An oral drug, muvalaplin, has demonstrated significant reductions in lipoprotein(a) [Lp(a)] levels in a Phase 2 clinical trial, offering a potential new approach to managing cardiovascular risk associated with elevated Lp(a). The study, involving 233 participants with high Lp(a) levels and existing cardiovascular disease, diabetes, or familial hypercholesterolemia, was conducted across 43 sites in multiple countries and assessed the efficacy and safety of muvalaplin over a 12-week period.
Significant Lp(a) Reduction with Muvalaplin
Participants were randomized to receive either placebo or muvalaplin at dosages of 10 mg/d, 60 mg/d, or 240 mg/d. The results indicated that muvalaplin produced substantial, placebo-adjusted reductions in Lp(a) levels. Specifically, the 240 mg/d dosage led to an 85.8% reduction in Lp(a) as measured by an intact Lp(a) assay and a 68.9% reduction as measured by an apolipoprotein(a) assay.
Safety and Tolerability
Importantly, muvalaplin was found to be well-tolerated across all dosage levels, with no significant safety concerns emerging during the trial. This is a crucial factor, as many existing therapies for lipid management can have adverse side effects, limiting their applicability for some patients.
Mechanism of Action
Muvalaplin functions by inhibiting the assembly of the lipoprotein(a) particle, a novel approach compared to other therapies that primarily target apolipoprotein(a) expression. This oral therapy disrupts the noncovalent interaction between apolipoprotein(a) and apolipoprotein B, preventing the formation of Lp(a) particles. This mechanism mimics naturally occurring apolipoprotein(a) variants that cannot interact with apolipoprotein B and result in low lipoprotein(a) levels.
Context and Implications
Elevated Lp(a) is a genetically determined risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Current therapeutic options are limited, and there are no approved pharmacotherapies specifically for lowering Lp(a) levels. Genetic epidemiology studies suggest that substantial Lp(a) reductions (85 to 250 nmol/L) may be necessary to lower cardiovascular risk. The results from this study indicates that muvalaplin could potentially fill this unmet medical need.
Study Details
The Phase 2 trial was a randomized, double-blind, placebo-controlled study. Participants were adults aged 40 years or older with Lp(a) concentrations of 175 nmol/L or greater and at high risk of cardiovascular events. The primary endpoint was the percentage change in Lp(a) from baseline to week 12. Secondary endpoints included the proportion of participants achieving Lp(a) concentrations less than 125 nmol/L, percentage changes in apolipoprotein B and high-sensitivity C-reactive protein.
Future Directions
While the results are promising, further research is needed to determine whether muvalaplin reduces cardiovascular events and its role in the prevention of cardiovascular disease. Longer-term studies are necessary to evaluate the sustained efficacy and safety of muvalaplin. According to Stephen J. Nicholls, MBBS, PhD, Victorian Heart Institute, Monash University, and corresponding author of the study, future studies are needed to determine whether muvalaplin reduces clinical events and plays a role in the prevention of cardiovascular disease.
