Alnylam Pharmaceuticals, the leading RNAi therapeutics company, hosted its R&D Day in New York City, unveiling significant pipeline advancements and platform innovations that position the company for sustained growth across multiple therapeutic areas.
Expanding the TTR Franchise with Next-Generation Therapies
Alnylam scientists provided details on the TRITON Phase 3 program for nucresiran, the company's next-generation transthyretin (TTR) silencer. This investigational therapy has demonstrated potential for greater than 95% TTR knockdown with twice-annual dosing, positioning it as a potential best-in-class treatment.
The TRITON program consists of two key trials: TRITON-PN in patients with hereditary ATTR amyloidosis with polyneuropathy, aimed at rapid market entry, and TRITON-CM, an event-driven cardiovascular outcomes trial in approximately 1,200 patients with ATTR amyloidosis with cardiomyopathy. The primary endpoint for TRITON-CM will be a composite of all-cause mortality and cardiovascular events, with regulatory approval anticipated around 2030 if successful.
The company also shared new data from the landmark HELIOS-B study of vutrisiran in ATTR amyloidosis with cardiomyopathy. Prespecified analyses with near-complete data through month 42 showed vutrisiran reduced all-cause mortality by 36% in the overall population and by 39% in the monotherapy population compared to placebo. Vutrisiran is currently under FDA review for ATTR amyloidosis with cardiomyopathy, with a PDUFA target action date of March 23, 2025.
"As we advance our flagship TTR franchise, we are excited to share Phase 3 development plans for our next-generation TTR silencer, nucresiran, which has best-in-class potential," said Pushkal Garg, M.D., Chief Medical Officer of Alnylam.
Transforming Hypertension Treatment with Zilebesiran
Alnylam outlined key design elements of a pivotal Phase 3 trial for zilebesiran in hypertension, scheduled to begin later this year. This global, event-driven trial will enroll up to 11,000 patients across more than 30 countries, focusing on patients with uncontrolled hypertension despite taking at least two antihypertensive medications.
The primary endpoint will be a 4-point MACE (Major Adverse Cardiovascular Events), a composite of non-fatal myocardial infarctions, non-fatal strokes, cardiovascular deaths, and hospitalizations for heart failure or urgent heart failure visits.
Enrollment is now complete for the KARDIA-3 Phase 2 trial evaluating zilebesiran in combination with at least two antihypertensives in high cardiovascular risk patients with uncontrolled hypertension. Results from KARDIA-3, expected in the second half of 2025, will further inform the design of the Phase 3 trial. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.
Expanding Neuroscience Portfolio with Promising Clinical Data
Alnylam presented additional data from both single-ascending dose and multiple dose parts of its Phase 1 study of mivelsiran in early-onset Alzheimer's disease. The data demonstrated potent and durable reduction of soluble APPβ—a key marker of target engagement—in the cerebrospinal fluid, along with an encouraging safety profile. The company is also evaluating mivelsiran as a potential treatment for cerebral amyloid angiopathy, a major cause of hemorrhagic stroke.
Scientists also provided an update on the ALN-HTT02 program, which employs a highly differentiated exon-1-targeting approach to lower huntingtin (HTT) for Huntington's disease. The Phase 1b single-ascending-dose study in adult patients with Huntington's disease continues to progress, with substantial data expected at a medical congress in 2026. ALN-HTT02 is being developed in partnership with Regeneron.
Emerging Clinical Programs Targeting Metabolic Disorders and Bleeding Conditions
Alnylam shared data on ALN-4324, which targets GRB14 for the treatment of type 2 diabetes and has the potential to be the first insulin sensitizer approved in more than 30 years. Preclinical data demonstrated approximately 90% knockdown of the target 22 days after a low-dose, subcutaneous injection, and improved insulin sensitivity without weight gain.
The company also presented updates on several obesity programs targeting INHBE in the liver and ACVR1C in adipose tissue, as well as combinations of targets. These programs aim to improve upon the tolerability and quality of weight loss achieved by currently available therapies.
Additionally, Alnylam scientists presented an update on ALN-6400, which targets liver-derived plasminogen and could represent a potential universal hemostatic agent for bleeding disorders without the risk of thrombosis. Data from the first cohort of participants in the Phase 1 study demonstrated favorable impact on an ex-vivo hemostasis assay. This is particularly significant given that more than 3 million people in the U.S. are affected by bleeding disorders with limited treatment options.
Platform Innovation Driving Future Growth
Alnylam outlined its vision to unlock every major tissue for RNAi therapeutics by 2030. Scientists presented new preclinical data on delivery solutions with best-in-class potential for adipose, muscle, heart, and kidney tissue. The company also shared updates on its approach to crossing the blood-brain barrier, as well as emerging technology to enable combination therapy.
Manufacturing innovations were highlighted, including enzymatic ligation, which has the potential to revolutionize the production of RNAi therapeutics to meet growing demand and improve efficiency.
"Alnylam is driving the field of RNAi therapeutics into the future, with a sustainable innovation engine that continues to generate transformative medicines while simultaneously expanding what's possible for RNAi with platform advances," Dr. Garg emphasized. "We are on track to meet our ambitious pipeline and platform expansion goals as we seek to address additional diseases, to deliver RNAi therapeutics to all major tissue types by 2030, and to realize the full potential of our pioneering technology."
The company remains on track to meet its ambitious "2-2-5" pipeline and platform expansion goal announced at R&D Day in 2023, which includes filing Investigational New Drug (IND) applications for nine new Alnylam-led programs by the end of 2025—two in new tissues, two in the central nervous system, and five in the liver.
Alnylam's R&D Day presentations reinforced the company's position at the forefront of RNAi therapeutics development, with a robust pipeline of potential blockbuster therapies addressing significant unmet medical needs across multiple therapeutic areas.
