Hemin

− Achieved Fourth Quarter and Full Year 2025 Global Net Product Revenues of $995 Million and $2,987 Million, Respectively, Representing 121% and 81% Growth Compared to Same Periods in 2024 – − Attained GAAP and non-GAAP Profitability for Full Year 2025, with Sustainable Growth in Operating Income Expected – − Launched “ Alnylam 2030 ” Strategy Focused on Scaling Alnylam through Durable ATTR Leadership, Long-Term Sustainable Innovation, and Exceptional Financial Results – − Announced 2026 Pipeline Goals, Including 4 Clinical Readouts, 3 Ongoing Pivotal Studies, 3 Phase 2 Study Initiations, and 3+ New IND Filings – − Reiterates Net Product Sales Guidance and Provides Additional 2026 Financial Guidance – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the fourth quarter and full year ended December 31, 2025 and reviewed recent business highlights. “2025 was a year of key accomplishments for Alnylam, highlighted by the landmark approval of AMVUTTRA for ATTR-CM in the U.S., which drove total net product revenues of nearly $3 billion, or 81% growth year-over-year, and propelled us to profitability. We also achieved great progress across our portfolio, initiating three Phase 3 studies, expanding our pipeline with four proprietary CTAs, and launching a potential best-in-class enzymatic ligation-based RNAi manufacturing platform,” said Yvonne Greenstreet, M.D., Chief Executive Officer of Alnylam. “Further, we are excited to have recently unveiled our new set of five-year aspirational goals, Alnylam 2030 , under which we aim to achieve global TTR leadership with a durable franchise; grow through innovation by delivering therapies that prevent, halt, or reverse disease; and scale with financial discipline and agility. By pursuing these ambitious goals, we believe Alnylam will drive substantial patient impact by addressing serious unmet medical needs around the world and create substantial long-term shareholder value.” Fourth Quarter 2025 and Recent Significant Business Highlights Total TTR: AMVUTTRA ® (vutrisiran) & ONPATTRO ® (patisiran) Achieved global net product revenues for AMVUTTRA and ONPATTRO for the fourth quarter of $827 million and $32 million, respectively, together representing 151% total TTR growth compared to Q4 2024, and full year 2025 revenues of $2,314 million and $173 million, respectively, together representing 103% total TTR growth compared to full year 2024. Presented new analyses from the HELIOS-B Phase 3 clinical trial of vutrisiran in patients with ATTR-CM at the American Heart Association Scientific Sessions 2025 . Cardiovascular magnetic resonance (CMR) and echocardiographic analyses demonstrated that treatment with vutrisiran resulted in significant changes indicating significant improvement on multiple functional and structural cardiac parameters. CMR imaging showed amyloid regression in 22% of vutrisiran treated patients with no regression found in patients who received placebo. Treatment with vutrisiran preserved kidney function in HELIOS-B patients, and reduced risk of death and cardiovascular events in patients with advanced chronic kidney disease. Total Rare: GIVLAARI ® (givosiran) & OXLUMO ® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the fourth quarter of $87 million and $50 million, respectively, together representing 26% total Rare growth compared to Q4 2024, and full year 2025 revenues of $308 million and $191 million, respectively, together representing $500 million in revenues and 18% total Rare growth compared to full year 2024. Other Highlights Initiated a Phase 2 clinical trial of ALN-4324 , an investigational RNAi therapeutic targeting GRB14 for type 2 diabetes mellitus. Initiated a Phase 1 clinical trial of ALN-2232 , an investigational RNAi therapeutic targeting ACVR1C in adipose tissue for obesity and weight management. Advanced two new programs ( ALN-4285 and ALN-4915 ) into clinical development in healthy volunteers. Announced the planned expansion of its state-of-the-art manufacturing facility in Norton, Massachusetts. The Company plans to invest $250 million to develop the industry's first fully dedicated, proprietary siRNA enzymatic-ligation manufacturing facility. This new enzymatic-ligation platform, siRELIS™, is expected to meaningfully expand capacity, significantly reduce production costs, and position the Company to support future launches across its growing pipeline of potential new medicines. Additional Business Updates Announced changes to the Company's Board of Directors, including the departures of Mike Bonney and Carolyn Bertozzi, Ph.D., and the appointment of Stuart Arbuckle. Key Upcoming Events The Company will host an investor webinar marking the one-year anniversary of the FDA approval of AMVUTTRA in ATTR-CM on March 24, 2026. The Company will highlight progress in delivering for ATTR-CM patients and the long-term growth and durability of its flagship TTR franchise. In the first half of 2026, Alnylam expects to: Complete enrollment in the cAPPricorn-1 Phase 2 clinical trial of mivelsiran in patients with cerebral amyloid angiopathy. Initiate a Phase 2 clinical trial of mivelsiran in patients with Alzheimer's disease. Initiate a Phase 2 clinical trial of