Scientists have developed the world’s first drug, muvalaplin, to treat high levels of lipoprotein(a). Lipoprotein(a) is a type of “bad cholesterol” and elevated blood levels are linked to increased risk of heart attacks and strokes.1,2 It is controlled by genetics and does not respond to treatment, diet, or lifestyle changes. Twenty percent of the world’s population has dangerously high levels of lipoprotein(a), with the highest prevalence in those of African and South Asian descent.3-5 Until now, there has been no way to treat this crummy class of cholesterol.6
Phase I trial results of the drug, published in the Journal of the American Medical Association, have garnered attention in the scientific community. Muvalaplin successfully lowered lipoprotein(a) levels by up to 65%.1,7 “Lipoprotein(a) is essentially a silent killer with no available treatment, this drug changes that,” says professor Stephen Nicholls, cardiologist and Director of the Monash University’s Victorian Heart Institute and Victorian Heart Hospital, in a press release by Monash Health.
Low lipoproteins, high safety
In the phase I clinical trial, Dr. Nicholls and his team confirmed that their novel cholesterol buster is safe, has few side effects, and works well to lower lipoprotein(a) levels.1,7
Muvalaplin significantly lowered lipoprotein(a) levels, compared to the placebo, with a 63%-65% reduction at doses of 100 mg or higher after two weeks. Fifty-nine healthy volunteers with high lipoprotein(a) levels (≥30 mg/dL), aged 18-69, received muvalaplin or a placebo daily for 14 days. The once daily pill lowered their bad cholesterol levels for as long as the volunteers took the drug. Levels returned to baseline within one to two months of stopping the drug, depending on the dose.
Muvalaplin did not affect the levels of the most commonly measured lipids for heart health: total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, or apo B100 levels, demonstrating that the drug only affects lipoprotein(a). Testing these markers was important to ensure there are no safety concerns or negative side effects related to these other lipids.
The researchers also investigated the effects of the drug at higher doses to see if it was safe for daily use. Another group of 59 healthy participants aged 18-69 received muvalaplin or a placebo daily for 14 days, but these participants specifically had elevated lipoprotein(a) levels (≥30 mg/dL). Again, the dose was gradually increased for each group, starting at 30 mg and going up to 800 mg.
Most side effects were mild, temporary, and resolved without any lasting problems. The most common symptoms were headache, back pain, fatigue, diarrhea, abdominal pain, nausea, and acne. At the highest tested doses of the drug slightly decreased blood clotting, however, this was a small effect. Clotting problems are a common side effect of many drugs used to treat high blood pressure and cardiovascular disease and once the participants stopped taking the drug, it returned to normal levels.
The game changer
Professor Stephen Nicholls adds, “This drug is a game-changer in more ways than one.”
Now, with phase II clinical trials in progress, doctors hope to find out whether muvalaplin is clinically effective at reducing lipoprotein(a)-induced heart attacks by the end of 2024.8
What is lipoprotein(a)?
Lipoprotein(a) is similar to low-density lipoprotein (LDL or “bad cholesterol”), but it has an extra protein called apo(a) attached to it. This protein, rich in carbohydrates, shares similarities with plasminogen, a protein involved in blood clot breakdown. Apo(a) comes in different sizes, and smaller sizes are linked to higher lipoprotein(a) levels in the blood.5
Elevated lipoprotein(a) levels can dangerously increase the risk of cardiovascular diseases like atherosclerosis (plaque buildup in arteries), coronary artery disease, stroke, and thrombosis (blood clot formation).4-5 It encourages plaque buildup in arteries by promoting inflammation and attracting white blood cells to vessel walls. It also hinders blood clot breakdown, increasing clot formation risk.4-5
Your lipoprotein(a) level is mainly determined by what variant of the lipoprotein(a) (LPA) gene you have. Like many genetic characteristics, these variants can be more or less prevalent across populations. People of African descent tend to have higher levels of lipoprotein (a) on average, compared to those of White and Asian backgrounds. Other environmental and medical factors like age, sex, and certain medical conditions can also play a minor role.4-5
If you are concerned about your lipoprotein(a) levels, discuss getting a blood test with your doctor!
References
- World first drug to target form of previously untreatable life-threatening “bad cholesterol.” EurekAlert! Published Aug 28, 2023. Accessed May 14, 2024. https://www.eurekalert.org/news-releases/999728
- About lipoprotein (a) (no date) Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/heart-disease-family-history/about/about-lipoprotein-a.html?CDC_AAref_Val=https%3A%2F%2Fwww.cdc.gov%2Fgenomics%2Fdisease%2Flipoprotein_a.htm (Accessed: 17 May 2024).
- Reyes-Soffer, G. (2021) ‘The impact of Race and ethnicity on lipoprotein(a) levels and cardiovascular risk’, Current Opinion in Lipidology, 32(3), pp. 163–166. doi:10.1097/mol.0000000000000753.
- Farzam, K., Zubair, M. and Senthilkumaran, S. (2024) Lipoprotein a, StatPearls [Internet]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK570621/ (Accessed: 31 May 2024).
- Enkhmaa, B., Anuurad, E. and Berglund, L. (2016) ‘Lipoprotein (a): Impact by ethnicity and environmental and medical conditions’, Journal of Lipid Research, 57(7), pp. 1111–1125. doi:10.1194/jlr.r051904.
- Wilson, D.P. et al. (2022) ‘Use of lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association’, Journal of Clinical Lipidology, 16(5). doi:10.1016/j.jacl.2022.08.007.
- Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial. JAMA. 2023;330(11):1042-1053. doi:https://doi.org/10.1001/jama.2023.16503
- Hooper, A.J., Fernando, P.M. and Burnett, J.R. (2024) ‘Potential of muvalaplin as a lipoprotein(a) inhibitor’, Expert Opinion on Investigational Drugs, 33(1), pp. 5–7. doi:10.1080/13543784.2024.2302592.