Oral Muvalaplin effectively lowers lipoprotein (a) with no serious adverse effects, shows Initial phase 1 trial

Recent studies have suggested that Lipoprotein(a) (Lp[a]) is associated with aortic stenosis and atherosclerotic disease. Bonding between apolipoprotein(a) (apo[a]) and apo B100 leads to the formation of Lp(a). So, there is interest in developing effective approaches that will lower Lp(a) levels and reduce cardiovascular risk.

Muvalaplin is the first oral agent specifically developed to lower Lp(a) levels by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.

Stephen J. Nicholls, Monash University, Clayton, Victoria, Australia, and colleagues aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin in a phase 1 randomized, double-blind, parallel-design study representing the initial evaluation of its effects in humans.

The study enrolled 114 participants (55 assigned to a single-ascending dose; and 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands. 105 participants completed the trial.

The single ascending dose treatment assessed the effect of a single muvalaplin dose ranging from 1 mg to 800 mg or placebo taken by health participants with any Lp(a) level. On the other hand, the multiple ascending dose treatment evaluated the effect of taking daily muvalaplin doses (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.

The study outcomes included pharmacokinetics, tolerability, safety, and exploratory pharmacodynamic biomarkers.

The study led to the following findings:

• 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.

"Initial phase 1 clinical findings demonstrate that muvalaplin effectively lowers Lp(a) with no serious adverse effects," the researchers wrote. However, they suggest the need for longer and larger trials to further evaluate tolerability, safety, and the effect of muvalaplin on lipoprotein (a) levels and cardiovascular outcomes.

Reference:

Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial. JAMA. Published online August 28, 2023. doi:10.1001/jama.2023.16503