ALN-6400 in a second bleeding disorder. In the second half of 2026, Alnylam expects to announce clinical de-risking data from several pipeline programs, including: Results from Phase 1 and Phase 2 clinical trials of ALN-6400 in healthy volunteers and patients with hereditary hemorrhagic telangiectasia (HHT), respectively. Results from a Phase 1 clinical trial of ALN-HTT02 in patients with Huntington's disease. Results from a Phase 1 clinical trial of ALN-2232 in obesity and weight management. Financial Results for the Fourth Quarter and Full Year 2025 Three Months Ended December 31, Twelve Months Ended December 31, (In thousands, except per share amounts) 2025 2024 2025 2024 Total revenues $ 1,097,033 $ 593,166 $ 3,713,937 $ 2,248,243 GAAP Income (loss) from operations $ 131,718 $ (105,159 ) $ 501,578 $ (176,885 ) Non-GAAP Income (loss) from operations $ 203,350 $ (13,514 ) $ 849,813 $ 95,199 GAAP Net income (loss) $ 111,543 $ (83,763 ) $ 313,747 $ (278,157 ) Non-GAAP Net income (loss) $ 169,753 $ 8,048 $ 683,644 $ (3,051 ) GAAP Net income (loss) per common share — basic $ 0.84 $ (0.65 ) $ 2.39 $ (2.18 ) GAAP Net income (loss) per common share — diluted $ 0.82 $ (0.65 ) $ 2.33 $ (2.18 ) Non-GAAP Net income (loss) per common share — basic $ 1.28 $ 0.06 $ 5.22 $ (0.02 ) Non-GAAP Net income (loss) per share — diluted $ 1.25 $ 0.06 $ 5.08 $ (0.02 ) For an explanation of our use of non-GAAP financial measures, refer to the “Use of Non-GAAP Financial Measures” section later in this press release and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measure, see the tables at the end of this press release. Revenue Summary Three Months Ended December 31, (In thousands, except percentages) 2025 2024 % Change At CER* Net product revenues: AMVUTTRA $ 826,588 $ 286,510 189 % 187 % ONPATTRO 31,687 56,103 (44 )% (45 )% Total TTR net product revenues 858,275 342,613 151 % 149 % GIVLAARI 86,796 64,645 34 % 32 % OXLUMO 49,646 43,573 14 % 10 % Total Rare net product revenues 136,442 108,218 26 % 23 % Total net product revenues 994,717 450,831 121 % 119 % Net revenues from collaborations: Roche 32,954 12,014 174 % 174 % Regeneron Pharmaceuticals 7,834 30,657 (74 )% (74 )% Novartis AG — 60,003 (100 )% (100 )% Other 155 4,274 (96 )% (96 )% Total net revenues from collaborations 40,943 106,948 (62 )% (62 )% Royalty revenue 61,373 35,387 73 % 73 % Total revenues $ 1,097,033 $ 593,166 85 % 83 % * Change at constant exchange rates, or CER, represents percent change calculated as if exchange rates had remained unchanged from those used during the three months ended December 31, 2024. CER is a non-GAAP financial measure. Twelve Months Ended December 31, (In thousands, except percentages) 2025 2024 % Change At CER* Net product revenues: AMVUTTRA $ 2,313,836 $ 970,450 138 % 137 % ONPATTRO 172,789 252,857 (32 )% (32 )% Total TTR net product revenues 2,486,625 1,223,307 103 % 102 % GIVLAARI 308,487 255,871 21 % 20 % OXLUMO 191,437 167,050 15 % 13 % Total Rare net product revenues 499,924 422,921 18 % 17 % Total net product revenues 2,986,549 1,646,228 81 % 80 % Net revenues from collaborations: Roche 394,881 119,489 230 % 230 % Regeneron Pharmaceuticals 113,957 302,798 (62 )% (62 )% Novartis AG — 79,759 (100 )% (100 )% Other 44,528 8,175 445 % 445 % Total net revenues from collaborations 553,366 510,221 8 % 8 % Royalty revenue 174,022 91,794 90 % 90 % Total revenues $ 3,713,937 $ 2,248,243 65 % 64 % * Change at constant exchange rates, or CER, represents growth calculated as if exchange rates had remained unchanged from those used during the twelve months ended December 31, 2024. CER is a non-GAAP financial measure. Total Net Product Revenues Net product revenues increased 121% and 81% at actual currency during the three and twelve months ended December 31, 2025, respectively, compared to the same periods in 2024, and 119% and 80% at CER, respectively. The increases were primarily due to growth from AMVUTTRA revenues driven by increased patient demand, mainly in patients with ATTR-CM in the U.S., which was partially offset by a decreased number of patients on ONPATTRO, and due to growth from an increased number of patients on GIVLAARI and OXLUMO. Net Revenues from Collaborations Net revenues from collaborations decreased $66 million during the three months ended December 31, 2025, as compared to the same period in 2024, primarily due to revenue recognized under our license agreement with Novartis associated with the achievement of a specified Leqvio commercialization milestone during the three months ended December 31, 2024. Net revenues from collaborations increased by $43 million during the twelve months ended December 31, 2025, as compared to the same period in 2024, primarily driven by recognition of $300 million of milestone revenue under our collaboration with Roche in September 2025 associated with the dosing of the first patient in the ZENITH Phase 3 clinical trial of zilebesiran and recognition of a $30 million payment in connection with the amendment to our agreement with Vir Biotechnology in March 2025. In comparison, during 2024, we recognized $185 million in revenues under our collaboration with Regeneron as we modified the collaboration in June 