Givosiran Sodium

Achieved global net product revenues for AMVUTTRA and ONPATTRO for the first quarter of $310 million and $49 million , respectively, representing 36% growth compared to Q1 2024. Achieved global net product revenues for GIVLAARI and OXLUMO for the first quarter of $67 million and $42 million , respectively, representing 8% growth compared to Q1 2024. Strong progress making AMVUTTRA available for ATTR-CM in various global markets. Received U.S. FDA approval of the supplemental New Drug Application (sNDA) for AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. Received approval from ANVISA ( Brazilian Health Regulatory Agency ) for ATTR-CM. Received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval of vutrisiran for the treatment of ATTR-CM. Marketing authorization applications based on data from the landmark HELIOS-B Phase 3 clinical trial are currently under review by several global health agencies including the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Presented new data from HELIOS-B at the American College of Cardiology Scientific Session 2025, further supporting vutrisiran’s compelling therapeutic profile, including: Echocardiographic data demonstrating that treatment with vutrisiran led to significant improvements in diastolic function and attenuation of declines in left ventricular (LV) and right ventricular (RV) systolic function at Month 18, compared to placebo. HELIOS-B included the largest systematic echocardiographic study conducted to date in an ATTR pivotal trial. An exploratory subgroup analysis demonstrating that vutrisiran reduced all-cause mortality and recurrent cardiovascular events compared to placebo across a range of baseline heart failure severities in patients with ATTR-CM. These data were also published in the Journal of the American College of Cardiology . A separate analysis confirming that vutrisiran significantly maintained or improved functional capacity, and patient-reported health status and quality of life, compared to placebo over 30 months. These data were also published in the Journal of the American College of Cardiology . Presented updates from the Company’s robust pipeline and organic platform at R&D Day. Disclosed two new clinical programs: ALN-6400, targeting liver-derived plasminogen, which could represent a universal hemostatic agent for the treatment of bleeding disorders without the risk of thrombosis. ALN-4324, targeting GRB14, a potential insulin sensitizer for the treatment of type 2 diabetes. Alnylam announces today that a Phase 1 clinical trial for ALN-4324 has been initiated. Shared encouraging data from our expanding neuroscience franchise, including an update on the new ALN-HTT02 program, which has a highly differentiated exon-1-targeting approach to lower huntingtin (HTT) for Huntington’s disease. Presented new preclinical data on delivery solutions with best-in-class potential for adipose, muscle, heart, and kidney tissue and for crossing the blood-brain barrier, supporting Alnylam’s aspiration to unlock every major tissue for RNAi therapeutics by 2030. Received U.S. FDA approval of the supplemental New Drug Application (sNDA) for AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. Received approval from ANVISA ( Brazilian Health Regulatory Agency ) for ATTR-CM. Received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval of vutrisiran for the treatment of ATTR-CM. Marketing authorization applications based on data from the landmark HELIOS-B Phase 3 clinical trial are currently under review by several global health agencies including the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Echocardiographic data demonstrating that treatment with vutrisiran led to significant improvements in diastolic function and attenuation of declines in left ventricular (LV) and right ventricular (RV) systolic function at Month 18, compared to placebo. HELIOS-B included the largest systematic echocardiographic study conducted to date in an ATTR pivotal trial. An exploratory subgroup analysis demonstrating that vutrisiran reduced all-cause mortality and recurrent cardiovascular events compared to placebo across a range of baseline heart failure severities in patients with ATTR-CM. These data were also published in the Journal of the American College of Cardiology . A separate analysis confirming that vutrisiran significantly maintained or improved functional capacity, and patient-reported health status and quality of life, compared to placebo over 30 months. These data were also published in the Journal of the American College of Cardiology . Disclosed two new clinical programs: ALN-6400, targeting liver-derived plasminogen, which could represent a universal hemostatic agent for the treatment of bleeding disorders without the risk of thrombosis. ALN-4324, targeting GRB14, a potential insulin sensitizer for the treatment of type 2 diabetes. Alnylam announces today that a Phase 1 clinical trial for ALN-4324 has been initiated. Shared encouraging data from our expanding neuroscience franchise, including an update on the new ALN-HTT02 program, which has a highly differentiated exon-1-targeting approach to lower huntingtin (HTT) for Huntington’s disease. Presented new preclinical data on delivery solutions with best-in-class potential for adipose, muscle, heart, and kidney tissue and for crossing the blood-brain barrier, supporting Alnylam’s aspiration to unlock every major tissue for RNAi therapeutics by 2030. ALN-6400, targeting liver-derived plasminogen, which could represent a universal hemostatic agent for the treatment of bleeding