Alnylam Pharmaceuticals, Inc. (Alnylam) 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.
By harnessing the RNAi pathway, the company has developed a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics comprise small interfering RN...
Alnylam Pharmaceuticals, Inc. (Alnylam) 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.
By harnessing the RNAi pathway, the company has developed a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics comprise small interfering RNA, or siRNA, that function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made. As of December 31, 2024, the company’s efforts to advance this revolutionary approach had 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. It utilizes an 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. It is also advancing 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 trials, and a definable path for drug development, regulatory approval, patient access, and commercialization.
In early 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 in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis 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 TTR-type familial amyloidosis with polyneuropathy, and in multiple additional countries. In February 2025, ONPATTRO received regulatory approval from the Brazilian Health Regulatory Agency, or ANVISA, for the treatment of ATTR amyloidosis with cardiomyopathy.
AMVUTTRA is approved in the U.S. for the treatment of hereditary transthyretin-mediated amyloidosis, or 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 transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries. Regulatory reviews continue in other territories. In June 2024, the company reported positive topline results from the HELIOS-B clinical trial of vutrisiran (the generic name of AMVUTTRA) in patients with ATTR amyloidosis with cardiomyopathy and announced that it planned to proceed with global regulatory filings seeking approval of AMVUTTRA as a potential treatment for ATTR amyloidosis with cardiomyopathy. In August and September 2024, it reported detailed results from the HELIOS-B clinical trial. On October 9, 2024, the company announced that it had filed a supplemental New Drug Application, or sNDA, with the United States Food and Drug Administration, or the FDA, using a Priority Review Voucher. In November 2024, the FDA accepted the company's sNDA submission for review for vutrisiran, with an action date set for March 23, 2025, under the Prescription Drug User Fee Act, or PDUFA. Vutrisiran is also under regulatory review by the European Medicines Agency, or the EMA, ANVISA, the Japanese Health Authority, or PMDA, and the Colombian Health Authority, or INVIMA.
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 other countries. Regulatory filings for givosiran (the generic name of GIVLAARI) in additional territories are pending or planned during 2025 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 UK for the treatment of PH1 in all age groups. OXLUMO has also been approved in several other countries, and regulatory filings for lumasiran (the generic name of OXLUMO) in additional territories are pending or planned during 2025 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 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 approved in China and Japan, and as of the end of January 2025, Leqvio had been registered in more than 100 countries.
In addition to its marketed products, 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, it is advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen in development for the treatment of hypertension. In 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. In March 2024, the company reported positive topline results from its KARDIA-2 clinical trial, which is designed to evaluate 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.
The company is advancing nucresiran (formerly ALN-TTRsc04), an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. In November 2024, it announced positive new results from the ongoing Phase 1 study of nucresiran in healthy volunteers. These results demonstrated that a single dose of nucresiran at 300 mg or higher resulted in mean reductions of serum TTR of greater than 90% from baseline achieved at Day 15 and sustained through at least Day 180.
The company is also advancing mivelsiran (formerly ALN-APP), an investigational RNAi therapeutic targeting amyloid precursor protein in development for the treatment of Alzheimer’s disease, or AD, and cerebral amyloid angiopathy, or CAA. In October 2024, the company announced positive initial results from the multiple dose portion of the Phase 1 clinical trial of mivelsiran in patients with early-onset AD.
The company has additional late-stage investigational programs advancing toward potential commercialization, including fitusiran for the treatment of hemophilia, which is being advanced by its collaborator Genzyme Corporation, a Sanofi Company, or Sanofi, and for which a New Drug Application, or NDA, has been filed with the FDA with a target action date of March 28, 2025, and cemdisiran for the treatment of complement-mediated diseases, which its collaborator, Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing in combination with pozelimab in Phase 3 clinical trials in myasthenia gravis and geographic atrophy and as a monotherapy in a Phase 3 clinical trial in paroxysmal nocturnal hemoglobinuria.
In further support of its Alnylam P5x25 strategy and in view of its evolving risk profile, the company remains focused on the continued evolution of its global infrastructure, including key objectives, such as optimizing its global structure for execution in key markets, enhancing performance consistent with its values, and continuing to strengthen its culture. It continues to build its global compliance program to drive its evolution and enhancement through the launch of new systems and leveraging data analytics to strengthen the efficiency and effectiveness of its program. Building from its global Code of Business Conduct and Ethics, the company’s 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. Collection of components, such as risk assessment and monitoring; policies, procedures, and guidance; training and communications; dedicated resources; and systems and processes supporting activities, such as third-party engagements, investigations, and remediation, as well as the company’s enterprise risk management program; its program and related controls are built to enhance its business processes, structures, and controls across its global operations, and to empower ethical decision-making.
