Vitamin a Deficiency

- Encouraging start to first independent launch with TRYNGOLZATM - - On track for second independent launch with donidalorsen PDUFA August 21, 2025 - - Increasing 2025 financial guidance by more than 20% - CARLSBAD, Calif. --(BUSINESS WIRE)--Apr. 30, 2025-- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results for the first quarter ended March 31, 2025 . “With an encouraging start to the TRYNGOLZA launch for familial chylomicronemia syndrome, the first of four independent launches expected over the next two years, Ionis’ new chapter as a fully integrated, commercial-stage biotechnology company is well underway,” said Brett P. Monia , Ph.D., chief executive officer, Ionis. “We look forward to continued momentum this year, including our second independent launch for donidalorsen in hereditary angioedema and Phase 3 results for olezarsen for severe hypertriglyceridemia in the third quarter. We also continue to advance our next wave of wholly owned neurology medicines, including ION582 for Angelman syndrome, which is on track to start Phase 3 development shortly. Our advancing pipeline of transformational medicines, together with strong commercial and financial execution, position Ionis to deliver increasing value for all stakeholders.” First Quarter 2025 Summary Financial Results(1): Three months ended March 31 , 2025 2024 (amounts in millions) Total revenue $ 132 $ 119 Operating expenses $ 278 $ 269 Operating expenses on a non-GAAP basis $ 249 $ 238 Loss from operations $ (146 ) $ (150 ) Loss from operations on a non-GAAP basis $ (117 ) $ (119 ) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Recent Financial Highlights Revenue increased 10% in the first quarter of 2025 compared to the same period last year, driven by higher commercial revenue including new TRYNGOLZA product revenue following approval in late December and higher SPINRAZA and WAINUA royalty revenue Operating expenses increased slightly in the first quarter of 2025 driven by commercialization efforts for TRYNGOLZA, donidalorsen and WAINUA Increased 2025 financial guidance reflects recent successful licensing transactions: Full Year 2025 Guidance Previous Guidance New Guidance Revenue > $600 million $725-750 million Operating loss on a non-GAAP basis < $495 million < $375 million Cash, cash equivalents and short-term investments ~$1.7 billion ~$1.9 billion Recent Highlights - Marketed Medicines TRYNGOLZATM (olezarsen), the first-ever treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet, generated net product sales of over $6 million in its first full quarter following approval in the U.S. on December 19, 2024 Commercialization rights in countries outside of the U.S. , Canada and China licensed to Sobi EU approval decision anticipated in H2:2025 WAINUATM (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) achieved commercial and regulatory milestones: Generated sales of $39 million resulting in royalty revenue of $9 million in the first quarter of 2025 Launch underway in numerous countries, including the EU following approval by the European Commission (EC); additional global submissions in progress to expand WAINUA access SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $424 million resulting in royalty revenue of $48 million in the first quarter of 2025 Higher dose nusinersen under review for marketing approval in U.S. (PDUFA date of September 22, 2025 ) and EU Commercialization rights in countries outside of the U.S. , Canada and China licensed to Sobi EU approval decision anticipated in H2:2025 Generated sales of $39 million resulting in royalty revenue of $9 million in the first quarter of 2025 Launch underway in numerous countries, including the EU following approval by the European Commission (EC); additional global submissions in progress to expand WAINUA access Higher dose nusinersen under review for marketing approval in U.S. (PDUFA date of September 22, 2025 ) and EU Recent Highlights - Late-Stage Wholly Owned Pipeline Olezarsen on track for topline Phase 3 data from supportive ESSENCE study in Q2:2025 and pivotal CORE and CORE2 studies in patients with severe hypertriglyceridemia (sHTG) in Q3:2025, positioning olezarsen to potentially treat this second, more prevalent patient population with high unmet need Published Phase 3 study design and baseline characteristics for CORE, CORE2 and ESSENCE studies in the American Heart Journal , highlighting the potential to generate robust and meaningful data Donidalorsen on track for launch this year as the first RNA-targeted prophylactic treatment for people with hereditary angioedema (HAE), assuming approval: Under review for marketing approval in U.S. (PDUFA date of August 21, 2025 ) and EU Presented positive Phase 2 open label extension (OLE) study data demonstrating an overall sustained mean reduction in HAE attack rates of 96% in patients treated up to 196 weeks with every four weeks or every eight weeks dosing Published