disorders without the risk of thrombosis. ALN-4324, targeting GRB14, a potential insulin sensitizer for the treatment of type 2 diabetes. Alnylam announces today that a Phase 1 clinical trial for ALN-4324 has been initiated. Net product revenues increased 28% and 30% at actual currency and CER, respectively, during the three months ended March 31, 2025 , as compared to the same period in 2024, due to growth from AMVUTTRA driven by increased patient demand, partially offset by a decrease in ONPATTRO due to patient switches to AMVUTTRA, as well as an increased number patients on GIVLAARI. Net revenues from collaborations decreased during the three months ended March 31, 2025 , as compared to the same period in 2024, primarily due to recognition of $65.0 million of revenue associated with a milestone under our Roche Collaboration from dosing the first patient in the zilebesiran KARDIA-3 clinical trial during the three months ended March 31, 2024 , which did not reoccur during the three months ended March 31, 2025 . This was partially offset by increased revenue recognized in connection with our Regeneron Collaboration during the three months ended March 31, 2025 as a result of an increase in activities under our licensed programs and recognition of a $30.0 million payment in connection with the amendment to our agreement with Vir Biotechnology, Inc. in March 2025 . Cost of goods sold as a percentage of net product revenues was consistent during the three months ended March 31, 2025 , as compared to the same period in 2024. GAAP R&D expenses increased during the three months ended March 31, 2025 , as compared to the same period in 2024, primarily due to: increased stock-based compensation expense; and increased clinical trial expenses primarily associated with zilebesiran in the KARDIA-3 clinical trial and mivelsiran in the cAPPRicorn-1 clinical trial due to increased Phase 2 activities, as well as startup activities and other clinical trial expenses associated with zilebesiran in the KARDIA-6 cardiovascular outcomes trial and nucresiran in the TRITON-CM Phase 3 clinical trial in patients with ATTR amyloidosis with cardiomyopathy. increased stock-based compensation expense; and increased clinical trial expenses primarily associated with zilebesiran in the KARDIA-3 clinical trial and mivelsiran in the cAPPRicorn-1 clinical trial due to increased Phase 2 activities, as well as startup activities and other clinical trial expenses associated with zilebesiran in the KARDIA-6 cardiovascular outcomes trial and nucresiran in the TRITON-CM Phase 3 clinical trial in patients with ATTR amyloidosis with cardiomyopathy. decreased expenses within other clinical programs, specifically the HELIOS-B Phase 3 clinical trial of vutrisiran due to the wind-down of clinical activities. GAAP and non-GAAP SG&A expenses increased during the three months ended March 31, 2025 , as compared to the same period in 2024, primarily due to increased marketing investment associated with the promotion of our TTR therapies and increased employee compensation expenses. Interest expense for the three months ended March 31, 2025 of $38.6 million included interest of $35.0 million attributed to the liability related to the sale of future Leqvio royalties. Other expense, net for the three months ended March 31, 2025 of $59.7 million included a charge associated with the change in fair value of the development derivative liability of $58.9 million , attributed to valuation updates primarily driven by the regulatory approval of AMVUTTRA for the treatment ATTR-CM. During the three months ended March 31, 2025 , we recorded a provision for income taxes of $15.9 million , primarily due to income generated in Switzerland . We will utilize deferred tax assets in Switzerland to offset current cash tax liabilities and will continue to maintain a full valuation allowance against our net deferred tax assets in the U.S. and certain deferred tax assets in Switzerland . Cash, cash equivalents and marketable securities were $2.63 billion as of March 31, 2025 , as compared to $2.69 billion as of December 31, 2024 , with the decrease primarily driven by operating activities. Net cash used in operating activities for the three months ended March 31, 2025 of $118.3 million , included $61.7 million of payments associated with the liability related to the sale of future Leqvio royalties allocated to interest. Net cash provided by financing activities for the three months ended March 31, 2025 of $44.1 million , included $5.3 million of payments associated with an achieved development milestone for the development derivative liability.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced moderated poster presentations of new data from the landmark HELIOS-B Phase 3 clinical trial, which evaluated vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM) in a population representative of today’s patients. Data were presented at the American College of Cardiology’s Annual Scientific Session (ACC.25) held in Chicago, Illinois. These data build upon the body of clinical evidence which supported the recent U.S. Food and Drug Administration (FDA) approval of AMVUTTRA® (vutrisiran) for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of transthyretin, addressing the disease at its source, with four subcutaneous doses per year. “The HELIOS-B study continues to deliver a robust data package showcasing the unique, differentiated value of vutrisiran as a first-line treatment option that can enable patients with ATTR-CM to live longer, better, and healthier lives,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “Data