, representing 46% total TTR reported year-over-year growth compared to Q2 2022. The acceleration of growth in the U.S. market is particularly noteworthy, as Q2 2023 growth was 72% compared to Q2 2022, marking the fourth consecutive quarter of greater than 70% total TTR growth in the U.S. since the launch of AMVUTTRA in mid-2022. Attained over 3,490 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of June 30, 2023. Total Ultra-Rare: GIVLAARI® (givosiran) & OXLUMO® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the second quarter of $58 million and $24 million, respectively, representing 37% total Ultra-Rare reported year-over-year growth compared to Q2 2022. Attained over 570 patients worldwide on commercial GIVLAARI treatment as of June 30, 2023. Attained over 350 patients worldwide on commercial OXLUMO treatment as of June 30, 2023. Leqvio® (inclisiran) Launch in the U.S. and other markets is ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education. Novartis announced that the FDA approved a label update for Leqvio to enable earlier use in patients with elevated LDL-C who have an increased risk of heart disease, as an adjunct to diet and statin therapy. R&D Highlights Presented new results from an interim analysis of data from the open-label extension (OLE) period of the APOLLO-B Phase 3 study of patisiran, demonstrating continued evidence of sustained benefit across measures of functional capacity and health status and quality of life, as well as cardiac stress and injury. Patisiran demonstrated a safety pro with that observed in the 12-month double-blind period, with no new safety findings. Submitted these 18-month data from the APOLLO-B Phase 3 study to the U.S. FDA as part of the sNDA review for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis. Announced that the U.S. FDA has set a date of September 13, 2023 for the meeting of the Cardiovascular and Renal Drugs Advisory Committee to review the sNDA for patisiran. As previously announced, the FDA has set an action date of October 8, 2023 under the Prescription Drug User Fee Act. The Company announces today that a U.S. Expanded Access Program (EAP) for patisiran that was initiated in August 2022 has fully enrolled, with 200 patients across 20 centers in less than a year. The patisiran EAP aims to provide access to patisiran for patients with ATTR amyloidosis with cardiomyopathy who have had an inadequate response to or cannot tolerate currently available treatment. Published results from Phase 1 study of zilebesiran in the New England Journal of Medicine, showing that, compared to placebo, zilebesiran was associated with dose-dependent reductions in serum AGT, achieving tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after single doses of ≥200 mg of zilebesiran. Zilebesiran also demonstrated an acceptable safety pro continued clinical development. Completed enrollment in the KARDIA-2 Phase 2 study, evaluating the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of another antihypertensive medication. Topline results are expected in early 2024. Reported updated positive interim results for the ongoing single ascending dose (SAD) portion of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD) at the 2023 Alzheimer’s Association International Conference (AAIC). Sanofi announced that results from the ATLAS-INH and ATLAS-A/B studies evaluating the efficacy and safety of fitusiran were published respectively in The Lancet and The Lancet Haematology, reinforcing the potential of investigational fitusiran to transform the current standard of care and address unmet needs for all types of hemophilia, regardless of inhibitor status. Additional Key Pipeline Progress: Presented nine-month results from the randomized treatment extension period of the HELIOS-A study of vutrisiran in patients with they polyneuropathy of hATTR amyloidosis at the Italian Association for the Study of the Peripheral Nervous System Presented findings from a Phase 1 study of ALN-HSD in healthy adults and patients with nonalcoholic steatohepatitis at the European Association for the Study of the Liver (EASL) Congress 2023. Additional Business Updates Announced today that the U.S. Attorney’s Office for the District of Massachusetts has concluded and closed its investigation regarding the marketing and promotion of ONPATTRO, with no action being taken against the company. Announced today that Akshay Vaishnaw, M.D., Ph.D., Alnylam’s President and key scientific leader, will be transitioning to a new role within the organization, serving as Alnylam’s first Chief Innovation Officer. In this new role Akshay will become the Company’s key innovation leader, focused on the future of its R&D engine. Entered into a global strategic collaboration with Roche for the co-development and co-commercialization of zilebesiran. As announced earlier today, Alnylam has entered into an exclusive worldwide license agreement with Agios Pharmaceuticals to develop and commercialize a novel preclinical siRNA targeting TMPRSS6 as a potential disease-modifying treatment for patients with polycythemia vera and related iron-overload disorders. Published 2022 Corporate Responsibility