Inclisiran sodium

—Becomes first company to showcase four routes of synthesis for approved siRNA therapeutic asset— —Joint poster with Bachem demonstrates superiority of Company’s double-stranded RNA ligases compared to wild-type enzymes— —Management to host conference call today at 4:30 pm EST to discuss data— REDWOOD CITY, Calif., Nov. 14, 2024 (GLOBE NEWSWIRE) -- Codexis, Inc. (NASDAQ: CDXS), a leading provider of enzymatic solutions for efficient and scalable therapeutics manufacturing, today announced data from three presentations at the TIDES Europe annual meeting being held November 12-14, 2024, in Hamburg, Germany. The data demonstrate the Company’s rapid advancement of its Enzyme Catalyzed Oligonucleotide (ECO) Synthesis™ manufacturing platform and establish Codexis’ position at the forefront of enzymatic synthesis technology to enable to ongoing expansion of RNAi therapeutics. Codexis Demonstrates First-ever Enzymatic Synthesis of Approved siRNA Therapeutic During an oral Spotlight Presentation, Codexis unveiled the successful end-to-end enzymatic synthesis of an entire approved siRNA therapeutic asset, inclisiran. Codexis enzymatically synthesized the full-length sense and antisense strands of the molecule, including the enzymatic incorporation of a tissue-targeting moiety to the sense strand. To date, this process has only been completed utilizing phosphoramidite chemistry, a process that involves the use of harsh chemical conditions and vast amounts of toxic organic solvents. By contrast, Codexis’ ECO Synthesis manufacturing platform operates under milder, aqueous conditions, that improves product quality and dramatically decreases chemical waste production. In addition to this fully enzymatic route of synthesis, the Company demonstrated similar outcomes utilizing three routes of enzymatic ligation to produce the siRNA therapeutic asset, combining oligonucleotide fragments made by sequential enzymatic synthesis and traditional phosphoramidite chemistry. Key data from the presentation include: Achieved incorporation efficiency of >98% during sequential enzymatic oligo synthesisSuccessfully attached the tri-GalNAc tissue-targeting moiety by enzymatic ligationObtained full-length oligonucleotides of equal quality and yields, using ligation of short fragments made with enzymes or by traditional phosphoramidite chemistry Now that Codexis has successfully achieved this unprecedented milestone, the Company will continue to optimize its process for robustness, scaled-up quantities and improved purity with the goal of providing customers with siRNA material of comparable or better quality to phosphoramidite chemistry. The Company anticipates ramping up manufacturing of siRNA in quantities for preclinical testing following the successful build out of its ECO Synthesis Innovation Lab at the end of this year. Codexis Double-stranded RNA Ligase Demonstrates Superior Performance to Wild-type Enzymes Two additional presentations focused on results of direct comparisons of Codexis’ engineered double-stranded RNA (dsRNA) ligases and wild-type (WT) enzymes when used to combine short oligonucleotide fragments to synthesize full-length siRNA therapeutic compounds. In a joint poster with Bachem, one of the world’s leading CDMOs in oligonucleotide manufacturing, the data provided compelling external validation of the superior performance of Codexis ligases over existing wild-type enzymes in use today. Codexis enzymes demonstrated superior performance over wild-type enzymes across both volumetric productivity and substrate versatility. These dsRNA ligases outperformed on multiple substrate designs and enabled a higher conversion rate of oligonucleotide fragments into siRNA at increased concentrations of raw materials. In a separate TIDES Talk presentation, Codexis demonstrated improved performance of its dsRNA ligase over WT enzymes based on real customer case studies executed through the Company’s RNA Ligase Screening and Optimization Services, launched in May 2024. Codexis’ engineered ligases delivered robust, in-process performance, including higher substrate loading, faster reaction times and improved conversation at elevated temperatures. These data demonstrate the Company’s ability to accelerate delivery of lead ligase variants to customers and optimize process conditions for a customer’s specific asset. The slide decks from both presentations as well as the joint poster with Bachem are now available in the Investor Relations section the Codexis corporate website, www.codexis.com/investors. Conference Call and Webcast Codexis management will host a conference call beginning at 4:30 pm Eastern Time on Thursday, November 14, 2024, to discuss the data presented during the conference. The live call can be accessed by dialing 877-705-2976 (domestic) or 201-689-8798 (international). A live webcast to accompany the conference call can be accessed on the Codexis Investor Relations website, where a replay will be available for 90 days. A telephone replay of the call will be available for 48 hours by dialing 877-660-6853 (domestic) or 