An experimental drug could be game-changing for millions of Americans with a higher genetic risk of cardiovascular disease. In clinical trial data published over the weekend, Eli Lilly’s lepodisiran was found to dramatically reduce people’s levels of a dangerous kind of cholesterol called lipoprotein(a), or Lp(a).
Eli Lilly announced the peer-reviewed results of its Phase 2 trial of lepodisiran on Sunday, which involved over 300 people genetically predisposed to high Lp(a). People taking the highest doses of lepodisiran experienced a 94% drop in Lp(a) levels up to a year later. The findings indicate that lepodisiran could soon become the first treatment of its kind for this common genetic risk factor.
The cholesterol in our bodies is transported through several different types of lipoproteins. Low-density lipoprotein, or LDL, is often known as the bad kind of cholesterol since too much of it can raise the risk of plaque building up in our arteries (atherosclerosis), which then increases the chances of having heart attacks, strokes, and other cardiovascular problems.
Lp(a) is a form of LDL that can similarly raise the risk of plaque buildup. But unlike classic LDL, Lp(a) levels are largely determined by our genetics, not lifestyle. It’s estimated that about one in five people worldwide are genetically predisposed to have high Lp(a), and there is no existing intervention that can reduce Lp(a)—at least for now.
Our genes contain the instructions needed for cells to produce proteins, but this only happens when the genes are expressed. Our bodies sometimes use a specific form of RNA to silence this expression of genes, called small interfering RNA (siRNA). In recent years, scientists have developed siRNA-based drugs that work on the same principle, such as lepodisiran. Lepodisiran inhibits the liver’s production of apolipoprotein(a), a key component of Lp(a).
In the phase 2 ALPACA trial, 320 people with high Lp(a) were randomly assigned to five conditions; three groups were given two subcutaneous injections of lepodisiran at the start of the study and six months later in varying doses. Another group was given the highest dose of lepodisiran at the start of the study and a placebo six months later. And the last group only received placebo.
Everyone given lepodisiran experienced a reduction in Lp(a) compared to placebo. But those on the highest dose saw a drastic 94% reduction in Lp(a) by the six-month mark. People given only a single injection of the highest dose did experience a slight rebound in Lp(a) a year later (an overall 88% reduction), while people given two injections had a 95% reduction in Lp(a) a year later. The findings were published in the New England Journal of Medicine.
Phase 2 trials are primarily used to further test a drug’s safety and find its optimal dose. So there will need to be more research to confirm these findings. But coupled with the earlier data, lepodisiran appears to be generally safe, with no serious reported adverse events related to the treatment in this latest trial. And given how dramatic these results are, outside experts are understandably excited about the drug’s future.
“It’s remarkable,” Eric Brandt, director of preventive cardiology at the University of Michigan Health Frankel Cardiovascular Center in Ann Arbor, who was not involved with the study, told NBC News. “These drugs have the potential to nearly eliminate that lipoprotein.”
Eli Lilly has already started to enroll volunteers for its Phase 3 trial of lepodisiran. If the drug continues to perform as hoped, it could become the latest accomplishment for siRNA-based therapies. In 2021, the Food and Drug Administration approved Alnylam Pharmaceuticals and Novartis’ Leqvio as a LDL-lowering treatment for people with certain genetic conditions or poorly controlled atherosclerosis.
