Lp(a), known as LP little “a” (Lp is lipoprotein), is an independent risk factor for cardiovascular disease. The easiest way to think about Lp(a) is that it’s a genetically determined type of cholesterol carrier that makes the other risky cholesterols worse if it’s elevated.
The problem has been two-fold –
1. Lp(a) has only recently been measured by most doctors (I’ve been measuring it for about 10 years), and
2. Very little will change the Lp(a) level by much.
As a consequence of #1, many patients who suffer “surprise” events (they have “normal” cholesterol but usual tests) are ultimately found to have elevated Lp(a).
#2 leads to the strategy that lowering other cholesterol risks in the hope that you could avoid the consequences.
The article attached reports the first successful attempt to meaningfully lower the Lp(a) (62%) with an oral medication, without screwing other stuff up, at least in an obvious way. Phase I trials are small, and are testing for safety, but this one actually shows promise for efficacy as well. For people with elevated Lp(a) this could be a real gamechanger. It’s early, but fingers crossed.
Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation
A Randomized Clinical Trial
Key Points
Question Can muvalaplin, an orally administered small molecule inhibitor of lipoprotein(a) (Lp[a]) formation, achieve safe and tolerable plasma concentrations adequate to reduce steady-state Lp(a) levels without modulating plasminogen activity in humans?
Findings In this first-in-human phase 1 study involving healthy participants, muvalaplin administered orally as single ascending doses ranging from 1 mg to 800 mg and as multiple ascending doses ranging from 30 mg to 800 mg for 14 days caused dose-dependent plasma concentration increases. Muvalaplin administration was not associated with concerns about safety or tolerability, and it reduced Lp(a) levels but not plasminogen activity.
Meaning The observed safety, tolerability, pharmacokinetics, and exploratory pharmacodynamics of muvalaplin in healthy participants support further clinical evaluation in patients with elevated Lp(a) levels.
Abstract
Importance Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.
Objective To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.
Design, Setting, and Participants This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.
Interventions The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.
Main Outcomes and Measures Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.
Results 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.
Conclusion Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.