ALN-KHK

▲8月15-16日 苏州2024生物医药创新者峰会 扫码报名  注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。 8月1日，全球领先的RNAi治疗公司Alnylam Pharmaceuticals (Nasdaq: ALNY)，发布2024年第二季度业绩：2024年上半年总收入11.54亿美元，同比增长80.9%；净产品收入77.53亿美元，同比增长33.2%，这主要得益于AMVUTTRA因患者需求增加而实现的强劲增长，以及使用GIVLAARI和OXLUMO疗法患者人数的增加。其中2024 Q2总收入6.6亿美元，同比增长107%；净产品收入4.1亿美元，同比增长34.1%。 2024年合并净产品收入指导上调至15.75亿美元至16.5亿美元。 主要产品收入情况 Alnylam目前上市了五款药物，其中Leqvio由诺华获得了开发、生产和商业化的全球权利，据诺华财报2024 Q2销售额1.82亿美元，同比增长134%，2024 H1销售额为3.33亿美元，已接近2023年全年销售额。(全球首款PCSK9 siRNA业绩出炉，国内9家布局) 其他四款RNAi产品ONPATTRO、AMVUTTRA、GIVLAARI和OXLUMO 2024 H1全球总净产品收入为7.75亿美元（约56.12亿元）;2024 Q2全球总净产品收入为4.1亿美元（约29.69亿元）。 ATTR-PN siRNA产品：ONPATTRO(patisiran)和AMVUTTRA（vutrisiran） 总TTR继续保持增长势头，第二季度ONPATTRO和AMVUTTRA的全球总产品净收入为3.07亿美元，与2024 Q1相比，总TTR季度增长率为16%，与2023 Q2相比，年增长率为37%，其中美国的年增长率为40%。 Onpattro在2024 H1销售额14.65亿美元，同比下降24.5%；2024 Q2销售额7724.4万美元，同比下降16%。Onpattro是首款获得FDA批准的RNAi疗法（2018年8月获批），用于治疗由遗传性转甲状腺素蛋白淀粉样变性引起的周围神经疾病（多发性神经病）成人患者。 Amvuttra2024 H1销售额4.25亿美元，同比增长81.8%；2024 Q2销售额2.3亿美元，同比增长74%。该药物在2022年6月获得FDA批准，用于治疗成人遗传性转甲状腺素蛋白淀粉样变性伴多发性神经病(hATTR-PN)，这是全球第5款获批上市的siRNA疗法，也是FDA批准的首款只需每3个月皮下注射一次，就能够逆转神经病损伤的RNAi疗法，同年9月获得欧盟批准。 两款罕见病产品：GIVLAARI® (givosiran) & OXLUMO® (lumasiran) GIVLAARI 和OXLUMO在第二季度实现全球总净产品收入1.03亿美元。与2024 Q1相比，季度总增长率为2%；与 2023Q2相比，年增长率为25%。 GIVLAARI 2024 H1销售额1.2亿美元，同比增长13.6%；2024 Q2销售额6212.7万美元，同比增长7%。GIVLAARI（givosiran）是以ALAS1为靶点的 RNAi 疗法，已在美国和巴西获批用于治疗成人急性肝性卟啉症 (AHP)。欧盟也批准 GIVLAARI 用于治疗成人和 12 岁及以上青少年的急性肝性卟啉症。 OXLUMO 2024 H1销售额8325.7万美元，同比增长72.11%；2024 Q2销售额4060.8万美元，同比增长68%。受强劲需求推动，美国地区销售额大增79%。OXLUMO是针对HAO1的RNAi疗法，该药物主要用于治疗1型原发性高草酸尿症(PH1)。 研发亮点 6月24日，Alnylam公布了RNAi治疗药物vutrisiran的HELIOS-B 3期研究达到了主要终点和所有次要终点，包括基线tafamidis使用情况、ATTR疾病类型和疾病严重程度。根据此积极结果，Alnylam将使用优先审评券向美国FDA递交补充新药申请。（大涨35%！Alnylam 心脏病RNAi疗法3期研究成功） 4月，Anlynam宣布了其针对肝脏表达的血管紧张素原（AGT）的研究型RNAi疗法Zilebesiran的KARDIA-2 2期研究达到了主要终点和次要终点。结果表明，Zilebesiran组患者的平均收缩压实现了具有临床意义和统计学意义的降低，并且其具有令人鼓舞的安全性和耐受性。（一年两针！罗氏/Anlynam高血压RNAi疗法最新进展公布） 启动了针对脑淀粉样血管病（CAA）患者的cAPPricorn-1 2期研究，研究对象为 mivelsiran (ALN-APP)。 启动了ALN-KHK 1期研究的B部分，该研究正在开发中，用于治疗2型糖尿病。 合作伙伴赛诺菲向中国、巴西和美国提交了血友病研究药物fitusiran的监管申请，FDA 的目标行动日期为2025年3月28日。 其他业务更新 更新与 Regeneron 的合作协议。 根据修订后的许可协议，Regeneron获得cemdisiran作为单一疗法的独家权利，以换取1000万美元的预付款、某些监管里程碑以及cemdisiran作为单一疗法销售额的低两位数版税。Cemdisiran是一种皮下给药的研究性RNA干扰疗法，靶向C5补体，主要用于治疗补体蛋白引起的相关疾病。 由于Regeneron选择退出mivelsiran在CAA和阿尔茨海默病领域的进一步合作开发和合作商业化，因此Alnylam现在拥有mivelsiran在所有适应症领域的全部全球开发和商业化权利。如果mivelsiran获得批准，Regeneron将有资格从其销售额中获得较低的两位数版税。 公司管线 关于Alnylam Alnylam Pharmaceutical率先将RNA干扰（RNAi）技术转化为一类全新的创新药物，有望改变那些患有罕见病和流行病且需求尚未得到满足的患者的生活。自2002 年成立以来，Alnylam一直引领着RNAi革命，并将继续实现将科学可能性转化为现实的大胆愿景。Alnylam的商业RNAi治疗产品包括 ONPATTRO® (patisiran)、AMVUTTRA® (vutrisiran)、GIVLAARI® (givosiran)、OXLUMO® (lumasiran) 和Leqvio® (inclisiran)，后者正由Alnylam的合作伙伴诺华开发和商业化。Alnylam 拥有丰富的在研药物产品线，包括多个处于后期开发阶段的候选产品。Alnylam 正在实施其 "Alnylam P5x25 "战略，通过可持续创新和出色的财务业绩，在罕见病和常见病领域提供变革性药物，造福全球患者，从而成为一家领先的生物技术公司。 参考资料：公司财报 版权声明：本文转自生物药大时代，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 8月15日  C馆C103  临床开发论坛 大会主席：杨修诰，石药集团，高级医学总监；郑航，重庆医科大学，教授 会议日程 主持人：孟杰天，安徽万邦，首席医学官 09:00-09:25 从临床角度看中枢神经系统药物的临床开发策略及案例分享 申华琼 | 纽欧申医药，创始人&CEO 09:25-09:50 新药临床研发的适应症选择策略 朱永红 | 岸迈生物，CMO 09:50-10:15 关键临床试验失败案例分析 陈  霞 | 泰格医药，高级副总裁&首席医学官 10:15-10:40 抗体偶联药物（ADCs）的剂量优化相关临床研究及安全管理措施分析  杨修诰 | 石药集团，高级医学总监 10:40-11:05 从临床角度看ADC开发的挑战和前景 石  燕 | 启德医药，首席医学官 11:05-11:30 中国制造，出海有多难？ 杜一鸣 | 海和药物，高级副总裁 11:30-12:10 圆桌：中国创新药注册及临床全球化操作技术的短板？ 