At the KAHN CENTER, we have developed a specialty in diagnosing and managing the genetic cholesterol particle called Lipoprotein(a) or Lp(a). This is found in up to 25% of all person by a simple blood test but most doctors do not check for it.
Elevated Lp(a) concentrations are associated with atherosclerotic cardiovascular disease and calcific aortic valve disease.
There is no FDA approved medication for lowering Lp(a) but several pharmaceutical companies are in phase 3 trials hoping to prove a benefit to lowering Lp(a).
The safety and efficacy of lepodisiran, made by Lilly, an extended-duration, small interfering RNA targeting hepatic synthesis of lipoprotein(a), are unknown. A short term phase 2 trial was
recently reported. STUDY
We randomly assigned participants in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180, all administered by subcutaneous injection. Data from the two groups that received lepodisiran at a dose of 400 mg at baseline were pooled for the primary analysis. The primary end point was the time-averaged percent change from baseline in the serum lipoprotein(a) concentration (lepodisiran difference from placebo [i.e., placebo-adjusted]) during the period from day 60 to day 180.
The rates of heart attack, stroke, procedures and death were not end-points in this small and short trial.
STUDY RESULTS
A total of 320 participants underwent randomization; the median baseline lipoprotein(a) concentration was 253.9 nmol/l.
The percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was −40.8 percentage points in the 16-mg lepodisiran group and went all the way up to −93.9 percentage pointsin the pooled 400-mg groups.
Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group.
CONCLUSIONS
Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration in an impressive amount with apparent safety in this small trial.
The study was not intended to measure the rates of heart attacks, deaths and other outcomes. That is the role of the ongoing Phase 3 study of this drug in over 10,000 patients that may be completed by 2029. Until then, this drug will not be available for use in patients outside the placebo controlled research study.
The future is bright for patients with a high Lp(a) level but the first drug to reach market is at least a year away and is anticipated to be very expensive.
For now, the KAHN CENTER has effective protocols to manage Lp(a).
