Two investigational drugs, muvalaplin developed by Eli Lilly and zerlasiran developed by Silence Therapeutics, have demonstrated promising results in Phase II trials for lowering lipoprotein(a) [Lp(a)], a significant risk factor for atherosclerotic cardiovascular disease. The findings, presented at the American Heart Association conference and published in JAMA, suggest potential new avenues for addressing this unmet medical need.
Muvalaplin: An Oral Small Molecule
Muvalaplin, Eli Lilly's candidate, is an orally administered small molecule designed to lower Lp(a) by blocking cellular interactions between apolipoprotein(a) and apolipoprotein B100. The Phase II trial included 233 participants with Lp(a) levels of 175 nmol/L or higher who had known cardiovascular disease, diabetes, or familial hypercholesterolemia. Participants were administered doses of 10 mg/day, 60 mg/day and 240 mg/day, as well as placebo. The trial results were measured at 12 weeks.
The study revealed that muvalaplin induced reductions of up to 86% in Lp(a) levels compared to placebo, depending on the dose given and assay used to measure the results. Stephen Nicholls, a professor of cardiology at Monash University who led the Lilly trial, emphasized the significance of these findings, stating, "Current cholesterol-lowering therapies are not approved to lower lipoprotein(a) levels, highlighting an unmet need for people living with cardiovascular disease. These data represent a needed scientific advancement with the potential to reduce the risk of cardiovascular events such as heart attacks or strokes with a once-daily pill."
Zerlasiran: An Injectable siRNA Therapy
Silence Therapeutics is developing zerlasiran, an injectable small interfering RNA (siRNA) therapy that targets Lp(a). The Phase II trial involved 178 participants with stable atherosclerotic cardiovascular disease and Lp(a) levels above 125 nmol/L. Participants had three doses injected at 16-week or 24-week intervals and were followed up at 36 and 60 weeks. The three doses tested were 450 mg every 24 weeks, 300 mg every 16 weeks and 300 mg every 24 weeks versus placebo.
The results showed that zerlasiran achieved reductions of up to 86% in Lp(a) levels at 36 weeks. Steven Nissen, chief academic officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic and the Silence study’s lead author, noted, "Elevated Lp(a) impacts at least 20% of the global population and is a major cause for morbidity and mortality globally...I’m excited about the potential for gene-silencing approaches to help these patients."
The most common adverse event associated with zerlasiran was an injection site reaction, which occurred in approximately 7% of participants.
Clinical Implications and Future Directions
Both muvalaplin and zerlasiran met their primary endpoints in the Phase II trials, demonstrating significant reductions in Lp(a) levels. While other advanced therapies are in development to treat high levels of Lp(a), most are injectable, potentially giving Lilly’s oral therapy an advantage in terms of ease of administration and cost.
It remains to be seen whether these Lp(a) reductions will translate into improved cardiovascular outcomes in the long term. Further research is needed to establish if the therapies actually reduce cardiovascular events.
