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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.

Abstract Technological advances in multimodal wearable and connected devices have enabled the measurement of human movement and physiology in naturalistic settings. The ability to collect continuous activity monitoring data with digital devices in real-world environments has opened unprecedented opportunity to establish clinical digital phenotypes across diseases. Many traditional assessments of physical function utilized in clinical trials are limited because they are episodic, therefore, cannot capture the day-to-day temporal fluctuations and longitudinal changes in activity that individuals experience. In order to understand the sensitivity of gait speed as a potential endpoint for clinical trials, we investigated the use of digital devices during traditional clinical assessments and in real-world environments in a group of healthy younger (n = 33, 18–40 years) and older (n = 32, 65–85 years) adults. We observed good agreement between gait speed estimated using a lumbar-mounted accelerometer and gold standard system during the performance of traditional gait assessment task in-lab, and saw discrepancies between in-lab and at-home gait speed. We found that gait speed estimated in-lab, with or without digital devices, failed to differentiate between the age groups, whereas gait speed derived during at-home monitoring was able to distinguish the age groups. Furthermore, we found that only three days of at-home monitoring was sufficient to reliably estimate gait speed in our population, and still capture age-related group differences. Our results suggest that gait speed derived from activities during daily life using data from wearable devices may have the potential to transform clinical trials by non-invasively and unobtrusively providing a more objective and naturalistic measure of functional ability.