About Alnylam Pharmaceuticals Inc

Alnylam Pharmaceuticals, Inc. operates as a global commercial-stage biopharmaceutical company. The company is developing novel therapeutics based on ribonucleic acid interference, or RNAi. RNAi is a naturally occurring biological pathway within cells for sequence-specific silencing and regulation of gene expression. As of December 31, 2023, the company’s efforts to advance this revolutionary approach have yielded the approval of five first-in-class RNAi-based medicines, ONPATTRO (patisiran), AMVUTTRA (vutrisiran), GIVLAARI (givosiran), OXLUMO (lumasiran) and Leqvio (inclisiran). The company’s research and development strategy is to target genetically validated genes that have been implicated in the cause or pathway of human disease. The company utilizes a N-acetylgalactosamine (GalNAc) conjugate approach or lipid nanoparticle (LNP) to enable hepatic delivery of siRNAs. For delivery to the central nervous system, or CNS, and the eye (ocular delivery), the company is utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand. During 2023, the company continued to advance approaches for heart, skeletal muscle, and adipose tissue delivery of siRNAs. The company’s focus is on clinical indications where there is a high unmet need, a genetically validated target, early biomarkers for the assessment of clinical activity in Phase 1 clinical studies, and a definable path for drug development, regulatory approval, patient access and commercialization. In 2021, the company launched its Alnylam P5x25 strategy, which focuses on its planned transition to a top-tier biotech company by the end of 2025. ONPATTRO is approved by the United States Food and Drug Administration, or the FDA, for the treatment of hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis, with polyneuropathy in adults and has also been approved in the European Union, or EU, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries, including Brazil. In August 2022, the company reported positive results from the APOLLO-B Phase 3 study of patisiran (the non-branded name of ONPATTRO) in patients with ATTR amyloidosis with cardiomyopathy, and in December 2022, the company submitted a supplemental New Drug Application, or sNDA, to the FDA for patisiran as a potential treatment for the ATTR amyloidosis with cardiomyopathy. On September 13, 2023, the FDA’s Cardiovascular and Renal Drugs Advisory Committee, or CRDAC, voted 9:3 that patisiran’s benefits outweigh its risks for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, with cardiomyopathy. AMVUTTRA is approved in the U.S. for the treatment of hATTR amyloidosis with polyneuropathy in adults, in the EU and the United Kingdom, or U.K., for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of TTR type familial amyloidosis with polyneuropathy, and in additional countries, including Brazil, Argentina, Switzerland and Canada. Regulatory filings continue in other territories with submissions currently under review or planned for 2024 and beyond. GIVLAARI is approved in the U.S. for the treatment of adults with acute hepatic porphyria, or AHP, in the EU for the treatment of AHP in adults and adolescents aged 12 years and older, and in several additional countries, including Brazil, Canada, Australia, Switzerland and Japan. Regulatory filings for givosiran (the non-branded drug name for GIVLAARI) in other territories are pending or planned during 2024 and beyond. OXLUMO is approved in the U.S. for the treatment of primary hyperoxaluria type 1, or PH1, to lower urinary and plasma oxalate levels in pediatric and adult patients, and in the EU and the U.K. for the treatment of PH1 in all age groups. OXLUMO has also been approved in Brazil, Switzerland, Canada, Israel and Qatar, and additional regulatory filings in other territories are pending or planned during 2024 and beyond. Leqvio (inclisiran), the company’s fifth product, is being developed and commercialized by its collaborator Novartis AG, or Novartis, and has received marketing authorization from the European Commission, or EC, for the treatment of adults with hypercholesterolemia or mixed dyslipidemia and from the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, or HeFH, or clinical atherosclerotic cardiovascular disease, or ASCVD, who require additional lowering of low-density lipoprotein cholesterol, or LDL-C. In the third quarter of 2023, Leqvio was approved in China and Japan, and as of the end of January 2024, Leqvio had been approved in more than 90 countries. In addition to its marketed products, the company has multiple late-stage investigational programs advancing toward potential commercialization. These programs include the company’s wholly owned programs: vutrisiran (the non-branded drug name for AMVUTTRA) for the treatment of ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy; as well as fitusiran for the treatment of hemophilia, which is being