Hyperoxaluria, Primary

Allogene’s AlloCAR T™ Autoimmune Disease Platform Leverages Arbor’s CRISPR Gene-Editing Technology First Allogeneic CAR T Phase 1 Clinical Trial in Autoimmune Disease Expected to Initiate in Early 2025 March 12, 2024 -- Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T™) products for cancer and autoimmune disease, and Arbor Biotechnologies, Inc. (“Arbor”), a biotechnology company discovering and developing the next generation of genetic medicines, today announced a non-exclusive, global gene editing licensing agreement for use of Arbor’s proprietary CRISPR gene-editing technology in Allogene’s next generation AlloCAR T platform for the treatment of autoimmune disease (AID). “The potential for CAR T as a therapeutic option for autoimmune disease has captured the collective imagination of the scientific community,” said Zachary Roberts, M.D., Ph.D., Executive Vice President of Research & Development and Chief Medical Officer of Allogene. “Accordingly, this excitement created a new field for CAR T that has become quickly crowded, making differentiation key for future success. This agreement provides us access to Arbor’s proprietary gene-editing technology and know-how, allowing us to develop what we believe will be the most effective and broadly accessible CAR T approach for the treatment of autoimmune disease.” Allogene has applied its deep understanding of CAR T research and development to design next-generation allogeneic CAR T investigational products with a goal of reduced or chemotherapy-free conditioning that the Company believes can sustain the scale of the AID market while also meeting the unique requirements for these patients where they seek care. Allogene’s first AID AlloCAR T investigational product is expected to enter Phase 1 clinical trials in early 2025. “Our strategy has long been to align ourselves with industry leaders who are working to harness the power of gene editing to change treatment paradigms and improve patient outcomes,” said Devyn Smith, Ph.D., Chief Executive Officer of Arbor. “We look forward to our collaboration with Allogene as they leverage our extensive gene-editing technologies to develop novel, differentiated allogeneic CAR T therapeutics for autoimmune diseases.” Arbor Biotechnologies® is a next-generation gene editing company based in Cambridge, Mass. Combining the promise of CRISPR with advanced computational AI-driven discovery, high-throughput screening, and robust protein engineering approaches, our scientific co-founders Feng Zhang and David Walt laid the groundwork for our proprietary discovery engine, that has yielded an extensive portfolio of novel genomic editors. We envision a future of gene editing that extends beyond simple knockdowns to include reverse transcriptases, nuclease excisions and large insertions. This affords us the potential to treat a broad spectrum of patients, from those with ultra-rare to the most common genetically defined diseases. Guided by a deep understanding of the molecular basis of disease and our access to a unique suite of optimized genomic editors, we are rapidly advancing our development programs with an initial focus on genetically defined liver-mediated and CNS diseases. As we advance toward the clinic with our first therapeutic candidate in primary hyperoxaluria type I, we look to expand our strategic partnerships around in vivo genomic editing across multiple therapeutic areas and ex vivo cell therapy programs to broaden the reach of our novel gene editing technologies. For more information, visit arbor.bio. Allogene Therapeutics, with headquarters in South San Francisco, is a clinical-stage biotechnology company pioneering the development of allogeneic chimeric antigen receptor T cell (AlloCAR T™) products for cancer and autoimmune disease. Led by a management team with significant experience in cell therapy, Allogene is developing a pipeline of “off-the-shelf” CAR T cell product candidates with the goal of delivering readily available cell therapy on-demand, more reliably, and at greater scale to more patients. For more information, please visit www.allogene.com, and follow @AllogeneTx on X (formerly Twitter) and LinkedIn. The content above comes from the network. if any infringement, please contact us to modify.

