A Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics, and Pharmacokinetics of Zilebesiran in Japanese Patients With Mild to Moderate Hypertension

The purpose of this study is to evaluate the safety, tolerability, efficacy, pharmacodynamics (PD) and pharmacokinetics (PK) of zilebesiran in Japanese patients with mild to moderate hypertension.

Start Date07 Jun 2024

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

NCT06272487 / RecruitingPhase 2

A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Adult Patients With High Cardiovascular Risk and Hypertension Not Adequately Controlled by Standard of Care Antihypertensive Medications

The purpose of this study is to evaluate the effect of zilebesiran as add-on therapy in patients with high cardiovascular risk and hypertension not adequately controlled by standard of care antihypertensive medications.

Start Date29 Feb 2024

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

NCT05103332 / Active, not recruitingPhase 2

A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication

The purpose of this study is to evaluate the effect of zilebesiran on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of zilebesiran as add-on therapy.

Start Date05 Nov 2021

Sponsor / Collaborator

Alnylam Pharmaceuticals, Inc.

100 Clinical Results associated with Zilebesiran

100 Translational Medicine associated with Zilebesiran

100 Patents (Medical) associated with Zilebesiran

Literatures (Medical) associated with Zilebesiran

01 Dec 2023·Giornale italiano di cardiologia (2006)

[Gene therapy for hypertension: focus on zilebesiran].

Article

Author: Angeli, Fabio ; Bartolini, Claudia ; Zappa, Martina ; Verdecchia, Paolo

02 Nov 2023·Expert review of clinical pharmacology

Emerging insights and future prospects for therapeutic application of siRNA targeting angiotensinogen in hypertension

Article

Author: Addison, Melisande L ; Ranasinghe, Priyanga ; Webb, David J

INTRODUCTION:

Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA (small interfering ribonucleic acid) therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, and durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach.

AREAS COVERED:

This article describes the molecular basis for durability over months and the 24-h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a siRNA targeting hepatic angiotensinogen, which reduces blood pressure (BP) by up to 20 mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran.

EXPERT OPINION:

Further studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime BP due to 24-h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran.

01 Nov 2023·Hypertension (Dallas, Tex. : 1979)

Novel Pharmacological Approaches in the Treatment of Hypertension: A Focus on RNA-Based Therapeutics

Review

Author: Addison, Melisande L ; Ranasinghe, Priyanga ; Webb, David J

Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LR X , and the small-interfering RNA, zilebesiran. Conjugation to N-acetylgalactosamine enables targeted delivery to hepatocytes, where endosomal storage, slow leakage, and small-interfering RNA recycling (for zilebesiran) result in knockdown over several months. Indeed, zilebesiran has an impressive and durable effect on systolic BP, reduced by up to 20 mm Hg and sustained for 6 months after a single administration, likely due to its very effective knockdown of angiotensinogen, without causing acute kidney injury or hyperkalemia. By contrast, IONIS-AGT-LR X caused less knockdown and marginal effects on BP. Future studies should evaluate any loss of efficacy relating to antidrug antibodies, safety issues associated with long-term angiotensinogen suppression, and broader benefits, especially in the context of common comorbidities such as type 2 diabetes and chronic kidney disease.

News (Medical) associated with Zilebesiran

02 May 2024

·www.biospace.com

Alnylam Pharmaceuticals Reports First Quarter 2024 Financial Results and Highlights Recent Period Activity

