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Abstract Vupanorsen (PF‐07285557) is a second‐generation tri‐N‐acetyl galactosamine (GalNAc3)‐antisense oligonucleotide targeted to angiopoietin‐like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi‐purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double‐blind, placebo‐controlled, single‐ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20–65 years) with elevated triglycerides (TG). Participants were randomized (1:1:1) to vupanorsen (80:160 mg) or placebo (N = 4 each). Vupanorsen 160 mg was a first‐in‐human (FIH) dose level. Vupanorsen was well‐tolerated with no treatment‐related adverse events reported for either dose. Absorption into the systemic circulation was rapid with median time to maximum concentration (Tmax) of 3.5 and 2.0 h, for vupanorsen 80 and 160 mg, respectively. Following maximum concentration (Cmax), vupanorsen underwent multiphasic decline characterized by a relatively fast initial distribution phase followed by slower terminal elimination phase, with elimination half‐life (t1/2) of 397 and 499 h (80, 160 mg), respectively. Area under the concentration–time curve (AUC) and Cmax increased in a greater than dose‐proportional manner. Pharmacodynamic markers (ANGPTL3, TG, and other key lipids) were reduced with vupanorsen versus placebo. Vupanorsen was safe and well‐tolerated in healthy Japanese participants with elevated TG. This study provided FIH data for vupanorsen 160 mg. Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose‐finding study. ClinicalTrials.gov: NCT04459767.