showing beneficial effects on cardiac systolic and diastolic function are novel and indicate the direct impact of vutrisiran in cardiac structure and function of patients living with ATTR-CM. These findings, together with the observed improvements in functional capacity, health status and quality of life, as well as the reductions in all-cause mortality and cardiovascular events, demonstrate the rapid, broad, and sustained impacts of vutrisiran on ATTR-CM and underscore the importance of early intervention for this progressive and ultimately fatal disease.” Moderated Poster Presentations: The Relationship Between Cardiac Structure, Function, and Clinical Outcomes and the Impact of Vutrisiran from the HELIOS-B Trial New echocardiographic data from the HELIOS-B Phase 3 clinical trial, the largest systematic echocardiographic study in a pivotal trial, demonstrated that treatment with vutrisiran improved echocardiographic cardiac function. Vutrisiran treatment led to significant improvements in diastolic function and attenuation of declines in left ventricular (LV) and right ventricular (RV) systolic function at Month 18, compared to placebo. Baseline measures of LV and RV systolic function, as well as indices of diastolic function, were shown to provide important prognostic information beyond clinical characteristics and biomarker-based staging systems. Notably, worsening LV and RV systolic function over 18 months was significantly associated with an increased risk of subsequent all-cause death, highlighting the importance of these parameters in assessing disease progression. The improved clinical outcomes of patients receiving vutrisiran in HELIOS-B may be mediated by its impact on cardiac function. Impact of Baseline Heart Failure Severity on Efficacy of Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy in the HELIOS-B Trial: A Subgroup Analysis An exploratory subgroup analysis demonstrated that vutrisiran reduced all-cause mortality and recurrent cardiovascular events across a range of baseline heart failure severities in patients with ATTR-CM. The greatest benefit was observed in patients with earlier, less severe disease, underscoring the need for timely diagnosis and early intervention. Similar effects were seen in the monotherapy population and across additional endpoints, including functional capacity and cardiac biomarkers, reinforcing the efficacy of vutrisiran regardless of disease stage. These results were recently published in JACC. Maintenance or Improvement of Functional Capacity, Health Status, and Quality of Life with Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy: Data from the HELIOS-B Study A separate analysis confirmed that vutrisiran significantly maintained or improved functional capacity, and patient-reported health status and quality of life, compared to placebo over 30 months. Greater proportions of patients treated with vutrisiran preserved or improved 6-minute walk test distance and Kansas City Cardiomyopathy Questionnaire scores at clinically meaningful thresholds. These findings provide further evidence of vutrisiran’s ability to deliver meaningful benefits beyond reducing mortality and cardiovascular events. These results were recently published in JACC. An additional Flatboard Poster presentation, “Real-World Persistency on Tafamidis: An Analysis of U.S. Insurance Claims Data” will be presented on Monday, March 31 at 10:30 am (CDT), 11:30 am (EDT). To view the results presented at ACC.25, please visit Capella. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection by a healthcare professional, AMVUTTRA is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and is approved in the U.S. for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About ATTR Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000 – 300,000 people worldwide.1-4 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 for 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 include ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), which are being developed and commercialized by Alnylam, and Leqvio® (inclisiran) and Qfitlia™ (fitusiran), which are being developed and commercialized by Alnylam’s partners, Novartis and Sanofi, respectively. 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 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, Alnylam’s expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR-CM, including the ability of vutrisiran to reduce mortality and cardiovascular events in ATTR-CM patients; the potential of vutrisiran to become a first-line therapy for ATTR-CM; the potential of vutrisiran to enable ATTR-CM patients to live longer, better and healthier lives; and the potential for early treatment with vutrisiran to have beneficial effects in ATTR-CM patients 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 P5x25” goals; 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; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, 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 manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products; the outcome of litigation; the potential risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2024 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 Alnylam’s views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. 1 Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med. 2015;47(8):625-638. 2 Gertz MA. Am J Manag Care. 2017;23(7):S107-S112. 3 Conceicao I, Gonzalez-Duarte A, Obici L, et al. J Peripher Nerv Syst. 2016;21:5-9. 4 Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8:31.