positive patient-reported outcomes (PROs) from Phase 3 OASIS-HAE study in Allergy showing donidalorsen significantly improved quality of life (QoL) and other PROs compared to placebo ION582 on track to initiate Phase 3 development in Angelman syndrome (AS) in Q2:2025 Published Phase 3 study design and baseline characteristics for CORE, CORE2 and ESSENCE studies in the American Heart Journal , highlighting the potential to generate robust and meaningful data Under review for marketing approval in U.S. (PDUFA date of August 21, 2025 ) and EU Presented positive Phase 2 open label extension (OLE) study data demonstrating an overall sustained mean reduction in HAE attack rates of 96% in patients treated up to 196 weeks with every four weeks or every eight weeks dosing Published positive patient-reported outcomes (PROs) from Phase 3 OASIS-HAE study in Allergy showing donidalorsen significantly improved quality of life (QoL) and other PROs compared to placebo Recent Highlights - Partnered Pipeline Pelacarsen Phase 3 Lp(a) HORIZON study design and baseline characteristics published in the American Heart Journal highlighting the potential to generate robust and meaningful data Licensed sapablursen global development and commercialization rights to Ono Pharmaceutical Co. generating $280 million in an upfront payment, with the potential to earn up to $660 million in additional payments plus royalties in the mid-teen percentage range on annual net sales IONIS-MAPTRx (BIIB080) received FDA Fast Track designation for the treatment of Alzheimer’s disease First Quarter 2025 Financial Results “We are increasing our 2025 financial guidance including raising revenue guidance by more than 20 percent due to our strong first quarter results and recent successful licensing transactions. We are also substantially improving our operating loss and cash guidance and now expect to end the year with approximately $1.9 billion in cash. Our strong financial position and commitment to drive operating leverage position Ionis to advance our strategic priorities and successfully navigate the dynamic macroeconomic environment,” said Elizabeth L. Hougen , chief financial officer, Ionis. “Our first quarter results reflected encouraging early performance in the TRYNGOLZA launch, adding product revenue to our P&L for the first time. Moving forward, the three additional independent launches anticipated over the next couple of years position Ionis to deliver substantial and growing product revenue. This product revenue coupled with anticipated increasing royalty revenue from multiple partner launches and disciplined investment, position Ionis to achieve sustained positive cash flow.” Revenue Ionis’ revenue was comprised of the following: Three months ended March 31 , 2025 2024 Revenue (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $ 6 $ - Total product sales, net 6 - Royalty revenue: SPINRAZA royalties 48 38 WAINUA royalties 9 1 Other royalties 7 10 Total royalty revenue 64 49 Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 6 9 Other revenue - 1 Total other commercial revenue 6 10 Total commercial revenue 76 59 Research and development revenue: Collaborative agreement revenue 46 49 WAINUA joint development revenue 10 11 Total research and development revenue 56 60 Total revenue $ 132 $ 119 Commercial revenue for the first quarter of 2025 increased 28% compared to the same period in 2024, driven in part by revenue from U.S. product sales from the launch of TRYNGOLZA. Higher royalty revenues from SPINRAZA, WAINUA and QALSODY also contributed to the year over year increase. The remainder of the Company’s revenue came from programs under its R&D collaborations, reflecting the value that Ionis’ pipeline and technology continues to generate. Operating Expenses SG&A expenses increased in the first quarter of 2025 compared to the same period in 2024 primarily due to the launches of WAINUA and TRYNGOLZA, and advancing launch preparation activities for donidalorsen. This increase was partially offset by a decrease in R&D expenses as several late-stage studies ended. Overall, this led to a slight increase in total operating expenses. Balance Sheet As of March 31, 2025 , Ionis’ cash, cash equivalents and short-term investments were $2.1 billion , compared to $2.3 billion at December 31, 2024 . Ionis’ working capital decreased over the same period primarily due to the Company’s lower cash and short-term investments balance. Ionis generated $280 million from the global license of sapablursen in the second quarter. Webcast Management will host a conference call and webcast to discuss Ionis’ first quarter 2025 results at 11:30 a.m. Eastern time on Wednesday, April 30, 2025 . Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company’s first quarter 2025 earnings slides click here. Ionis’ Marketed Medicines INDICATION for TRYNGOLZA™ (olezarsen) TRYNGOLZA™ (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. INDICATION for WAINUA™ (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the 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. For more information about SPINRAZA and QALSODY, visit https://www.spinraza.com/ and https://www.qalsody.com/, respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s). About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology and select 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), LinkedIn and Instagram. Ionis’ Forward-looking Statement This press release includes forward-looking statements regarding Ionis’ business, financial guidance and the therapeutic and commercial potential of our 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 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 December 31, 2024 , and most recent Form 10-Q, which are on file with the Securities and Exchange Commission . Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, “Ionis,” “Company,” “we,” “our” and “us” all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals ® is a registered trademark of Ionis Pharmaceuticals, Inc. TRYNGOLZATM is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics ® is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. SPINRAZA® and QALSODY® are registered trademarks of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. IONIS PHARMACEUTICALS, INC. SELECTED FINANCIAL INFORMATION Condensed Consolidated Statements of Operations (In Millions, Except Per Share Data) Three months ended March 31 , 2025 2024 (unaudited) Revenue: Commercial revenue: Product sales, net $ 6 $ - Royalty revenue 64 49 Other commercial revenue 6 10 Total commercial revenue 76 59 Research and development revenue: Collaborative agreement revenue 46 49 WAINUA joint development revenue 10 11 Total research and development revenue 56 60 Total revenue 132 119 Expenses: Cost of sales 1 2 Research, development and patent 201 214 Selling, general and administrative 76 53 Total operating expenses 278 269 Loss from operations (146 ) (150 ) Other income (expense): Interest expense related to the sale of future royalties (19 ) (18 ) Other income, net 18 25 Loss before income tax expense (147 ) (143 ) Income tax expense - - Net loss $ (147 ) $ (143 ) Basic and diluted net loss per share $ (0.93 ) $ (0.98 ) Shares used in computing basic and diluted net loss per share 159 146 IONIS PHARMACEUTICALS, INC. Reconciliation of GAAP to Non-GAAP Basis: Condensed Consolidated Operating Expenses, Loss From Operations, and Net Loss (In Millions) Three months ended March 31 , 2025 2024 (unaudited) As reported research, development and patent expenses according to GAAP $ 201 $ 214 Excluding compensation expense related to equity awards (20 ) (22 ) Non-GAAP research, development and patent expenses $ 181 $ 192 As reported selling, general and administrative expenses according to GAAP $ 76 $ 53 Excluding compensation expense related to equity awards (9 ) (9 ) Non-GAAP selling, general and administrative expenses $ 67 $ 44 As reported operating expenses according to GAAP $ 278 $ 269 Excluding compensation expense related to equity awards (29 ) (31 ) Non-GAAP operating expenses $ 249 $ 238 As reported loss from operations according to GAAP $ (146 ) $ (150 ) Excluding compensation expense related to equity awards (29 ) (31 ) Non-GAAP loss from operations $ (117 ) $ (119 ) As reported net loss according to GAAP $ (147 ) $ (143 ) Excluding compensation expense related to equity awards and related tax effects (29 ) (31 ) Non-GAAP net loss $ (118 ) $ (112 ) Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP loss from operations, and non-GAAP net loss were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis’ non-GAAP results is consistent with how Ionis’ management internally evaluates the performance of its operations. IONIS PHARMACEUTICALS, INC. Condensed Consolidated Balance Sheets (In Millions) March 31 , 2025 December 31 , 2024 (unaudited) Assets: Cash, cash equivalents and short-term investments $ 2,145 $ 2,298 Contracts receivable 40 92 Other current assets 234 230 Property, plant and equipment, net 103 94 Right-of-use assets 159 162 Other assets 132 127 Total assets $ 2,813 $ 3,003 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $ 81 $ 79 Other current liabilities 169 229 1.75% convertible senior notes, net 566 565 0% convertible senior notes, net 629 629 Liability related to sale of future royalties, net 536 542 Long-term lease liabilities 159 162 Long-term obligations, less current portion 56 52 Long-term deferred contract revenue 141 157 Total stockholders’ equity 476 588 Total liabilities and stockholders’ equity $ 2,813 $ 3,003 Key 2025 and 2026 Value Driving Events(1) New Product Launches Program Indication 2025 2026 Donidalorsen ( U.S. ) HAE • TRYNGOLZA ( U.S. ) FCS Achieved WAINZUA (EU) ATTRv-PN Achieved Olezarsen ( U.S. ) sHTG • Zilganersen ( U.S. ) Alexander disease • Regulatory Actions Program Indication Regulatory Action 2025 2026 Donidalorsen HAE U.S. approval decision • EU