Vitamin a Deficiency

- Recommendation based on NEURO-TTRansform Phase 3 results showing WAINZUA demonstrated consistent and sustained benefit improving neuropathy impairment and quality of life versus placebo CARLSBAD, Calif., Oct. 21, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) announced today that Ionis' and AstraZeneca's WAINZUA (eplontersen) has been recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) in the European Union (EU) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, commonly referred to as hATTR-PN or ATTRv-PN. If approved by the European Commission, WAINZUA will be the only approved medicine in the EU for the treatment of ATTRv-PN that can be self-administered monthly via an auto-injector. The CHMP based its opinion on the positive NEURO-TTRansform Phase 3 trial which showed that through 66 weeks, patients treated with WAINZUA demonstrated consistent and sustained benefit on the co-primary endpoints of serum transthyretin (TTR) concentration and neuropathy impairment measured by modified Neuropathy Impairment Score +7 (mNIS+7), and key secondary endpoint of quality of life (QoL) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) versus external placebo. WAINZUA continued to demonstrate a favorable safety and tolerability profile throughout the NEURO-TTRansform trial. ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis and, without treatment, is generally fatal within a decade. WAINZUA is a once-monthly RNA-targeted medicine designed to reduce the production of TTR protein at its source. "Hereditary transthyretin-mediated amyloidosis with polyneuropathy remains a progressive and debilitating disease in Europe and other parts of the world, despite currently available medicines," said Brett P. Monia, Ph.D., chief executive officer, Ionis. "The CHMP recommendation is an important step toward making WAINZUA available in Europe, which, if approved, will be the only medicine in the EU for the treatment of transthyretin-mediated amyloidosis with polyneuropathy that can be self-administered monthly via an auto-injector. We are proud to partner with AstraZeneca whose global leadership and expertise positions our alliance to rapidly and effectively bring WAINZUA to many people living with hereditary transthyretin-mediated amyloidosis with polyneuropathy in Europe, pending the EMA's decision." In December 2023, eplontersen was approved in the U.S. for the treatment of ATTRv-PN, under the brand name WAINUA™ (eplontersen). WAINUA is now gaining approvals in additional countries worldwide, including Canada. As part of a global development and commercialization agreement, AstraZeneca and Ionis are commercializing WAINUA in the U.S. The companies are seeking regulatory approval in Europe and other parts of the world where AstraZeneca has exclusive rest of world commercialization and development rights. Eplontersen has also been granted Orphan Drug Designation in the U.S. and in the EU for the treatment of transthyretin-mediated amyloidosis (ATTR). Eplontersen is also currently being evaluated in the global CARDIO-TTRansform Phase 3 study for the treatment of adults with ATTR-CM. The trial is fully enrolled with more than 1,400 patients – making it the largest, most comprehensive study to date in this patient population. More information on the CARDIO-TTRansform study (NCT04136171) is available at . About TTR Amyloidosis ATTR is caused by the accumulation of liver-derived misfolded TTR protein in tissues, such as the heart and the peripheral nerves, causing organ damage and failure. ATTR then causes complications, leading to cardiovascular, neurological and renal diseases such as heart failure and chronic kidney disease. There are both hereditary (ATTRv) and non-hereditary (wild-type) forms of ATTR. ATTR is a rapidly progressive and fatal disease that requires timely recognition of symptoms. ATTR has several phenotypes including ATTR-cardiomyopathy (CM), which predominantly impacts the heart, potentially leading to heart failure, ATTR-polyneuropathy (PN), which predominantly affects the peripheral nervous system and mixed phenotype, where patients experience symptoms of both. Worldwide, there are an estimated 300,000 – 500,000 patients with ATTR-CM and about 10,000 – 40,000 patients with ATTRv-PN. About NEURO-TTRansform NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN at week 35, week 66 and week 85. The final analysis comparing eplontersen to an external placebo group was completed at week 66. All patients were then followed on treatment until week 85 and evaluated four weeks after the last dose in an end-of-trial assessment. Following treatment and the end-of-trial assessments, patients were eligible to enter an open-label extension study to continue receiving eplontersen once every four weeks or enter a 20-week post-treatment evaluation period, which is still ongoing. Full results from the NEURO-TTRansform trial were published in The Journal of the American Medical Association (JAMA) demonstrating the benefit of eplontersen across the spectrum of ATTRv-PN at 35, 66 and 85 weeks of treatment. About WAINZUA / WAINUA™ (eplontersen) Eplontersen is a once-monthly RNA-targeted medicine that provides upstream suppression of transthyretin (TTR) production and is designed to precisely target and reduce the production of TTR protein at its source in the liver. WAINZUA has been approved in the U.S. and Canada under the brand name WAINUA™ (eplontersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, commonly referred to as hATTR-PN or ATTRv-PN. Please see link for full U.S. Prescribing Information. WAINZUA is not yet approved for any indication in Europe. U.S. INDICATION for WAINUA™ (eplontersen) WAINUA injection for subcutaneous use 45 mg is indicated for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA™ (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see link to U.S. Full Prescribing Information for WAINUA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter) and LinkedIn. Ionis Forward-looking Statements This press release includes forward-looking statements regarding eplontersen, Ionis' business, and the therapeutic and commercial potential of Ionis' commercial medicines, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions, or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at . Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. WAINUA™ is a trademark of AstraZeneca plc. Ionis Investor Contact: D. Wade Walke, Ph.DD. [email protected] 760-603-2331 Ionis Media Contact: Daria Binder [email protected] 760-603-4679 SOURCE Ionis Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

