Muvalaplin, an Oral Agent for Lowering Lp(a), Shows Promise in Phase 1 Trial


Data from a phase 1 trial in healthy adults indicates muvalaplin, an oral agent, could find a role in lowering Lp(a).

Stephen Nicholls, MD | Credit: Monash University

Stephen Nicholls, MD
Credit: Monash University

An oral agent for lowering lipoprotein(a) (Lp[a]) could be a reality in the near future, with results of a phase 1 trial at the European Society of Cardiology (ESC) Congress 2023 demonstrating use of muvalaplin could reduce Lp(a) levels by up to 65%.

A first-in-human phase 1 study of healthy participants examining muvalaplin, which is billed as the first oral drug ever developed to target Lp(a), results demonstrated use lowered Lp(a) plasma levels within 24 hours after the initial dose and induced even greater reductions on repeated dosing, with 93% of participants achieving an Lp(a) plasma level less than 50 mg/dL and no reports of tolerability concerns or clinically significant adverse effects.

“Lp(a) is essentially a silent killer with no available treatment, this drug changes that,” said principal investigator Stephen Nicholls, MD, director of the Monash Victorian Heart Institute and Victorian Heart Hospital.

An orally administered small molecule, muvalaplin inhibits Lp(a) formation through blockage of the apo(a)-apo B100 interaction while avoiding interaction with plasminogen. Sponsored by Eli Lilly and Company, the current study was led by Nicholls and an international team of colleagues to determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.1

With this in mind, the study was designed as a randomized, double-blind, parallel-design trial conducted among a cohort of 114 healthy participants at a single site in the Netherlands. Once identified for inclusion, patients were randomized into a single-ascending dose or multiple-ascending dose groups. In total, 55 were assigned to the single-ascending dose group and 59 were assigned to the multiple-ascending dose group.1

Per trial protocol, the single ascending dose intervention assessed the effect of a single dose of ranging from 1-800 mg or placebo taken by healthy participants with any Lp(a) level. In contrast, the multiple ascending dose treatment assessed the effect of taking daily doses ranging from 30-800 mg or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.1

The single-ascending dose group had a mean age of 29 (standard deviation [SD], 10) years, 64% were female, and 91% were White. Among the single ascending dose group, the baseline median Lp(a) levels were 10.3 mg/dL (Interquartile range [IQR], 9.9-41.2) and the LDL cholesterol levels were 104.4 mg/dL (IQR, 81.2-123.7 mg/dL). The multi-ascending dose group had a mean age of 32 (SD, 15) years, 58% were females, and 80% were White. Among the multiple ascending dose group, the median baseline Lp(a) levels were 58.3 mg/dL (IQR, 38.4-79.8) and the LDL cholesterol levels were 116.0 mg/dL (IQR, 100.5-127.6).1

Overall, 89 patients in the trial received muvalaplin and 25 received placebo therapy. In total, 105 participants finished the study.1

Upon analysis, there was no evidence of an association between tolerability concerns or clinically significant adverse events observed in the trial. Further analysis demonstrated doses of 30-800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70-414 hours.1

When assessing change in Lp(a) levels, results suggested use of muvalaplin lowered Lp(a) plasma levels within 24 hours of the first dose, with the reductions increasing in magnitude with repeated dosing. The maximum placebo-adjusted Lp(a) observed in the trial was 63-65% and investigators underlined 93% of participants achieved Lp(a) plasm levels less than 50 mg/dL, with similar effects at daily doses of 100 mg or more. Additionally, investigators pointed out there were no clinically significant changes in plasminogen levels or activity during the trial.1

“When it comes to treating high Lp(a), a known risk factor for cardiovascular disease, our clinicians currently have no effective tools in their kit,” Nicholls added.2 “This drug is a gamechanger in more ways than one. Not only do we have an option for lowering an elusive form of cholesterol, but being able to deliver it in an oral tablet means it will be more accessible for patients.”


  1. 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
  2. Monash University. World first drug to target form of previously untreatable life-threatening “bad cholesterol.” Monash Victorian Heart Institute. August 29, 2023. Accessed August 31, 2023.
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