Abstract 13951: Safety, Tolerability and Efficacy of Single-dose Amg 890, a Novel Sirna Targeting Lp(a), in Healthy Subjects and Subjects With Elevated Lp(a)

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Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of > 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

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