Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a)

"BACKGROUND

Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration small interfering RNA (siRNA) targeting hepatic lipoprotein(a) synthesis, are unknown.

METHODS

In this randomized trial, 320 participants with a median baseline lipoprotein(a) concentration of 253.9 nmol/L received lepodisiran (16 mg, 96 mg, or 400 mg) or placebo via subcutaneous injection. The primary endpoint was the placebo-adjusted time-averaged percent change in lipoprotein(a) from day 60 to day 180.

RESULTS

The placebo-adjusted reductions in lipoprotein(a) were:

16 mg: −40.8 percentage points (95% CI, −55.8 to −20.6)

96 mg: −75.2 percentage points (95% CI, −80.4 to −68.5)

400 mg (pooled): −93.9 percentage points (95% CI, −95.1 to −92.5)

At day 360, reductions persisted at −94.8 percentage points (400 mg group). Serious adverse events were unrelated to lepodisiran; mild injection-site reactions occurred in ≤12% of participants.

CONCLUSIONS

Lepodisiran significantly and durably reduced lipoprotein(a) concentrations with a favorable safety profile. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.)"

"BACKGROUND

Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration small interfering RNA (siRNA) targeting hepatic lipoprotein(a) synthesis, are unknown.

METHODS

In this randomized trial, 320 participants with a median baseline lipoprotein(a) concentration of 253.9 nmol/L received lepodisiran (16 mg, 96 mg, or 400 mg) or placebo via subcutaneous injection. The primary endpoint was the placebo-adjusted time-averaged percent change in lipoprotein(a) from day 60 to day 180.

RESULTS

The placebo-adjusted reductions in lipoprotein(a) were:

16 mg: −40.8 percentage points (95% CI, −55.8 to −20.6)

96 mg: −75.2 percentage points (95% CI, −80.4 to −68.5)

400 mg (pooled): −93.9 percentage points (95% CI, −95.1 to −92.5)

At day 360, reductions persisted at −94.8 percentage points (400 mg group). Serious adverse events were unrelated to lepodisiran; mild injection-site reactions occurred in ≤12% of participants.

CONCLUSIONS

Lepodisiran significantly and durably reduced lipoprotein(a) concentrations with a favorable safety profile. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.)"