Australian, American, British and Dutch researchers have reported success in phase II clinical trials of a small interfering RNA-based drug for treating elevated lipoprotein (a) levels. The report is published in the Journal of the American Medical Association.
Lipoprotein (a), or Lp(a), is a lipoprotein in blood plasma that resembles low-density lipoproteins (LDL, the reservoir of "bad" cholesterol). In addition to apoB-100, which is characteristic of LDL, it contains apolipoprotein (a), a high-molecular protein that resembles plasminogen, covalently binds to apoB-100 and has a high affinity for the vascular wall, i.e. it promotes the accumulation of cholesterol in it. The structure and concentration of Lp(a) vary greatly among individuals, are virtually independent of diet and have virtually no response to standard lipid-lowering agents. Elevated levels of this lipoprotein are observed in approximately one-fifth of the world's population and are an independent high-risk factor for atherosclerosis, coronary heart disease, aortic valve stenosis, thrombosis, and stroke.
Several pharmacological approaches to lowering Lp(a) levels are currently being tested: blockade of apolipoprotein(a) binding to apoB-100 with a small molecule drug (it has successfully passed phase II trials), post-transcriptional silencing of the LPA gene encoding Lp(a) in the liver, as well as inactivation of this gene by DNA base editing (this drug has already been administered to the first patients). Zerlasiran (SLN360) belongs to the second approach. It is a drug conjugated to N-acetylgalactosamine (it is recognized by liver cells) small interfering RNA (siRNA), which suppresses LPA expression by degrading its messenger RNA. Satisfactory preliminary data on its efficacy and safety were obtained in phase I clinical trials, which allowed moving on to larger trials.
Steven Nissen of the Cleveland Clinic and colleagues conducted the ALPACAR-360 phase 2, double-blind, randomized, placebo-controlled trial at 26 sites in Europe and South Africa. They enrolled 178 patients (mean age 63.7 years; 25.8 percent women) with serum Lp(a) levels of 125 or more (mean 213) nanomoles per liter and stable cardiovascular disease. They were randomly assigned to receive subcutaneous administration of either 450 milligrams of zerlasiran twice 24 weeks apart, 300 milligrams three times 16 weeks apart, 300 milligrams twice 24 weeks apart, or placebo.
By week 36 of therapy, the time-averaged least-squares reductions in Lp(a) in the active treatment groups compared with placebo averaged −85.6, −82.8, and −81.3 percent, respectively, and the median changes were −94.5, −96.4, and −90.0 percent. The most common adverse event was an injection site reaction, with mild pain reported by 2.3 to 7.1 percent of participants during the first day. During the trial, 20 serious adverse events were reported in 17 patients, all of which were considered unrelated to treatment.
Thus, the miRNA drug zilnasiran in the tested doses effectively reduces elevated Lp(a) levels and is well tolerated by patients. Its phase III trials are currently underway.
The first siRNA-based drug approved for use was patisiran for the treatment of hereditary transthyrein amyloidosis, the second was givosiran for the treatment of acute hepatic porphyria. Also currently licensed are lumasiran and inclisiran for the treatment of primary hyperoxaluria type 1 and hypercholesterolemia, respectively.