advanced by its collaborator Genzyme Corporation, a Sanofi Company, or Sanofi; and cemdisiran for the treatment of complement-mediated diseases, where its collaborator Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with pozelimab in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria. As part of its Alnylam P5x25 strategy, the company has multiple drivers of future growth, including the development of transformative medicines to treat prevalent disease. In addition to Leqvio, the company is advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension. In November 2021, the company reported positive interim data from the ongoing Phase 1 clinical trial of zilebesiran, and initiated the KARDIA Phase 2 clinical trials for zilebesiran. KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually. In September 2023, the company reported positive topline results from KARDIA-1. The company anticipates reporting topline results from KARDIA-2 in early 2024. In July 2023, the company entered into a Collaboration and License Agreement, or the Roche Collaboration and License Agreement, with F. Hoffmann-La Roche Ltd. and Genentech, Inc. or, collectively, Roche, pursuant to which it established a worldwide, strategic collaboration for the joint development and commercialization of zilebesiran. The company is also advancing ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy. In 2023, the company reported positive interim results from the ongoing single ascending dose part of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease. These results establish the first human translation of the company’s proprietary C16-siRNA conjugate platform for CNS delivery and are the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic. The company maintains focus on its global compliance program to drive its evolution and enhancement in view of the Alnylam P5x25 strategy. Building from the company’s global Code of Business Conduct and Ethics, its compliance program is designed to empower its employees and those with whom it works to execute on its strategy consistent with its values and in compliance with applicable laws and regulations, and to mitigate risk. Based on its expertise in RNAi therapeutics and broad intellectual property estate, the company has formed collaborations with leading pharmaceutical and life sciences companies to support its development and commercialization efforts, including Regeneron, Roche, Novartis (which acquired its collaborator The Medicines Company, or MDCO, in 2020), Sanofi, Vir Biotechnology, Inc., or Vir, Dicerna Pharmaceuticals, Inc. (acquired by Novo Nordisk A/S, or Novo Nordisk, in December 2021), or Dicerna, and PeptiDream, Inc., or PeptiDream. Product Pipeline The company’s broad pipeline, including five approved products and multiple late and early-stage investigational RNAi therapeutics, addresses unmet needs in several disease areas, and spans indications in rare, specialty and select prevalent diseases. As of December 31, 2023, the company had received marketing approval for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and Novartis has received approval for Leqvio, in each case in certain territories for the specific indications approved in each such territory, with additional regulatory submissions pending. TTR Franchise Transthyretin Amyloidosis (ATTR) ATTR amyloidosis is a rare, serious, life-threatening, multisystem disease encompassing hATTR amyloidosis and wild-type ATTR, or wtATTR, amyloidosis, which results from either hereditary (genetic variant in TTR gene) or nonhereditary (ageing) causes, respectively. In ATTR amyloidosis, misfolded TTR proteins accumulate as amyloid fibrils in multiple organs and tissue types. hATTR amyloidosis can include sensory and motor neuropathy, autonomic neuropathy and cardiac symptoms and is a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy. wtATTR amyloidosis predominantly manifests as cardiomyopathy and heart failure symptoms, although patients may experience other manifestations due to extra-cardiac amyloid deposition. ONPATTRO (patisiran) ONPATTRO (patisiran) is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR mRNA, thereby reducing the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues to halt or improve the progression of disease. Patisiran has received Orphan Drug Designations in the U.S., EU and Japan; specific Orphan Drug Designations vary by country/region. ONPATTRO (patisiran) – hATTR Amyloidosis with Polyneuropathy ONPATTRO is the first ever FDA-approved RNAi therapeutic and based on data from the APOLLO Phase 3 study, it became the company’s first product to receive marketing approval. In the U.S. and Canada, ONPATTRO is indicated for the treatment of hATTR amyloidosis with polyneuropathy in adults. In the EU, Switzerland, Brazil and Israel, ONPATTRO is indicated for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy, and in Japan, ONPATTRO is