An experimental medication may significantly impact the lives of millions of Americans with a genetic predisposition to cardiovascular disease. Recent clinical trial data released by Eli Lilly indicates that lepodisiran, the experimental drug, substantially lowers levels of lipoprotein(a), or Lp(a), a type of cholesterol.
Eli Lilly shared the peer-reviewed results of its Phase 2 trial of lepodisiran, which involved over 300 participants genetically predisposed to high Lp(a), on Sunday. Participants receiving the highest doses of lepodisiran experienced a 94% decrease in Lp(a) levels for up to a year. These results suggest that lepodisiran could become the first treatment specifically targeting this prevalent genetic risk factor.
Cholesterol in the human body is transported by various lipoproteins. Low-density lipoprotein (LDL) is often labeled as harmful cholesterol, as excessive amounts can lead to plaque buildup in the arteries (atherosclerosis), increasing the probability of heart attacks, strokes, and other cardiovascular issues.
Lp(a) is a form of LDL and can also contribute to plaque accumulation. Unlike typical LDL, Lp(a) levels are largely determined by genetics, not by lifestyle. It is estimated that around one in five people globally has a genetic predisposition to elevated Lp(a) levels, with no current intervention available to reduce Lp(a)—as of now.
Genes provide the instructions for cells to produce proteins, but this only occurs when the genes are expressed. The body may use a specific type of RNA, known as small interfering RNA (siRNA), to silence this gene expression. In recent years, scientists have developed siRNA-based drugs like lepodisiran, which functions on this principle. Lepodisiran reduces the liver’s production of apolipoprotein(a), a primary component of Lp(a).
In the Phase 2 ALPACA trial, 320 individuals with high Lp(a) were randomly assigned to one of five groups. Three groups received two subcutaneous injections of lepodisiran at the beginning of the study and six months later at various doses, while another group received the highest dose initially and a placebo later. The final group only received a placebo.
Every participant given lepodisiran experienced a reduction in Lp(a) compared to those on placebo. Those on the highest dose saw a 94% reduction in Lp(a) by six months. Participants receiving just one injection of the highest dose saw a slight rebound in Lp(a) after a year (an 88% overall reduction), while those receiving two injections had a 95% reduction after a year. These findings were published in the New England Journal of Medicine.
Phase 2 trials primarily evaluate a drug’s safety and optimal dosing. Further research is required to verify these findings. However, combined with earlier data, lepodisiran seems generally safe, with no severe adverse events related to the treatment reported in the latest trial. The remarkable results have sparked excitement among outside experts regarding the drug’s potential.
Eric Brandt, director of preventive cardiology at the University of Michigan Health Frankel Cardiovascular Center in Ann Arbor, expressed enthusiasm, indicating that these drugs could nearly eliminate lipoprotein(a).
Eli Lilly has already commenced volunteer enrollment for its Phase 3 trial of lepodisiran. Should the drug continue to show favorable results, it may join the growing list of siRNA-based therapies. In 2021, the Food and Drug Administration approved Alnylam Pharmaceuticals and Novartis’ Leqvio as an LDL-lowering treatment for individuals with specific genetic conditions or uncontrolled atherosclerosis.
