Rapid 94% Reduction in Genetic Cholesterol with Lepodisiran

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Rapid 94% Reduction in Genetic Cholesterol with Lepodisiran

Rapid 94% Reduction in Genetic Cholesterol with Lepodisiran

Single Dose of Lepodisiran Reduces Genetic Cholesterol by 94% within a Year, Promising Cardiovascular Risk Reduction.

A groundbreaking study conducted on a new medication called lepodisiran has shown a remarkable reduction in genetically inherited bad cholesterol levels over nearly a year with just one injection.

This medication has the potential to eliminate a risk factor for cardiovascular diseases that currently lacks effective treatments.

Rapid 94% Reduction in Genetic Cholesterol with Lepodisiran

The cholesterol variant, lipoprotein(a) or Lp(a), shares some characteristics with low-density lipoprotein (LDL) cholesterol, commonly known as “bad” cholesterol. Similar to LDL cholesterol, Lp(a) contributes to arterial plaque build-up, reducing blood flow to the heart, brain, and other parts of the body, thereby posing a risk for cardiovascular diseases. However, high levels of Lp(a) are largely genetic and are not significantly impacted by exercise, diet, or existing medications. Presently, there are no effective treatments for high Lp(a) levels.

Researchers conducted the first human trial of a novel therapy named lepodisiran and found that a single injection of this drug could significantly reduce Lp(a) to undetectable levels within approximately a year by disrupting its production mechanism.

The lead author of the study, Steven Nissen, commented, “How do you combat a risk factor primarily determined by genes? One highly effective approach is by interfering with the genes, and this is precisely the aim of lepodisiran and other novel therapies.”

Lepodisiran functions as a small interfering RNA (siRNA) that renders the messenger RNA involved in producing Lp(a) ineffective. Lepodisiran attaches to N-acetylgalactosamine (GalNAc), allowing it to enter liver cells possessing the GalNAc receptor, where the assembly of Lp(a) particles occurs.

The study recruited 48 participants with abnormal Lp(a) levels, with 12 randomly assigned to receive a placebo and 36 to receive a single subcutaneous injection of lepodisiran. Within the lepodisiran group, 6 participants received varying doses: 4, 12, 32, 96, 304, or 608 milligrams. After three days of in-hospital monitoring, participants were discharged and followed up with blood tests over 48 weeks. None of the participants had heart disease.

Researchers observed a rapid increase in the drug’s blood concentration, reaching its peak at 10.5 hours and returning to baseline within 48 hours, possibly due to the rapid transfer of the drug from the bloodstream to the liver. At the highest dose of 608 milligrams, Lp(a) levels in the blood dropped rapidly and were undetectable by day 29. Between days 29 and 281, the levels remained undetectable, with a slight increase, and by 48 weeks, the median Lp(a) levels were 94% lower than the baseline.

They noted that lower doses of lepodisiran resulted in shorter durations of effectiveness, but patients taking a 304-milligram dose still experienced a 75% reduction in Lp(a) levels at 48 weeks. The drug demonstrated good tolerance.

Nissen stated, “We believe this therapy holds great promise. These data indicate that lepodisiran is safe and significantly effective in reducing Lp(a), almost entirely eliminating it with a long-lasting effect. We’ll learn more after the ongoing phase two studies.”

Current phase two clinical trials are testing the medication on individuals with high Lp(a) levels and a high risk of early heart attacks or strokes.

Nissen added, “If further trials demonstrate the safety of this drug, lepodisiran, and its ability to reduce heart attacks and strokes, it will be good news for patients as it addresses a risk factor we’ve been unable to treat effectively. This drug could be administered annually, akin to vaccinating individuals with high Lp(a) levels.”

Sponsored by Alnylam Pharmaceuticals, the study was presented at the American Heart Association’s 2023 Scientific Sessions and published in the Journal of the American Medical Association.