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Muvalaplin for Inhibition of Lipoprotein(a) Formation

In a phase 1 pharmacokinetics and pharmacodynamics trial, muvalaplin was safe and well-tolerated and lowered lipoprotein(a) (Lp[a]) levels up to 65% after 14 days of daily administration. An orally administered small molecule inhibitor of Lp(a) formation, muvalaplin acts by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.

The dose-ranging trial enrolled 114 participants in the Netherlands. During a single ascending dose phase, 55 participants received a single muvalaplin dose ranging from 1 mg to 800 mg or placebo. A multiple ascending dose phase included 59 participants who were randomized to daily muvalaplin doses of 30 mg to 800 mg daily or placebo for 14 days.

Based on outcomes of safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers, the study showed the following: “Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.”

Source: JAMA