American and Australian researchers conducted clinical trials and found that taking muvalapline effectively reduces elevated levels of lipoprotein (a) in the blood of patients with high cardiovascular risk. A report on the work was published in the Journal of the American Medical Association.
Lipoprotein (a), or Lp(a), is a type of plasma lipoprotein that resembles low-density lipoprotein (LDL), the cholesterol of which is called "bad". Unlike LDL, in addition to apoB-100, it contains apolipoprotein (a), a high-molecular protein resembling plasminogen that covalently binds to apoB-100 and has a high affinity for the vascular wall. The structure and serum concentration of Lp(a) vary greatly among individuals; they are determined by genetic characteristics and are virtually independent of diet. Its elevated level is an independent risk factor for atherosclerosis, coronary heart disease, aortic valve stenosis, thrombosis, and stroke.
Most lipid-lowering agents do not act on it (there is some evidence of moderate efficacy of atorvastatin); high doses of nicotinic acid and, in severe cases, LDL apheresis are usually used. Other agents are in development, including antisense oligonucleopeptides. Muvalapline is an orally administered small molecule that blocks the interaction of apolipoprotein (a) with apoB-100, thereby preventing Lp(a) assembly.
Following the success of the phase 1 pilot studies, Stephen Nicholls of Monash University and colleagues in the US conducted a double-blind, randomised, placebo-controlled phase 2 trial of KRAKEN in 43 clinics in Asia, Europe, Australia, Brazil and the US. They enrolled 233 patients (median age 66 years; 33 per cent women) with Lp(a) levels of 175 nanomoles per litre or higher and coronary artery disease, diabetes or familial hypercholesterolemia. They were randomly assigned in a 1:2:2:2 ratio to receive 10, 60 or 240 milligrams of the active drug per day or placebo.
After 12 weeks of therapy, 10, 60, and 240 milligrams of muvalapline produced mean reductions in Lp(a) compared with placebo of 47.6, 81.7, and 85.8 percent for the intact Lp(a) serum assay and 40.4, 70.0, and 68.9 percent for the apolipoprotein(a) assay. Active therapy at these doses resulted in reductions in Lp(a) levels below 125 nanomoles per liter (an extremely high-risk indicator) in 64.2, 95.9, and 96.7 percent of participants for the former assay and in 38.9, 81.9, and 77.4 percent for the latter. It also produced significant reductions in oxidized phospholipids apolipoproteins B and a and in LDL-cholesterol.
Muvalapline was well tolerated. The incidence of adverse events was not significantly different between the active treatment and placebo groups and was about six percent. These included diarrhea, nausea, respiratory infections, back and muscle pain, uterine leiomyoma, and anemia. No increases in high-sensitivity C-reactive protein (an indicator of inflammation), liver enzymes, or bilirubin were recorded.
In conclusion, oral mulvalapline for 12 weeks effectively reduced serum Lp(a) levels regardless of assay type and was well tolerated. Its effect on cardiovascular risk remains to be established in larger, longer-term trials.
Earlier, British and New Zealand researchers reported encouraging results from a clinical trial of DNA base editing to treat heterozygous familial hypercholesterolemia. However, recruitment was then suspended due to serious adverse events in one participant until the cause and possible connection with the drug were determined.