Achieved Fourth Quarter and Full Year 2023 Global Net Product Revenues of $346 Million and $1,241 Million, Respectively, Representing 39% Annual Growth Compared to 2022 Company Announces Updated Statistical Analysis Plan and Timing for HELIOS-B Phase 3 Study of Vutrisiran Announces U.S. FDA Clearance to Initiate Multiple-Dosing in ALN-APP Phase 1 Study Provides 2024 Combined Net Product Revenue Guidance of $1,400 Million to $1,500 Million, in Addition to Collaboration and Royalty Revenue and Operating Expense Guidance CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the fourth quarter and full year ended December 31, 2023 and reviewed recent business highlights. “2023 was a year of strong execution at Alnylam. We delivered robust product revenue growth across our four wholly-owned commercial medicines, with $1.24 billion in global net product revenues, and achieved over 5,000 patients now being treated with an Alnylam commercial medicine. We also extended our leadership in RNAi with the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic, strengthened our business for the future through a landmark partnership with Roche and delivered solid financial performance,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “Looking ahead to 2024, we are excited for a number of important milestones across the pipeline, including results from the HELIOS-B Phase 3 study of vutrisiran as well as the KARDIA-2 Phase 2 study of zilebesiran, and six clinical study starts. This progress sets us up for delivering on our Alnylam P5x25 goals of becoming a top-tier biotech company delivering sustained innovation and exceptional financial results.” Fourth Quarter 2023 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO® (patisiran) & AMVUTTRA® (vutrisiran) Achieved global net product revenues for ONPATTRO and AMVUTTRA for the fourth quarter of $79 million and $175 million, respectively, representing 10% total TTR quarterly growth compared to Q3 2023, and full year 2023 revenues of $355 million and $558 million, respectively, representing 40% total TTR annual growth compared to full year 2022. Attained over 4,060 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2023. Total Ultra-Rare: GIVLAARI® (givosiran) & OXLUMO® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the fourth quarter of $59 million and $33 million, respectively, representing 11% total Ultra-Rare quarterly growth compared to Q3 2023, and full year 2023 revenues of $219 million and $110 million, respectively, representing 35% total Ultra-Rare annual growth compared to full year 2022. Attained over 650 patients on commercial GIVLAARI and over 430 patients on commercial OXLUMO worldwide as of December 31, 2023. R&D Highlights Alnylam announces today updates to the statistical analysis plan for the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy. These will include updates to the primary and secondary endpoint structure, as well as study exposure. Topline results are expected to be available in late June or early July. Details will be discussed on the conference call this morning. Published results from Phase 3 APOLLO-B study of patisiran in the New England Journal of Medicine. Presented positive initial Phase 1 results with ALN-TTRsc04 demonstrating rapid knockdown achieved by a single dose with mean serum TTR reduction up to 97%, with durability supporting potential for annual dosing and an encouraging safety profile. Presented positive results from the KARDIA-1 Phase 2 dose-ranging study of zilebesiran, an investigational RNAi therapeutic in development to treat hypertension patients at high cardiovascular risk, during the American Heart Association (AHA) Scientific Sessions. Announces today that the U.S. Food and Drug Administration (FDA) has provided clearance to initiate the multiple-dose part (Part B) of the ongoing Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy. 