indicated for the treatment of TTR type familial amyloidosis with polyneuropathy. Patisiran (the non-branded name for ONPATTRO) was also evaluated in a Phase 4 study in hATTR amyloidosis patients with polyneuropathy due to a T60A or V122I variant. Patisiran – ATTR Amyloidosis with Cardiomyopathy In December 2022, the company submitted an sNDA to the FDA for ONPATTRO for the treatment cardiomyopathy of ATTR amyloidosis based on the positive results from the APOLLO-B Phase 3 study. On October 6, 2023, the FDA issued a CRL indicating that the sNDA for patisiran could not be approved in its present form. An sNDA submission for ONPATTRO for the treatment of ATTR amyloidosis with cardiomyopathy was submitted in Brazil in 2023. APOLLO-B Phase 3 Study In 2022, the company announced that the APOLLO-B Phase 3 study, a randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate the efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy, met the primary endpoint of change from baseline in the six-minute walk test, or 6-MWT, at 12 months compared to placebo with a median difference of 14.7 meters (p-value 0.0162) favoring patisiran. In November 2023, the company reported new results from an interim analysis of exploratory data from the open-label extension, or OLE, period of the APOLLO-B Phase 3 study. The 24-month findings indicate that the favorable effects on functional capacity and health status and quality of life, as measured by the 6-MWT and the KCCQ-OS, respectively, observed during the double-blind period were sustained with continued patisiran treatment during the OLE period. Patients treated with patisiran through 24 months also appear to have maintained relative stability of NT-proBNP and Troponin I levels, measures of cardiac stress and injury, respectively. AMVUTTRA (vutrisiran) AMVUTTRA (vutrisiran) is a subcutaneously administered RNAi therapeutic targeting TTR. With its rapid knockdown, it targets and silences TTR mRNA, thereby reducing the production of TTR protein before it is made. AMVUTTRA utilizes its ESC+ delivery platform, designed for increased potency and high metabolic stability to allow for quarterly subcutaneous administration. Vutrisiran has received Orphan Drug Designation in the U.S., EU and Japan; specific Orphan Drug Designations vary by country/region. AMVUTTRA (vutrisiran) – hATTR Amyloidosis with Polyneuropathy In June 2022, AMVUTTRA was approved by the FDA for the treatment of hATTR amyloidosis with polyneuropathy in adults based on positive 9-month results from the HELIOS-A Phase 3 study that evaluated the efficacy and safety of AMVUTTRA in patients with hATTR amyloidosis with polyneuropathy. In September 2022, AMVUTTRA was approved in the EU and the U.K. for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, and in Japan for the treatment of TTR type familial amyloidosis with polyneuropathy. In December 2022, AMVUTTRA was approved in Brazil for the treatment of hATTR amyloidosis in adults. In 2023, AMVUTTRA received regulatory approval in Argentina, Switzerland and Canada for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and launched in several additional countries. Regulatory filings in additional territories are currently under review and additional filings are planned for 2024. HELIOS-A Phase 3 Study Initiated in late 2018, the HELIOS-A Phase 3 trial is a randomized, open-label Phase 3 study in hATTR amyloidosis patients. The primary endpoint is the mean change from baseline in the modified Neuropathy Impairment Score +7, or mNIS+7, at nine months as compared to the external placebo control arm of the previously completed APOLLO Phase 3 study of patisiran, upon which the approval of ONPATTRO was based. The two secondary endpoints at nine months were changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, or Norfolk QoL-DN, score and gait speed assessed by the timed 10-meter walk test, both compared to external placebo. In February 2023, the company reported topline results from the HELIOS-A randomized treatment extension, or RTE, portion of the study, through month nine. Non-inferiority of the 50mg biannual regimen (vs 25mg quarterly) was established, as demonstrated by mean serum TTR reduction over nine months. Vutrisiran also continued to demonstrate an acceptable safety profile. In the RTE study there were six deaths, of which five occurred on the 50 mg biannual arm and one occurred on the 25 mg quarterly arm, after the patient dropped out of the study. Vutrisiran – ATTR Amyloidosis with Cardiomyopathy Vutrisiran is also in development as a potential treatment for patients with ATTR amyloidosis with cardiomyopathy in the ongoing HELIOS-B Phase 3 study. HELIOS-B Phase 3 Study The HELIOS-B Phase 3 study, initiated in late 2019, is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vutrisiran in patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy. Patients were randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months. The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular events. In February 2024, the company updated the HELIOS-B statistical analysis plan and announced that the primary endpoint will be tested in parallel in two populations: the overall population and the population of patients not on tafamidis at the time of enrollment onto the study, which it refers to as the monotherapy population. The monotherapy population constitutes approximately 60% of the patients enrolled in the study. The secondary endpoints will include change from baseline in 6-MWT, change from baseline in KCCQ-OS, all-cause mortality, and change from baseline in New York Heart Association class, with additional exploratory endpoints being evaluated. The company also announced in February 2024, that it had increased the minimum follow-up on the study from 30 to 33 months, with variable follow-up to 36 months. Enrollment in the HELIOS-B study was completed significantly ahead of schedule, with 655 ATTR amyloidosis patients across 123 activated sites in 33 countries. Topline results from the HELIOS-B study are expected in late June or early July 2024. ALN-TTRsc04 – ATTR Amyloidosis ALN-TTRsc04 is an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis that utilizes the company’s IKARIA technology and provides the potential for greater than 90% target gene silencing with once annual dosing. In December 2023, the company announced positive initial results in the Phase 1 study of ALN-TTRsc04 in healthy volunteers. Other Marketed Products GIVLAARI (givosiran) — Acute Hepatic Porphyria (AHP) The company’s RNAi therapeutic, GIVLAARI (givosiran), is the first GalNAc-conjugate RNA therapeutic to be approved. GIVLAARI works by specifically reducing induced liver aminolevulinic acid synthase 1 mRNA, leading to reduction of toxins associated with attacks and other disease manifestations of AHP. In the United States (U.S.), GIVLAARI (givosiran) injection for subcutaneous use is approved for the treatment of adults with AHP. GIVLAARI was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations in the U.S. In March 2020, the EC granted marketing authorization in the European Union (EU) for GIVLAARI for the treatment of AHP in adults and adolescents aged 12 years and older. GIVLAARI was reviewed under accelerated assessment by the EMA and had previously been granted PRIME and Orphan Drug Designations in the EU. The company received additional marketing authorizations for GIVLAARI for the treatment of AHP in adults in Brazil, Canada, and marketing authorizations for GIVLAARI for the treatment of AHP in adults and adolescents in Japan, Argentina, Australia, Switzerland and Taiwan. The company has also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Israel, Colombia, Mexico and Kuwait, and additional regulatory filings are pending or planned in 2024 and beyond. The company estimates there are approximately 3,000 AHP patients diagnosed in the U.S. and EU with active disease. Each type of AHP results from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. AHP disproportionately impacts women of working and childbearing age, and symptoms of the disease vary widely. OXLUMO (lumasiran)— Primary Hyperoxaluria Type 1 (PH1) OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1, or HAO1, developed for the treatment of PH1. HAO1 encodes glycolate oxidase, or GO, an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 mRNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate, the toxic metabolite responsible for the clinical manifestations of PH1. OXLUMO utilizes its ESC-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. In November 2020, the EC granted marketing authorization for OXLUMO (lumasiran) for the treatment of PH1 in all age groups, following a positive Committee for Medicinal Products for Human Use, or CHMP, opinion. OXLUMO was previously granted an Accelerated Assessment and a PRIME Designation by the EMA and an Orphan Designation in the EU. Also, in November 2020, OXLUMO (lumasiran) subcutaneous injection was approved by the FDA for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients. OXLUMO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease Designations. With the approval of OXLUMO, the FDA granted the company a pediatric rare disease priority review voucher. The company has also received additional marketing authorizations for OXLUMO in Brazil, the U.K., Switzerland, Canada, Israel and Qatar, and regulatory filings in other territories are pending and additional filings are planned for 2024 and beyond. The regulatory approvals of OXLUMO in the U.S. and EU were based on positive results from both the ILLUMINATE-A and ILLUMINATE-B Phase 3 pivotal studies of lumasiran in patients with PH1. Lumasiran was also evaluated in ILLUMINATE-C – a global Phase 3 study in PH1 patients of all ages with advanced PH1, which resulted in the FDA approval of a label