Report. Upcoming Events In mid- and late 2023: Alnylam intends to report topline results from the KARDIA-1 Phase 2 study of zilebesiran. Alnylam intends to report topline results from the Phase 1 study of ALN-TTRsc04. Alnylam intends to report topline results from the Phase 1 study of ALN-KHK. Vir is conducting multiple trials evaluating the potential for ALN-HBV02 (VIR-2218) and VIR-3434 to achieve a functional cure for chronic hepatitis B. Phase 2 data readouts are on track for Q4 2023. - Vir also announced that initial Phase 2 data readouts for the SOLSTICE trial evaluating ALN-HBV02 (VIR-2218) and VIR-3434 as monotherapy and in combination for the treatment of people living with chronic hepatitis delta, the most aggressive form of viral hepatitis, are expected in Q4 2023. Financial Results for the Quarter Ended June 30, 2023 Three Months Ended June 30, (in thousands, except per share amounts) 2023 2022 Net product revenues $ 305,705 $ 213,515 Net revenue from collaborations $ 5,844 $ 9,025 Royalty revenue $ 7,205 $ 2,278 GAAP Operating loss $ (229,831 ) $ (191,686 ) Non-GAAP Operating loss* $ (154,029 ) $ (161,215 ) GAAP Net loss $ (276,024 ) $ (277,402 ) Non-GAAP Net loss* $ (201,622 ) $ (245,834 ) GAAP Net loss per common share - basic and diluted $ (2.21 ) $ (2.29 ) Non-GAAP Net loss per common share - basic and diluted* $ (1.62 ) $ (2.03 ) * For an explanation of our use of non-GAAP financial measures see page 8 and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measures, see page 15. Net Product Revenues Three Months Ended June 30, Year over Year % Growth (in thousands, except percentages) 2023 2022 As Reported At CER* ONPATTRO net product revenues $ 91,458 $ 153,428 (40 )% (40 )% AMVUTTRA net product revenues 132,136 — N/A N/A Total TTR net product revenues $ 223,594 $ 153,428 46 % 47 % GIVLAARI net product revenues 57,899 45,150 28 % 28 % OXLUMO net product revenues 24,212 14,937 62 % 62 % Total net product revenues $ 305,705 $ 213,515 43 % 44 % * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the second quarter 2022. CER is a Non-GAAP measure. Net product revenues increased 43% at actual currency during the second quarter 2023, as compared to the prior year, and 44% at CER. The increase is primarily related to growth in our TTR product revenues driven by the launch of AMVUTTRA in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies. Net Revenues from Collaborations Net revenues from collaborations decreased 35% during the second quarter 2023, as compared to the prior year, primarily due to operating variability, such as the level of work reimbursed, in our collaboration with Regeneron. Operating Expenses Three Months Ended June 30, 2023 vs 2022 (in thousands, except percentages) 2023 2022 % Change* Cost of goods sold $ 75,336 $ 34,038 121 % Cost of goods sold as a percentage of net product revenues 24.6 % 15.9 % 8.7 % Cost of collaborations $ 10,034 $ 6,770 48 % GAAP research and development expenses $ 248,526 $ 205,712 21 % Non-GAAP research and development expenses $ 215,725 $ 195,074 11 % GAAP selling, general and administrative expenses $ 214,689 $ 169,984 26 % Non-GAAP selling, general and administrative expenses $ 171,688 $ 150,151 14 % *For dollar values, we calculate the percentage of change during Q2 2023 compared to Q2 2022. For cost of goods sold as a percentage of net product revenues, we calculate the basis point change during Q2 2023 compared to Q2 2022. Cost of Goods Sold Cost of goods sold as a percent of product sales increased during the second quarter 2023, as compared to the prior year, primarily due to cancelling manufacturing commitments for ONPATTRO and other adjustments to inventory as ongoing patients continue to switch to AMVUTTRA. Costs of goods sold as a percentage of net product revenues also increased as royalties owed to third parties increased driven by the growth of AMVUTTRA following its launch in Q3 2022. These increases were offset by lower manufacturing costs for AMVUTTRA compared with ONPATTRO. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the second quarter 2023, as compared to the prior year, primarily due to increased development expenses associated with our KARDIA-1 / KARDIA-2 (zilebesiran) clinical studies and increased compensation and related expenses as a result of increased headcount to support our R&D pipeline. GAAP R&D expenses further increased due to increased stock-based compensation expense primarily related to certain performance-based awards. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the second quarter 2023, as compared to the prior year, primarily due to increased headcount and other investments supporting our strategic growth including the global launch of AMVUTTRA. GAAP SG&A expenses further increased due to increased stock-based compensation expense primarily related to certain performance-based awards. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.06 billion as of June 30, 2023 compared to $2.19 billion as of December 31, 2022 with the decrease primarily due to our operating loss in the six months ended June 30, 2023. The adjustments to the non-GAAP measures provided in the financial results above and in the financial guidance below are described under “Use of Non-GAAP Financial Measures” later in this press release. A reconciliation of our GAAP to non-GAAP results presented in this release is included in the tables at the end of this press release. 