杨修诰 | 石药集团，高级医学总监 刘艳玮 | 武田中国，副总裁 ，武田大中华区注册事务部负责人 杜一鸣 | 海和药物，高级副总裁 石   燕 | 启德医药 首席医学官 12:10-13:30 午餐 13:30-13:55 从临床视角看抗肿瘤创新药的临床开发策略及案例分享 隋  红 | 浙江瀛康生物医药有限公司，医学总监 13:55-14:20 神经退行性疾病药物发展：从过去看未来 陈柏州 | 加立生科，CEO 14:20-14:45 嘉宾行程确认中 苏州信诺维 14:45-15:10 司美格鲁肽临床开发策略及要点 孟杰天 | 安徽万邦，首席医学官（CMO） 15:10-15:35 AI医学翻译及自动临床试验方案撰写案例 嘉宾行程确定中 15:35-16:00 以终为始-数据分析驱动，提高创新药临床开发成功率 戴鲁燕 | 粹羽咨询，创始人 扫码报名参会 【关于药融圈】 药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the second quarter ended June 30, 2024 and reviewed recent business highlights. “Alnylam delivered strong results across the business in the second quarter. We achieved a robust 34% year-over-year growth, with global net product revenues of $410 million, primarily driven by our TTR business, leading to an upward revision of our combined net product revenue guidance for the year. On the clinical side, we announced positive topline results from the HELIOS-B Phase 3 study of vutrisiran, showing that it improved cardiovascular outcomes, including an impressive 35-36% mortality benefit, in patients with ATTR cardiomyopathy,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “With these outstanding results in hand, and assuming successful regulatory review and approval, we believe we are positioned to deliver significant long-term topline growth, providing the capacity for strategic investment in our highly productive organic R&D platform, and further advancing us toward our Alnylam P 5 x25 goals and becoming a leading global biotech company.” Second 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 second quarter of $77 million and $230 million, respectively, representing 16% total TTR quarterly growth compared to Q1 2024, and 37% annual growth compared to Q2 2023, including 40% annual growth in the U.S. Total Rare: GIVLAARI ® (givosiran) & OXLUMO ® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the second quarter of $62 million and $41 million, respectively, representing 2% total Rare quarterly growth compared to Q1 2024, and 25% annual growth compared to Q2 2023. R&D Highlights Announced positive topline results from the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM). The study met the primary endpoint, demonstrating statistically significant reductions of 28% and 33% in the composite of all-cause mortality and recurrent cardiovascular events in the overall and monotherapy populations, respectively. Reduced all-cause mortality by 36% and 35% in the overall and monotherapy populations, respectively, in a pre-specified secondary endpoint. Demonstrated clinically significant improvements vs. placebo on key measures of disease progression, including functional capacity, quality of life, and physician assessment of disease severity. Observed consistent effects in all key subgroups, including baseline tafamidis use. Demonstrated encouraging safety, consistent with vutrisiran’s established profile. Reported positive results from the KARDIA-2 Phase 2 study of investigational zilebesiran added to standard-of-care antihypertensives in patients with inadequately controlled hypertension. Initiated dosing in the cAPPricorn-1 Phase 2 study of investigational mivelsiran (ALN-APP) in patients with cerebral amyloid angiopathy (CAA). Initiated Part B of the Phase 1 study of ALN-KHK , in development for the treatment of Type 2 diabetes mellitus. Our collaboration partner, Sanofi, submitted regulatory filings for the investigational agent for hemophilia, fitusiran , in China, Brazil, and the U.S., with an FDA target action date of March 28, 2025. Our collaboration partner, Vir Biotechnology, reported new data for investigational elebsiran at the European Association for the Study of