expansion for the treatment of PH1 patients to lower plasma oxalate levels. In addition, the CHMP of the EMA delivered a positive opinion recommending variation to the marketing authorization of OXLUMO based on ILLUMINATE-C data from patients with advanced PH1 in September 2022. Leqvio (inclisiran) — Hypercholesterolemia The company’s RNAi therapeutic Leqvio, developed and commercialized by its collaborator, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower LDL-C, and is the first RNAi therapeutic approved for a highly prevalent disease. Leqvio is a subcutaneously administered RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9, or PCSK9, to reduce LDL-C levels via an RNAi mechanism of action and could help improve outcomes for patients with ASCVD, a deadly form of cardiovascular disease. In December 2020, following a positive CHMP opinion, the EC granted marketing authorization for Leqvio (inclisiran) for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet: in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximally tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. In December 2021, the FDA approved Leqvio as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD who require additional lowering of LDL-C. In July 2023, the FDA approved an expanded indication for Leqvio to include treatment of adults with high LDL-C and who are at increased risk of heart disease. Leqvio has also been granted Orphan Drug Designation in the U.S. for the treatment of homozygous familial hypercholesterolemia, or HoFH. In the third quarter of 2023, Leqvio was approved in China and Japan, and as of the end of January 2024, Leqvio had been approved in over 90 countries. In February 2013, the company and MDCO (acquired by Novartis in January 2020) entered into a license and collaboration agreement pursuant to which it granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases. Multiple additional Phase 3 trials are ongoing, including cardiovascular outcomes trials, ORION-4 and the Novartis initiated VICTORION-2-PREVENT. Additional Late-Stage Clinical Development Programs Fitusiran — Hemophilia Fitusiran is an investigational, subcutaneously administered RNAi therapeutic targeting antithrombin, or AT, for the treatment of hemophilia A and B, with and without inhibitors, that is being advanced by the company’s collaborator, Sanofi. Fitusiran is being evaluated in the ATLAS Phase 3 program. Sanofi presented positive results from the ATLAS-A/B and ATLAS-INH Phase 3 studies of fitusiran in December 2021, and in July 2022, Sanofi presented positive results from the Phase 3 ATLAS-PPX study evaluating the efficacy and safety of once-monthly fitusiran (80 mg) in adults and adolescents with severe hemophilia A or B who were previously treated with prior factor or bypassing agent prophylaxis. In 2023, Sanofi presented positive results from the ATLAS-OLE Phase 3 extension study of fitusiran, demonstrating a substantially improved safety profile and 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 an NDA for fitusiran to the FDA in 2024. Fitusiran has received both U.S. and EU Orphan Drug Designations for the treatment of hemophilia A and B. In January 2018, the company and Sanofi entered into an amendment to its 2014 collaboration, as well as the ALN-AT3 Global License Terms, which as further amended in April 2019 are referred to as the A&R AT3 License Terms, pursuant to which Sanofi has global rights to develop and commercialize fitusiran and any back-up products. Cemdisiran — Complement-Mediated Diseases Cemdisiran is a subcutaneously administered, investigational RNAi therapeutic targeting the C5 component of the complement pathway in development for the treatment of complement-mediated diseases. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in a broad range of human diseases including immunoglobulin A nephropathy, or IgAN, myasthenia gravis, and paroxysmal nocturnal hemoglobinuria, amongst others. In June 2022, the company announced positive topline results from the Phase 2 study of cemdisiran as a monotherapy in adult patients with IgAN. In November 2022, Regeneron exercised its right to opt-out of the cemdisiran monotherapy program. Cemdisiran is Phase 3 ready as a monotherapy for IgAN, and the company is evaluating options for further development. Cemdisiran is also being evaluated by the company’s collaborator, Regeneron, in combination with Regeneron’s anti-C5 monoclonal antibody, pozelimab, in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria. Regeneron’s decision to opt-out of the monotherapy program has no impact on Regeneron’s ongoing efforts under a separate license agreement to develop cemdisiran in combination with pozelimab. Early-Stage Clinical Development Programs Zilebesiran— Hypertension Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting AGT, in development for the treatment of hypertension in high unmet need populations. The