In Reply We disagree with Drs Endo and Kami that the long duration of action of lepodisiran raises special safety concerns. Although we acknowledged in the article that a small phase 1 trial cannot definitively establish the safety of any new therapeutic agent, the observed incidence of minor concerns among participants shows no patterns suggestive of drug-induced adverse effects. Like many contemporary nucleic acid therapeutic agents, lepodisiran is conjugated with N-acetylgalactosamine, which facilitates rapid uptake of the drug by hepatocytes via asialoglycoprotein receptors expressed nearly exclusively in the liver. As a result of active hepatic uptake, the time during which lepodisiran is present in the systemic circulation is very short, with plasma levels undetectable by 48 hours after subcutaneous injection. The short presence in the circulation reduces the likelihood of systemic adverse effects. Other N-acetylgalactosamine–conjugated therapeutic agents in clinical use have prolonged effects without any major toxicity with administration as infrequently as twice per year.