approval decision • TRYNGOLZA FCS EU approval decision • Olezarsen sHTG U.S. submission • U.S. approval decision • Zilganersen Alexander disease U.S. submission • U.S. approval decision • Nusinersen (higher dose) SMA U.S. and EU submissions Achieved U.S. approval decision • WAINZUA ATTRv-PN EU approval decision Achieved Pelacarsen Lp(a)- CVD U.S. submission • Bepirovirsen HBV Regulatory submission(s) • Regulatory decision(s) • Key Phase 3 Clinical Events Program Indication Event 2025 2026 Olezarsen sHTG CORE, CORE2 and Essence data • Zilganersen Alexander disease Phase 3 data • ION582 Angelman syndrome Phase 3 study start • Phase 3 enrollment completion • Pelacarsen Lp(a)-CVD Lp(a) HORIZON data • Bepirovirsen HBV B-Well data • Eplontersen ATTR-CM CARDIO-TTRansform data • Sefaxersen IgAN IMAGINATION data • Ulefnersen FUS-ALS FUSION data • Timing expectations based on current assumptions and subject to change. • Indicates that the milestone is anticipated in the respective year. View source version on businesswire.com: https://www.businesswire.com/news/home/20250430859857/en/ Ionis Investor Contact: D. Wade Walke , Ph.D. IR@ionis.com 760-603-2331 Ionis Media Contact: Hayley Soffer media@ionis.com 760-603-4679 Source: Ionis Pharmaceuticals, Inc.

CAMBRIDGE, Mass. and MUMBAI, India, March 28, 2025 /PRNewswire/ -- Particles for Humanity and Hexagon Nutrition Limited are excited to announce their new partnership to help address vitamin A deficiency (VAD) in Africa. Hexagon Nutrition has licensed the rights to manufacture and distribute Particles for Humanity's lead product, PFH-VAP, for fortifying bouillon cubes across Africa. PFH-VAP, a more stable formulation of dry vitamin A palmitate, is designed for use in large scale food fortification in geographies with hot and humid climates. Particles for Humanity partnered with Hexagon because of their shared commitment to ensuring all people have access to adequate nutrition to grow and thrive. "By joining forces with Hexagon Nutrition, we can accelerate the production and distribution of this critical product, ensuring it reaches those who need vitamin A the most. Combining Particles for Humanity's research and development expertise with Hexagon's established global distribution network advances a shared goal: improving lives with stable vitamin A," said Sherri Oberg, CEO at Particles for Humanity. In West Africa, bouillon is consumed by 80% to 99% of all households. In many of these countries, bouillon consumption remains high in the lowest income communities, where VAD is most prevalent. Children without enough vitamin A have decreased rates of growth and development and an increased risk of infection and death from serious illness. Vitamin A is also a leading cause of night blindness in women and can become permanent in severe cases. Though widespread consumption makes bouillon an ideal vehicle for combatting VAD, commercial forms of vitamin A often degrade in hot and humid conditions like those found in parts of West Africa. PFH-VAP was designed to address this issue. As a result, fortifying bouillon with PFH-VAP could save thousands of child-lives annually and improve the lives of millions of children and women in Nigeria alone. Under this new partnership, Hexagon Nutrition will have 3-year exclusive rights to manufacture and distribute PFH-VAP for bouillon fortification. Together Hexagon Nutrition and Particles for Humanity are taking an important step to expand access to lifesaving micronutrients in Africa. "Improving nutrition globally is at the core of our business. PFH-VAP will be another strong asset in our product portfolio. We are excited to leverage Hexagon Nutrition's ingredient manufacturing and premixing expertise to advance innovation and reduce the burden of malnutrition," said Vikram Kelkar, Managing Director of Hexagon Nutrition Limited. Particles for Humanity transforms early-stage medical technology into products for people living in low and lower-middle income countries. Its rigorous product development process is based on end-user input. Particles for Humanity is funded solely with philanthropy and is focused on financially sustainable product opportunities. Visit or contact [email protected] Hexagon Nutrition is a differentiated and research-oriented pure-play nutrition company offering clinical nutrition solutions products, micronutrient premixes, and therapeutic products. Hexagon Nutrition has presence across retail pharmacies, hospitals, and prominent e-commerce players. Hexagon markets products across India and exports to more than 70 countries. SOURCE Particles for Humanity WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Mar 20, 2025 − Novel Mechanism of Action Delivers Rapid Knockdown of Transthyretin, Addressing the Disease at its Source – − Proven Consistency of Effect on Cardiovascular Outcomes, Function, and Quality of Life in ATTR-CM Population Representative of Today’s Patients – – Only Therapeutic Approved