2024 and provided Regeneron with an exclusive license to develop, manufacture and commercialize cemdisiran as a monotherapy, and also recognized $65 million of milestone revenue under our collaboration with Roche in March 2024 associated with the dosing of the first patient in the KARDIA-3 Phase 2 clinical trial of zilebesiran. Royalty Revenue Royalty revenue increased during the three and twelve months ended December 31, 2025, as compared to the same periods in 2024, due to increased volume and rate of royalties earned from global net sales of Leqvio by Novartis. Operating Expense Summary Three Months Ended December 31, Twelve Months Ended December 31, (In thousands, except percentages) 2025 2024 % Change 2025 2024 % Change Cost of goods sold $ 267,723 $ 102,649 161 % $ 677,166 $ 306,513 121 % % of net product revenues 26.9 % 22.8 % 22.7 % 18.6 % Cost of collaborations and royalties $ — $ 168 (100 )% $ 4,705 $ 16,857 (72 )% GAAP Research and development expenses $ 372,218 $ 300,169 24 % $ 1,319,775 $ 1,126,232 17 % Non-GAAP Research and development expenses $ 340,898 $ 259,544 31 % $ 1,166,380 $ 998,483 17 % GAAP Selling, general and administrative expenses $ 325,374 $ 295,339 10 % $ 1,210,713 $ 975,526 24 % Non-GAAP Selling, general and administrative expenses $ 285,062 $ 244,319 17 % $ 1,015,873 $ 831,191 22 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues increased during the three and twelve months ended December 31, 2025, as compared to the same periods in 2024, primarily as a result of increased sales of AMVUTTRA and an associated increase in the blended royalty rate payable on net sales of AMVUTTRA. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three and twelve months ended December 31, 2025, as compared to the same periods in 2024, primarily due to increased clinical trial expenses for the ZENITH Phase 3 clinical trial of zilebesiran, the TRITON-CM Phase 3 clinical trial of nucresiran in patients with ATTR-CM and the TRITON-PN Phase 3 clinical trial of nucresiran in patients with hATTR-PN, as well as increased employee compensation and related expenses to support our research and development pipeline and development expenses. Additionally, GAAP R&D expenses increased due to higher stock-based compensation expenses. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three and twelve months ended December 31, 2025, as compared to the same periods in 2024, primarily due to higher employee compensation costs, including stock-based compensation, mainly driven by higher headcount, and increased marketing investment associated with the commercial launch of AMVUTTRA in ATTR-CM. Other Financial Highlights Interest expense Interest expense for the three and twelve months ended December 31, 2025 of $65 million and $253 million, respectively, included interest of $38 million and $150 million, respectively, attributed to the liability related to the sale of future Leqvio royalties, and $25 million and $89 million, respectively, attributed to the liabilities related to the vutrisiran and zilebesiran development funding. Benefit from (provision for) income taxes During the three months year ended December 31, 2025, we recorded a benefit from income taxes of $25 million primarily related to the generation of Switzerland deferred tax assets, partially offset by additional U.S state income tax. During the twelve months ended December 31, 2025, we recorded a provision for income taxes of $9 million primarily related to U.S state income taxes, utilization of Switzerland net deferred tax assets, as well as taxable income from jurisdictions in which we are subject to tax. We will continue to utilize deferred tax assets in Switzerland to offset current cash tax liabilities and will continue to monitor the requirement for a valuation allowance against our net deferred tax assets in the U.S. and certain deferred tax assets in Switzerland. Financial position Cash, cash equivalents and marketable securities were $2.91 billion as of December 31, 2025, as compared to $2.69 billion as of December 31, 2024, with the increase primarily due to improved operating performance, proceeds from exercise of stock options, and net proceeds from the issuance of our 0.00% convertible senior notes due 2028, offset in part by cash paid for the partial repurchases of our 1.00% convertible senior notes due 2027. Net cash provided by operating activities for the three and twelve months ended December 31, 2025 included $23 million and $118 million, respectively, of payments associated with the liability related to the sale of future Leqvio royalties recorded to interest expense, as well as $30 million and $85 million, respectively, of payments associated with the liabilities related to vutrisiran and zilebesiran development funding recorded to interest expense. A reconciliation of our GAAP to non-GAAP results for the three and twelve months ended December 31, 2025 and 2024, is included in the tables at the end of this press release. 