2023 Financial Guidance Full year 2023 financial guidance is reiterated and consists of the following: Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO1,2 $1,200 million – $1,285 million Net Product Revenue Growth vs. 2022 at reported Fx rates1 34% to 44% Net Product Revenue Growth vs. 2022 at constant exchange rates* 34% to 44% Net revenues from collaborations and royalties $100 million – $175 million GAAP R&D and SG&A expenses $1,790 million – $1,885 million Non-GAAP R&D and SG&A expenses3 $1,575 million – $1,650 million 1 Uses December 31, 2022 Fx rates including: 1 EUR = 1.07 USD and 1 USD = 131 JPY 2 Assumes U.S. sNDA approval of patisiran for ATTR amyloidosis with cardiomyopathy by the PDUFA date on October 8, 2023 3 Excludes $215-$235 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the twelve months ended December 31, 2022. CER is a Non-GAAP measure. Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and certain losses outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The non-GAAP financial measures we present include Non-GAAP Operating loss, Non-GAAP Net loss, Non-GAAP Net loss per common share – basic and diluted and Non-GAAP R&D and SG&A expenses. The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses and realized and unrealized losses on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the realized and unrealized losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. Percentage changes in revenue growth at CER, also a non-GAAP financial measure, are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between historical GAAP and non-GAAP measures presented in this release is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss second quarter 2023 results as well as expectations for the future via conference call on Thursday, August 3, 2023 at 8:30 am ET. To access the call, please register online at . Participants are requested to register at a minimum 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company’s website at . An archived webcast will be available on the Alnylam website approximately two hours after the event. About ONPATTRO® (patisiran) ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information, visit ONPATTRO.com. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic approved in the United States for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double‑stranded small interfering RNA (siRNA) that targets mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA). Using Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, AMVUTTRA is designed for increased potency and high metabolic stability to allow for subcutaneous injection once every three months (quarterly). Results from the pivotal HELIOS-A Phase 3 study demonstrate AMVUTTRA rapidly reduces serum TTR levels, has the potential to reverse neuropathy impairment relative to baseline and improves other key measures of disease burden relative to external placebo in patients with the polyneuropathy of hATTR amyloidosis. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About GIVLAARI® (givosiran) GIVLAARI (givosiran) is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information, visit GIVLAARI.com. About OXLUMO® (lumasiran) OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. OXLUMO has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety pro to that observed in ILLUMINATE-A. In the ILLUMINATE-C study, OXLUMO resulted in substantial reductions in plasma oxalate in patients with advanced PH1. Across all three studies, injection site reactions (ISRs) were the most common drug-related adverse reaction. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly beginning one month after the last loading dose at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, including the full U.S. Prescribing Information, visit OXLUMO.com. About LNP Technology Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram. Alnylam Forward Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition; Alnylam’s ability to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs, including as may arise from the recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial pro the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential risks of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval. ALNYLAM PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended Six Months Ended June 30, 2023 June 30, 2022 June 30, 2023 June 30, 2022 Statements of Operations Revenues: Net product revenues $ 305,705 $ 213,515 $ 582,033 $ 400,387 Net revenues from collaborations 5,844 9,025 42,306 34,970 Royalty revenue 7,205 2,278 13,705 2,720 Total revenues 318,754 224,818 638,044 438,077 Operating costs and expenses: Cost of goods sold 75,336 34,038 116,768 57,495 Cost of collaborations and royalties 10,034 6,770 23,471 18,940 Research and development 248,526 205,712 479,095 375,605 Selling, general and administrative 214,689 169,984 398,348 324,455 