the Liver (EASL) Congress 2024. Vir also received Fast Track Designation for tobevibart and elebsiran for the treatment of hepatitis delta infection. Additional Business Updates Updated collaboration agreements with Regeneron. Amended license agreement under which Regeneron gains exclusive rights to cemdisiran as a monotherapy in exchange for a $10 million upfront payment, certain regulatory milestones, and low double-digit royalties on sales of cemdisiran as a monotherapy. Alnylam now has full global development and commercialization rights to mivelsiran in all indications, as Regeneron opted out of further co-development and co-commercialization of mivelsiran, in development for CAA and Alzheimer's disease. Regeneron will be eligible to receive low double-digit royalties on sales of mivelsiran, if approved. Published 2023 Corporate Responsibility Report Upcoming Events Alnylam announced today that detailed results from the HELIOS-B Phase 3 study of vutrisiran will be presented as a Hot Line Oral Presentation at the European Society of Cardiology (ESC) Congress on Friday, August 30, 2024, at 11:00 am BST (6:00 am ET) in London, UK. The Company will host a webcast to discuss the results at 1:00 pm BST (8:00 am ET). The Company also announced today that it will host a TTR Investor Day on October 9, 2024 in New York City. This event will feature presentations from Alnylam senior leaders and external experts related to the Company’s TTR business. A live webcast of the event will also be available. In mid- and late 2024, Alnylam intends to: Submit a supplemental New Drug Application (sNDA) for vutrisiran to the FDA using a Priority Review Voucher. Initiate a Phase 3 study of ALN-TTRsc04 in patients with ATTR-CM at or around year-end. Report interim results from Part B of the Phase 1 study of mivelsiran (ALN-APP) in patients with Alzheimer’s disease. Initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end. Initiate a Phase 1 study of ALN-BCAT , in development for the treatment of hepatocellular carcinoma. File 3 Investigational New Drug (IND) applications by year-end. Financial Results for the Quarter Ended June 30, 2024 Three Months Ended June 30, (In thousands, except per share amounts) 2024 2023 Net product revenues $ 410,088 $ 305,705 Net revenue from collaborations $ 227,338 $ 5,844 Royalty revenue $ 22,399 $ 7,205 GAAP Operating income (loss) $ 48,614 $ (229,831 ) Non-GAAP Operating income (loss) $ 137,902 $ (154,029 ) GAAP Net loss $ (16,889 ) $ (276,024 ) Non-GAAP Net income (loss) $ 73,766 $ (201,622 ) GAAP Net loss per common share - basic and diluted $ (0.13 ) $ (2.21 ) Non-GAAP Net income (loss) per common share - basic $ 0.58 $ (1.62 ) Non-GAAP net income (loss) per common share - diluted $ 0.56 $ (1.62 ) 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. Net Product Revenues Three Months Ended June 30, Year over Year % Growth (In thousands, except percentages) 2024 2023 As Reported At CER* ONPATTRO net product revenues $ 77,244 $ 91,458 (16 )% (15 )% AMVUTTRA net product revenues 230,109 132,136 74 % 77 % Total TTR net product revenues 307,353 223,594 37 % 39 % GIVLAARI net product revenues 62,127 57,899 7 % 8 % OXLUMO net product revenues 40,608 24,212 68 % 68 % Total Rare net product revenues 102,735 82,111 25 % 26 % Total net product revenues $ 410,088 $ 305,705 34 % 35 % * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the second quarter 2023. CER is a non-GAAP measure. Total net product revenues increased 34% and 35% at actual