− Achieved First Quarter 2024 Global Net Product Revenues of $365 Million, Representing 32% Year-Over-Year Growth Compared to Q1 2023, Including Continued Momentum from Total TTR Delivering 29% Year-Over-Year Growth – − Demonstrated Strong Progress with Zilebesiran Hypertension Program with Positive Results from KARDIA-2 Phase 2 Study and Initiation of KARDIA-3 Phase 2 Study – − Remain on Track to Report Topline Results from HELIOS-B Phase 3 Study of Vutrisiran in Late June or Early July – − Reiterated 2024 Financial Guidance, Including Combined Net Product Revenues of $1,400 Million to $1,500 Million – CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the first quarter ended March 31, 2024 and reviewed recent business highlights. “2024 is off to a strong start, with exceptional commercial performance where we delivered $365 million in global net product revenues, representing 32% year-over-year growth for our four wholly owned products. We also made great progress with our pipeline, particularly with the zilebesiran program in hypertension, for which we reported positive results from the KARDIA-2 Phase 2 study, and initiated the KARDIA-3 Phase 2 study,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “Looking ahead, we are eagerly awaiting topline results from the HELIOS-B Phase 3 study of vutrisiran in late June or early July, potentially expanding our leadership in ATTR amyloidosis. Additionally, we look forward to early-stage developments with mivelsiran (formerly ALN-APP), where we expect to start a Phase 2 study in cerebral amyloid angiopathy in the coming months. These achievements position us well to deliver on our Alnylam P5x25 goals of becoming a top-tier biotech company delivering sustained innovation and exceptional financial results.” First Quarter 2024 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO® (patisiran) & AMVUTTRA® (vutrisiran) Continued growth momentum in total TTR, achieving global net product revenues for ONPATTRO and AMVUTTRA for the first quarter of $69 million and $195 million, respectively, representing 4% total TTR quarterly growth compared to Q4 2023 and 29% annual growth compared to Q1 2023. Total Rare: GIVLAARI® (givosiran) & OXLUMO® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the first quarter of $58 million and $43 million, respectively, representing 9% total Rare quarterly growth compared to Q4 2023 and 40% annual growth compared to Q1 2023. R&D Highlights Announced updates to the statistical analysis plan for the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy, including adjustments to the primary and secondary endpoints and analysis period. Topline results remain on track to be reported in late June or early July. Reported positive results from the KARDIA-2 Phase 2 study of zilebesiran added to standard-of-care antihypertensives in patients with inadequately controlled hypertension. Initiated the global KARDIA-3 Phase 2 study of zilebesiran in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard of care antihypertensive medications. Study initiation triggered a $65 million milestone payment from Roche. Published results from the Phase 2 KARDIA-1 study of zilebesiran in the Journal of the American Medical Association (JAMA). Received clearance from the U.S. Food and Drug Administration (FDA) to initiate the multiple-dose part (Part B) of the ongoing Phase 1 study of mivelsiran (formerly ALN-APP) in early onset Alzheimer’s disease. The FDA has confirmed that multiple-dosing in the Phase 1 study may proceed at doses up to 180 mg given every six months, which covers all dose regimens planned to be explored in Part B. A partial clinical hold remains for higher or more frequent dosing regimens. Presented new preclinical data for ALN-HTT02, an investigational RNAi therapeutic targeting huntingtin (HTT) in development for the treatment of Huntington’s disease at the CHDI Foundation’s 19th Annual Huntington’s Disease Therapeutics Conference. Upcoming Events In early and mid-2024, Alnylam intends to: Report topline results from the HELIOS-B Phase 3 study of vutrisiran in late June or early July. Initiate a Phase 2 study of mivelsiran (formerly ALN-APP) in patients with cerebral amyloid angiopathy. Initiate Part B of the Phase 1 study of ALN-KHK, in development for the treatment of Type 2 diabetes mellitus. Initiate a Phase 1 study of ALN-BCAT, in development for the treatment of hepatocellular carcinoma. Financial Results for the Quarter Ended March 31, 2024 Three Months Ended March 31, (In thousands, except per share amounts) 2024 2023 Net product revenues $ 365,163 $ 276,328 Net revenue from collaborations $ 118,548 $ 36,462 Royalty revenue $ 10,622 $ 6,500 GAAP Operating loss $ (43,435 ) $ (149,807 ) Non-GAAP Operating gain (loss) $ 1,912 $ (109,860 ) GAAP Net loss $ (65,935 ) $ (174,101 ) Non-GAAP Net loss $ (20,666 ) $ (131,887 ) GAAP Net loss per common share - basic and diluted $ (0.52 ) $ (1.40 ) Non-GAAP Net loss per common share - basic and diluted $ (0.16 ) $ (1.06 ) 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 measures, see the table at the end of this press release. Net Product Revenues Three Months Ended March 31, Year over Year % Growth (In thousands, except percentages) 2024 2023 As Reported At CER* ONPATTRO net product revenues $ 69,217 $ 102,493 (32)% (33)% AMVUTTRA net product revenues 195,241 101,768 92% 93% Total TTR net product revenues 264,458 204,261 29% 30% GIVLAARI net product revenues 58,056 47,906 21% 21% OXLUMO net product revenues 42,649 24,161 77% 75% Total Rare net product revenues 100,705 72,067 40% 39% Total net product revenues $ 365,163 $ 276,328 32% 32% * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the first quarter 2023. CER is a Non-GAAP measure. Total net product revenues increased 32% at both actual currency and CER during the three months ended March 31, 2024, as compared to the same period in 2023, due to strong growth from AMVUTTRA driven by increased patient demand, as well as increased patients on our GIVLAARI and OXLUMO therapies. Net Revenues from Collaborations Net revenues from collaborations increased 225% during the three months ended March 31, 2024, as compared to the same period in 2023, primarily due to revenue recognized under our collaboration and license agreement with