ANGPTL3 Inhibition is the Newest Advance in Lipid-Lowering Therapies
The major therapies aimed at lowering lipid levels in the bloodstream all derive from the discovery of human mutants who exhibit low blood lipids and a lesser burden of atherosclerosis and cardiovascular mortality. The therapies aim at recapturing some of the effects of these mutations, which inevitably means that they confer smaller benefits than possessing the mutation over the full course of life. Over time these therapies have moved from small molecule drugs to the present approach of small interfering RNA to directly inhibit expression of specific genes. ANGPLT3 is the latest target, and here note the clinical trial performance of one of the ANGPLT3 inhibition therapies presently in development. It improves on statins in its effects on blood lipids, but the experience of PCKS9 inhibitors, also an improvement over statins, demonstrates that this approach of lowering circulating lipids can only slow the progression of atherosclerotic plaque, not reduce the size of existing plaques, no matter how much blood lipids are lowered.
A small interfering RNA (siRNA) investigational therapy that inhibits a gene involved in lipoprotein metabolism has been shown in a clinical trial to significantly reduce levels of different types of cholesterol and triglycerides in individuals with mixed hyperlipidemia, a condition in which fats build up in the blood. Researchers found the RNA interference (RNAi)-based therapy zodasiran to be a potentially promising option for substantially reducing a number of atherogenic lipoproteins while requiring less frequent dosing than conventional therapies.
Zodasiran (Arrowhead Pharmaceuticals) targets a specific gene expressed in hepatocytes known as angiopoietin-like protein 3 (ANGPTL3), which plays a role in regulating levels of low-density lipoprotein (LDL), non-HDL cholesterol (a measure of all the "bad" cholesterol in the blood including LDL), and triglycerides. Various research has identified these components as increasing risk of atherosclerotic cardiovascular disease.
In the phase 2b global trial (known as ARCHES-2) of 204 participants with mixed hyperlipidemia who received zodasiran (50, 100, and 200 mg) and background therapy of standard of care medications including statins, the researchers observed substantial reductions in all lipid level parameters monitored. These included lowering triglycerides by 54 to 74 percent compared to placebo, LDL cholesterol by up to 20 percent, non-HDL cholesterol by up to 36 percent, and remnant cholesterol by 73 to 82 percent. Remnant cholesterol measures the amount of "leftover" or remnant very-low-density lipoprotein (VLDL) particles. It is measured by adding up HDL and LDL and subtracting that sum from the individual's total cholesterol. Researchers suggested that based on prior genetic studies the magnitude of remnant cholesterol reduction evidenced by zodasiran in their study could translate into a 20 percent decrease in recurrent major cardiac events.