Efficacy and Safety of Pelacarsen in Black/African American and Hispanic Participants with Elevated Lipoprotein(a) and Established Atherosclerotic Cardiovascular Disease: The Randomized Controlled Lp(a)FRONTIERS EXPANSION Study

Background: Black and Hispanic individuals may experience a disproportionate burden of lipoprotein(a) [Lp(a)]-associated atherosclerotic cardiovascular disease (ASCVD) risk, and ASCVD-related mortality, yet remain underrepresented in cardiovascular (CV) clinical trials. Efficacy and safety data on Lp(a)-targeted therapies in these populations are limited. Methods: Lp(a)FRONTIERS EXPANSION was a randomized, double-blind, phase 3b, placebo-controlled trial assessing the efficacy and safety of pelacarsen, an Lp(a)-targeted therapy, in US Black/African American and Hispanic participants with elevated Lp(a) (≥125 nmol/L) and ASCVD. Eligible adults were randomized 2:1 to monthly subcutaneous pelacarsen 80 mg or placebo for 12 months, followed by 16 weeks of safety follow-up. Enrollment spanned May 2024−March 2025. The primary endpoint was change in log-transformed Lp(a) from baseline at Week 52, analyzed using a mixed model for repeated measures. Results: Overall, 423 participants were randomized, with 422 analyzed (282 to pelacarsen; 140 to placebo). The population comprised 64.5% (n=272) Black/non-Hispanic, 30.1% (n=127) nonBlack/Hispanic, and 5.5% (n=23) Black/Hispanic. Trial completion rates were 90.1% and 91.4% for pelacarsen and placebo groups, respectively; median (Q1, Q3) baseline Lp(a) levels were 232.70 nmol/L (165.80, 301.50) and 219.25 nmol/L (166.95, 293.65). Geometric mean ratio (GMR) of Lp(a) to baseline at Week 52 was 0.14 (95% CI: 0.12, 0.16) with pelacarsen and 0.98 (95% CI: 0.80, 1.20) with placebo; GMR between groups (pelacarsen/placebo) was 0.14 (95% CI: 0.11, 0.18; P<0.0001), equivalent to an 86% placebo-adjusted reduction. Treatment-emergent adverse events (TEAEs) occurred in 66.0% (n=186) of participants receiving pelacarsen and 61.4% (n=86) receiving placebo; serious TEAEs occurred in 17.0% (n=48) and 15.0% (n=21), respectively. TEAE-related treatment discontinuations were 6.0% (n=17) with pelacarsen and 3.6% (n=5) with placebo. Conclusions: This study is the first to demonstrate robust Lp(a) lowering with pelacarsen, which was generally well tolerated, in US Black/African American and Hispanic participants, populations disproportionately impacted by Lp(a)-associated CV risk. Registration: URL:https://clinicaltrials.gov Unique Identifier: NCT06267560