Abstract Body (Do not enter title and authors here): Hypothesis and Purpose: High plasma concentrations of lipoprotein(a) [Lp(a)] associate with an increased risk of atherosclerotic cardiovascular (CV) disease and calcific aortic valve stenosis. There are no pharmacological therapies approved to reduce Lp(a), and current therapies in CV outcomes trials are all injectable. Muvalaplin is an oral molecule that disrupts the interaction between apo(a) and Apo B, preventing Lp(a) particle formation. In a Phase 1 trial, muvalaplin was well tolerated and decreased Lp(a) concentrations within 24 hours of the initial dose with further reductions after daily dosing for 14 days. This Phase 2 study further assessed the efficacy and tolerability of muvalaplin.
Study Design and Methods: This was a Phase 2, randomized, double-blind, placebo-controlled study.
Sample Size: 233 patients across 44 sites in 8 countries.
Population Studied: Patients at least 40 years old with Lp[a] ≥175 nmol/L at high risk for CV events defined as: prior coronary artery disease, stroke, peripheral arterial disease, familial hypercholesterolemia, or type 2 diabetes.
Intervention: Patients were randomly assigned to receive muvalaplin 10, 60, or 240 mg, or matching placebo daily, for 12 weeks in a 1:2:2:2 ratio.
Power Calculations: Assuming a standard deviation of 20%, a 2-sided alpha level of 0.05 and 10% dropout rate, 30 completers for the 10 mg group and 60 completers for each of the other groups would provide >99% power to detect a treatment difference of 60% reduction for the primary endpoint of muvalaplin compared with placebo. Power calculations were conducted using a two-sample Student's t-test.
Primary Endpoint: Percent change in Lp(a) from baseline through Week 12.
Secondary Endpoints: Secondary end points included the proportion of patients achieving Lp(a) <125 nmol/L at Week 12 and percent change from baseline to Week 12 for ApoB and hsCRP.
Outcome: The effects of 12-week treatment with muvalaplin on Lp(a) levels, including the estimated time course, distribution of responses, and proportion of responders, will be presented, along with analyses of ApoB, LDL-C, plasminogen activity, and adverse events.
Conclusions: These findings will inform future large-scale trials of muvalaplin to determine whether it will be a clinically effective therapy for patients with elevated Lp(a) levels at high risk for CV events.