currency and CER, respectively, during the three months ended June 30, 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 GIVLAARI and OXLUMO. Net Revenues from Collaborations Net revenues from collaborations during the three months ended June 30, 2024, included approximately $185 million of revenue, which was previously deferred, upon modifying our collaboration agreement with Regeneron. As part of the modification to the collaboration agreement, we granted Regeneron exclusive license rights to cemdisiran monotherapy. Operating Expenses Three Months Ended June 30, (In thousands, except percentages) 2024 2023 Cost of goods sold $ 67,271 $ 75,336 Cost of goods sold as a percentage of net product revenues 16.4 % 24.6 % Cost of collaborations and royalties $ 1,401 $ 10,034 GAAP research and development expenses $ 294,142 $ 248,526 Non-GAAP research and development expenses $ 246,027 $ 215,725 GAAP selling, general and administrative expenses $ 248,397 $ 214,689 Non-GAAP selling, general and administrative expenses $ 207,224 $ 171,688 Cost of Goods Sold Cost of goods sold as a percentage of net product revenues decreased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to higher costs in 2023 associated with cancelled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses did not occur in 2024. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to increased costs associated with our preclinical activities, increased clinical research expenses associated with startup activities for the zilebesiran and mivelsiran clinical studies, and increased employee compensation expenses. GAAP R&D expenses further increased in the second quarter of 2024, compared with 2023, due to increased stock-based compensation expense. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.62 billion as of June 30, 2024, as compared to $2.44 billion as of December 31, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with stock option exercises. 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 has been updated as follows: Provided 2/15/2024 Updated 8/1/2024 Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO 1 $1,400 million - $1,500 million $1,575 million - $1,650 million Net Product Revenue Growth vs. 2023 at reported FX rates 1 13% to 21% 27% to 33% Net Product Revenue Growth vs. 2023 at CER* 13% to 21% 28% to 34% Net revenues from collaborations and royalties $325 million - $425 million $575 million - $650 million GAAP R&D and SG&A expenses $1,900 million - $2,050 million $2,000 million - $2,150 million Non-GAAP R&D and SG&A expenses 2 $1,675 million - $1,775 million $1,775 million - $1,875 million 1 Uses June 30, 2024 FX rates including: 1 EUR = 1.07 USD and 1 USD = 161 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 second quarter 2024 results as well as expectations for the future via conference call on Thursday, August 1, 2024 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 investors.alnylam.com/events . 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, 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. 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 profile consistent 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 P 5 x25 ” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. 