Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study.

Purpose: Olpasiran, an N-acetyl galactosamine-conjugated, hepatocyte-targeted, small interfering RNA, is being developed to reduce plasma lipoprotein (Lp)-(a) concentration by directly targeting the LPA gene. This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of a single SC injection of olpasiran in healthy, Japanese and non-Japanese participants.

Methods: In this Phase I, open-label, parallel-design study, Japanese participants were randomized in a 1:1:1:1 ratio to receive a single 3, 9, 75, or 225 mg dose of olpasiran. Non-Japanese participants received a single 75 mg dose of olpasiran. The primary end points were pharmacokinetic parameters, including Cmax, AUCinf, tmax, and t1/2. Tolerability and change in Lp(a) concentration were also assessed. Findings: A total of 27 enrolled participants had a mean (SD) age of 48.0 (12.5) years. Olpasiran Cmax and AUCinf were increased in an approximately dose-proportional manner in the Japanese groups. Mean (SD) Cmax values were 242 (121.0) and 144 (71.3) ng/mL, and mean (SD) AUCinf values were 3550 (592.0) and 2620 (917.0) h·ng/mL, in the Japanese and non-Japanese groups, respectively, given 75 mg of olpasiran. Median tmax ranged from 3.0 to 9.0 hours and mean (SD) t1/2 ranged from 4.0 (0.3) to 6.9 (1.6) hours across all groups. The maximal Lp(a) reduction occurred at day 57, with mean (SD) Lp(a) percentage reductions from baseline ranging from 56.0% (21.0%) to 99.0% (0.2%). A reductions in Lp(a) was observed as early as day 4. All adverse events were mild in severity, with no serious or fatal adverse events. No clinically important changes in tolerability-related laboratory analytes or vital signs were observed. Implications: In this population of healthy Japanese participants, dose-proportional increases in exposure and reduced Lp(a) in a dose-dependent manner were found with single 3, 9, 75, and 225 mg doses of olpasiran. The magnitude and durability of Lp(a) reductions were similar between the Japanese and non-Japanese groups. Olpasiran was well tolerated, with no clinically important adverse events or laboratory or vital sign abnormalities.