Total operating costs and expenses 548,585 416,504 1,017,682 776,495 Loss from operations (229,831 ) (191,686 ) (379,638 ) (338,418 ) Other (expense) income: Interest expense (30,035 ) (42,609 ) (58,990 ) (84,971 ) Interest income 21,075 1,899 39,730 2,911 Other expense, net (35,418 ) (42,277 ) (47,673 ) (93,551 ) Total other expense, net (44,378 ) (82,987 ) (66,933 ) (175,611 ) Loss before income taxes (274,209 ) (274,673 ) (446,571 ) (514,029 ) Provision for income taxes (1,815 ) (2,729 ) (3,554 ) (3,714 ) Net loss $ (276,024 ) $ (277,402 ) $ (450,125 ) $ (517,743 ) Net loss per common share - basic and diluted $ (2.21 ) $ (2.29 ) $ (3.62 ) $ (4.29 ) Weighted-average common shares used to compute basic and diluted net loss per common share 124,659 120,896 124,387 120,646 ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) (Unaudited) June 30, 2023 December 31, 2022 ASSETS Current assets: Cash and cash equivalents $ 657,800 $ 866,394 Marketable debt securities 1,372,451 1,297,890 Marketable equity securities 27,256 28,122 Accounts receivable, net 220,635 237,963 Inventory 100,453 128,962 Prepaid expenses and other current assets 145,452 132,916 Total current assets 2,524,047 2,692,247 Property, plant and equipment, net 527,474 523,494 Operating lease right-of-use assets 208,801 215,136 Restricted investments 49,388 49,390 Other assets 92,686 66,092 Total assets $ 3,402,396 $ 3,546,359 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 59,746 $ 98,094 Accrued expenses 598,530 545,460 Operating lease liability 42,074 41,967 Deferred revenue 35,377 42,105 Liability related to the sale of future royalties 33,650 40,289 Total current liabilities 769,377 767,915 Operating lease liability, net of current portion 253,416 261,339 Deferred revenue, net of current portion 213,391 193,791 Convertible debt 1,018,843 1,016,942 Liability related to the sale of future royalties, net of current portion 1,298,446 1,252,015 Other liabilities 257,054 212,580 Total liabilities 3,810,527 3,704,582 Commitments and contingencies (Note 13) Stockholders’ deficit: Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of March 31, 2023 and December 31, 2022 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 124,241 shares issued and outstanding as of March 31, 2023; 123,925 shares issued and outstanding as of December 31, 2022 1,250 1,240 Additional paid-in capital 6,647,173 6,454,540 Accumulated other comprehensive loss (37,080 ) (44,654 ) Accumulated deficit (7,019,474 ) (6,569,349 ) Total stockholders’ deficit (408,131 ) (158,223 ) Total liabilities and stockholders’ deficit $ 3,402,396 $ 3,546,359 This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam’s Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2022. ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended Six Months Ended June 30, 2023 June 30, 2022 June 30, 2023 June 30, 2022 Reconciliation of GAAP to Non-GAAP research and development: GAAP research and development $ 248,526 $ 205,712 $ 479,095 $ 375,605 Less: Stock-based compensation expenses (32,801 ) (10,638 ) (49,033 ) (22,255 ) Non-GAAP research and development $ 215,725 $ 195,074 $ 430,062 $ 353,350 Reconciliation of GAAP to Non-GAAP selling, general and administrative: GAAP selling, general and administrative $ 214,689 $ 169,984 $ 398,348 $ 324,455 Less: Stock-based compensation expenses (43,001 ) (19,833 ) (66,716 ) (37,509 ) Non-GAAP selling, general and administrative $ 171,688 $ 150,151 $ 331,632 $ 286,946 Reconciliation of GAAP to Non-GAAP operating loss: GAAP operating loss $ (229,831 ) $ (191,686 ) $ (379,638 ) $ (338,418 ) Add: Stock-based compensation expenses 75,802 30,471 115,749 59,764 Non-GAAP operating loss $ (154,029 ) $ (161,215 ) $ (263,889 ) $ (278,654 ) Reconciliation of GAAP to Non-GAAP net loss: GAAP net loss $ (276,024 ) $ (277,402 ) $ (450,125 ) $ (517,743 ) Add: Stock-based compensation expenses 75,802 30,471 115,749 59,764 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (1,400 ) 1,097 867 32,258 Non-GAAP net loss $ (201,622 ) $ (245,834 ) $ (333,509 ) $ (425,721 ) Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted: GAAP net loss per common share - basic and diluted $ (2.21 ) $ (2.29 ) $ (3.62 ) $ (4.29 ) Add: Stock-based compensation expenses 0.61 0.25 0.93 0.50 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (0.01 ) 0.01 0.01 0.27 Non-GAAP net loss per common share - basic and diluted $ (1.62 ) $ (2.03 ) $ (2.68 ) $ (3.53 ) Please note that the figures presented above may not sum exactly due to rounding ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF GAAP TO NON-GAAP PRODUCT REVENUE GROWTH AT CONSTANT CURRENCY (Unaudited) June 30, 2023 Three Months Ended Six Months Ended ONPATTRO net product revenue growth, as reported (40) % (33) % Add: Impact of foreign currency translation — 1 ONPATTRO net product revenue growth at constant currency (40) % (32) % AMVUTTRA net product revenue growth, as reported N/A N/A Add: Impact of foreign currency translation N/A N/A AMVUTTRA net product revenue growth at constant currency — % — % Total TTR net product revenue growth, as reported 46 % 47 % Add: Impact of foreign currency translation 1 3 Total TTR net product revenue growth at constant currency 47 % 50 % GIVLAARI net product revenue growth, as reported 28 % 32 % Add: Impact of foreign currency translation — 1 GIVLAARI net product revenue growth at constant currency 28 % 33 % OXLUMO net product revenue growth, as reported 62 % 64 % Add: Impact of foreign currency translation — 2 OXLUMO net product revenue growth at constant currency 62 % 66 % Total net product revenue growth, as reported 43 % 45 % Add: Impact of foreign currency translation 1 3 Total net product revenue growth at constant currency 44 % 48 %