201-612-7415 (international), access ID #13726635. About RNAi Therapeutics Manufacturing Ribonucleic acid (RNA) as a therapeutic modality has gained tremendous traction in recent years with the growing number of messenger RNA (mRNA) vaccines and small interfering RNA (siRNA) candidates advancing in clinical studies. However, large-scale production of RNA interference (RNAi) therapeutics using traditional chemical synthesis faces complex challenges in nucleic acid quality and quantity, as well as overall economics. With over 450 RNAi therapies currently in clinical development, including more than 40 assets in Phase 2 and Phase 3 clinical trials targeting disease indications impacting millions of patients, RNAi therapeutic demand is projected to outpace current production capabilities by the end of the decade. About the ECO Synthesis Manufacturing Platform Codexis’ proprietary Enzyme Catalyzed Oligonucleotide (ECO) Synthesis™ manufacturing platform is being designed to address scalability and cost limitations by potentially enabling the commercial-scale manufacture of RNAi therapeutics through an enzymatic route. The Company presented groundbreaking data at the TIDES USA 2024 annual meeting demonstrating the enzymatic synthesis of a full-length sense strand of the oligonucleotide lumasiran, a commercially available siRNA therapeutic, as well as shorter sense strand fragments of a second siRNA therapeutic asset, givosiran. The data demonstrate that Codexis consistently achieved coupling efficiency greater than 98%, which is equivalent to what is seen with phosphoramidite chemistry; executed the enzymatic addition of a conjugation moiety to the lumasiran strand; and confirmed the lack of notable impurities typically observed in oligonucleotide synthesis via phosphoramidite chemistry. A recording of the presentation, along with slides and the data press release, can be found on the Codexis corporate website. About Codexis Codexis is a leading provider of enzymatic solutions for efficient and scalable therapeutics manufacturing that leverages its proprietary CodeEvolver® technology platform to discover, develop and enhance novel, high-performance enzymes and other classes of proteins. Codexis enzymes solve for real-world challenges associated with small molecule pharmaceuticals manufacturing and nucleic acid synthesis. The Company is currently developing its proprietary ECO Synthesis™ manufacturing platform to enable the scaled manufacture of RNAi therapeutics through an enzymatic route. Codexis’ unique enzymes can drive improvements such as higher yields, reduced energy usage and waste generation, improved efficiency in manufacturing and greater sensitivity in genomic and diagnostic applications. For more information, visit https://www.codexis.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “suggest,” “target,” “on track,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. To the extent that statements contained in this press release are not descriptions of historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management, including, but not limited to, the ability of an enzymatic oligonucleotide synthesis process to complement, replace or improve upon traditional chemical synthesis; the potential of the Company’s ECO Synthesis™ platform and double-stranded RNA (dsRNA) ligase screening and optimization services to meet customers’ needs and to create value for Codexis and its customers by enabling commercial-scale manufacture of RNAi therapeutics; completion of the ECO Synthesis Innovation Lab by the end of 2024, and other anticipated technical and commercial milestones related to the ECO Synthesis™ platform and the dsRNA ligase program, and public announcements related thereto; ability of the Company to obtain new development collaborators on its ECO Synthesis technology; the potential for the Company’s dsRNA ligases to have improved scalability and reduced manufacturing costs compared to wild types or non-ligation methods; potential details and features of the ECO Synthesis™ platform such as it being scalable and able to reduce manufacturing costs, as well as having higher quality, purity and yield, and improved sustainability than existing methods; and the future demand for RNAi therapeutics. You should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors that are, in some cases, beyond Codexis’ control and that could materially affect actual results. Factors that could materially affect actual results include, among others: Codexis’ dependence on its licensees and collaborators; if any of its collaborators terminate their development programs under their respective license agreements with Codexis; Codexis may need additional capital in the future in order to expand its business; if Codexis is unable to successfully develop new technology such as its ECO Synthesis™ manufacturing platform and dsRNA ligase; Codexis’ dependence on a limited number of products and customers, and potential adverse effects to Codexis’ business if its customers’ products are not received well in the markets; whether the end markets for Codexis’ customers’ products develop and remain viable; if competitors and potential competitors who have greater resources and experience than Codexis develop products and technologies that make Codexis’ products and technologies obsolete; Codexis’ ability to comply with debt covenants under its loan facility; if Codexis is unable to accurately forecast financial and operational performance; and market and economic conditions may negatively impact Codexis business, financial condition and share price. Additional information about factors that could materially affect actual results can be found in Codexis’ Annual Report on Form 10-K for the year ended December 31, 2023 filed with the Securities and Exchange Commission (“SEC”) on February 28, 2024 and in Codexis’ Quarterly Report on Form 10-Q for the quarter ended September 30, 2024 filed with the SEC on October 31, 2024, including under the caption “Risk Factors,” and in Codexis’ other periodic reports filed with the SEC. Codexis expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law. For More Information Investor ContactCarrie McKim(336) 608-9706ir@codexis.com Media ContactLauren Musto(650) 421-8205media@codexis.com

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the third quarter ended September 30, 2024 and reviewed recent business highlights. “ Alnylam continued to deliver robust results commercially and clinically in the third quarter. We achieved 34% year-over-year growth, with global net product revenues of $420 million, primarily driven by our TTR business. Further with TTR, we continued to share data for vutrisiran in ATTR-CM, with detailed HELIOS-B results presented at the European Society of Cardiology Congress, and supportive echocardiographic and biomarker data presented at the Heart Failure Society of America Annual Scientific Meeting 2024. We’re pleased to have submitted regulatory filings in the U.S. and EU, keeping us on track for a potential U.S. launch in early 2025 and other markets later in the year,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “ We also made great strides with our pipeline, sharing new results today from the Phase 1 study of mivelsiran in patients with Alzheimer’s disease and initiating a Phase 1 study for ALN-HTT02 in adult patients with Huntington’s disease earlier in the third quarter. With this execution, we have continued to progress toward achieving our Alnylam P 5 x25 goals and becoming a leading global biotech company.” Third Quarter 2024 and Recent Significant Business Highlights Commercial Performance Total TTR: ONPATTRO ® (patisiran) & AMVUTTRA ® (vutrisiran) Continued growth momentum in total TTR, achieving global net product revenues for ONPATTRO and AMVUTTRA for the third quarter of $50 million and $259 million, respectively, which combined represent 34% TTR annual growth compared to Q3 2023. Total Rare: GIVLAARI ® (givosiran) & OXLUMO ® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the third quarter of $71 million and $40 million, respectively, which combined represent 34% Rare annual growth compared to Q3 2023. R&D Highlights Presented detailed results from the positive HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) at the European Society of Cardiology Congress (ESC). Additional data from HELIOS-B, including echocardiographic and biomarker data, were presented at the Heart Failure Society of America Annual Scientific Meeting 2024 (HFSA). Based on these positive results, Alnylam submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) using a Priority Review Voucher, as well as a Type II Variation to the European Medicines Agency (EMA), for vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy. Today announced positive initial results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with Alzheimer’s disease. Following a second 50 mg dose of mivelsiran at month 6, further reductions of sAPPβ were observed at month 7, with patients achieving greater than 90% lowering of sAPPβ. No new safety signals have been identified, and no significant abnormalities have been seen on CSF safety labs such as total protein and CSF white cell count, or on the exploratory biomarker neurofilament light chain. Presented the design of the cAPPricorn-1 Phase 2 study of mivelsiran in patients with cerebral amyloid angiopathy (CAA) at the 2024 International CAA Conference. Initiated a Phase 1 study of ALN-HTT02 in adult patients with Huntington’s disease. Exon1 targeting strategy and design of the Phase 1 study were presented at the European Huntington's Disease Network (EHDN) & Enroll-HD 2024 Congress. Nonclinical data supporting the tolerability of deep and sustained HTT-lowering in wild-type nonhuman primates after single and repeated intrathecal administration of ALN-HTT02 were also shared. Today announced the decision to suspend further clinical development of ALN-KHK , an investigational RNAi therapeutic targeting ketohexokinase for the treatment of type 2 diabetes mellitus. This decision reflects portfolio prioritization efforts to allocate clinical, managerial and financial resources carefully to bring transformative