in the U.S. to Address Both Cardiomyopathy and Polyneuropathy Manifestations of ATTR Amyloidosis − – Alnylam Offers Multiple Programs to Support Broad and Seamless Patient Access; Majority of Patients Expected to Pay $0 in Out-of-Pocket Costs for AMVUTTRA – – Alnylam to Host Conference Call Today at 6:00 pm ET – CAMBRIDGE, Mass. --(BUSINESS WIRE)--Mar. 20, 2025-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced the U.S. Food and Drug Administration (FDA) approval of the supplemental New Drug Application (sNDA) for its RNAi therapeutic, AMVUTTRA® (vutrisiran), 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. The approval expands the indication for AMVUTTRA, which now becomes the first and only therapeutic approved by the FDA for the treatment of ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20250319752041/en/ AMVUTTRA® (vutrisiran) product logo ATTR-CM is a devastating, rapidly progressive, and ultimately fatal disease estimated to affect approximately 150,000 people in the U.S. and over 300,000 people worldwide. There is no cure for ATTR-CM, and the deposition of misfolded transthyretin (TTR) fibrils causes irreversible damage over time which can lead to premature death. Today, most patients remain undiagnosed and untreated, and a significant portion of those who are treated with commonly used therapies experience disease progression. “The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal advancement for patients, providing a new and clinically differentiated treatment option that has been shown to improve outcomes, including cardiovascular mortality, and reduce progression for those living with this devastating disease,” said Yvonne Greenstreet , MBChB, Chief Executive Officer of Alnylam . “I would like to extend my deepest gratitude to the patients who participated in our clinical trials, their families and caregivers, the clinical researchers, regulators, and my colleagues at Alnylam who made this approval possible. Today represents a significant milestone in our nearly twenty years of partnership with the ATTR amyloidosis community, but we are not stopping here. We will continue to innovate for patients with ATTR amyloidosis so they can live longer, better, healthier lives.” AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of TTR, addressing the disease at its source, with only four convenient subcutaneous doses per year. By rapidly knocking down TTR production, AMVUTTRA substantially decreases deposition of TTR fibrils, which form amyloid and cause irreversible cardiovascular damage and premature death in patients with ATTR-CM. “This FDA approval provides an opportunity to further transform ATTR-CM treatment with a new mechanism of action. The HELIOS-B clinical trial found that vutrisiran allowed patients to live longer, experience fewer hospitalizations, and improve how they function and feel,” said Ronald Witteles, M.D., HELIOS-B Investigator, Professor of Medicine at Stanford University School of Medicine and Co-Director of the Stanford Amyloid Center . “The trial enrolled patients who mirror the real-world population with this disease, and I am very encouraged by vutrisiran’s ability to demonstrate meaningful clinical benefits across both cardiovascular outcomes and multiple measures of disease progression. This is a very exciting day for patients with this challenging disease.” This approval is based on the HELIOS-B Phase 3 clinical trial which evaluated AMVUTTRA for the treatment of ATTR-CM. The trial achieved statistical significance compared to placebo on all 10 pre-specified primary and secondary endpoints. The results were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine . In the overall population, AMVUTTRA reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events by 28% during the double-blind treatment period of up to 36 months. Mortality in this population was significantly reduced by 36% through 42 months in a pre-specified secondary endpoint analysis which included up to 36 months of the double-blind period plus six months of open-label extension. In the monotherapy population, AMVUTTRA significantly reduced the risk of ACM and recurrent CV events by 33% in the double-blind period and significantly reduced the risk of mortality by 35% through 42 months. As compared to patients treated with placebo, patients treated with AMVUTTRA also experienced preservation of functional capacity and quality of life, as well as early improvements in biomarkers NT-proBNP and troponin I, which are predictive of cardiovascular outcomes. The safety and tolerability of AMVUTTRA are well-established, as demonstrated in the positive HELIOS-A clinical trial for AMVUTTRA in hATTR-PN which resulted in FDA approval in 2022 and over 5,000 patient-years exposure to-date, globally. In that study, the most common adverse reactions in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). No new safety concerns were identified in the HELIOS-B clinical trial