An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Olpasiran in Chinese Participants With Elevated Serum Lipoprotein(a).

Abstract

Introduction: Cardiovascular disease (CVD) remains a major cause of premature mortality and disability worldwide, with China ranking among the highest in CVD deaths. Lipoprotein(a) (Lp(a)) is a circulating lipoprotein particle that, when elevated, may increase CVD risk. Reduced Lp(a) levels with existing cardiovascular treatments are modest, and evidence confirming whether lowering Lp(a) leads to cardiovascular benefit is lacking. Olpasiran (AMG 890), a liver cell-targeting small interfering RNA, has been shown to elicit profound Lp(a) reductions with an acceptable safety profile and is being evaluated in clinical trials worldwide. Therefore, investigating olpasiran's treatment potential for cardiovascular risk reduction in the Chinese population is important.

Participants and methods: This is a phase 1, open-label, randomized, single-dose, parallel-group study in Chinese participants with elevated serum Lp(a). Participants with serum Lp(a) concentrations ≥70 nmol/L (or approximately ≥27 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of olpasiran (75 or 225 mg). Olpasiran pharmacokinetic (PK) results were the primary endpoints; treatment-emergent adverse events (TEAEs), clinical laboratory tests, 12-lead electrocardiograms (ECGs), vital signs, lipids, and serum Lp(a) concentrations were the secondary endpoints.

Results: Twenty-four participants (12 per dose group) were randomized, and 23 participants completed the study. After reaching maximal serum concentrations (75 mg: 167 ng/mL; 225 mg: 667 ng/mL) in ∼3 hours, olpasiran concentrations in both groups declined rapidly and were predominantly cleared from circulation within 3 days. Sustained reductions in Lp(a) concentrations from baseline were observed for both doses, with maximal reductions seen on day 57 (75 mg: -94.8%; 225 mg: -99.2%). All TEAEs associated with olpasiran were mild/moderate in severity, with four participants in the 225 mg dose group experiencing five mild TEAEs at the injection site. No notable treatment- or dose-related trends in clinical laboratory evaluations, vital signs, ECGs, physical examinations, or lipid panel results were identified, and no TEAEs leading to discontinuation or deaths were reported.

Discussion: Results from this study, as well as previous studies, indicate that olpasiran effectively and safely reduces Lp(a) levels in a similar manner across different ethnic populations.

Conclusions: Olpasiran administration (75 and 225 mg) was safe and well-tolerated in Chinese participants, and olpasiran PK and Lp(a) responses are generally consistent with those observed in East Asian/non-East Asian participants. Dose adjustments of olpasiran based on ethnicity are therefore not warranted, and work investigating the effects of olpasiran treatment on long-term cardiovascular risk in East Asian populations should continue.