2026 Financial Guidance Full-year 2026 financial guidance is summarized below: Total TTR net product revenues (AMVUTTRA, ONPATTRO) 1 $4,400 million - $4,700 million Total Rare net product revenues (GIVLAARI, OXLUMO) 1 $500 million - $600 million Total net product revenues 1 $4,900 million - $5,300 million Net product revenues growth vs. 2025 at currency exchange rates as of December 31, 2025 2 64% - 77% Net product revenues growth vs. 2025 at constant exchange rates 2 64% - 77% Net revenues from collaborations and royalties $400 million - $500 million Non-GAAP R&D and SG&A expenses 3 $2,700 million - $2,800 million 1 Full-year 2026 guidance utilizing currency exchange rates as of December 31, 2025: 1 EUR = 1.17 USD and 1 USD = 157 JPY 2 Representing growth calculated as if the exchange rates had remained unchanged from those used in 2025, which is a non-GAAP financial measure 3 Excludes $300 million - $400 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains or losses outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses, loss related to convertible debt, and realized and unrealized gains or losses on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the loss related to convertible debt because the Company believes the item is a non-recurring transaction outside the ordinary course of the Company’s business. The Company has excluded the impact of the realized and unrealized gains or losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. Percentage changes in revenue growth at CER are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss fourth quarter and full year 2025 results as well as expectations for the future via conference call on Thursday, February 12, 2026 at 8:30 am ET. A live audio webcast of the call will be available on the Investors section of the Company’s website at . An archived webcast will be available on the Alnylam website approximately two hours after the event. 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 for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and 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 ONPATTRO ® (patisiran) ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of adults with hATTR amyloidosis with polyneuropathy. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information , visit ONPATTRO.com . About GIVLAARI ® (givosiran) GIVLAARI (givosiran) is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal trial, GIVLAARI was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information , visit GIVLAARI.com . About OXLUMO ® (lumasiran) OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Contacts Alnylam Pharmaceuticals, Inc. Christine Akinc (Investors and Media) 617-682-4340 Josh Brodsky (Investors) 617-551-8276 Read full story here

ALS and FTD remain challenging diseases to treat” — Alan Herbert CHARLESTOWN, MA, UNITED STATES, December 19, 2025 / EINPresswire.com / -- In a paper just published in the journal Antioxidants, the expansion of disease-causing DNA repeats is linked to the formation of a complex that generates superoxide anions toxic to neurons. The repeat expansion is found in Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease) and in cases of Frontal Temporal Dementia. The paper, “ G-Quadruplexes Abet Neuronal Burnout in ALS and FTD,” by Alan Herbert of InsideOutBio, describes how these repeats fold into four-stranded structures called G-quadruplexes (GQs). The GQ formed has a propensity to bind hemin, a normal cellular constituent. The complex acts as a peroxidase, generating oxygen radicals that damage nerve cells and contribute to disease outcomes. Hemin is a normal cellular component. It is essential for ATP generation by mitochondria. Hemin usually complexes generate the highly reactive oxygen radicals that help mitochondria convert food into energy. The binding of hemin to GQ also enhances its production of oxygen radicals. The process occurs in the cytoplasm, where the repeat RNA can form the GQ that activates hemin. This “peroxidase” activity of the GQ-hemin complex is usually suppressed by cellular proteins that bind to it. In some cases, protein variants that are unable to suppress superoxide production increase the risk of disease. Preventing the formation of the GQ-hemin peroxidase offers a potentially new treatment option. These therapeutics are currently under investigation but are not ready for clinical use. This paper captures the expanding knowledge on the role of flipons in health and disease. Flipons are repeat elements present in our genome that encode RNAs able to fold into unusual structures. Besides G-quadruplexes, they can also form left-handed Z-RNA and three-stranded triplex structures. Flipons are a focus of InsideOutBio. About InsideOutBio: InsideOutBio is a start-up focused on developing a novel class of proprietary therapeutics to 'light' up tumors for the immune system to kill by reprogramming self/nonself pathways within cancer cells. Dr. Herbert leads discovery at InsideOutBio. His work on Z-DNA was foundational to the discovery of flipons. These statements about InsideOutBio comply with Safe-Harbor laws. They are forward-looking and involve known and unknown risks and uncertainties. They are not guarantees of future performance, and undue reliance should not be placed on them. Alan Herbert InsideOutBio, Inc +1 617-800-7531 email us here Visit us on social media: X Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.