of patients with ATTR-CM. “Despite recent advances, there remains a significant need for patients living with ATTR-CM and I’ve witnessed, firsthand, the impact that ATTR amyloidosis can have on families, including diminished quality of life and the loss of loved ones,” said Muriel Finkel , President of the Amyloidosis Support Groups. “The availability of this groundbreaking treatment option is a significant moment for patients living with ATTR amyloidosis. It represents a beacon of hope for our community.” AMVUTTRA in hATTR-PN is covered by insurers for ~99% of patients with the majority paying $0 out-of-pocket. Similar broad coverage and out-of-pocket costs are expected in ATTR-CM given comparable payer dynamics and the clinical value demonstrated in the HELIOS-B clinical trial. Alnylam has a proven track record of working closely with payers to ensure broad patient access to our medicines, including pioneering innovative value-based agreements linked to clinical outcomes that ensure value and predictability for payers. Alnylam offers multiple support services and resources for patients prescribed its products through Alnylam Assist®, the only in-house patient support program in ATTR-CM. Alnylam Assist® is designed to provide one-on-one support for patients and their healthcare teams to help navigate the treatment journey, and includes a Quick Start program that provides eligible patients who encounter coverage delays or delays in treatment with an initial dose at no cost. In addition, Alnylam Assist® offers support with insurance coverage, financial assistance, and disease and treatment education for a seamless start to the AMVUTTRA treatment experience. Physicians and patients can learn more about Alnylam’s patient support services by visiting AlnylamAssist.com/amvuttra or calling 1-833-256-2748. Marketing authorization applications based on HELIOS-B data are currently under review by several global health agencies including the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Alnylam remains on track to proceed with additional global regulatory submissions for vutrisiran in 2025. Visit AMVUTTRA.com/attr-cm for more information. Investor Webcast Information Alnylam management will discuss the FDA approval of AMVUTTRA for ATTR-CM via webcast today at 6:00 pm 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 Company’s website approximately two hours after the event. INDICATIONS AND IMPORTANT SAFETY INFORMATION Indications AMVUTTRA® (vutrisiran) is indicated 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. polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. Important Safety Information Reduced Serum Vitamin A Levels and Recommended Supplementation AMVUTTRA 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 In a study of patients with hATTR-PN, the most common adverse reactions that occurred in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). In a study of patients with ATTR-CM, no new safety issues were identified. 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 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 with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit 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 safety and efficacy of AMVUTTRA for the treatment of ATTR-CM and hATTR-PN; that FDA approval of AMVUTTRA for ATTR-CM represents a pivotal advancement for patients, providing a new and clinically differentiated treatment option for ATTR-CM; the ability of AMVUTTRA to improve outcomes and reduce progression for patients with ATTR-CM; Alnylam’s ability to continue to innovate for patients with ATTR amyloidosis; the ability of AMVUTTRA or any of Alnylam’s other products or product candidates to enable patients with ATTR amyloidosis to live longer, better and/or healthier lives; the potential for AMVUTRA to transform the treatment of ATTR-CM; the ability of AMVUTTRA to provide ATTR-CM patients with benefits comparable to the clinical benefits observed in the HELIOS-B clinical trial; Alnylam’s expectations that AMVUTTRA in ATTR-CM will have coverage and out-of-pocket cost dynamics similar to AMVUTTRA’s coverage and out-of-pocket cost dynamics in hATTR-PN; and the potential receipt and timing of any future marketing authorizations or the timing of any future 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” 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. View source version on businesswire.com: https://www.businesswire.com/news/home/20250319752041/en/ Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom (Investors and Media) +1-617-682-4340 Josh Brodsky (Investors) +1-617-551-8276 Source: Alnylam Pharmaceuticals, Inc. For Media Inquiries, please contact: Christine Lindenboom Chief Corporate Communications Officer media@alnylam.com 617-682-4340 For Investor Inquiries, please contact: Josh Brodsky VP, Investor Relations & Corporate Communications investors@alnylam.com 617-551-8276 Essential assets and documents related to Alnylam