Eli Lilly's muvalaplin, an investigational oral small-molecule inhibitor, has demonstrated promising results in a Phase II trial for patients with elevated lipoprotein(a) (Lp[a]) levels and at high risk for cardiovascular events. The findings, presented at the American Heart Association's (AHA) 2024 conference, highlight muvalaplin's potential to significantly reduce Lp(a) levels, addressing a critical unmet need in cardiovascular disease management.
Targeting Lipoprotein(a) with Muvalaplin
Muvalaplin targets Lp(a), a lipoprotein associated with increased cardiovascular disease risk. Elevated Lp(a) levels are linked to a higher risk of atherosclerotic conditions, including coronary artery disease and stroke. The drug inhibits the assembly process of Lp(a) particles by blocking the interaction between apo(a) and apoB100, a crucial step in Lp(a) formation, thereby reducing Lp(a) levels in the blood. This mechanism offers a direct approach to lowering Lp(a), which current therapies do not effectively target.
Phase II Trial Results
The Phase II trial randomly assigned patients to receive muvalaplin at doses of 10mg, 60mg, 240mg, or a placebo daily for 12 weeks. The primary endpoint was the percentage change in Lp(a) levels from baseline to week 12, assessed using both a commercially available assay and a sandwich assay employing antibodies targeting apo(a) and apoB.
The results showed significant reductions in Lp(a) levels, with the intact Lp(a) assay demonstrating reductions of up to 85.8% and the traditional apo(a)-based assay showing reductions of up to 70%. Higher doses of muvalaplin (60mg and 240mg) consistently and robustly lowered Lp(a) levels. However, the variability observed with the apo(a)-based assay underscores the challenges in accurately measuring the impact of Lp(a) disruptors using traditional methods.
Secondary Endpoints and Additional Benefits
Secondary endpoints included the proportion of patients achieving Lp(a) levels less than 125nmol/L at week 12 and the percentage change from baseline to week 12. Using the intact assay, over 90% of patients reached this target at higher doses, compared to 80% with the apo(a)-based assay. Muvalaplin also resulted in placebo-adjusted reductions in apoB of up to 16.1% and LDL cholesterol of up to 21.3%, with greater reductions at higher doses. Additionally, oxidized phospholipids, which contribute to the atherogenicity of Lp(a), were markedly reduced, with oxidized phospholipids associated with apo(a) decreasing by 73.0% and those associated with apoB decreasing by 67.2%. The drug was generally well-tolerated among patients.
Expert Commentary and Future Directions
Key opinion leaders (KOLs) have emphasized the significant unmet need for treatments specifically targeting Lp(a), as currently no pharmacological therapies are approved for this purpose. Most therapies in development are injectable nucleic acid-based agents that inhibit apo(a) synthesis. KOLs have expressed strong enthusiasm for muvalaplin, highlighting it as the first oral therapy capable of effectively lowering Lp(a) levels. This could represent a major breakthrough for patients with elevated Lp(a), offering a new, targeted approach to reduce cardiovascular risk. The oral formulation of muvalaplin also provides a more accessible and convenient option for long-term management, potentially improving patient adherence.
Further studies are necessary to evaluate the long-term effects of muvalaplin on Lp(a) levels and cardiovascular outcomes. Limitations of the current study include the 12-week evaluation period and the fact that the intact Lp(a) assay used is not yet clinically available and is still undergoing validation. It also remains unclear whether apo(a) bound to muvalaplin has any biological effects.