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 Roche, Regeneron, Sanofi, and Novartis (which acquired its collaborator The Medicines Company, or MDCO, in 2020).
Product Pipeline
The company’s broad pipeline includes five approved products and multiple late and early-stage investigational RNAi therapeutics across a broad range of disease areas and indications. These clinical-stage therapeutics have not been approved by the FDA, EMA, or any other health authority, and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics.
As of December 31, 2024, 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
About Transthyretin Amyloidosis (ATTR)
ATTR amyloidosis is an underdiagnosed, rapidly progressive and fatal disease that affects multiple parts of the body, including the heart, nerves, and digestive system. There are two forms of ATTR – hATTR and wild-type ATTR, which can manifest in a variety of ways. ATTR with cardiomyopathy – including hereditary and wild-type forms – affects greater than 300,000 people worldwide, while hATTR with polyneuropathy affects fewer than 30,000 people worldwide.
ONPATTRO (patisiran)
ONPATTRO (patisiran) is an intravenously administered RNAi therapeutic targeting 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 was 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 was also evaluated in a Phase 4 clinical trial in hATTR amyloidosis patients with polyneuropathy due to a T60A or V122I variant.
ONPATTRO (patisiran) - ATTR Amyloidosis with Cardiomyopathy
In February 2025, ONPATTRO received regulatory approval from the Brazilian Health Regulatory Agency, or ANVISA, for the treatment of ATTR amyloidosis with cardiomyopathy. The company does not plan to pursue label expansions for ONPATTRO in other regions.
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 the company’s ESC+ delivery platform and is 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. AMVUTTRA was subsequently approved in the EU, UK, Argentina, Switzerland, and Canada 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 Brazil for the treatment of hATTR amyloidosis in adults. AMVUTTRA has launched in several additional countries, and regulatory filings in additional territories are under review, with additional filings planned for 2025.
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 clinical trial. In June 2024, the company reported positive topline results from the HELIOS-B clinical trial of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy. In August and September 2024, it reported detailed results from the HELIOS-B clinical trial, and on October 9, 2024, the company announced that it had filed an sNDA with the FDA, using a Priority Review Voucher. It later announced on October 16, 2024, that it had submitted a Type II Variation to the EMA. In November 2024, the FDA accepted the company’s sNDA submission for review for vutrisiran, with an action date set for March 23, 2025, under PDUFA. Vutrisiran is also under regulatory review by the EMA, ANVISA, PMDA, and INVIMA. Additional filings are planned for 2025 and beyond.
HELIOS-B Phase 3 Study
The HELIOS-B Phase 3 clinical trial, initiated in late 2019, was a randomized, double-blind, placebo-controlled, multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis with cardiomyopathy. The secondary endpoints evaluated included change from baseline in 6-minute walk test, or 6-MWT, change from baseline in Kansas City Cardiomyopathy Questionnaire, or KCCQ-OS, all-cause mortality, and change from baseline in New York Heart Association, or NYHA, class, with additional exploratory endpoints evaluated. The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months. After the double-blind period, all eligible patients remaining on the study were able to receive vutrisiran in an open-label extension period of HELIOS-B.
Efficacy and Safety Results
In June 2024, the company announced positive topline results, noting that the study met the primary endpoint, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events during the double-blind period in both the overall population and in the monotherapy population. In the overall population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28%, with similar reductions in both the mortality and cardiovascular events components of the endpoint. Mortality in the overall population was reduced by 31% during the double-blind period and by 36% up to 42 months. In the monotherapy population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 33% and reduced the risk of mortality by 35% up to 42 months. As a component of the primary endpoint, a non-significant reduction of 30% in mortality was observed in the monotherapy population during the double-blind period. The study also demonstrated statistically significant improvements across all secondary endpoints in both the overall and monotherapy populations. This includes key measures of disease progression: 6-MWT, KCCQ, and NYHA Class at Month 30.
In the HELIOS-B clinical trial, the safety and tolerability profiles of vutrisiran were consistent with what had been established in the approved patient population, as well as earlier clinical studies.