Roche, including $65 million of milestone revenue associated with dosing the first patient in the zilebesiran KARDIA-3 clinical trial, and an increase in revenue recognized under our collaboration agreement with Regeneron as a result of an increase in activities under our research services arrangement and licensed programs. Operating Expenses Three Months Ended March 31, (In thousands, except percentages) 2024 2023 Cost of goods sold $ 54,613 $ 41,432 Cost of goods sold as a percentage of net product revenues 15.0 % 15.0 % Cost of collaborations and royalties $ 11,363 $ 13,437 GAAP research and development expenses $ 260,995 $ 230,569 Non-GAAP research and development expenses $ 241,780 $ 214,337 GAAP selling, general and administrative expenses $ 210,797 $ 183,659 Non-GAAP selling, general and administrative expenses $ 184,665 $ 159,944 Cost of Goods Sold Cost of goods sold as a percentage of net product revenues was consistent during the three months ended March 31, 2024, as compared to the same period in 2023, primarily due to increased royalties related to higher AMVUTTRA sales volume, partially offset by one-time favorability attributed to reduced ONPATTRO manufacturing cancellation fees. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three months ended March 31, 2024, as compared to the same period in 2023, primarily due to increased development expenses associated with zilebesiran in the KARDIA-2 and KARDIA-3 clinical studies, increased expenses associated with our HELIOS-B study leading up to the topline data readout in late June or early July 2024, increased costs associated with our preclinical activities, specifically our CNS programs, and increased headcount and infrastructure expenses to support our R&D pipeline. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three months ended March 31, 2024, as compared to the same period in 2023, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased headcount and other investments supporting our strategic growth. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.37 billion as of March 31, 2024 compared to $2.44 billion as of December 31, 2023 with the decrease primarily due our operating loss in the first quarter 2024. A reconciliation of our GAAP to non-GAAP results for the quarter is included in the tables at the end of this press release. 2024 Financial Guidance Full year 2024 financial guidance is reiterated as follows: Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO1 $1,400 million - $1,500 million Net Product Revenue Growth vs. 2023 at reported FX rates1 13% to 21% Net Product Revenue Growth vs. 2023 at CER* 13% to 21% Net revenues from collaborations and royalties $325 million - $425 million GAAP R&D and SG&A expenses $1,900 million - $2,050 million Non-GAAP R&D and SG&A expenses2 $1,675 million - $1,775 million 1 Uses January 31, 2024 FX rates including: 1 EUR = 1.08 USD and 1 USD = 147 JPY 2 Primarily excludes $225 - $275 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses *CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the twelve months ended December 31, 2023. CER is a Non-GAAP measure. Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses and realized and unrealized losses on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the realized and unrealized losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. Percentage changes in revenue growth at CER are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss first quarter 2024 results as well as expectations for the future via conference call on Thursday, May 2, 2024 at 8:30 am ET. To access the call, please register online at . Participants are requested to register at least 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. 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 ONPATTRO® (patisiran) ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of adults with hATTR amyloidosis with polyneuropathy. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information, visit ONPATTRO.com. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic approved in the United States for the treatment of adults with hATTR amyloidosis with polyneuropathy. It is a double-stranded small interfering RNA (siRNA) that targets mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). Using Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, AMVUTTRA is designed for increased potency and high metabolic stability to allow for subcutaneous injection once every three months (quarterly). Results from the pivotal HELIOS-A Phase 3 study demonstrate AMVUTTRA rapidly reduces serum TTR levels, has the potential to reverse neuropathy impairment relative to baseline and improves other key measures of disease burden relative to external placebo in patients with the polyneuropathy of hATTR amyloidosis. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About GIVLAARI® (givosiran) GIVLAARI (givosiran) is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information, visit GIVLAARI.com. About OXLUMO® (lumasiran) OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. OXLUMO has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety pro to that observed in ILLUMINATE-A. In the ILLUMINATE-C study, OXLUMO resulted in substantial reductions in plasma oxalate in patients with advanced PH1. Across all three studies, injection site reactions (ISRs) were the most common drug-related adverse reaction. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly beginning one month after the last loading dose at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, including the full U.S. Prescribing Information, visit OXLUMO.com. About LNP Technology Alnylam has licenses to Arbutus Biopharma lipid nanoparticle (LNP) intellectual property for use in RNAi therapeutic products using LNP technology. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam 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 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 aspiration to become a top-tier biotech company, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing commercial products, and Alnylam’s projected commercial and financial performance, including the expected range of net product revenues and net revenues from collaborations and royalties for 2024, the expected range of aggregate annual GAAP and non-GAAP R&D and SG&A expenses for 2024, the expected timing of topline data from the HELIOS-B Phase 3 clinical study, and the planned achievement of its “Alnylam P5x25” strategy, 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 discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran, zilebesiran, and ALN-APP; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the approved indications for AMVUTTRA in the future; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial pro the future without the need for future equity financing; the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products, including Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the risk of future government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval. ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) March 31, 2024 December 31, 2023 ASSETS (Unaudited) Current assets: Cash and cash equivalents $ 681,879 $ 812,688 Marketable debt securities 1,678,147 1,615,516 Marketable equity securities 11,256 11,178 Accounts receivable, net 321,377 327,787 Inventory 93,988 89,146 Prepaid expenses and other current assets 201,960 126,382 Total current assets 2,988,607 2,982,697 Property, plant and equipment, net 523,460 526,057 Operating lease right-of-use assets 195,468 199,732 Restricted investments 49,390 49,391 Other assets 67,461 72,003 Total assets $ 3,824,386 $ 3,829,880 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 78,148 $ 55,519 Accrued expenses 698,865 713,013 Operating lease liability 41,672 41,510 Deferred revenue 76,850 102,753 Liability related to the sale of future royalties 46,174 54,991 Total current liabilities 941,709 967,786 Operating lease liability, net of current portion 237,829 243,101 Deferred revenue, net of current portion 185,506 188,175 Convertible debt 1,021,732 1,020,776 Liability related to the sale of future royalties, net of current portion 1,336,892 1,322,248 Other liabilities 319,990 308,438 Total liabilities 4,043,658 4,050,524 Commitments and contingencies (Note 13) Stockholders’ deficit: Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of March 31, 2024 and December 31, 2023 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 126,463 shares issued and outstanding as of March 31, 2024; 125,794 shares issued and outstanding as of December 31, 2023 1,265 1,259 Additional paid-in capital 6,881,977 6,811,063 Accumulated other comprehensive loss (26,988 ) (23,375 ) Accumulated deficit (7,075,526 ) (7,009,591 ) Total stockholders’ deficit (219,272 ) (220,644 ) Total liabilities and stockholders’ deficit $ 3,824,386 $ 3,829,880 This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam’s Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2023. ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2024 March 31, 2023 Statements of Operations Revenues: Net product revenues $ 365,163 $ 276,328 Net revenues from collaborations 118,548 36,462 Royalty revenue 10,622 6,500 Total revenues 494,333 319,290 Operating costs and expenses: Cost of goods sold 54,613 41,432 Cost of collaborations and royalties 11,363 13,437 Research and development 260,995 230,569 Selling, general and administrative 210,797 183,659 Total operating costs and expenses 537,768 469,097 Loss from operations (43,435 ) (149,807 ) Other (expense) income: Interest expense (35,253 ) (28,955 ) Interest income 29,645 18,655 Other expense, net (14,544 ) (12,255 ) Total other expense, net (20,152 ) (22,555 ) Loss before income taxes (63,587 ) (172,362 ) Provision for income taxes (2,348 ) (1,739 ) Net loss $ (65,935 ) $ (174,101 ) Net loss per common share - basic and diluted $ (0.52 ) $ (1.40 ) Weighted-average common shares used to compute basic and diluted net loss per common share 126,138 124,111 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2024 March 31, 2023 Reconciliation of GAAP to Non-GAAP Research and development: GAAP Research and development $ 260,995 $ 230,569 Less: Stock-based compensation expenses (19,215 ) (16,232 ) Non-GAAP Research and development $ 241,780 $ 214,337 Reconciliation of GAAP to Non-GAAP Selling, general and administrative: GAAP Selling, general and administrative $ 210,797 $ 183,659 Less: Stock-based compensation expenses (26,132 ) (23,715 ) Non-GAAP Selling, general and administrative $ 184,665 $ 159,944 Reconciliation of GAAP to Non-GAAP Operating gain (loss): GAAP Operating loss $ (43,435 ) $ (149,807 ) Add: Stock-based compensation expenses 45,347 39,947 Non-GAAP Operating gain (loss) $ 1,912 $ (109,860 ) Reconciliation of GAAP to Non-GAAP Other expense, net: GAAP Other expense, net $ (20,152 ) $ (22,555 ) (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (78 ) 2,267 Non-GAAP Other expense, net $ (20,230 ) $ (20,288 ) Reconciliation of GAAP to Non-GAAP Net loss: GAAP Net loss $ (65,935 ) $ (174,101 ) Add: Stock-based compensation expenses 45,347 39,947 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (78 ) 2,267 Non-GAAP Net loss $ (20,666 ) $ (131,887 ) Reconciliation of GAAP to Non-GAAP Net loss per common share- basic and diluted: GAAP Net loss per common share - basic and diluted $ (0.52 ) $ (1.40 ) Add: Stock-based compensation expenses 0.36 0.32 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities — 0.02 Non-GAAP Net loss per common share - basic and diluted $ (0.16 ) $ (1.06 ) Please note that the figures presented above may not sum exactly due to rounding ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF GAAP TO NON-GAAP PRODUCT REVENUE GROWTH AT CONSTANT CURRENCY (Unaudited) Three Months Ended March 31, 2024 Total TTR net product revenue growth, as reported 29% Add: Impact of foreign currency translation 1 Total TTR net product revenue growth at constant currency 30% GIVLAARI net product revenue growth, as reported 21% Add: Impact of foreign currency translation — GIVLAARI net product revenue growth at constant currency 21% OXLUMO net product revenue growth, as reported 77% Add: Impact of foreign currency translation (2) OXLUMO net product revenue growth at constant currency 75% Total net product revenue growth, as reported 32% Add: Impact of foreign currency translation — Total net product revenue growth at constant currency 32% Total revenue growth, as reported 55% Add: Impact of foreign currency translation — Total revenue growth at constant currency 55%

