AHA24: Lilly’s muvalaplin shows strong Lp(a) reduction in mid-stage trial

Eli Lilly has announced that its experimental oral drug, muvalaplin, designed to selectively inhibit lipoprotein(a) [Lp(a)], successfully achieved the primary endpoint in a Phase II clinical trial. The results indicated significant reductions in Lp(a) levels over a 12-week period. These findings were unveiled at the American Heart Association’s (AHA) scientific sessions and simultaneously published in JAMA.

Muvalaplin, a small molecule inhibitor, functions by preventing the interaction between apolipoprotein(a) [apo(a)] and apolipoprotein B, a key step in the formation of Lp(a). Ruth Gimeno, the group Vice President of diabetes and metabolic research at Lilly Research Labs, highlighted that while injectable treatments targeting Lp(a) are currently in Phase III trials, muvalaplin's results represent the first positive Phase II data for an oral treatment option.

The Phase II KRAKEN study included 233 participants with Lp(a) levels of at least 175 nmol/L and conditions like atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolaemia. The trial participants were randomly assigned to receive either 10 mg, 60 mg, or 240 mg of oral muvalaplin, or a placebo, over a span of 12 weeks. The primary goal was to assess the percentage change in Lp(a) concentrations at the 12-week mark.

Results demonstrated that muvalaplin significantly reduced Lp(a) levels across all three dosage groups. At the highest dose, the reductions were as high as 85.8% using the intact Lp(a) assay and 70.0% with the apo(a) assay, compared to the placebo. Furthermore, a substantial percentage of participants attained Lp(a) levels below 125 nmol/L at the end of the 12 weeks; using the intact Lp(a) assay, these percentages were 64.2% for the 10 mg group, 95.9% for the 60 mg group, and 96.7% for the 240 mg group, compared to just 6.0% in the placebo group. When analyzed with the apo(a) assay, the figures were 38.9%, 81.9%, and 77.4% for the 10 mg, 60 mg, and 240 mg groups respectively, against 3.6% in the placebo group.

Additionally, participants receiving muvalaplin in the 60 mg and 240 mg groups experienced significant reductions in apoB levels. The safety profile of muvalaplin was comparable to that of the placebo, with similar rates of adverse events. Notably, there were no reported deaths, and the rate of discontinuation due to adverse effects was low.

Beyond muvalaplin, Eli Lilly's cardiovascular (CV) disease pipeline includes lepodisiran, a siRNA targeting Lp(a), which was originally licensed from Dicerna Pharmaceuticals in 2018 before Dicerna's acquisition by Novo Nordisk. Lilly is also investigating the use of its GLP-1 agonist, Mounjaro/Zepbound (tirzepatide), to enhance cardiovascular outcomes in patients with diabetes and/or obesity.

This progress in developing muvalaplin signifies a promising advancement in oral treatments for high Lp(a) levels, potentially offering a novel approach to managing cardiovascular risks associated with elevated Lp(a).