medicines to patients. Additional Business Updates Alnylam hosted a TTR Investor Day featuring presentations from Alnylam senior leaders and an external expert related to the Company's TTR business. A replay of the webcast is available on the Company's website. Appointed Robert Hesslein as Chief Legal Officer and Corporate Secretary. Named one of Fast Company Top 100 Workplaces for Innovators in 2024. Recognized by Science magazine as a Top Employer for the sixth consecutive year. Upcoming Events Alnylam will present additional findings from the ongoing Phase 1 study of ALN-TTRsc04 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions 2024. The Company plans to share its Phase 3 development plan for ALN-TTRsc04 in the first quarter of 2025. Alnylam intends to initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end. Financial Results for the Quarter Ended September 30, 2024 Three Months Ended September 30, (In thousands, except per share amounts) 2024 2023 Net product revenues $ 420,146 $ 313,153 Net revenue from collaborations $ 57,387 $ 427,472 Royalty revenue $ 23,386 $ 9,905 GAAP Operating (loss) income $ (76,905 ) $ 213,867 Non-GAAP Operating (loss) income $ (31,101 ) $ 277,804 GAAP Net (loss) income $ (111,570 ) $ 147,753 Non-GAAP Net (loss) income $ (64,199 ) $ 228,534 GAAP Net (loss) income per common share - basic $ (0.87 ) $ 1.18 Non-GAAP Net (loss) income per common share - basic $ (0.50 ) $ 1.83 GAAP Net (loss) income per common share - diluted $ (0.87 ) $ 1.15 Non-GAAP Net (loss) income per common share - diluted $ (0.50 ) $ 1.74 For an explanation of our use of non-GAAP financial measures refer to the “Use of Non-GAAP Financial Measures” section later in this press release and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measure, see the tables at the end of this press release. Net Product Revenues Three Months Ended September 30, Year over Year % Growth (In thousands, except percentages) 2024 2023 As Reported At CER* ONPATTRO net product revenues $ 50,293 $ 81,589 (38)% (38)% AMVUTTRA net product revenues 258,590 148,680 74% 75% Total TTR net product revenues 308,883 230,269 34% 35% GIVLAARI net product revenues 71,043 54,148 31% 31% OXLUMO net product revenues 40,220 28,736 40% 40% Total Rare net product revenues 111,263 82,884 34% 34% Total net product revenues $ 420,146 $ 313,153 34% 35% * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the third quarter 2023. CER is a non-GAAP measure. Total net product revenues increased 34% and 35% at actual currency and CER, respectively, during the three months ended September 30, 2024, as compared to the same period in 2023, due to an increased number of patients receiving AMVUTTRA, GIVLAARI, and OXLUMO, partially offset by a decrease in patients receiving ONPATTRO primarily driven by switching to AMVUTTRA. Net Revenues from Collaborations Net revenues from collaborations decreased during the three months ended September 30, 2024, as compared to the same period in 2023, due to less revenue recognized under our collaborations with Roche and Regeneron. During 2023, we recognized $310 million of revenue from the upfront payment we received from Roche and a $65 million cumulative adjustment from the $100 million milestone we received in connection with our Regeneron Collaboration for achieving certain criteria during early clinical development for mivelsiran (formerly ALN-APP). Operating Expenses Three Months Ended September 30, (In thousands, except percentages) 2024 2023 Cost of goods sold $ 81,980 $ 79,473 Cost of goods sold as a percentage of net product revenues 19.5 % 25.4 % Cost of collaborations and royalties $ 3,925 $ 4,836 GAAP research and development expenses $ 270,926 $ 253,179 Non-GAAP research and development expenses $ 251,132 $ 224,024 GAAP selling, general and administrative expenses $ 220,993 $ 199,175 Non-GAAP selling, general and administrative expenses $ 194,983 $ 164,393 Cost of Goods Sold Cost of goods sold as a percentage of net product revenues decreased during the three months ended September 30, 2024, as compared to the same period in 2023, primarily due to higher costs in 2023 associated with cancelled manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the use of patisiran for the treatment of patients with ATTR amyloidosis with cardiomyopathy for which we did not receive regulatory approval in the U.S., offset by increased rate of royalties payable on net sales of AMVUTTRA. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three months ended September 30, 2024, as compared to the same period in 2023, primarily due to increased costs associated with our preclinical activities as we develop our clinical pipeline of RNAi therapeutics targeting multiple tissues, increased clinical trial expenses associated with increased Phase 2 activities for the zilebesiran KARDIA-3 clinical trial, and increased employee compensation expenses. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three months ended September 30, 2024, as compared to the same period in 2023, primarily due to higher costs associated with marketing investments to promote our TTR therapies and prepare for the potential launch of AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy, and employee compensation. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.78 billion as of September 30, 2024, as compared to $2.44 billion as of December 31, 2023, with the increase primarily due to improved operating performance and increased net proceeds from the issuance of common stock in connection with stock option exercises. A reconciliation of our GAAP to non-GAAP financial results for the quarter is included in the tables at the end of this press release. 2024 Financial Guidance Full year 2024 financial guidance is reiterated and consists of the following: Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO 1 $1,575 million - $1,650 million Net Product Revenue Growth vs. 2023 at reported FX rates 1 27% to 33% Net Product Revenue Growth vs. 2023 at CER* 28% to 34% Net revenues from collaborations and royalties $575 million - $650 million GAAP R&D and SG&A expenses $2,000 million - $2,150 million Non-GAAP R&D and SG&A expenses 2 $1,775 million - $1,875 million 1 Uses June 30, 2024 FX rates including: 1 EUR = 1.07 USD and 1 USD = 161 JPY 2 Primarily excludes $225 - $275 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, 2023. 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 non-recurring gains 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 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 GAAP and non-GAAP measures is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss third quarter 2024 results as well as expectations for the future via conference call on Thursday, October 31, 2024 at 8:30 am ET. 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 adults with hATTR amyloidosis with polyneuropathy. 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 adults with hATTR amyloidosis with polyneuropathy. 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, GIVLAARI 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 lipid nanoparticle (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 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 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, statements regarding Alnylam’s expectations regarding the potential launch of AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy in the U.S. in early 2025 and in other countries later in 2025; Alnylam’s advancement towards its “Alnylam P 5 x25” strategy and aspiration to become a leading global biotech company; the potential for Alnylam to advance its research and development programs, including the timing of Alnylam’s presentation of data and sharing of the development plan for ALN-TTRsc04 and initiation of a Phase 2 clinical trial for mivelsiran in patients with Alzheimer’s Disease; and Alnylam’s projected commercial and financial performance, including the expected range of net product revenues and net revenues from collaborations and royalties for 2024, and the expected range of aggregate annual GAAP and non-GAAP R&D and SG&A expenses for 2024, 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, risks and uncertainties relating to: 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 vutrisiran, zilebesiran, ALN-TTRsc04 and mivelsiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including 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; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the approved indications for 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 Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the risk of future government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 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 other filings that Alnylam makes with the SEC. 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. Vutrisiran 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. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) September 30, 2024 December 31, 2023 ASSETS (Unaudited) Current assets: Cash and cash equivalents $ 1,099,920 $ 812,688 Marketable debt securities 1,671,993 1,615,516 Marketable equity securities 8,322 11,178 Accounts receivable, net 353,852 327,787 Inventory 75,987 89,146 Prepaid expenses and other current assets 145,350 126,382 Total current assets 3,355,424 2,982,697 Property, plant and equipment, net 506,997 526,057 Operating lease right-of-use assets 196,408 199,732 Restricted investments 68,592 49,391 Other assets 77,618 72,003 Total assets $ 4,205,039 $ 3,829,880 LIABILITIES AND STOCKHOLDERS’ EQUITY (DEFICIT) Current liabilities: Accounts payable $ 70,805 $ 55,519 Accrued expenses 946,168 713,013 Operating lease liability 42,144 41,510 Deferred revenue 71,030 102,753 Liability related to the sale of future royalties 90,516 54,991 Total current liabilities 1,220,663 967,786 Operating lease liability, net of current portion 236,030 243,101 Deferred revenue, net of current portion 1,012 188,175 Convertible debt 1,023,654 1,020,776 Liability related to the sale of future royalties, net of current portion 1,333,849 1,322,248 Other liabilities 357,477 308,438 Total liabilities 4,172,685 4,050,524 Commitments and contingencies (Note 13) Stockholders’ equity (deficit): Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of September 30, 2024 and December 31, 2023 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 128,841 shares issued and outstanding as of September 30, 2024; 125,794 shares issued and outstanding as of December 31, 2023 1,289 1,259 Additional paid-in capital 7,259,876 6,811,063 Accumulated other comprehensive loss (24,826 ) (23,375 ) Accumulated deficit (7,203,985 ) (7,009,591 ) Total stockholders’ equity (deficit) 32,354 (220,644 ) Total liabilities and stockholders’ equity (deficit) $ 4,205,039 $ 3,829,880 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, 2023. ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended Nine Months Ended September 30, 2024 September 30, 2023 September 30, 2024 September 30, 2023 Statements of Operations Revenues: Net product revenues $ 420,146 $ 313,153 $ 1,195,397 $ 895,186 Net revenues from collaborations 57,387 427,472 403,273 469,778 Royalty revenue 23,386 9,905 56,407 23,610 Total revenues 500,919 750,530 1,655,077 1,388,574 Operating costs and expenses: Cost of goods sold 81,980 79,473 203,864 196,241 Cost of collaborations and royalties 3,925 4,836 16,689 28,307 Research and development 270,926 253,179 826,063 732,274 Selling, general and administrative 220,993 199,175 680,187 597,523 Total operating costs and expenses 577,824 536,663 1,726,803 1,554,345 (Loss) income from operations (76,905 ) 213,867 (71,726 ) (165,771 ) Other (expense) income: Interest expense (34,376 ) (30,893 ) (102,887 ) (89,883 ) Interest income 32,146 25,425 90,973 65,155 Other expense, net (29,528 ) (57,658 ) (99,777 ) (105,331 ) Total other expense, net (31,758 ) (63,126 ) (111,691 ) (130,059 ) (Loss) income before income taxes (108,663 ) 150,741 (183,417 ) (295,830 ) Provision for income taxes (2,907 ) (2,988 ) (10,977 ) (6,542 ) Net (loss) income $ (111,570 ) $ 147,753 $ (194,394 ) $ (302,372 ) Net (loss) income per common share - basic $ (0.87 ) $ 1.18 $ (1.53 ) $ (2.43 ) Net (loss) income per common share - diluted $ (0.87 ) $ 1.15 $ (1.53 ) $ (2.43 ) Weighted-average common shares - basic 128,590 125,220 127,159 124,667 Weighted-average common shares - diluted 128,590 131,337 127,159 124,667 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended September 30, 2024 September 30, 2023 Reconciliation of GAAP to Non-GAAP Research and development: GAAP Research and development $ 270,926 $ 253,179 Less: Stock-based compensation expenses (19,794 ) (29,155 ) Non-GAAP Research and development $ 251,132 $ 224,024 Reconciliation of GAAP to Non-GAAP Selling, general and administrative: GAAP Selling, general and administrative $ 220,993 $ 199,175 Less: Stock-based compensation expenses (26,010 ) (34,782 ) Non-GAAP Selling, general and administrative $ 194,983 $ 164,393 Reconciliation of GAAP to Non-GAAP Operating (loss) income: GAAP Operating (loss) income $ (76,905 ) $ 213,867 Add: Stock-based compensation expenses 45,804 63,937 Non-GAAP Operating (loss) income $ (31,101 ) $ 277,804 Reconciliation of GAAP to Non-GAAP Net (loss) income: GAAP Net (loss) income $ (111,570 ) $ 147,753 Add: Stock-based compensation expenses 45,804 63,937 Add: Realized and unrealized loss on marketable equity securities 1,567 16,844 Non-GAAP Net (loss) income $ (64,199 ) $ 228,534 Reconciliation of GAAP to Non-GAAP Net (loss) income per common share- basic: GAAP Net (loss) income per common share - basic $ (0.87 ) $ 1.18 Add: Stock-based compensation expenses 0.36 0.51 Add: Realized and unrealized loss on marketable equity securities 0.01 0.13 Non-GAAP Net (loss) income per common share - basic $ (0.50 ) $ 1.83 Reconciliation of GAAP to Non-GAAP Net (loss) income per common share- diluted: GAAP Net (loss) income per common share - diluted $ (0.87 ) $ 1.15 Add: Stock-based compensation expenses 0.36 0.49 Add: Realized and unrealized loss on marketable equity securities 0.01 0.13 Non-GAAP Net (loss) income per common share - diluted $ (0.50 ) $ 1.74 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) September 30, 2024 Three Months Ended ONPATTRO net product revenue growth, as reported (38 )% Add: Impact of foreign currency translation — ONPATTRO net product revenue growth at constant currency (38 )% AMVUTTRA net product revenue growth, as reported 74 % Add: Impact of foreign currency translation 1 AMVUTTRA net product revenue growth at constant currency 75 % Total TTR net product revenue growth, as reported 34 % Add: Impact of foreign currency translation 1 Total TTR net product revenue growth at constant currency 35 % GIVLAARI net product revenue growth, as reported 31 % Add: Impact of foreign currency translation — GIVLAARI net product revenue growth at constant currency 31 % OXLUMO net product revenue growth, as reported 40 % Add: Impact of foreign currency translation — OXLUMO net product revenue growth at constant currency 40 % Total net product revenue growth, as reported 34 % Add: Impact of foreign currency translation 1 Total net product revenue growth at constant currency 35 %