Nucresiran (formerly ALN-TTRsc04) – ATTR Amyloidosis
Nucresiran is an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis that utilizes the company's IKARIA technology and provides the potential to achieve deeper and more durable rapid knockdown of TTR, allowing for less frequent dosing. In December 2023 and November 2024, the company announced positive initial results in the Phase 1 study of nucresiran in healthy volunteers. Single doses of 300 mg or higher of nucresiran achieved rapid knockdown with a mean TTR reduction of greater than 90% at Day 15. A peak mean TTR reduction of 96% was achieved at Day 29, and a mean TTR reduction of greater than 90% was sustained at Day 180. At all dose levels evaluated as of December 31, 2024, single doses of nucresiran have been well tolerated. The majority of adverse events across doses have been mild, and none have been considered to be related to treatment. There have been no safety signals identified, including no injection site reactions and no liver-related signals.
These Phase 1 results suggest nucresiran has the potential to offer over 90% max TTR reduction and to be administered once annually. Nucresiran has received orphan drug designation in the U.S.
Other Marketed Products
GIVLAARI (givosiran) — Acute Hepatic Porphyria (AHP)
AHP refers to a family of ultra-rare, genetic diseases characterized by potentially life-threatening attacks, and for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP comprises four types: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and aminolevulinic acid dehydratase-deficiency porphyria. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions, such as viral gastroenteritis, irritable bowel syndrome, and appendicitis. Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease, or liver disease, including hepatocellular carcinoma.
The company's RNAi therapeutic, GIVLAARI, is the first GalNAc-conjugate RNA therapeutic to be approved. GIVLAARI works by specifically reducing induced liver aminolevulinic acid synthase 1 mRNA, leading to a reduction of toxins associated with attacks and other disease manifestations of AHP, and is administered by subcutaneous injection.
GIVLAARI is approved in the U.S. for the treatment of adults with AHP and in the EU for the treatment of AHP in adults and adolescents aged 12 years and older. GIVLAARI has also received marketing authorizations for the treatment of AHP in adults in Brazil and Canada, and for the treatment of AHP in adults and adolescents in Japan, the UK, Argentina, Australia, Switzerland, Israel, and Taiwan. The company has also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Colombia, Mexico, South Korea, and Kuwait; and additional regulatory filings are pending or planned in 2025 and beyond.
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 the company’s ESC-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
OXLUMO is the first approved pharmaceutical therapy for PH1. OXLUMO is approved in the U.S. for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients, and has received marketing authorization in the EU for the treatment of PH1 in all age groups. OXLUMO has also received additional marketing authorizations in Argentina, Australia, Brazil, the UK, Switzerland, Canada, Israel, Taiwan, Oman, and Qatar, and regulatory filings in other territories are pending, with additional filings planned for 2025 and beyond.
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 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.
Leqvio is approved in the U.S. as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including HeFH, to reduce LDL-C. Leqvio is approved in the EU 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. As of the end of January 2025, Leqvio had been approved in over 100 countries. Multiple additional Phase 3 clinical trials of Leqvio are ongoing, including two cardiovascular outcomes trials in secondary prevention, ORION-4 co-sponsored by Novartis and Oxford University, and the Novartis-sponsored VICTORION-2-PREVENT.
In February 2013, the company and MDCO (acquired by Novartis in January 2020) entered into a license and collaboration agreement pursuant to which the company 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. Following its acquisition of MDCO, Novartis has all of the rights and obligations under the MDCO agreement.
Additional Late-Stage Clinical Development Programs
Fitusiran — Hemophilia
Hemophilia is a hereditary bleeding disorder characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective fibrin clot formation, thereby resulting in recurrent bleeds into joints, muscles, and major internal organs. There are approximately 200,000 people living with hemophilia A and hemophilia B worldwide. Standard treatment for people with hemophilia involves replacement of the deficient clotting factor either as prophylaxis or on-demand therapy, which can lead to a temporary restoration of thrombin generation capacity. However, with current factor replacement treatments, people with hemophilia are at risk of developing neutralizing antibodies, or inhibitors, to their replacement factor, a very serious complication affecting as many as one third of people with severe hemophilia A and a smaller fraction of people with hemophilia B. People who develop inhibitors become refractory to replacement factor therapy and are twice as likely to be hospitalized for a bleeding episode.