KARDIA-1 and KARDIA-2 Phase 2 clinical studies of zilebesiran were initiated in June and November 2021, respectively. KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually, and KARDIA-2 is evaluating the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by a standard of care antihypertensive medication. In September 2023, the company reported positive topline results from KARDIA-1, with zilebesiran meeting the primary endpoint and demonstrating greater than 15mmHg reduction of systolic blood pressure at three months of treatment compared to placebo at the two highest single doses evaluated. The company announced that it completed enrollment of patients in the KARDIA-2 Phase 2 study in July 2023, with topline results expected in early 2024. In July 2023, the company announced a collaboration with Roche to co-develop and co-commercialize zilebesiran. As part of this collaboration, the company announced an update to the clinical development plan to include a new Phase 2 study, KARDIA-3, which is a multi-agent combination study in patients with uncontrolled hypertension and high CV risk. The KARDIA-3 clinical study is expected to initiate in 2024. Elebsiran – Chronic Hepatitis B and D Virus Infection Elebsiran is a subcutaneously administered, investigational RNAi therapeutic targeting the HBV genome for the treatment of chronic HBV infection, which is being advanced by the company’s collaborator, Vir. Elebsiran is designed to inhibit expression of all HBV proteins, including hepatitis B surface antigen. Almost one-third of the world’s population have previous or current HBV infection. Worldwide, more than 250 million people are chronically infected with HBV, and an estimated 1 million people die each year from complications of chronic HBV, such as cirrhosis and hepatocellular carcinoma. Current treatment options include life-long suppressive antiviral therapies. There is a significant need for safe and convenient novel therapeutics that restore the host immune response, leading to control of the virus after a finite duration of therapy, which is the definition of a functional cure. The company has the right to opt into a profit-sharing arrangement for elebsiran prior to the start of a Phase 3 study. ALN-APP – Alzheimer’s Disease and Cerebral Amyloid Angiopathy ALN-APP is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein, or APP, in development in collaboration with Regeneron for the treatment of Alzheimer’s disease, or AD, and cerebral amyloid angiopathy, or CAA. ALN-APP is the first program utilizing the company’s C16 conjugate technology, which enables enhanced delivery to cells in the CNS, to enter clinical development. In 2022, the company initiated a Phase 1 study of ALN-APP in patients with early-onset AD, and in April 2023 and July 2023, the company reported positive interim results from the ongoing single ascending dose part of the Phase 1 study. Further exploration of single doses of ALN-APP is ongoing in Part A of the Phase 1 study. In addition, the multiple-dose part of the study, Part B, is enrolling patients from Part A and has received regulatory approval to proceed in Canada, where the majority of the Part A clinical trial patients were enrolled. In February 2024, the company announced that the FDA has provided clearance to initiate Part B of the Phase 1 study at sites in the U.S. The FDA 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 in place in the U.S. for higher or more frequent dosing regimens. The company also expects to initiate a Phase 2 study of ALN-APP in CAA in early 2024. ALN-HSD – Non-alcoholic Steatohepatitis ALN-HSD is a subcutaneously administered, investigational RNAi therapeutic targeting HSD17B13 that is being developed by its collaborator, Regeneron, for the treatment of NASH. NASH is a highly prevalent chronic liver disease in which inflammation and liver cell injury are caused by accumulation of hepatic fat. In September 2022, the company and Regeneron reported on positive results from a Phase 1 study of ALN-HSD in healthy volunteers and patients with NASH. In December 2022, the company further elaborated on these results demonstrating robust target engagement and safety profile that supports continued clinical development. In late 2022, the company opted-out of the further development and commercialization of ALN-HSD, and Regeneron will be leading development and commercialization of the ALN-HSD program from Phase 2 onward. Additional Early-Stage and Pre-clinical Programs In addition to the programs, the company is advancing other earlier-stage pipeline programs, including ALN-KHK for Type 2 diabetes mellitus and ALN-PNP for NASH. The company filed CTAs for each of its ALN-KHK and ALN-PNP programs during 2023. During 2024, the company plans to file three new investigational new drug applications, or INDs, or CTAs from its organic product engine. Collaboration and Licensing Strategy The company’s