− Type II Variation Submission Based on the Positive HELIOS-B Phase 3 Study in which Vutrisiran Significantly Reduced the Risk of Death and Cardiovascular Events Relative to Placebo – CAMBRIDGE, MA, USA I October 16, 2024 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNA interference (RNAi) therapeutics company, today announced the submission of a Type II Variation to the European Medicines Agency (EMA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM). Vutrisiran is the generic name for AMVUTTRA ® , which is currently approved in the European Union (EU) for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. “Today marks another important milestone in our journey to bring RNAi therapeutics to patients with high unmet need around the world,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “ATTR-CM is a rapidly progressive, debilitating, and life-threatening disease that is an increasingly recognized cause of heart failure. Vutrisiran rapidly knocks down TTR, and in the HELIOS-B study treatment with vutrisiran substantially reduced all-cause mortality and cardiovascular events, underscoring the potential of this therapy for those living with the disease. We look forward to working closely with the EMA with the aim to bring this new treatment option to patients as soon as possible.” The regulatory application is based on positive results from the pivotal HELIOS-B Phase 3, randomized, double-blind, placebo-controlled multicenter global study which met all 10 of its primary and secondary endpoints across both the overall and monotherapy populations, each with statistical significance. The findings demonstrated the effects of vutrisiran on outcomes of mortality and cardiovascular events, as well as functional capacity (6-minute walk test), quality of life (Kansas City Cardiomyopathy Questionnaire), and heart failure symptoms and severity (NYHA class) in patients with ATTR-CM. The safety profile of vutrisiran in HELIOS-B was consistent with the established profile of the drug for hATTR amyloidosis in adult patients with polyneuropathy. In HELIOS-B, rates of adverse events (AEs), serious AEs, severe AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. Detailed results from the HELIOS-B study were published in The New England Journal of Medicine . A supplemental New Drug Application (sNDA) for vutrisiran has been submitted to the U.S. Food and Drug Administration (FDA) for the treatment of ATTR-CM. Additional regulatory submissions are planned globally. AMVUTTRA ® (vutrisiran) INDICATION AND IMPORTANT SAFETY INFORMATION Indication In Europe and the UK, vutrisiran is indicated for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. Important Safety Information Reduced Serum Vitamin A Levels and Recommended Supplementation Vutrisiran treatment leads to a decrease in serum vitamin A levels. Supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients taking vutrisiran. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). Adverse Reactions The most frequently occurring adverse reactions in patients treated with vutrisiran were pain in extremity and arthralgia. Other commonly reported adverse reactions with vutrisiran were dyspnoea, injection site reaction and increase in blood alkaline phosphatase. For additional information about vutrisiran, please see the full Summary of Product Characteristics . About AMVUTTRA ® (vutrisiran) AMVUTTRA ® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of variant and wild‑type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, vutrisiran is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease. 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. 5 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. 6 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. 5 This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam (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 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. 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. 5 Elbashir SM, Harborth J, Lendeckel W, et al. Nature . 2001;411(6836):494-498. 6 Zamore P. Cell . 2006;127(5):1083-1086. SOURCE: Alnylam Pharmaceuticals

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that two new data sets from the HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), were presented in the Late Breaking Clinical Research Session 1 at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2024, which was held virtually. An open access recording of Alnylam presentations will be available on the HFSA website following the session. Progression in ATTR-CM is associated with cardiac wall thickening, deterioration in systolic and diastolic function and increases in biomarkers of cardiac stress and injury, NT-pro-BNP and Troponin I. “ Consistent with demonstrated improvements in outcomes and health status, these new data show that vutrisiran attenuated measures of disease progression across multiple domains of cardiac structure and function, NT-proBNP and troponin I, in a contemporary ATTR-CM patient population,” said Pushkal Garg, M.D., Chief Medical Officer, Alnylam. “ These data demonstrate that rapid knockdown of TTR leads to an early impact on cardiac biomarkers and echocardiographic parameters, indicative of a potential disease-modifying effect, and underscores the benefit of treating patients with