On 18 November 2024, at the American Heart Association’s (AHA) 2024 conference in Chicago, Illinois, US, during a late-breaking session on the topic of New Targets and New Treatments: Advances in Lipid Therapeutics, Stephen Nicholls MBBS, PhD, director of the Victorian Heart Hospital and Victorian Heart Institute, presented findings from the Phase II trial investigating the dose effects of Eli Lilly’s muvalaplin in patients with elevated lipoprotein(a) (Lp[a]) levels and at high risk for cardiovascular events.

Muvalaplin is an investigational, oral, small-molecule inhibitor that targets Lp(a), a lipoprotein linked to increased cardiovascular disease risk. Elevated Lp(a) levels are associated with a higher likelihood of atherosclerotic conditions, including coronary artery disease and stroke. Muvalaplin works by inhibiting the assembly process of Lp(a) particles by blocking the interaction between apo(a) and apoB100 – a crucial step in Lp(a) formation – therefore reducing Lp(a) levels in the blood. This innovative approach is being investigated as a potential treatment for individuals with elevated Lp(a) levels, a condition that currently available therapies do not directly target.

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Patients were randomly assigned in a 1:2:2:2 ratio to receive muvalaplin at doses of 10mg, 60mg, 240mg or a matching placebo daily for 12 weeks. The primary analysis assessed changes in Lp(a) levels from baseline to week 12 using two Lp(a) assays: the commercially available assay that is commonly used and a sandwich assay employing antibodies targeting apo(a) and apoB.

Nicholls explained that the primary endpoint of the study — the percentage change in Lp(a) levels from baseline to week 12 — showed reductions of up to 85.8% using the intact Lp(a) assay and up to 70% with the traditional apo(a)-based assay. Higher doses of muvalaplin, specifically the 60mg and 240mg doses, demonstrated consistent and robust lowering of Lp(a). While high doses of muvalaplin effectively lowered Lp(a), the variability observed with the apo(a)-based assay highlighted challenges in using traditional methods to accurately measure the true impact of an Lp(a) disruptor.

Secondary endpoints included the proportion of patients achieving Lp(a) levels of less than 125nmol/L at week 12 and the percentage change from baseline to week 12. With the intact assay, more than 90% of patients reached this target, compared to 80% with the apo(a)-based assay at higher doses. Muvalaplin also resulted in placebo-adjusted reductions in apoB of up to 16.1% and low-density lipoprotein (LDL) cholesterol of up to 21.3%, with greater reductions observed at higher doses. Oxidized phospholipids, which are thought to play a key role in the increased atherogenicity of Lp(a), were markedly reduced. Specifically, oxidised phospholipids associated with apo(a) decreased by 73.0%, and those associated with apoB decreased by 67.2%. Overall, muvalaplin was found to be well-tolerated in patients.

Nicholls further elaborated on the limitations of the study. He explained that the study evaluated the effects of muvalaplin over 12 weeks, and the impact of longer-term treatment requires further investigation. Additionally, the intact Lp(a) assay used in the study is not yet available for clinical use and is still undergoing validation. It also remains unclear whether apo(a) bound to muvalaplin has any biological effects. The primary analysis excluded participants who permanently discontinued the study drug, but a modified intent-to-treat analysis demonstrated similar Lp(a) reductions.

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Key opinion leaders (KOLs) interviewed by GlobalData have highlighted the significant unmet need for treatments specifically targeting Lp(a). Currently, no pharmacological therapies are approved to lower Lp(a) levels. Most therapies under development are injectable nucleic acid-based agents that inhibit apo(a) synthesis. KOLs expressed strong enthusiasm for muvalaplin, noting that it represents the first oral therapy capable of effectively lowering Lp(a) levels. This innovative treatment could offer a major breakthrough for patients struggling with elevated Lp(a), providing a new, targeted approach to reduce cardiovascular risk. Additionally, muvalaplin’s oral formulation makes it a more accessible and convenient option for the long-term management of elevated Lp(a), potentially improving patient adherence. Further studies are needed to evaluate the long-term effects of muvalaplin on Lp(a) levels and cardiovascular outcomes. GlobalData’s Dyslipidemia: Seven-Market Drug Forecast and Market Analysis report forecasts that muvalaplin will generate sales of $17.82 billion by 2032 across the seven major markets (7MM: France, Germany, Japan, Italy, Spain, the UK and the US).