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 aspiration to become a leading global 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 potential submission of a sNDA for AMVUTTRA for patients with ATTR amyloidosis with cardiomyopathy by mid- to late 2024 for FDA review, the use of a Priority Review Voucher in connection with the submission of a sNDA for AMVUTTRA for patients with ATTR amyloidosis with cardiomyopathy, and the advancement towards its “Alnylam P 5 x25” 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 P 5 x25 ” 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 mivelsiran; 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 profile in the future without the need for future equity financing; 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. Vutrisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. 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) June 30, 2024 December 31, 2023 ASSETS (Unaudited) Current assets: Cash and cash equivalents $ 968,492 $ 812,688 Marketable debt securities 1,646,268 1,615,516 Marketable equity securities 9,889 11,178 Accounts receivable, net 309,481 327,787 Inventory 83,981 89,146 Prepaid expenses and other current assets 154,745 126,382 Total current assets 3,172,856 2,982,697 Property, plant and equipment, net 517,159 526,057 Operating lease right-of-use assets 198,303 199,732 Restricted investments 49,391 49,391 Other assets 71,925 72,003 Total assets $ 4,009,634 $ 3,829,880 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 73,980 $ 55,519 Accrued expenses 808,643 713,013 Operating lease liability 41,656 41,510 Deferred revenue 69,009 102,753 Liability related to the sale of future royalties 61,963 54,991 Total current liabilities 1,055,251 967,786 Operating lease liability, net of current portion 239,352 243,101 Deferred revenue, net of current portion 2,402 188,175 Convertible debt 1,022,688 1,020,776 Liability related to the sale of future royalties, net of current portion 1,342,580 1,322,248 Other liabilities 350,428 308,438 Total liabilities 4,012,701 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 June 30, 2024 and December 31, 2023 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 128,021 shares issued and outstanding as of June 30, 2024; 125,794 shares issued and outstanding as of December 31, 2023 1,281 1,259 Additional paid-in capital 7,122,704 6,811,063 Accumulated other comprehensive loss (34,637 ) (23,375 ) Accumulated deficit (7,092,415 ) (7,009,591 ) Total stockholders’ deficit (3,067 ) (220,644 ) Total liabilities and stockholders’ deficit $ 4,009,634 $ 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 Six Months Ended June 30, 2024 June 30, 2023 June 30, 2024 June 30, 2023 Statements of Operations Revenues: Net product revenues $ 410,088 $ 305,705 $ 775,251 $ 582,033 Net revenues from collaborations 227,338 5,844 345,886 42,306 Royalty revenue 22,399 7,205 33,021 13,705 Total revenues 659,825 318,754 1,154,158 638,044 Operating costs and expenses: Cost of goods sold 67,271 75,336 121,884 116,768 Cost of collaborations and royalties 1,401 10,034 12,764 23,471 Research and development 294,142 248,526 555,137 479,095 Selling, general and administrative 248,397 214,689 459,194 398,348 Total operating costs and expenses 611,211 548,585 1,148,979 1,017,682 Income (loss) from operations 48,614 (229,831 ) 5,179 (379,638 ) Other (expense) income: Interest expense (33,258 ) (30,035 ) (68,511 ) (58,990 ) Interest income 29,182 21,075 58,827 39,730 Other expense, net (55,705 ) (35,418 ) (70,249 ) (47,673 ) Total other expense, net (59,781 ) (44,378 ) (79,933 ) (66,933 ) Loss before income taxes (11,167 ) (274,209 ) (74,754 ) (446,571 ) Provision for income taxes (5,722 ) (1,815 ) (8,070 ) (3,554 ) Net