business strategy is to develop and commercialize a broad pipeline of RNAi therapeutic products directed towards transformative rare, specialty and select prevalent diseases. As part of this strategy, the company has entered into, and expects to enter into additional, collaboration and licensing agreements as a means of obtaining resources, capabilities and funding to advance its investigational RNAi therapeutic programs. The company’s collaboration strategy is to form collaborations that create significant value for itself and its collaborators in the advancement of RNAi therapeutics as a new class of innovative medicines. Product Collaborations Regeneron In April 2019, the company entered into a global, strategic collaboration with Regeneron to discover, develop and commercialize RNAi therapeutics for a broad range of diseases by addressing therapeutic targets expressed in the eye and CNS, in addition to a select number of targets expressed in the liver, which it refers to as the Regeneron Collaboration. The Regeneron Collaboration is governed by a Master Agreement, referred to as the Regeneron Master Agreement, which became effective in May 2019. In August 2019, the company and Regeneron entered into a co-co collaboration agreement covering the continued development of cemdisiran, its C5 siRNA Phase 3 ready for IgAN as a monotherapy and a license agreement covering evaluation of anti-C5 antibody-siRNA combinations for C5 complement-mediated diseases, including evaluating the combination of Regeneron’s pozelimab and cemdisiran. Roche In July 2023, the company entered into the Roche Collaboration and License Agreement with Roche, pursuant to which it established a worldwide, strategic collaboration for the joint development of pharmaceutical products containing zilebesiran. Under the Roche Collaboration and License Agreement, the company granted to Roche co-exclusive rights to develop zilebesiran worldwide and commercialize zilebesiran in the U.S., exclusive rights to commercialize zilebesiran outside the U.S., and non-exclusive rights to manufacture zilebesiran for the development and commercialization of zilebesiran outside the U.S. Novartis In February 2013, the company and MDCO entered into a license and collaboration agreement pursuant to which it granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases. Under the MDCO agreement, the company had responsibility for the development of inclisiran until Phase 1 Completion, as defined in the MDCO agreement. Sanofi In January 2014, the company entered into a global, strategic collaboration with Sanofi to discover, develop and commercialize RNAi therapeutics to treat orphan diseases, referred to as the 2014 Sanofi collaboration. The 2014 Sanofi collaboration superseded and replaced the previous collaboration between the company and Sanofi entered into in October 2012 to develop and commercialize RNAi therapeutics targeting TTR for the treatment of hATTR amyloidosis, including patisiran and revusiran, in Japan and the Asia-Pacific region. In January 2018, the company and Sanofi entered into an amendment to its 2014 Sanofi collaboration. In connection and simultaneously with entering into the 2018 amendment to the 2014 Sanofi collaboration, it and Sanofi also entered into the Exclusive TTR License and the AT3 License Terms. As a result, the company has the exclusive right to pursue the further global development and commercialization of all TTR products, including ONPATTRO, AMVUTTRA and any back-up products, and Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products. In April 2019, the company and Sanofi agreed to further amend the 2014 Sanofi collaboration to conclude the research and option phase and to amend and restate the AT3 License Terms pursuant to the A&R AT3 License Terms, to modify certain of the business terms. The material collaboration terms for fitusiran were unchanged. Under the A&R AT3 License Terms, the company is eligible to receive tiered royalties of 15% to 30% based on global annual net sales of fitusiran and up to 15% based on global annual net sales of any back-up products controlled by Sanofi, in each case by Sanofi, its affiliates and its sublicensees. Vir In October 2017, the company and Vir entered into a collaboration and license agreement, or the Vir Agreement, pursuant to which it granted to Vir an exclusive license to develop, manufacture and commercialize elebsiran (formerly ALN-HBV02), for all uses and purposes other than certain excluded fields, as set forth in the Vir Agreement. In addition, the company granted Vir an exclusive option for up to four additional RNAi therapeutics programs for the treatment of infectious diseases. Strategic Financing Collaboration The Blackstone Group Inc. In April 2020, the company entered into a strategic financing collaboration with certain affiliates of Blackstone to accelerate its advancement of RNAi therapeutics. Other