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. Reported updated positive interim results for the ongoing single ascending dose portion of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease at the 2023 Alzheimer’s Association International Conference and at the 16th Clinical Trials in Alzheimer’s Disease conference. Presented positive initial Phase 1 results with ALN-KHK demonstrating robust target engagement and an encouraging safety profile, supporting continued development as a novel treatment for type 2 diabetes mellitus. Filed an Investigational New Drug (IND) application for ALN-BCAT, an investigational RNAi therapeutic targeting β-catenin in development for the treatment of hepatocellular carcinoma. Sanofi presented positive results from the ATLAS-OLE Phase 3 extension study of fitusiran, demonstrating a substantially improved safety pro consistent bleed protection in people with hemophilia A or B, with or without inhibitors. Specifically, the risk of thrombosis was reduced, with rates comparable to those reported in the general hemophilia population. Sanofi expects to submit a New Drug Application (NDA) to the FDA in 2024. Additional Business Updates Ranked #1 on Boston Globe’s Top Places to Work list for 2023 in the “Largest Employer” category. Recognized by Science magazine as a Top Employer for the fifth consecutive year. Upcoming Events Alnylam announces today that results from the KARDIA-2 Phase 2 study of zilebesiran will be presented in a Late-Breaker presentation at the American College of Cardiology Scientific Sessions 2024 on April 7, 2024 in Atlanta, Georgia. In early 2024, Alnylam intends to: Report topline results from the HELIOS-B Phase 3 study of vutrisiran in late June or early July. Initiate the KARDIA-3 Phase 2 study of zilebesiran. Initiate a Phase 2 study of ALN-APP in patients with cerebral amyloid angiopathy. Initiate Part B of the Phase 1 study of ALN-KHK. Initiate a Phase 1 study of ALN-BCAT. Financial Highlights for the Fourth Quarter and Year End 2023 Three Months Ended December 31, Twelve Months Ended December 31, (In thousands, except per share amounts) 2023 2022 2023 2022 Net product revenues $ 346,288 $ 261,675 $ 1,241,474 $ 894,329 Net revenue from collaborations $ 76,407 $ 70,645 $ 546,185 $ 134,912 Royalty revenue $ 17,023 $ 2,715 $ 40,633 $ 8,177 GAAP Operating loss $ (116,404 ) $ (188,614 ) $ (282,175 ) $ (785,072 ) Non-GAAP Operating loss $ (74,410 ) $ (145,847 ) $ (60,495 ) $ (554,423 ) GAAP Net loss $ (137,870 ) $ (207,493 ) $ (440,242 ) $ (1,131,156 ) Non-GAAP Net loss $ (96,643 ) $ (171,522 ) $ (201,618 ) $ (790,609 ) GAAP Net loss per common share - basic and diluted $ (1.10 ) $ (1.68 ) $ (3.52 ) $ (9.30 ) Non-GAAP Net loss per common share - basic and diluted $ (0.77 ) $ (1.39 ) $ (1.61 ) $ (6.50 ) 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 December 31, Twelve Months Ended December 31, (In thousands) 2023 2022 2023 2022 ONPATTRO net product revenues $ 79,006 $ 122,221 $ 354,546 $ 557,608 AMVUTTRA net product revenues 175,254 68,566 557,838 93,795 Total TTR net product revenues 254,260 190,787 912,384 651,403 GIVLAARI net product revenues 59,298 47,058 219,251 173,144 OXLUMO net product revenues 32,730 23,830 109,839 69,782 Total net product revenues $ 346,288 $ 261,675 $ 1,241,474 $ 894,329 Year over Year % Growth Three Months Ended December 31, 2023 Twelve Months Ended December 31, 2023 As Reported At CER* As Reported At CER* Total TTR net product revenues 33 % 31 % 40 % 40 % GIVLAARI net product revenues 26 % 24 % 27 % 26 % OXLUMO net product revenues 37 % 32 % 57 % 55 % Total net product revenues 32 % 30 % 39 % 39 % * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in 2022. CER is a non-GAAP measure. Net product revenues increased 32% and 39% at actual currency during the three and twelve months ended December 31, 2023, respectively, compared to the same periods in 2022, and 30% and 39% at CER, respectively. The increases are primarily due to increased patients on our commercial TTR therapies driven by the launch of AMVUTTRA in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies. Net Revenues from Collaborations Net revenues from collaborations increased 8% and 305% during the three and twelve months ended December 31, 2023, respectively, as compared to the same periods in 2022, primarily due to revenue recognized under our Collaboration and License Agreement with Roche, as executed in July 2023, and revenue recognized under our Novartis Collaboration Agreement associated with the achievement of specified commercialization and regulatory milestones. Operating Expenses Three Months Ended December 31, Twelve Months Ended December 31, (In thousands) 2023 2022 2023 2022 Cost of goods sold $ 71,975 $ 46,172 $ 268,216 $ 140,174 Cost of goods sold as a percentage of net product revenues 20.8 % 17.6 % 21.6 % 15.7 % Cost of collaborations and royalties $ 13,883 $ 5,094 $ 42,190 $ 28,643 GAAP research and development expenses $ 272,141 $ 262,039 $ 1,004,415 $ 883,015 Non-GAAP research and development expenses $ 253,056 $ 245,095 $ 907,142 $ 790,854 GAAP selling, general and administrative expenses $ 198,123 $ 210,344 $ 795,646 $ 770,658 Non-GAAP selling, general and administrative expenses $ 175,214 $ 184,521 $ 671,239 $ 632,170 Cost of Goods Sold Cost of goods sold as a percentage of net product revenues increased during the three and twelve months ended December 31, 2023, respectively, as compared to the same periods in 2022, primarily due to increased volume and rate of royalties payable on net sales of AMVUTTRA associated with tiered royalty percentages, in addition to increased excess and obsolete charges primarily due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR amyloidosis with cardiomyopathy indication for patisiran for which we did not receive regulatory approval. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three and twelve months ended December 31, 2023, compared to the same periods in 2022, primarily due to increased headcount and infrastructure expenses to support our R&D pipeline, development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran Phase 2 studies, and manufacturing and research related expenses associated with our pre-clinical and developmental activities. GAAP R&D expenses further increased during the twelve month period due to increased stock-based compensation expense related to the accounting for certain performance-based awards during the period. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses decreased during the three months ended December 31, 2023, compared to the same period in 2022, primarily due to increased legal expenses in 2022 associated with the Patent Infringement Lawsuits we filed in March 2022 and the Department of Justice investigation, which closed in August 2023, and increased expenses in support of the global launch of AMVUTTRA in the third quarter of 2022. GAAP and non-GAAP SG&A expenses increased during the twelve months ended December 31, 2023, compared to the same period in 2022, primarily due to increased headcount and other strategic investments in support of the global launch of AMVUTTRA and other expenses to support our strategic growth. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.44 billion as of December 31, 2023, compared to $2.19 billion as of December 31, 2022, with the increase primarily due to the receipts of a $310 million upfront payment from Roche in connection with our partnership to co-develop and co-commercialize zilebesiran, a $100 million payment from Regeneron in connection with the achievement of certain criteria during early clinical development for our CNS program, ALN-APP, and nearly $150 million from employee option award exercises, offset by our operating loss for the year. A reconciliation of our GAAP to non-GAAP results for the current quarter is included in the tables at the end of this press release. 2024 Financial Guidance Full year December 31, 2024 financial guidance consists of the following: Combined net product revenues for AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO1 $1,400 million – $1,500 million Net Product Revenue Growth vs. 2023 at reported Fx rates1 13% – 21% Net Product Revenue Growth vs. 2023 at constant exchange rates* 13% – 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, as applicable, stock-based compensation expenses, realized and unrealized (gains) losses on marketable equity securities and loss on the extinguishment of debt. 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 (gains) 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. The Company has excluded the loss on the extinguishment of debt because the Company believes the item is a non-recurring transaction outside the ordinary course of the Company’s business. Percentage changes in revenue growth at CER are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss fourth quarter and full year 2023 results as well as expectations for the future via conference call on Thursday, February 15, 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 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 most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) 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. CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) December 31, 2023 December 31, 2022 ASSETS Current assets: Cash and cash equivalents $ 812,688 $ 866,394 Marketable debt securities 1,615,516 1,297,890 Marketable equity securities 11,178 28,122 Accounts receivable, net 327,787 237,963 Inventory 89,146 128,962 Prepaid expenses and other current assets 126,382 132,916 Total current assets 2,982,697 2,692,247 Property, plant