Lowering antithrombin, or AT, may promote the generation of sufficient levels of thrombin needed to form an effective fibrin clot and prevent bleeding. This rationale is supported by human genetic data suggesting that co-inheritance of thrombophilic mutations, including AT deficiency, may ameliorate bleeding in hemophilia.
Fitusiran is an investigational, subcutaneously administered RNAi therapeutic targeting AT for the treatment of hemophilia A and B, with and without inhibitors, that is being advanced by its collaborator, Sanofi. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to prevent bleeding. AT acts by inactivating thrombin and other coagulation factors, and plays a key role in normal hemostasis by helping to limit the process of fibrin clot formation.
Early-Stage Clinical Development Programs
Zilebesiran — Hypertension
Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, a protein that plays an important role in regulating blood pressure, that is in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade, which has a demonstrated role in blood pressure regulation, and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.
The KARDIA-1 Phase 2 clinical trial 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 the KARDIA-1 clinical trial, with zilebesiran meeting the primary endpoint and demonstrating greater than 15 mmHg reduction of systolic blood pressure at three months of treatment compared to placebo at the two highest single doses evaluated. The KARDIA-2 Phase 2 clinical trial 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 April 2024, the company reported positive topline results from the KARDIA-2 clinical trial, with zilebesiran meeting the primary endpoint and demonstrating additive, placebo-adjusted reductions of up to 12.1 mmHg in 24-hour mean systolic blood pressure at Month 3 when zilebesiran was added to a thiazide-like diuretic, calcium channel blocker, or angiotensin receptor blocker.
In April 2024, the company initiated the KARDIA-3 Phase 2 clinical trial, which is evaluating zilebesiran as an add-on therapy in high cardiovascular risk patients with uncontrolled hypertension despite receiving two or more antihypertensives. The company plans to announce topline results from KARDIA-3, and to initiate a Phase 3 cardiovascular outcomes trial of zilebesiran, in the second half of 2025.
In July 2023, the company announced a collaboration with Roche to co-develop and co-commercialize zilebesiran. As part of its collaboration with Roche, the company is also developing ALN-AGT01 RVR-001, a reversal agent for zilebesiran using its REVERSIR platform. The company initiated a Phase 1 clinical trial of ALN-AGT01 RVR-001 in healthy volunteers in November 2024.
Elebsiran (formerly ALN-HBV02 (VIR-2218)) — Chronic Hepatitis B and D Virus Infection
Elebsiran (formerly ALN-HBV02 (VIR-2218)) is a subcutaneously administered, investigational RNAi therapeutic targeting the HBV genome for the treatment of chronic HBV infection, which is being advanced by its 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 safety and efficacy of elebsiran as part of a treatment regimen for chronic HBV infection is being assessed in the ongoing Phase 2 MARCH trial. Vir has also evaluated elebsiran in combination with tobevibart for the treatment of chronic hepatitis D virus, or CHD, and Vir expects to initiate a Phase 3 registrational study to evaluate the combination of elebsiran and tobevibart in CHD in the first half of 2025. The company has the right to opt into a profit-sharing arrangement for elebsiran prior to the start of a Phase 3 study.
Mivelsiran (formerly ALN-APP) — Alzheimer’s Disease and Cerebral Amyloid Angiopathy
Mivelsiran is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein, or APP, in development in collaboration with Regeneron for the treatment of AD, and CAA. Genetic mutations that increase production of APP or alter its cleavage cause early-onset AD, early-onset CAA, or both. Mivelsiran is designed to decrease APP mRNA in the CNS to decrease synthesis of APP protein and all downstream intracellular and extracellular APP-derived cleavage products, including amyloid beta (Aß). Reducing APP protein production is expected to reduce the secretion of Aß peptides that aggregate into extracellular amyloid deposits in AD and CAA, and reduce the intraneuronal APP cleavage products that may trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD. Mivelsiran 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 early 2022, the company initiated a Phase 1 clinical trial of mivelsiran in patients with early-onset AD, and in April 2023 and July 2023, it reported positive interim results from the ongoing single ascending dose part of the Phase 1 clinical trial. Further exploration of single doses of mivelsiran is ongoing in Part A of the Phase 1 clinical trial. In addition, the multiple-dose part of the study, Part B, is enrolling. In February 2024, the company announced that the FDA had provided clearance to initiate Part B of the Phase 1 clinical trial at sites in the U.S. The FDA confirmed that multiple-dosing in the Phase 1 clinical trial 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.