Collaboration and License Agreements Dicerna Pharmaceuticals, Inc. In 2020, the company and Dicerna entered into a Patent Cross-License Agreement, pursuant to which each party agreed to cross-license its respective intellectual property related to its lumasiran program and Dicerna’s nedosiran program, each for the treatment of PH. In addition, in April 2020, the company and Dicerna (acquired by Novo Nordisk in December 2021) formed a development and commercialization collaboration on investigational RNAi therapeutics for the treatment of alpha-1 liver disease. Under the development and commercialization agreement, its ALN-AAT02 and Dicerna’s belcesiran (formerly DCR-A1AT), each in Phase 1/2 development, are being explored for the treatment of alpha-1 liver disease. In December 2023, the company received notice from Dicerna that they had exercised their termination right, without cause, under the development and collaboration agreement, effective May 2024. PeptiDream, Inc. In July 2021, the company entered into a license and collaboration agreement with PeptiDream to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver. Through this collaboration, the companies are collaborating to select and optimize peptides for targeted delivery of small siRNA molecules to a wide range of cell types and tissues via specific interactions with receptors expressed on the target cells. Novartis AG In January 2022, the company announced that it and Novartis, entered into a collaboration and license agreement, referred to as the Novartis License Agreement, pursuant to which it granted to Novartis an exclusive, worldwide license to develop, manufacture and commercialize siRNAs targeting end-stage liver disease, potentially leading to the development of a treatment designed to promote the regrowth of functional liver cells and to provide an alternative to transplantation for patients with liver failure. Ionis Pharmaceuticals, Inc. In January 2015, the company and Ionis Pharmaceuticals, Inc., or Ionis, entered into a second amended and restated strategic collaboration and license agreement, which it further amended in July 2015, or the 2015 Ionis agreement. The 2015 Ionis agreement provides for certain new exclusive target cross-licenses of intellectual property on eight disease targets, providing each company with exclusive RNA therapeutic license rights for four programs, and extended the parties’ existing non-exclusive technology cross-license, which was originally entered into in 2004 and was amended and restated in 2009, through April 2019. Intellectual Property, Proprietary Rights and Exclusivities Key Patents and Regulatory Exclusivities The company typically obtains protection of its product candidates with patents and patent applications directed to compositions of matter and their uses. Below is a summary of selected granted patents that the company owns or controls covering products marketed by it in the U.S. and Europe. In addition, in connection with the company’s FDA approval on August 10, 2018, the FDA granted ONPATTRO Orphan Drug Exclusivity, or ODE, until August 10, 2025. In connection with the company’s EMA approval on August 26, 2018, the EMA granted ONPATTRO Marketing Exclusivity and ODE until August 26, 2028. In addition, in connection with the company’s FDA approval on June 13, 2022, the FDA granted AMVUTTRA new chemical entity, or NCE, exclusivity until June 13, 2027. In connection with its EMA approval on September 15, 2022, the EMA granted AMVUTTRA Marketing Exclusivity and ODE until September 15, 2032. In addition, in connection with the company’s FDA approval on November 20, 2019, the FDA granted GIVLAARI NCE exclusivity until November 20, 2024, and ODE until November 20, 2026. In connection with its EMA approval on March 2, 2020, the EMA granted GIVLAARI Marketing Exclusivity and ODE until March 2, 2030. In addition, in connection with the company’s FDA approval on November 23, 2020, the FDA granted OXLUMO NCE exclusivity until November 23, 2025, and ODE until November 23, 2027. In connection with the company’s EMA approval on November 19, 2020, the EMA granted OXLUMO Marketing Exclusivity and ODE until November 19, 2030. Trademarks The company files trademarks to protect its corporate brand and its products. Typically, the company files trademark applications in the U.S., Europe and elsewhere in the world as appropriate. In addition to multiple pending trademark applications in the U.S. and other major countries, it has registered trademarks in the U.S., including but not limited to Alnylam and the Alnylam logo, as well as ONPATTRO and the ONPATTRO logo, AMVUTTRA and the AMVUTTRA logo, GIVLAARI and the GIVLAARI logo and OXLUMO and the OXLUMO logo. Alnylam Act and IKARIA are also trademarks and registered trademarks of the company. History Alnylam Pharmaceuticals, Inc. was founded in 2002. The company, a Delaware corporation, was incorporated in 2003.