Physicians' Academy for Cardiovascular Education

Oral Lp(a) inhibitor shows promise in phase 1 trial

News - Sep. 5, 2023

Muvalaplin, a Potent Small Molecule Inhibitor of Lipoprotein(a)

Presented at the ESC congress 2023 by: Stephen Nicholls, PhD - Melbourne, Australia

Introduction and methods

As Lp(a) has a causal role in atherosclerotic disease and aortic stenosis, lowering Lp(a) levels may offer an opportunity to further reduce CVD risk. At present, there are no pharmacological agents available that specifically lower Lp(a) levels in clinical practice and those in clinical development are injectable therapies.

Lp(a) is an LDL-like lipoprotein that is formed by noncovalent binding of apo(a) kringle IV domains 7 and 8 to lysine residues of apoB with subsequent covalent disulfide bonding. The oral small molecule muvalaplin disrupts the initial noncovalent interaction between apo(a) and apoB. In this phase 1 trial, the safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarker effects of muvalaplin were investigated.

This was a randomized, double-blind, parallel-design study in which healthy participants with BMI ≤30 kg/m² were enrolled at 1 site in the Netherlands. Single ascending-dose treatment was assessed by randomizing participants with any Lp(a) level (n=55) to a single dose of muvalaplin (1–800 mg) or placebo. For multiple ascending-dose treatment, participants with Lp(a) ≥30 mg/dL (n=59) were assigned to daily doses of muvalaplin (30–800 mg) or placebo for 14 days. Of the 114 participants, 105 completed the trial.

Main results


In this phase 1 trial, daily administration of muvalaplin for 14 days lowered Lp(a) levels up to 65%. There were no safety or tolerability concerns, nor a discernable effect on plasminogen activity. A phase 2 trial with muvalaplin in patients with elevated Lp(a) levels is currently ongoing.

The results of this study were simultaneously published in JAMA.

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