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the first quarter ended March 31, 2023 and reviewed recent business highlights. “The first quarter of 2023 saw continued strong commercial execution, driven by the ongoing launch of AMVUTTRA, delivering robust 48% growth in total product sales compared with the first quarter 2022. We also made significant progress with our broad pipeline, delivering positive first-in-human results for an RNAi therapeutic in the CNS from an interim analysis of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease. We believe this proof of concept is a significant catalyst for future potential growth for Alnylam with the expansion of our product engine to include tissues beyond the liver,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “We’re also excited for other key upcoming milestones from our pipeline, including topline Phase 2 results from the KARDIA-1 study of zilebesiran, which are expected mid-year. With this continued execution, we believe we are tracking well toward our Alnylam P 5 x25 goals of becoming a top-tier biotech company delivering sustained innovation and exceptional financial results.” First Quarter 2023 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO ® (patisiran) & AMVUTTRA ® (vutrisiran) Achieved global net product revenues for ONPATTRO and AMVUTTRA for the first quarter of $102 million and $102 million, respectively, representing 49% total TTR reported year-over-year growth compared to Q1 2022 and 54% growth on a CER* basis. Attained over 3,160 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of March 31, 2023. Total Ultra-Rare: GIVLAARI ® (givosiran) & OXLUMO ® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the first quarter of $48 million and $24 million, respectively, representing 45% total Ultra-Rare reported year-over-year growth compared to Q1 2022 and 48% on a CER* basis. Attained over 550 patients worldwide on commercial GIVLAARI treatment as of March 31, 2023. Attained over 300 patients worldwide on commercial OXLUMO treatment as of March 31, 2023. Leqvio ® (inclisiran) Launch in the U.S. and other markets is ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education. In the U.S. Leqvio is covered at or near label for 76% of patients 14 months after launch. More than 50% of Leqvio source of business in the U.S. is now through “Buy and Bill” acquisition model. R&D Highlights Reported positive interim results from the ongoing single ascending dose (SAD) part of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD). These results establish the first human translation of Alnylam’s proprietary C16-siRNA conjugate platform for central nervous system (CNS) delivery and are the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic. The Company announces today that it has submitted 18-month data from the APOLLO-B Phase 3 study to the U.S. FDA as part of the sNDA review for ONPATTRO ( patisiran ) for the treatment of the cardiomyopathy of ATTR amyloidosis. Sanofi announced that results from the ATLAS-INH and ATLAS-A/B studies evaluating the efficacy and safety of fitusiran were published respectively in The Lancet and The Lancet Haematology , reinforcing the potential of investigational fitusiran to transform the current standard of care and address unmet needs for all types of hemophilia, regardless of inhibitor status. Additional Key Pipeline Progress: Submitted an sNDA to the Brazilian Health Regulatory Agency (ANVISA) for ONPATTRO ( patisiran ) for the treatment of the cardiomyopathy of ATTR amyloidosis. Presented post-hoc analyses from the Phase 3 ENVISION study of givosiran in patients with AHP through Month 36 at the Hemostasis & Thrombosis Research Society (HTRS) Scientific Symposium. Presented preclinical data for ALN-HTT , for the potential treatment of Huntington’s disease, at the CHDI 18 th Annual Huntington’s Disease Therapeutics Conference, in collaboration with Regeneron. Announced today that dosing has been initiated in a Phase 1 study of ALN-KHK , for the potential treatment of type 2 diabetes. Regeneron announced that it has initiated a Phase 2 study of ALN-HSD in patients with NASH. Vir initiated the Phase 2 PREVAIL platform trial and its THRIVE/STRIVE sub-protocols evaluating combinations of ALN-HBV02 (VIR-2218) and VIR-3434 and/or PEG-IFN-α in two hepatitis B virus (HBV) patient populations, with the potential to evaluate other populations in the future. Initial data are expected in the first half of 2024. Additional Business Updates Appointed Peter Kellogg to its Board of Directors. Published 2022 Corporate Responsibility Report . Named Fast Company Top Workplace for Innovators . Ranked #6 for gender diversity among executive leadership and #1 for gender diversity among board of directors in the Eos Foundation’s Women’s Power Gap study. Upcoming Events Alnylam announces today that it intends to present 18-month results from the APOLLO-B Phase 3 study of patisiran at ESC-HF 2023, being held May 20-23, 2023 in Prague. Alnylam also announces today that it intends to present results from the Randomized Treatment Extension (RTE) of the HELIOS-A Phase 3 study evaluating a biannual dosing regimen of vutrisiran at the Italian Association for the Study of the Peripheral Nervous System (ASNP) conference, being held May 25-27, 2023 in Naples. In addition, in early and mid-2023: Alnylam intends to report topline results from the KARDIA-1 Phase 2 study of zilebesiran . Alnylam also intends to complete enrollment in the KARDIA-2 Phase 2 study of zilebesiran . Vir is conducting multiple trials evaluating the potential for ALN-HBV02 (VIR-2218) and VIR-3434 to achieve a functional cure for chronic HBV, which remain ongoing with readouts expected in 2023. Vir also announced that the Phase 2 SOLSTICE trial evaluating ALN-HBV02 (VIR-2218) and VIR-232 as monotherapy and in combination for the treatment of people living with chronic hepatitis D virus, the most aggressive form of viral hepatitis, remains ongoing with data expected in the second half of 2023. Financial Results for the Quarter Ended March 31, 2023 Three Months Ended March 31, (in thousands, except per share amounts) 2023 2022 Net product revenues $ 276,328 $ 186,872 Net revenue from collaborations $ 36,462 $ 25,945 Royalty revenue $ 6,500 $ 442 GAAP Operating loss $ (149,807 ) $ (146,732 ) Non-GAAP Operating loss $ (109,860 ) $ (117,439 ) GAAP Net loss $ (174,101 ) $ (240,341 ) Non-GAAP Net loss $ (131,887 ) $ (179,887 ) GAAP Net loss per common share – basic and diluted $ (1.40 ) $ (2.00 ) Non-GAAP Net loss per common share – basic and diluted $ (1.06 ) $ (1.49 ) Net Product Revenues Three Months Ended March 31, Year over Year % Growth (in thousands, except percentages) 2023 2022 As Reported At CER* ONPATTRO net product revenues $ 102,493 $ 137,009 (25 )% (23 )% AMVUTTRA net product revenues 101,768 ---- N/A N/A Total TTR net product revenues $ 204,261 $ 137,009 49 % 54 % GIVLAARI net product revenues 47,906 35,277 36 % 39 % OXLUMO net product revenues 24,161 14,586 66 % 70 % Total net product revenues $ 276,328 $ 186,872 48 % 52 % * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the first quarter 2022. CER is a Non-GAAP measure. Net product revenues increased 48% at actual currency during the first quarter 2023, as compared to the prior year, and 52% at CER. The increase is primarily related to growth in our TTR product revenues driven by the launch of AMVUTTRA in the U.S. in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies. Net Revenues from Collaborations Net revenues from collaborations increased 41% during the first quarter 2023, as compared to the prior year, primarily due to an increase in revenue from our collaboration arrangements with Regeneron attributed to an increase in reimbursable activities under our research services arrangement in addition to an increase in revenue recognized associated with licensed programs within the collaboration. Operating Expenses Three Months Ended March 31, 2023 vs. 2022 (in thousands, except percentages) 2023 2022 % Change* Cost of goods sold $ 41,432 $ 23,457 77 % Cost of goods sold as a percentage of net product revenues 15.0 % 12.6 % 2.4 % Cost of collaborations $ 13,437 $ 12,170 10 % GAAP research and development expenses $ 230,569 $ 169,893 36 % Non-GAAP research and development expenses $ 214,337 $ 158,276 35 % GAAP selling, general and administrative expenses $ 183,659 $ 154,471 19 % Non-GAAP selling, general and administrative expenses $ 159,944 $ 136,795 17 % * For dollar values, we calculate the percentage of change during Q1 2023 compared to Q1 2022. For cost of goods sold as a percentage of net product revenues, we calculate the basis point change during Q1 2023 compared to Q1 2022. Cost of Goods Sold Cost of goods sold as a percent of product sales increased during the first quarter 2023, as compared to the prior year, primarily due to increased royalties due to third parties driven by sales of AMVUTTRA partially offset by lower manufacturing costs for AMVUTTRA compared with ONPATTRO. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the first quarter 2023, as compared to the prior year, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the APOLLO-B (patisiran), HELIOS-B (vutrisiran), and KARDIA-1/KARDIA-2 (zilebesiran) clinical studies, and manufacturing related expenses associated with our pre-clinical activities. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the first quarter 2023, as compared to the prior year, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.07 billion as of March 31, 2023 compared to $2.19 billion as of December 31, 2022 with the decrease primarily due to our operating loss in the first quarter 2023. The adjustments to the non-GAAP measures provided in the financial results above and in the financial guidance below are described under “Use of Non-GAAP Financial Measures” later in this press release. A reconciliation of our GAAP to non-GAAP results presented in this release is included in the tables at the end of this press release. 