loss $ (16,889 ) $ (276,024 ) $ (82,824 ) $ (450,125 ) Net loss per common share - basic and diluted $ (0.13 ) $ (2.21 ) $ (0.66 ) $ (3.62 ) Weighted-average common shares used to compute basic and diluted net loss per common share 126,733 124,659 126,435 124,387 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended June 30, 2024 June 30, 2023 Reconciliation of GAAP to Non-GAAP Research and development: GAAP Research and development $ 294,142 $ 248,526 Less: Stock-based compensation expenses (48,115 ) (32,801 ) Non-GAAP Research and development $ 246,027 $ 215,725 Reconciliation of GAAP to Non-GAAP Selling, general and administrative: GAAP Selling, general and administrative $ 248,397 $ 214,689 Less: Stock-based compensation expenses (41,173 ) (43,001 ) Non-GAAP Selling, general and administrative $ 207,224 $ 171,688 Reconciliation of GAAP to Non-GAAP Operating income (loss): GAAP Operating income (loss) $ 48,614 $ (229,831 ) Add: Stock-based compensation expenses 89,288 75,802 Non-GAAP Operating income (loss) $ 137,902 $ (154,029 ) Reconciliation of GAAP Net loss to Non-GAAP Net income: GAAP Net loss $ (16,889 ) $ (276,024 ) Add: Stock-based compensation expenses 89,288 75,802 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 1,367 (1,400 ) Non-GAAP Net income (loss) $ 73,766 $ (201,622 ) Reconciliation of GAAP Net loss to Non-GAAP Net income (loss) per common share- basic: GAAP Net loss per common share - basic $ (0.13 ) $ (2.21 ) Add: Stock-based compensation expenses 0.70 0.61 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 0.01 (0.01 ) Non-GAAP Net income (loss) per common share - basic $ 0.58 $ (1.62 ) Reconciliation of GAAP Net loss to Non-GAAP Net income (loss) per common share- diluted: GAAP net loss per common share - diluted $ (0.13 ) $ (2.21 ) Add: Stock-based compensation expenses 0.70 0.61 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 0.01 (0.01 ) Less: Impact to earnings per common share as a result of diluted weighted-average common shares outstanding during the period* (0.02 ) — Non-GAAP net income (loss) per common share - diluted* $ 0.56 $ (1.62 ) *Diluted non-GAAP net income per share is calculated by dividing the non-GAAP net income by the weighted-average number of common shares and dilutive potential common share equivalents then outstanding during the period. The diluted weighted-average common shares outstanding for the three-months ended June 30, 2024 would be 132,061,000. 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) June 30, 2024 Three Months Ended ONPATTRO net product revenue growth, as reported (16 )% Add: Impact of foreign currency translation 1 ONPATTRO net product revenue growth at constant currency (15 )% AMVUTTRA net product revenue growth, as reported 74 % Add: Impact of foreign currency translation 3 AMVUTTRA net product revenue growth at constant currency 77 % Total TTR net product revenue growth, as reported 37 % Add: Impact of foreign currency translation 2 Total TTR net product revenue growth at constant currency 39 % GIVLAARI net product revenue growth, as reported 7 % Add: Impact of foreign currency translation 1 GIVLAARI net product revenue growth at constant currency 8 % OXLUMO net product revenue growth, as reported 68 % Add: Impact of foreign currency translation — OXLUMO net product revenue growth at constant currency 68 % Total net product revenue growth, as reported 34 % Add: Impact of foreign currency translation 1 Total net product revenue growth at constant currency 35 %