In October 2024, the company announced positive initial results from the multiple-dose Part B portion of the Phase 1 clinical trial, and it expects to report additional interim results from Part B of the Phase 1 clinical trial in AD in the second half of 2025. The company also expects to initiate a Phase 2 clinical trial of mivelsiran in patients with AD in the second half of 2025.
In July 2024, the company initiated dosing in the cAPPricorn-1 Phase 2 clinical trial of mivelsiran in patients with CAA.
In May 2024, Regeneron notified the company of its decision to opt-out of the further co-development of mivelsiran. As a result of Regeneron’s opt-out, the company has full global development and commercialization rights to mivelsiran in all indications.
ALN-HTT02 – Huntington’s Disease
ALN-HTT02 is an investigational, intrathecally administered RNAi therapeutic targeting huntingtin, or HTT, that is in development in collaboration with Regeneron for the treatment of HD. ALN-HTT02 is designed to target a conserved sequence in exon 1 of the HTT messenger RNA, thereby reducing the expression of all isoforms of HTT protein, including shorter exon 1-containing HTT fragments, which have been implicated in disease pathology but are missed by many other HTT-lowering therapeutic strategies. Beyond the more inclusive exon 1 targeting strategy, the company’s underlying C16-siRNA delivery platform may offer an opportunity to fully explore the potential efficacy of HTT-lowering via widespread distribution, deep and sustained lowering, and infrequent dosing regimens.
In September and November 2024, the company presented nonclinical data supporting the tolerability of deep and sustained HTT-lowering in wild-type nonhuman primates after single and repeated intrathecal administration of ALN-HTT02. The company also presented the design of a Phase 1b clinical trial. The Phase 1b clinical trial of ALN-HTT02 in adult patients with HD was initiated in late 2024, with the first patient dosed in November.
Additional Early-Stage and Preclinical Programs
During 2025, the company plans to file four or more new investigational new drug applications, or INDs, or CTAs from its organic product engine. The company also intends to continue to build on its progress with extrahepatic delivery during 2025, advancing its CNS programs under its collaboration with Regeneron, as well as continuing to advance its other extrahepatic delivery initiatives, including delivery to muscle and adipose tissues.
Collaboration and Licensing Strategy
The company's business strategy is to develop and commercialize a broad pipeline of RNAi therapeutic products directed across a broad range of disease areas and indications. 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.
Product Collaborations
Roche. In July 2023, the company entered into the Roche Collaboration and License Agreement, pursuant to which the company and Roche established a worldwide, strategic collaboration for the joint development of pharmaceutical products containing zilebesiran.
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 the company 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.
Sanofi. The company formed a broad strategic alliance with Sanofi in 2014. In January 2018, the company and Sanofi amended their 2014 collaboration and entered into the Exclusive License Agreement, referred to as the Exclusive TTR License, under which the company was granted exclusive rights to pursue the further global development and commercialization of all TTR products, including ONPATTRO, AMVUTTRA, and any back-up products, and the ALN-AT3 Global License Terms, referred to as the AT3 License Terms, under which Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.
Novartis. In February 2013, the company entered into an exclusive, worldwide license with MDCO (acquired by Novartis AG in January 2020), pursuant to which MDCO was granted the right to develop, manufacture, and commercialize RNAi therapeutics targeting proprotein convertase subtilisin/kexin type 9 for the treatment of hypercholesterolemia and other human diseases, including Leqvio.
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
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 company is collaborating with PeptiDream 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.
Dicerna Pharmaceuticals, Inc. In April 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 the company's lumasiran program and Dicerna’s nedosiran program, each for the treatment of PH.
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 they further amended in July 2015, or the 2015 Ionis agreement. The 2015 Ionis agreement provides for certain exclusive 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 through April 2019.
Intellectual Property, Proprietary Rights and Exclusivities
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 the company’s 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 ODE until November 20, 2026. In connection with the company’s 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, the company 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.
Manufacturing
In 2015, the company amended its manufacturing services agreement with Agilent Technologies, Inc., or Agilent, to provide for Agilent to supply, subject to any conflicting obligations under its third-party agreements, a specified percentage of the active pharmaceutical ingredients required for certain of its products in clinical development, as well as other products the parties may agree upon in the future. Agilent is the sole manufacturer of the active pharmaceutical ingredient for ONPATTRO, AMVUTTRA and GIVLAARI, and the company has entered into manufacturing services agreements with Agilent for such supply of ONPATTRO, AMVUTTRA and GIVLAARI.