2023 Financial Guidance 1 Full year 2023 financial guidance is reiterated and consists of the following: Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO 1,2 $1,200 million – $1,285 million Net Product Revenue Growth vs. 2022 at reported Fx rates 1 34% to 44% Net Product Revenue Growth vs. 2022 at constant exchange rates* 34% to 44% Net revenues from collaborations and royalties $100 million – $175 million GAAP R&D and SG&A expenses $1,790 million – $1,885 million Non-GAAP R&D and SG&A expenses 3 $1,575 million – $1,650 million 1 Uses December 31, 2022 Fx rates including: 1 EUR = 1.07 USD and 1 USD = 131 JPY 2 Assumes U.S. sNDA approval of patisiran for ATTR amyloidosis with cardiomyopathy by the PDUFA date on October 8, 2023 3 Excludes $215-$235 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the twelve months ended December 31, 2022. CER is a Non-GAAP measure. Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and certain losses outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses and realized and unrealized losses on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the realized and unrealized losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. Percentage changes in revenue growth at CER, also a non-GAAP financial measure, are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between historical GAAP and non-GAAP measures presented in this release is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss first quarter 2023 results as well as expectations for the future via conference call on Thursday, May 4, 2023 at 8:30 am ET. To access the call, please register online at https://register.vevent.com/register/BId2c9a28af23d4f119b97d77675d085dc . Participants are requested to register at a minimum 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events . An archived webcast will be available on the Alnylam website approximately two hours after the event. About ONPATTRO ® (patisiran) ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information , visit ONPATTRO.com . About AMVUTTRA ® (vutrisiran) AMVUTTRA ® (vutrisiran) is an RNAi therapeutic approved in the United States for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double‑stranded small interfering RNA (siRNA) that targets mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA). Using Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, AMVUTTRA is designed for increased potency and high metabolic stability to allow for subcutaneous injection once every three months (quarterly). Results from the pivotal HELIOS-A Phase 3 study demonstrate AMVUTTRA rapidly reduces serum TTR levels, has the potential to reverse neuropathy impairment relative to baseline and improves other key measures of disease burden relative to external placebo in patients with the polyneuropathy of hATTR amyloidosis. For more information about AMVUTTRA, including the full U.S. Prescribing Information , visit AMVUTTRA.com . About GIVLAARI ® (givosiran) GIVLAARI (givosiran) is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information , visit GIVLAARI.com . About OXLUMO ® (lumasiran) OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. OXLUMO has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. In the ILLUMINATE-C study, OXLUMO resulted in substantial reductions in plasma oxalate in patients with advanced PH1. Across all three studies, injection site reactions (ISRs) were the most common drug-related adverse reaction. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly beginning one month after the last loading dose at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, including the full U.S. Prescribing Information , visit OXLUMO.com . About LNP Technology Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO ® (patisiran), AMVUTTRA ® (vutrisiran), GIVLAARI ® (givosiran), OXLUMO ® (lumasiran), and Leqvio ® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “ Alnylam P 5 x25 ” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam , on LinkedIn , or on Instagram . Alnylam Forward Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “ Alnylam P 5 x25 ” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition; Alnylam’s ability to successfully execute on its “ Alnylam P 5 x25 ” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs, including as may arise from the recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval. ALNYLAM PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2023 March 31, 2022 Statements of Operations Revenues: Net product revenues $ 276,328 $ 186,872 Net revenues from collaborations 36,462 25,945 Royalty revenue 6,500 442 Total revenues 319,290 213,259 Operating costs and expenses: Cost of goods sold 41,432 23,457 Cost of collaborations and royalties 13,437 12,170 Research and development 230,569 169,893 Selling, general and administrative 183,659 154,471 Total operating costs and expenses 469,097 359,991 Loss from operations (149,807 ) (146,732 ) Other (expense) income: Interest expense (28,955 ) (42,362 ) Interest income 18,655 1,012 Other expense, net (12,255 ) (51,274 ) Total other expense, net (22,555 ) (92,624 ) Loss before income taxes (172,362 ) (239,356 ) Provision for income taxes (1,739 ) (985 ) Net loss $ (174,101 ) $ (240,341 ) Net loss per common share - basic and diluted $ (1.40 ) $ (2.00 ) Weighted-average common shares used to compute basic and diluted net loss per common share 124,111 120,393 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2023 March 31, 2022 Reconciliation of GAAP to Non-GAAP research and development: GAAP research and development $ 230,569 $ 169,893 Less: Stock-based compensation expenses (16,232 ) (11,617 ) Non-GAAP research and development $ 214,337 $ 158,276 Reconciliation of GAAP to Non-GAAP selling, general and administrative: GAAP selling, general and administrative $ 183,659 $ 154,471 Less: Stock-based compensation expenses (23,715 ) (17,676 ) Non-GAAP selling, general and administrative $ 159,944 $ 136,795 Reconciliation of GAAP to Non-GAAP operating loss: GAAP operating loss $ (149,807 ) $ (146,732 ) Add: Stock-based compensation expenses 39,947 29,293 Non-GAAP operating loss $ (109,860 ) $ (117,439 ) Reconciliation of GAAP to Non-GAAP net loss: GAAP net loss $ (174,101 ) $ (240,341 ) Add: Stock-based compensation expenses 39,947 29,293 Add: Realized and unrealized loss on marketable equity securities 2,267 31,161 Non-GAAP net loss $ (131,887 ) $ (179,887 ) Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted: GAAP net loss per common share - basic and diluted $ (1.40 ) $ (2.00 ) Add: Stock-based compensation expenses 0.32 0.24 Add: Realized and unrealized loss on marketable equity securities 0.02 0.26 Non-GAAP net loss per common share - basic and diluted $ (1.06 ) $ (1.49 ) Please note that the figures presented above may not sum exactly due to rounding ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF GAAP TO NON-GAAP PRODUCT REVENUE GROWTH AT CONSTANT CURRENCY (Unaudited) Three Months Ended March 31, 2023 ONPATTRO net product revenue growth, as reported (25 )% Add: Impact of foreign currency translation 2 ONPATTRO net product revenue growth at constant currency (23 )% AMVUTTRA net product revenue growth, as reported N/A Add: Impact of foreign currency translation N/A AMVUTTRA net product revenue growth at constant currency — % Total TTR net product revenue growth, as reported 49 % Add: Impact of foreign currency translation 5 Total TTR net product revenue growth at constant currency 54 % GIVLAARI net product revenue growth, as reported 36 % Add: Impact of foreign currency translation 3 GIVLAARI net product revenue growth at constant currency 39 % OXLUMO net product revenue growth, as reported 66 % Add: Impact of foreign currency translation 4 OXLUMO net product revenue growth at constant currency 70 % Total Ultra Rare net product revenue growth, as reported 45 % Add: Impact of foreign currency translation 3 Total Ultra Rare net product revenue growth at constant currency 48 % Total net product revenue growth, as reported 48 % Add: Impact of foreign currency translation 4 Total net product revenue growth at constant currency 52 % ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) (Unaudited) March 31, 2023 December 31, 2022 ASSETS Current assets: Cash and cash equivalents $ 672,245 $ 866,394 Marketable debt securities 1,372,574 1,297,890 Marketable equity securities 25,856 28,122 Accounts receivable, net 219,434 237,963 Inventory 131,879 128,962 Prepaid expenses and other current assets 119,030 132,916 Total current assets 2,541,018 2,692,247 Property, plant and equipment, net 523,032 523,494 Operating lease right-of-use assets 215,049 215,136 Restricted investments 49,388 49,390 Other assets 63,453 66,092 Total assets $ 3,391,940 $ 3,546,359 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 62,237 $ 98,094 Accrued expenses 508,599 545,460 Operating lease liability 43,055 41,967 Deferred revenue 35,794 42,105 Liability related to the sale of future royalties 23,706 40,289 Total current liabilities 673,391 767,915 Operating lease liability, net of current portion 259,399 261,339 Deferred revenue, net of current portion 191,257 193,791 Convertible debt 1,017,887 1,016,942 Liability related to the sale of future royalties, net of current portion 1,285,200 1,252,015 Other liabilities 224,046 212,580 Total liabilities 3,651,180 3,704,582 Commitments and contingencies (Note 13) Stockholders’ deficit: Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of March 31, 2023 and December 31, 2022 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 124,241 shares issued and outstanding as of March 31, 2023; 123,925 shares issued and outstanding as of December 31, 2022 1,243 1,240 Additional paid-in capital 6,522,091 6,454,540 Accumulated other comprehensive loss (39,124 ) (44,654 ) Accumulated deficit (6,743,450 ) (6,569,349 ) Total stockholders’ deficit (259,240 ) (158,223 ) Total liabilities and stockholders’ deficit $ 3,391,940 $ 3,546,359 This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam’s Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2022.