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Genetic bad cholesterol drops 60% in Australian drug trial

Australian researchers have found a potential oral medication developed to lower, by as much as 65%, levels of ‘bad’ cholesterol – lipoprotein(a), or Lp(a) – which affects some 20% to 25% of people around the world.

Until now, there has been no cure or approved specific treatment for lowering these levels, reports MedicalNewsToday, and because Lp(a) is genetic, lifestyle changes like diet and exercise that may benefit other types of cholesterol do not help.

Now, researchers from Monash University’s Victorian Heart Institute and Victorian Heart Hospital have found that an experimental oral medication developed to target Lp(a) was able to lower its levels by more than half during a first-in-human phase one clinical trial.

This study was recently published in the journal JAMA.

What is lipoprotein(a)?

Lipoproteins are a type of protein that transports cholesterol through the blood. There are two main types of lipoproteins: high-density lipoprotein (HDL) cholesterol, considered “good”, and low-density lipoprotein (LDL) cholesterol, considered “bad”.

Although the body needs some cholesterol for certain functions, too much LDL cholesterol can lead to atherosclerosis – where cholesterol builds up to form plaques on the inside walls of arteries, making it hard for blood to pump through.

Lp(a) is a form of LDL cholesterol that is “stickier” than other types, making it easier for the build-up to occur and arteries to become blocked.

The amount of Lp(a) in a person’s system is determined by their genetic history and ethnicity. For example, African Americans are at an increased risk for high Lp(a) compared with other ethnic groups.

Having a high level of Lp(a) can increase the risk of cardiovascular diseases like coronary heart disease and stroke.

Muvalaplin: a weapon against bad cholesterol?

In the current study, researchers conducted a clinical trial to assess an experimental medication called muvalaplin.

“Genetic and population studies show us that high Lp(a) levels are associated with a high risk of heart disease,” Dr Stephen Nicholls, cardiologist and director of Monash University’s Victorian Heart Institute and the Victorian Heart Hospital at Monash Health and lead author of this study, told Medical News Today.

“As much as 20% of the population have high levels. We don’t currently have specific therapies that lower levels, which may be important in the prevention of heart disease.”

He and his team looked at how well the drug worked, as well as its safety and tolerability in humans.

“Lp(a) forms when an LDL particle binds to the protein Apo(a). Muvalaplin essentially blocks that binding from happening in the liver and therefore prevents the formation of Lp(a). It would provide an oral option for the treatment of patients with high Lp(a) levels to reduce their risk of heart disease.”

Muvalaplin lowers Lp(a) by up to 65%

For this phase one clinical trial, the team recruited 114 healthy participants of different genders and ethnic backgrounds.

The purpose was to assess the safety and tolerability of muvalaplin, its pharmacokinetics (what happens to the drug in the body), as well as indicators of the drug’s effect on the target, Lp(a).

Participants either received a single dose of muvalaplin, an ascending dose where the amount taken was increased over time, or a placebo for 14 days.

At the end of the study, the Lp(a) levels of those who had received muvalaplin daily over the 14 days had dropped by as much as 65%.

The drugs was not associated with any tolerability concerns or clinically significant adverse effects.

The most commonly reported side effects  included headache, back pain, fatigue, abdominal pain, diarrhoea and nausea.

Under-recognised heart disease risk factor

Dr Cheng-Han Chen, an interventional cardiologist and medical director of the Structural Heart Programme at MemorialCare Saddleback Medical Centre in California, not involved in the research, said this research was definitely a step in the right direction.

“Lp(a) is a very hot topic right now in heart disease,” he said. “A number of studies are investigating how we can improve a patient’s health outcomes by covering that drug.

“There (are) other agents that are in clinical trials right now but they’re all injections… a patient would rather get pills than injections. It’s a big step in the right direction in terms of getting people be able to just take a pill rather than an injection.”

How else to lower Lp(a) levels

Right now, the only Food and Drug Administration (FDA) approved therapy for lowering Lp(a) is lipoprotein apheresis. This process physically removes lipoproteins from the blood and is only available for people with certain Lp(a) levels and other risk factors.

Researchers are currently looking at PCSK9 inhibitors as a possible treatment and a number of drug candidates are undergoing clinical trials.

Study details

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: a randomised clinical trial

Stephen Nicholls,  Steven Nissen,  Cynthia Fleming, et al.

Published in JAMA Network on 28 August 2023

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.


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.

To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.

Design, Setting, and Participants
This phase 1 randomised, 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.

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.

Among 114 randomised (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.

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.


MedicalNewsToday article – First oral drug for genetic bad cholesterol lowers levels by over 50% in clinical trial (Open access)


See more from MedicalBrief archives:


Doubt cast on targeting ‘bad’ cholesterol to curb heart disease risk


Race affects predictive value of ‘good’ cholesterol levels: US study


Cholesterol-cutting injections may cut risk of heart attacks







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