Oral inhibition
Nature paper unveils muvalaplin, an oral small molecule that blocks the very first step of Lp(a) particle assembly (Nature 2024)
Original title: Discovery of potent small-molecule inhibitors of lipoprotein(a) formation
Lp(a) forms when apolipoprotein(a) [apo(a)] first binds lysine residues of apolipoprotein B-100 (apoB-100) on an LDL particle via the Kringle IV type 7 and 8 (KIV7-8) domains, before a disulfide bond locks the two together. This study shows that this first binding step can be blocked with small molecules that interact directly with apo(a) KIV7-8. Through chemical optimisation and multivalency, the authors developed compounds with subnanomolar potency for inhibiting Lp(a) formation. Oral doses of prototype compounds and a potent multivalent disruptor, LY3473329 (muvalaplin), reduced Lp(a) levels in transgenic mice and cynomolgus monkeys. Although the multivalent molecules also bind rat plasminogen's Kringle domains and reduce plasmin activity, species-specific differences in plasminogen sequence suggest these inhibitors will lower Lp(a) without affecting plasminogen in humans. These findings underpin the clinical development of muvalaplin, already in phase 2 studies, as a potent, specific, orally administered Lp(a)-lowering agent.
Original abstract
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7-8. We identify compounds that bind to apo(a) KIV7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.