Clinical ResultPhase 3Phase 2Phase 1Financial Statement

24 Apr 2024

·www.globenewswire.com

[Ad hoc announcement pursuant to Art. 53 LR] Roche sales increase by 2% (CER) in first quarter with both divisions growing in high single digit ex COVID-19

Group sales grew by 2%1 at constant exchange rates (CER) (-6% in CHF), driven by the strong growth of newer medicines and diagnostics. Excluding COVID-19-related products, sales increased by 7%. Going forward, there will be no further material impact of COVID-19 sales declineDue to the appratioss fn of the Swiranc against most currencies, sales were 6% lower when reported in CHFPharmaceuticals Division base business2 grew by 7%, driven by strong sales of medicines to treat severe diseases, such as Vabysmo (eye diseases), Phesgo (breast cancer), Ocrevus (multiple sclerosis), Polivy (blood cancer) and Hemlibra (haemophilia A). Divisional sales growth was 2%, reflecting the impact of the expected decline in sales of the COVID-19 medicine Ronapreve Diagnostics Division base business2 grew by 8%, supported by growth across all regions because of demand for immunodiagnostic products, clinical chemistry tests and advanced staining solutions. As this growth was partially offset by the lower demand for COVID-19 tests, divisional sales grew by 2%Highlights in the first quarter: US approvals of Xolair (food allergies) and Alecensa (early-stage lung cancer)Positive phase III data for Xolair (food allergies), Columvi (blood cancer) and Ocrevus subcutaneous injection (multiple sclerosis); positive phase II results for zilebesiran (hypertension in people with high cardiovascular risk)New positive long-term data for Vabysmo (retinal vein occlusion, a severe eye disease) US approval for the first molecular test to screen for malaria in blood donorsUS Breakthrough Device Designation for blood test to support earlier Alzheimer’s disease diagnosis Outlook for 2024 confirmed Roche CEO Thomas Schinecker: “We had a strong start into the year, with both our divisions reporting high single digit growth in their base business – excluding COVID-19 sales. After this quarter, the COVID-19-related impact on sales is largely behind us. The appreciation of the Swiss franc versus most currencies impacted sales reported in Swiss francs compared to the same period last year. The uptake of our eye medicine Vabysmo continues its momentum. We are pleased about the US approval of Xolair as the first and only medicine for multiple food allergies. Further, we recently received the US approval for Alecensa in early-stage lung cancer. With an unprecedented 76% reduction in the risk of disease recurrence or death versus chemotherapy, Alecensa significantly improves upon the standard of care for this specific form of lung cancer. We are confident of growing our Group sales in the mid single digit range this year (at constant exchange rates) and therefore we confirm our outlook for 2024.” Sales CHF millions As % of sales % change January‒March 2024 2023 2024 2023 At CER In CHF Group 14,399 15,322 100.0 100.0 2 -6 Pharmaceuticals Division 10,921 11,608 75.8 75.8 2 -6 United States 5,692 5,763 39.5 37.6 5 -1 Europe 2,200 2,071 15.3 13.5 11 6 Japan 649 1,390 4.5 9.1 -45 -53 International* 2,380 2,384 16.5 15.6 12 0 Diagnostics Division 3,478 3,714 24.2 24.2 2 -6 All figures shown in the table were restated to reflect the shift of the Foundation Medicine (FMI) business from the Pharmaceuticals Division to the Diagnostics Division. *Asia-Pacific, CEETRIS (Central Eastern Europe, Türkiye, Russia and Indian subcontinent), Latin America, Middle East, Africa, Canada, others Outlook for 2024 confirmedRoche expects an increase in Group sales in the mid single digit range (CER). Core earnings per share are targeted to develop broadly in line with sales growth (CER), excluding the impact from the resolution of tax disputes in 2023. Roche expects to further increase its dividend in Swiss francs. Group salesIn the first three months of 2024, Group sales increased by 2% CER (-6% in CHF) to CHF 14.4 billion as strong demand for newer medicines as well as diagnostics products including immunodiagnostics, clinical chemistry tests and advanced staining solutions more than offset the anticipated decline in COVID-19-related sales and the impact of biosimilar/generic erosion. After this quarter, the impact of the drop in COVID-19-related sales is largely over and there will be no further material impact on Group sales. Excluding COVID-19-related products, sales increased by 7%. The appreciation of the Swiss franc against most currencies had a significant adverse impact on the sales reported in Swiss francs compared to constant exchange rates. Pharmaceuticals Division base business grew by 7%, while divisional sales increased by 2% to CHF 10.9 billion as the strong global demand for newer medicines to treat severe diseases was partially offset by the expected decline in COVID-19 Ronapreve sales. The eye medicine Vabysmo was the biggest growth driver, with Phesgo (breast cancer), Ocrevus (multiple sclerosis), Polivy (blood cancer) and Hemlibra (haemophilia A) being other significant contributors. Together, these medicines generated sales of CHF 4.2 billion, an increase of CHF 0.9 billion (at CER) from the first quarter of 2023. The negative impact of biosimilar/generic erosion on our medicines Lucentis (eye diseases, US commercialisation rights only), MabThera/Rituxan (blood cancer), Herceptin (breast and stomach cancer), Avastin (various types of cancer), Esbriet (lung disease) and Actemra/RoActemra (arthritis, COVID-19) totalled CHF 0.4 billion (at CER), in line with expectations. In the United States, sales increased by 5%, driven by strong demand for newer medicines such as Vabysmo, Polivy, Ocrevus, Phesgo and Evrysdi (spinal muscular atrophy) as well as for Xolair (allergies). This contrasted with lower sales of Lucentis, MabThera/Rituxan, Tecentriq (cancer immunotherapy), Esbriet, Avastin and Perjeta. In Europe, sales grew by 11%, with Vabysmo, Phesgo, Hemlibra, Evrysdi and Ocrevus being the key drivers. Sales in Japan were down by 45%, reflecting the base effect of the supply of Ronapreve to the government in the first quarter of 2023. Sales in the International region increased by 12%, driven by strong growth in Hemlibra, Perjeta, Phesgo, Ocrevus, Tecentriq and Vabysmo. In China, sales grew by 11% due to high demand for Xofluza (influenza), Perjeta, Avastin, Polivy and Tecentriq. The Diagnostics Division’s base business continued good growth (8%), boosted by demand for immunodiagnostic products, clinical chemistry tests and advanced staining solutions. This was partially offset by the expected sales decline of COVID-19-related products, leading to divisional sales growing at 2% to CHF 3.5 