Commercial Operations
The company has built and continues to scale global commercial operations designed to sequentially manage product launches across multiple geographies. The conduct of these commercial activities will continue to be dependent upon regulatory approvals and on agreements that the company has made or may make in the future with strategic collaborators, as follows with respect to the company’s first five approved products and the company’s late-stage clinical programs:
With respect to the company’s ATTR amyloidosis franchise, the company has global rights to develop and commercialize both ONPATTRO and AMVUTTRA;
With respect to the company’s Global Rare franchise, the company has global rights to develop and commercialize GIVLAARI and OXLUMO;
The company granted MDCO, which was acquired by Novartis in January 2020, global rights to develop and commercialize Leqvio; and
The company granted Sanofi global rights to develop and commercialize fitusiran and any back-ups.
Throughout the development of the company’s product candidates, the company has remained focused on keeping patients at the center of everything the company do. This patient focus has continued as the company has transitioned into commercialization. ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as the other programs the company is advancing to commercialization are focused on a broad range of disease areas and indications, and the company has been executing on the company’s strategy to make ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO and any future products successful, including through efforts to increase awareness and diagnosis. In addition, consistent with the company’s Alnylam P5x25 strategy, the company is now advancing RNAi therapeutics beyond rare diseases across a broad range of disease areas and indications. Beginning with the approval of Leqvio, which was the first RNAi therapeutic approved for a prevalent disease (hypercholesterolemia), the RNAi therapeutic profile supports the potential for expansion to prevalent diseases, including hypertension, NASH and diabetes, where there remains significant unmet need. The company is scaling its global commercial organization and infrastructure to support the company’s eventual expansion to commercialize RNAi therapeutics in prevalent diseases.
The company has a proactive market access strategy that includes entering into value-based agreements, or VBAs, with commercial payers in the U.S. and certain state Medicaid programs. The company has entered into VBAs with multiple commercial payers, including for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. In the company’s VBAs for GIVLAARI and OXLUMO the company offers a prevalence-based adjustment that provides that the company will pay a rebate if the number of patients identified within a plan population exceeds the expected disease prevalence. For OXLUMO, the company offers a VBA component called a patient need adjustment that provides payers with greater budget certainty for medicines administered across a broad range of patient age groups by paying a rebate if the average number of vials utilized by a plan member exceeds an established threshold. These adjustment seek to address an unknown that exists in the context of an ultra-rare disease. Discussions with additional payers continue for the company’s marketed products. Outside of the U.S., the company has made strong progress with patient access and have established availability of ONPATTRO, AMVUTTRA, OXLUMO and GIVLAARI in more than 60 markets through direct reimbursement or in partnership with the company’s distributors. In addition, the company has been encouraged by the strength of the adoption of AMVUTTRA in hATTR amyloidosis with polyneuropathy in key markets and expect continued expansion across global markets.
The company is continuing to augment the key components of its global commercial organization with a focus on successfully launching the company’s commercially approved products around the world and preparing for the anticipated commercial launches of additional RNAi therapeutics, assuming successful development and regulatory approval. With respect to the company’s approved products, throughout 2024, the company continued to build its commercial capabilities and to expand these capabilities to additional countries globally. The company is building a focused commercial team with broad experience in marketing, sales, patient access, patient services, distribution and product reimbursement, and incorporating and enhancing appropriate quality systems, compliance policies, systems and procedures, as well as implementing internal systems and infrastructure to support global commercial sales, and the establishment of patient-focused programs.
The company intends to leverage its existing commercial infrastructure to also support the launch of vutrisiran in ATTR-CM, assuming regulatory approval. In preparation for potential regulatory approvals, the company has implemented a compliance program to ensure that the company’s promotional activities remain focused solely on AMVUTTRA in hATTR amyloidosis with polyneuropathy until the company obtains approval to market vutrisiran for ATTR amyloidosis with cardiomyopathy in each market. The company’s Ethics & Compliance team has partnered with its Commercial and Medical Affairs leadership teams in the implementation of this program, which is focused on proactive messaging and training, field monitoring, and data analysis. For many territories/countries, the company may also utilize strategic partners, distributors or contract sales forces to assist in the commercialization of the company’s products.
History
Alnylam Pharmaceuticals, Inc., a Delaware corporation, was founded in 2002. The company was incorporated in 2003.
