Single‐Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N‐acetylgalactosamine–Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects

Vutrisiran (ALN‐TTRsc02) is a liver‐directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)‐mediated amyloidosis. This phase I, randomized, single‐blind, placebo‐controlled, single ascending dose study evaluated the pharmacodynamics, pharmacokinetics, and safety profile of subcutaneously administered vutrisiran (5–300 mg) in healthy subjects ( n = 80). Vutrisiran treatment achieved potent and sustained TTR reduction in a dose‐dependent manner, with mean maximum TTR reduction of 57–97%, maintained for ≥ 90 days post dose. Vutrisiran was rapidly absorbed (peak plasma concentration 3–5 hours post dose), had a short plasma half‐life (4.2–7.5 hours), and plasma concentrations increased in a dose‐proportional manner. Pharmacodynamic and pharmacokinetic results were similar in Japanese and non‐Japanese subjects. Vutrisiran had an acceptable safety profile; the most common treatment‐related adverse event was mild, transient injection site reactions in four (6.7%) vutrisiran‐treated subjects. The favorable pharmacokinetic, pharmacodynamic, and safety results observed here support vutrisiran's continued clinical development.