One-dose drug reduced genetic bad cholesterol by 94% for almost a year
Researchers have conducted the first human trials of a new drug, lepodisiran, and found that a single injection reduced lipoprotein(a) – a ‘bad’ cholesterol with a genetic basis – to undetectable levels for almost a year. It has the potential to eliminate a risk factor for cardiovascular disease for which there is currently no treatment.
A type of cholesterol, lipoprotein(a) or Lp(a), shares some characteristics with low-density lipoprotein (LDL) cholesterol, the so-called ‘bad’ cholesterol. Like LDL cholesterol, Lp(a) causes plaque to build up in arteries, reducing blood flow to the heart, brain, and other parts of the body, making it a risk factor for cardiovascular disease. However, because high Lp(a) levels are inherited, they’re largely unaffected by exercise, diet, or medications. There are no current treatments for high Lp(a).
Researchers have conducted the first human trials of a new therapeutic called lepodisiran and found that a single injection of the drug lowered Lp(a) to undetectable levels for almost a year by interfering with its mechanism of production.
“How do you beat a risk factor that’s largely genetic?” said Steven Nissen, lead author of the study. “One highly effective approach is to interfere with the gene, and that’s what lepodisiran and other new therapies are designed to do.”
Lepodisiran is a small interfering RNA (siRNA) that disables messenger RNA involved in producing apolipoprotein(a), a component essential for the assembly of Lp(a) particles that is synthesized in the liver. The drug is attached to the sugar N-Acetylgalactosamine (GalNAc), which allows it to be carried into liver cells possessing GalNAc receptors.
Of 48 participants with abnormal Lp(a) levels recruited for the study, 12 were randomly assigned to receive a placebo, and 36 were given a single subcutaneous injection of lepodisiran. In the lepodisiran group, six randomly received different doses: 4, 12, 32, 96, 304 or 608 mg. After three days of inpatient monitoring, the participants were discharged to home. Follow-up blood tests were done for 48 weeks after treatment. None of the participants had pre-existing heart disease.
The researchers found that blood levels of the medication rose quickly – peaking at 10.5 hours – and returned to baseline within 48 hours, likely because it was transported quickly out of the bloodstream and into the liver. With the highest dose of lepodisiran, 608 mg, blood levels of Lp(a) declined rapidly and were undetectable by day 29. Levels remained unmeasurable between days 29 and 281 and then rose slightly, with a median reduction of Lp(a) levels at 94% below baseline at 48 weeks.
They noted that the smaller doses of lepodisiran produced short-lasting effects, although Lp(a) levels remained down 75% at 48 weeks for those who received the 304 mg dose. The drug was well-tolerated.
“In our view, this therapeutic is very promising,” Nissen said. “These data indicate lepodisiran is safe, and its effectiveness at lowering Lp(a) was profound, with near-total elimination of Lp(a) that lasted for a long time. We’ll know more after the Phase 2 study, which is underway.”
The current Phase 2 clinical trial is testing the medication in people with both high Lp(a) levels and a high risk of early heart attack or stroke.
“If further trials show that this medication – lepodisiran – is safe and can reduce heart attacks and strokes, it would be good news for patients because it eliminates a risk factor we’ve been unable to treat,” Nissen said. “This medication could be a once-a-year injection similar to a vaccine for people with high Lp(a) levels.”
Source: American Heart Association