billion. Immunodiagnostic products, which include cardiac, oncology and thyroid tests, were the main growth drivers (10%). Additional growth impetus came from clinical chemistry (8%), advanced staining techniques in oncology (12%) and companion diagnostics (47%). As expected, the sales of COVID-19 tests further declined to CHF 0.1 billion in the first quarter of 2024 from CHF 0.3 billion in the corresponding period last year. Sales growth was reported across regions, with Europe, Middle East and Africa (EMEA) growing by 2%, Asia-Pacific by 1% and Latin America by 14%. North America recorded a decline of 1%, reflecting the drop in demand for COVID-19-related tests. Pharmaceuticals: key milestones in the first quarter of 2024 Compound Milestone Regulatory AlecensaLung cancer FDA approves Alecensa as first adjuvant treatment for people with ALK-positive early-stage lung cancer Approval based on phase III ALINA study showing Alecensa reduced the risk of disease recurrence or death by an unprecedented 76% in people with ALK-positive early-stage resected non-small cell lung cancer (NSCLC) This approval helps address an urgent unmet need, with about half of people living with early-stage NSCLC experiencing disease recurrence following surgery, despite adjuvant chemotherapyThe National Comprehensive Cancer Network (NCCN) Guidelines recommend routine testing for ALK, EGFR and PD-L1 biomarkers in people with early-stage NSCLC to inform adjuvant therapy selection More information: Media Release, 19 April 2024 Piasky Rare blood disease Chugai obtains regulatory approval for Piasky 340 mg for paroxysmal nocturnal haemoglobinuria in Japan Providing convenience of once every 4 week subcutaneous administration for treatment-naive patients, or for patients switching to this drug from other C5 inhibitors, with paroxysmal nocturnal haemoglobinuria (PNH), a designated intractable diseaseThis approval for not only treatment-naive PNH but also including patients switching from previously approved C5 inhibitors, is the first in the worldSecond approved drug that applies Chugai’s proprietary recycling antibody technology and also the fifth Chugai-originated global product More information: Investor Relations Update, 26 March 2024 Xolair Food allergy FDA approves Xolair as first and only medicine for children and adults with one or more food allergies Approval is based on data from the NIH-sponsored phase III OUtMATCH study, which showed a significantly higher proportion of food allergy patients as young as one year treated with Xolair could tolerate small amounts of peanut, milk, egg and cashew without an allergic reaction, compared to placebo More than 40% of children and more than 50% of adults with food allergies have experienced a severe reaction at least once in their lifetimeDetailed OUtMATCH results were featured in a late-breaking symposium at the 2024 American Academy of Allergy, Asthma & Immunology annual meeting More information: Media Release, 16 February 2024 Phase III, pivotal and other key readouts Ocrevus SCMultiple sclerosis Subcutaneous Ocrevus one-year data demonstrates near-complete suppression of clinical relapses and brain lesions in patients with progressive and relapsing forms of multiple sclerosis Results from the phase III study showed that subcutaneous (SC) injection was consistent with IV infusion and demonstrated near-complete suppression of relapse activity (97%) and MRI lesions (97.2%) through 48 weeksThe twice-yearly, 10-minute SC injection has the potential to expand the usage of Ocrevus to treatment centres without IV infrastructure or with IV capacity limitationsUS FDA and EMA accepted filings based on the data from OCARINA II, with EU approval anticipated mid-2024 and US approval anticipated in September 2024 More information: Media Release, 17 April 2024 ColumviBlood cancer Columvi meets primary endpoint of overall survival in people with relapsed or refractory diffuse large B-cell lymphoma in phase III STARGLO study Columvi, in combination with chemotherapy, demonstrated a statistically significant improvement in overall survival for people with relapsed or refractory diffuse large B-cell lymphomaData from the STARGLO study will be submitted to health authorities and presented at an upcoming medical meeting More information: Media Release, 15 April 2024 ZilebesiranCardiovascular diseases Roche and Alnylam present positive results from the phase II KARDIA-2 study of zilebesiran added to standard-of-care antihypertensives in patients with inadequately controlled hypertension The KARDIA-2 study met its primary endpoint demonstrating additive, placebo-adjusted systolic blood pressure reductions of up to 12.1 mmHg at month three. These results were statistically significant and clinically meaningfulZilebesiran demonstrated an encouraging safety and tolerability profile when added to standard of care antihypertensives Roche and Alnylam have initiated the phase II KARDIA-3 study in adults with uncontrolled hypertension at high cardiovascular risk. More information: Investor Relations Update, 7 March 2024 XolairFood allergies New England Journal of Medicine publishes phase III data showing Xolair significantly reduced allergic reactions across multiple foods in people with food allergies Detailed results from the NIH-sponsored phase III OUtMATCH study showed treatment with Xolair increased the amount of peanuts, tree nuts, egg, milk and wheat that people as young as one year consumed without an allergic reactionThe US FDA recently approved Xolair as the first and only medicine for children and adults with one or more food allergies Allergic reactions can be life-threatening and it is estimated that food-related anaphylaxis results in 30,000 medical events treated in emergency rooms in the US each year More information: Media Release, 25 February 2024 VabysmoSevere eye diseases New long-term data for Vabysmo show sustained retinal drying and vision improvements in retinal vein occlusion (RVO) Vabysmo sustained robust drying of retinal fluid, often associated with distorted or blurry visionUp to 60% of people receiving Vabysmo were able to extend treatment intervals to three or four months apart Detailed results from two global phase III RVO studies were presented at Angiogenesis, Exudation, and Degeneration 2024 More information: Media Release, 1 February 2024 Pharmaceuticals sales Sales CHF millions As % of sales % change January–March 2024 2023 2024 2023 At CER In CHF Pharmaceuticals Division 10,921 11,608 100.0 100.0 2 -6 United States 5,692 5,763 52.1 49.4 5 -1 Europe 2,200 2,071 20.1 17.8 11 6 Japan 649 1,390 5.9 12.0 -45 -53 International* 2,380 2,384 21.9 20.8 12 0 All figures shown in the table were restated to reflect the shift of the Foundation Medicine (FMI) business from the Pharmaceuticals Division to the Diagnostics Division. *Asia-Pacific, CEETRIS (Central Eastern Europe, Türkiye, Russia and Indian subcontinent), Latin America, Middle East, Africa, Canada, others Top 20 best-selling pharmaceuticals Total United States Europe Japan International CHF m % CHF m % CHF m % CHF m % CHF m % OcrevusMultiple sclerosis 1,658 8 1,180 5 310 8 - - 168 28 HemlibraHaemophilia A 1,040 8 592 -1 231 17 79 2 138 51 Perjeta3Breast cancer 936 -3 343 -7 171 -19 36 -19 386 14 TecentriqCancer immunotherapy 865 1 436 -9 210 12 86 -4 133 34 VabysmoEye diseases (nAMD, DME, RVO) 847 108 650 91 138 224 23 33 36 397 Actemra/RoActemra3RA, COVID-19 618 -2 278 -1 188 1 68 5 84 -15 Xolair3Asthma, allergies 496 10 496 10 - - - - - - Kadcyla3Breast cancer 483 3 186 -1 145 -2 21 -4 131 19 PhesgoBreast cancer 388 70 126 36 169 55 19 - 74 165 Herceptin3Breast and gastric cancer 364 -17 67 -22 77 -17 4 -41 216 -14 EvrysdiSpinal muscular atrophy 356 7 135 16 137 27 20 13 64 -29 AlecensaLung cancer 355 4 104 4 72 3 43 3 136 5 MabThera/Rituxan3Blood cancer, RA 351 -18 204 -21 39 -20 4 -20 104 -11 Avastin 3Various cancer types 324 -15 99 -22 21 -27 51 -33 153 3 Activase/TNKase3Cardiac diseases 296 4 282 4 - - - - 14 7 PolivyBlood cancer 250 81 117 166 54 42 44 2 35 181 Gazyva/Gazyvaro3Blood cancer 213 16 100 7 62 17 6 -19 45 47 Pulmozyme3Cystic fibrosis 112 -6 66 -15 20 0 - 27 26 22 Mircera3Anaemia 96 0 - - 10 -8 9 -25 77 6 CellCept3Immunosuppressant 94 0 5 -34 32 0 9 -10 48 8 ** Over 500% DME: diabetic macular oedema / nAMD: neovascular or ‘wet’ age-related macular degeneration / RVO: retinal vein occlusion / RA: rheumatoid arthritis Diagnostics: key milestones in the first quarter of 2024 Product Milestone Regulatory Elecsys pTau217 test Alzheimer’s disease FDA Breakthrough Device Designation for blood test to support earlier Alzheimer’s disease diagnosis The Elecsys pTau217 plasma biomarker test is being developed as part of an ongoing partnership between Roche and Eli Lilly and CompanyOnce approved, the test will aid healthcare providers in identifying amyloid pathology, a key feature of Alzheimer’s diseaseRoche and Lilly believe the test could play an important role in improving access to early and accurate Alzheimer’s diagnosis More information: Media Release, 11 April 2024 cobas Malaria testMalaria FDA approval for the first molecular test to screen for malaria in blood donors The cobas Malaria test is the first FDA-approved molecular test to screen US blood donors for malariaMalaria is a serious and potentially fatal parasitic infection most commonly transmitted by mosquitoes that can also be spread through blood transfusionRoche is dedicated to saving patients’ lives through diagnostic solutions that aid in the protection of the global blood supply from infectious diseases More information: Media Release, 26 March 2024 Diagnostics sales Sales CHF millions As % of sales % change January–March 2024 2023 2024 2023 At CER In CHF Diagnostics Division 3,478 3,714 100.0 100.0 2 -6 Customer areas4 Core Lab 1,925 1,928 55.4 51.9 9 0 Molecular Lab5 620 683 17.8 18.4 -3 -9 Near Patient Care6 570 774 16.4 20.8 -20 -26 Pathology Lab 363 329 10.4 8.9 19 10 Regions Europe, Middle East, Africa 1,188 1,253 34.2 33.8 2 -5 North America5 1,055 1,120 30.3 30.3 -1 -6 Asia-Pacific 992 1,098 28.5 29.4 1 -10 Latin America 243 243 7.0 6.5 14 0 More information on Roche sales in the first quarter of 2024: Q1 2024 presentationAppendix with tables About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. In recognising our endeavour to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the fifteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law.References[1] Unless otherwise stated, all growth rates and comparisons to the previous year in this document are at constant exchange rates (CER: average rates 2023) and all total figures quoted are reported in CHF.[2] Pharmaceuticals Division base business: excluding COVID-19 medicine Ronapreve.Diagnostics Division base business: excluding COVID-19-related products.[3] Products launched before 2015.[4] Core Lab: diagnostics solutions in the areas of immunoassays, clinical chemistry and CustomBiotech.Molecular Lab: diagnostics solutions for pathogen detection and monitoring, donor screening, sexual health and genomics, genomic tumour profiling.Near Patient Care: diagnostics solutions in emergency rooms, medical practices or directly with patients and integrated personalised diabetes management.Pathology Lab: diagnostics solutions for tissue biopsies and companion diagnostics.[5] Sales in the Molecular Lab customer area include sales from the Foundation Medicine business which moved under the responsibility of the Diagnostics Division from the Pharmaceuticals Division effective 1 January 2024. The comparative information for 2023 has been restated accordingly.[6] Sales in the new Near Patient Care customer area include sales from Diabetes Care and the Point of Care business, both previously shown as separate customer areas. The comparative information for 2023 has been restated accordingly. Cautionary statement regarding forward-looking statementsThis document contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this document, such as: (1) pricing and product initiatives of competitors; (2) legislative and regulatory developments and economic conditions; (3) delay or inability in obtaining regulatory approvals or bringing products to market; (4) fluctuations in currency exchange rates and general financial market conditions; (5) uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side effects of pipeline or marketed products; (6) increased government pricing pressures; (7) interruptions in production; (8) loss of or inability to obtain adequate protection for intellectual property rights; (9) litigation; (10) loss of key executives or other employees; and (11) adverse publicity and news coverage. The statement regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. Roche Global Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58 Nathalie AltermattPhone: +41 79 771 05 25 Simon GoldsboroughPhone: +44 797 32 72 915 Karsten KleinePhone: +41 79 461 86 83 Nina MählitzPhone: +41 79 327 54 74 Kirti PandeyPhone: +49 172 6367262 Dr. Rebekka SchnellPhone: +41 79 205 27 03 Sileia UrechPhone: +41 79 935 81 48 Roche Investor Relations Dr. Bruno EschliPhone: +41 61 68-75284e-mail: bruno.eschli@roche.com Dr. Sabine BorngräberPhone: +41 61 68-88027 e-mail: sabine.borngraeber@roche.com Dr. Birgit MasjostPhone: +41 61 68-84814e-mail: birgit.masjost@roche.com Investor Relations North America Loren Kalm Phone: +1 650 225 3217 e-mail: kalm.loren@gene.com Attachments Communications appendix tables_Q1 2024_Sales 24042024_MR_Roche_Q1results_EN