an RNAi therapeutic earlier in the course of disease. We remain confident that, with approval, vutrisiran has the potential to become a first-line therapy for ATTR amyloidosis with cardiomyopathy and are on track to complete multiple global regulatory submissions before the end of the year.” Analysis results New echocardiographic data demonstrated that treatment with vutrisiran slowed disease progression in a contemporary population of patients with ATTR-CM across multiple domains of cardiac structure and diastolic and systolic function at Month 30 as compared to placebo. The magnitude of the treatment effects with vutrisiran compared to placebo were similar or greater in the monotherapy population. Significant improvements in both diastolic and systolic function were observed as early as 12 months and 18 months, respectively, in the overall population. The Month 30 results in the overall population are detailed in the table below.* Overall population N=654 Cardiac Wall Structure Mean Left Ventricular Wall Thickness Change from Baseline, cm LS Mean difference (Vutrisiran – Placebo) -0.04 cm p=0.03 Left Ventricular Mass Index Change from Baseline, g/m2 LS Mean difference (Vutrisiran – Placebo) -10.6 g/m 2 p=0.0047 Left Ventricular Diastolic Function E/A Ratio Change from Baseline LS Mean difference (Vutrisiran – Placebo) -0.29 p=0.0434 E/e’ Ratio Change from Baseline LS Mean difference (Vutrisiran – Placebo) -1.82 p=0.00003 TDI Lateral e’ Change from Baseline, cm/s LS Mean ± SEM 0.55 cm/s p=0.0005 Left Ventricular Systolic Function Left Ventricular Ejection Fraction Change from Baseline, % LS Mean difference (Vutrisiran – Placebo) 2.03% p=0.02 Absolute Global Longitudinal Strain Change from Baseline, % LS Mean difference (Vutrisiran – Placebo) 1.23% p=0.000002 Left Ventricular Stroke Volume Change from Baseline, mL LS Mean difference (Vutrisiran – Placebo) 4.05 mL p=0.0007 *All p-values included within the table are nominal p-values. In addition, analyses of cardiac biomarkers NT-proBNP and troponin I were also presented. At Month 30, the relative reduction in the fold change in NT-proBNP in patients treated with vutrisiran compared to placebo was 32% in the overall population and 43% in the monotherapy population (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.68; nominal p-value 3.440E-12 and 0.57; nominal p-value 4.339E-12, respectively). At Month 30, relative reduction in the fold change of troponin I was 32% in the overall population and 45% in the monotherapy population (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.68; nominal p-value 1.566E-14 and 0.55; nominal p-value 9.684E-17, respectively). In the subgroup of patients receiving tafamidis at baseline, a relative reduction in the fold change of 18% was observed in NT-proBNP and 10% in troponin I (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.82; nominal p-value 0.0045 and 0.90; nominal p-value 0.0849, respectively) at Month 30. For both NTproBNP and troponin I, patients treated with vutrisiran demonstrated nominally significant reductions relative to placebo at 6 months. These results were consistent across all pre-specified subgroups, with a larger treatment effect observed in the monotherapy population. Detailed results from the HELIOS-B study were presented at the European Society of Cardiology annual congress on August 30, 2024, and simultaneously published in The New England Journal of Medicine . Alnylam plans to include a discussion of these data at its upcoming TTR Investor Day on Wednesday, October 9, 2024, at 8:30 am ET in New York City. The event will be webcast on the Investors section of the Company’s website, www.alnylam.com . A replay will be available on the Alnylam website within 48 hours after the event. HELIOS-B Study Design HELIOS-B (NCT: NCT04153149 ) was a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis with cardiomyopathy. The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months. After the double-blind period, all eligible patients remaining on the study to were able receive vutrisiran in an open-label extension period of HELIOS-B. IMPORTANT SAFETY INFORMATION Reduced Serum Vitamin A Levels and Recommended Supplementation AMVUTTRA® (vutrisiran) treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). Adverse Reactions The most common adverse reactions that occurred in patients treated with AMVUTTRA for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) were arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). For additional information about AMVUTTRA, please see the full Prescribing Information. About AMVUTTRA ® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of mutant and wild‑type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, 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. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease. 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. 5 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. 6 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. 5 This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam (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 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 amyloidosis with cardiomyopathy, including its potential to become a first-line therapy for patients with ATTR amyloidosis with cardiomyopathy, and the timing of Alnylam’s global regulatory submissions for vutrisiran 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” strategy; Alnylam’s ability to successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain 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; and any delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; as well as those risks 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 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. 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. 5 Elbashir SM, Harborth J, Lendeckel W, et al. Nature . 2001;411(6836):494-498. 6 Zamore P. Cell . 2006;127(5):1083-1086.