and equipment, net 526,057 523,494 Operating lease right-of-use assets 199,732 215,136 Restricted investments 49,391 49,390 Other assets 72,003 66,092 Total assets $ 3,829,880 $ 3,546,359 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 55,519 $ 98,094 Accrued expenses 713,013 545,460 Operating lease liability 41,510 41,967 Deferred revenue 102,753 42,105 Liability related to the sale of future royalties 54,991 40,289 Total current liabilities 967,786 767,915 Operating lease liability, net of current portion 243,101 261,339 Deferred revenue, net of current portion 188,175 193,791 Convertible debt 1,020,776 1,016,942 Liability related to the sale of future royalties, net of current portion 1,322,248 1,252,015 Other liabilities 308,438 212,580 Total liabilities 4,050,524 3,704,582 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 December 31, 2023 and December 31, 2022 — — Common stock, $0.01 par value per share, 250,000 shares authorized as of December 31, 2023 and December 31, 2022, respectively; 125,794 shares issued and outstanding as of December 31, 2023; 123,925 shares issued and outstanding as of December 31, 2022 1,259 1,240 Additional paid-in capital 6,811,063 6,454,540 Accumulated other comprehensive loss (23,375 ) (44,654 ) Accumulated deficit (7,009,591 ) (6,569,349 ) Total stockholders’ deficit (220,644 ) (158,223 ) Total liabilities and stockholders’ deficit $ 3,829,880 $ 3,546,359 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. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 (Unaudited) (Unaudited) Revenues: Net product revenues $ 346,288 $ 261,675 $ 1,241,474 $ 894,329 Net revenues from collaborations 76,407 70,645 546,185 134,912 Royalty revenue 17,023 2,715 40,633 8,177 Total revenues 439,718 335,035 1,828,292 1,037,418 Operating costs and expenses: Cost of goods sold 71,975 46,172 268,216 140,174 Cost of collaborations and royalties 13,883 5,094 42,190 28,643 Research and development 272,141 262,039 1,004,415 883,015 Selling, general and administrative 198,123 210,344 795,646 770,658 Total operating costs and expenses 556,122 523,649 2,110,467 1,822,490 Loss from operations (116,404 ) (188,614 ) (282,175 ) (785,072 ) Other (expense) income: Interest expense (31,338 ) (29,913 ) (121,221 ) (155,968 ) Interest income 30,406 14,077 95,561 24,808 Other expense, net (20,351 ) (2,571 ) (125,682 ) (134,175 ) Loss on the extinguishment of debt — — — (76,586 ) Total other expense, net (21,283 ) (18,407 ) (151,342 ) (341,921 ) Loss before income taxes (137,687 ) (207,021 ) (433,517 ) (1,126,993 ) Provision for income taxes (183 ) (472 ) (6,725 ) (4,163 ) Net loss $ (137,870 ) $ (207,493 ) $ (440,242 ) $ (1,131,156 ) Net loss per common share — basic and diluted $ (1.10 ) $ (1.68 ) $ (3.52 ) $ (9.30 ) Weighted-average common shares used to compute basic and diluted net loss per common share 125,613 123,266 124,906 121,689 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 Reconciliation of GAAP to Non-GAAP research and development: GAAP Research and development $ 272,141 $ 262,039 $ 1,004,415 $ 883,015 Less: Stock-based compensation expenses (19,085 ) (16,944 ) (97,273 ) (92,161 ) Non-GAAP Research and development $ 253,056 $ 245,095 $ 907,142 $ 790,854 Reconciliation of GAAP to Non-GAAP selling, general and administrative: GAAP Selling, general and administrative $ 198,123 $ 210,344 $ 795,646 $ 770,658 Less: Stock-based compensation expenses (22,909 ) (25,823 ) (124,407 ) (138,488 ) Non-GAAP Selling, general and administrative $ 175,214 $ 184,521 $ 671,239 $ 632,170 Reconciliation of GAAP to Non-GAAP operating loss: GAAP operating loss $ (116,404 ) $ (188,614 ) $ (282,175 ) $ (785,072 ) Add: Stock-based compensation expenses 41,994 42,767 221,680 230,649 Non-GAAP Operating loss $ (74,410 ) $ (145,847 ) $ (60,495 ) $ (554,423 ) Reconciliation of GAAP to Non-GAAP Other (expense) income: GAAP Total other expense, net $ (21,283 ) $ (18,407 ) $ (151,342 ) $ (341,921 ) (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (767 ) (6,796 ) 16,944 33,312 Add: Loss on the extinguishment of debt — — — 76,586 Non-GAAP Other expense, net $ (22,050 ) $ (25,203 ) $ (134,398 ) $ (232,023 ) Reconciliation of GAAP to Non-GAAP net loss: GAAP Net loss $ (137,870 ) $ (207,493 ) $ (440,242 ) $ (1,131,156 ) Add: Stock-based compensation expenses 41,994 42,767 221,680 230,649 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (767 ) (6,796 ) 16,944 33,312 Add: Loss on the extinguishment of debt — — — 76,586 Non-GAAP Net loss $ (96,643 ) $ (171,522 ) $ (201,618 ) $ (790,609 ) Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted: GAAP Net loss per common share - basic and diluted $ (1.10 ) $ (1.68 ) $ (3.52 ) $ (9.30 ) Add: Stock-based compensation expenses 0.33 0.35 1.77 1.90 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (0.01 ) (0.06 ) 0.14 0.27 Add: Loss on the extinguishment of debt — — — 0.63 Non-GAAP Net loss per common share - basic and diluted $ (0.77 ) $ (1.39 ) $ (1.61 ) $ (6.50 ) 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) December 31, 2023 Three Months Ended Twelve Months Ended Total TTR net product revenue growth, as reported 33 % 40 % Add: Impact of foreign currency translation (2 ) — Total TTR net product revenue growth at constant currency 31 % 40 % GIVLAARI net product revenue growth, as reported 26 % 27 % Add: Impact of foreign currency translation (2 ) (1 ) GIVLAARI net product revenue growth at constant currency 24 % 26 % OXLUMO net product revenue growth, as reported 37 % 57 % Add: Impact of foreign currency translation (5 ) (2 ) OXLUMO net product revenue growth at constant currency 32 % 55 % Total net product revenue growth, as reported 32 % 39 % Add: Impact of foreign currency translation (2 ) — Total net product revenue growth at constant currency 30 % 39 % Total revenue growth, as reported 31 % 76 % Add: Impact of foreign currency translation (2 ) — Total revenue growth at constant currency 29 % 76 % View source version on businesswire.com: Contacts Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom (Investors and Media) 617-682-4340 Josh Brodsky (Investors) 617-551-8276 Source: Alnylam Pharmaceuticals, Inc. View this news release online at:

Pictured: Nasdaq stock exchange headquarters in New York City/iStock, JHVEPhoto Metagenomi shares dropped 31% on Friday afternoon in a disappointing debut on the Nasdaq Global Select Market, highlighting the potential perils faced by preclinical biotechs seeking to go public, according to Seeking Alpha. The company’s stock opened at $10.25 per share, versus its initial public offering (IPO) price of $15 apiece. Shares of Metagenomi climbed to a high of $11.24 per share and dipped to a low of $9.80 on Friday. Last week, Metagenomi unveiled its initial plans to go public in an $86.9 million IPO, with plans to sell more than six million shares of its common stock for $15 to $17 apiece. The California-based company made its Nasdaq debut days later in an IPO priced at the lowest end of its target range, with the expectation of raising nearly $93.8 million. Though Metagenomi joins an impressive class of companies that have gone public this year, it also bucks the trend of IPOs that have raised more money than expected. Leading the pack is CG Oncology, whose $380 million IPO last month was a huge jump from its initial target of $180 million. ArriVent followed soon after, with its own upsized $175 million offering, up from its expectation of $135 million to $156 million. Alto Neuroscience, which went public earlier this month, likewise saw a larger final haul of $128.6 million versus its initial estimate of $89 million to $103 million. Kyverna Therapeutics is the latest biotech to upsize its IPO, bringing in $319 million in gross proceeds compared to its initial net earnings target of $182 million. Kyverna’s Nasdaq debut saw its stock surge nearly 60% following its IPO. The market’s tepid response to Metagenomi could be because it currently has no clinical-stage candidates. Instead, the biotech is banking on what it calls “the most diverse genome editing toolbox,” which it plans to leverage to target a wide variety of genetic diseases. According to its website, Metagenomi has developed a comprehensive set of tools—including base editors, programmable nucleases and RNA- and DNA-mediated integration systems—that it contends can address and target “essentially any codon in the human genome.” The company’s metagenomics-focused approach to diseases has attracted several high-pro including Moderna and Bayer, which contributed to the biotech’s $275 million Series B haul in January 2023. Using its toolbox, Metagenomi has developed several preclinical- and discovery-stage assets targeting a variety of indications, including hemophilia A, familial amyotrophic lateral sclerosis, Duchenne muscular dystrophy and cystic fibrosis. It also has a primary hyperoxaluria type 1 program in partnership with Moderna, and a transthyretin amyloidosis candidate in collaboration with Ionis. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.