Clinical ResultPhase 3Drug ApprovalBreakthrough TherapyPhase 2

08 Apr 2024

·endpts.com

Alnylam’s RNAi therapy passes second Phase 2 hypertension test, with third underway: #ACC24

Alnylam’s RNAi candidate successfully reduced 24-hour systolic blood pressure in patients with uncontrolled hypertension when added to standard of care in a mid-stage trial, reinforcing plans for a Phase 3 that will start once a separate, ongoing Phase 2 test is completed. The drug, dubbed zilebesiran, inhibits the synthesis of angiotensinogen (AGT) in the liver. AGT is the most upstream precursor of the renin-angiotensin-aldosterone system (RAAS) cascade, which plays a key role in blood pressure regulation, according to an Alnylam release . You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 2	US	Alnylam Pharmaceuticals, Inc.	07 Jul 2021
Hypertension	Phase 2	CA	Alnylam Pharmaceuticals, Inc.	07 Jul 2021
Hypertension	Phase 2	PR	Alnylam Pharmaceuticals, Inc.	07 Jul 2021
Hypertension	Phase 2	UA	Alnylam Pharmaceuticals, Inc.	07 Jul 2021
Hypertension	Phase 2	GB	Alnylam Pharmaceuticals, Inc.	07 Jul 2021
Alzheimer Disease	Phase 1	US	Alnylam Pharmaceuticals, Inc.	31 Dec 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05103332 (KARDIA-2, Corporate Publications) Manual	Phase 2	Hypertension	672	Indapamide 2.5 mg+Zilebesiran	kdrghtzoku(xpubxemaik) = livahoscfr oekmlgnkfl (wkoxxauqyu ) Met View more	Positive	07 Apr 2024
				Indapamide 2.5 mg+Placebo	gtpglerujo(jgbndijmub) = jlpirvqqvi fmhakrvgva (eijqutmrwm ) View more
NCT05103332 (KARDIA-2, Corporate Publications) Manual	Phase 2	Hypertension	672	Zilebesiran+Standard of Care Antihypertensives	fcblxlreqk(totpvsefgc) = Study Met the Primary Endpoint Demonstrating Clinically Significant Systolic Blood Pressure Reductions at Month 3 When Zilebesiran Was Added to a Diuretic, Calcium-Channel Blocker or Angiotensin Receptor Blocker pgsputxkmo (bsfldakawj ) Met	Positive	05 Mar 2024
				placebo+Standard of Care Antihypertensives
KARDIA-1 (PipelineReview) Manual	Phase 2	Hypertension	394	zilebesiran	zdnuzufcvo(zclcdmlqqt) = lwdkodngep aaqnzoppki (xlulokcqho ) View more	Positive	13 Nov 2023
				zilebesiran	zdnuzufcvo(zclcdmlqqt) = aznxclrbvm aaqnzoppki (xlulokcqho ) View more
NCT04936035 (KARDIA-1, AHA2023) Manual	Phase 2	Hypertension	377	Zilebesiran	nddkovdcoy(wgskytcyyq) = Reductions from baseline in 24-hour mean SBP were significantly greater for all zilebesiran regimens than placebo at Month 3 and Month 6 (p<0.0001, all comparisons), with consistent reductions in daytime and nighttime SBP. pmiwjuosan (ujepiapcld ) View more	Positive	11 Nov 2023
				Placebo
Corporate Publications Manual	Phase 1	Hypertension	112	zilebesiran	cjhgvayloh(vlxnbhborl) = ijtjjeiaqo ziupqzkoyg (yhrvzrdmry )	Positive	19 Jul 2023
				placebo	cjhgvayloh(vlxnbhborl) = tahtfbmxpg ziupqzkoyg (yhrvzrdmry )

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