Lipid-efficacy RCT · N Engl J Med 2025
ALPACA trial
Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a).
The bottom line
Lepodisiran produced large, dose-dependent and durable reductions in serum lipoprotein(a) with generally mild injection-site reactions, but this trial did not assess cardiovascular outcomes.
Primary lipid endpoint metUS status: Investigational
At a glance
- Medicine
- Lepodisiran at 16 mg, 96 mg, or 400 mg at baseline and again at day 180, or 400 mg at baseline and placebo at day 180, administered by subcutaneous injection
- Compared with
- Placebo at baseline and at day 180
- People
- 320
- Who took part
- Participants with elevated lipoprotein(a); median baseline Lp(a) concentration 253.9 nmol per liter
- Design
- randomized (1:2:2:2:2), placebo-controlled
- Follow-up
- 360 days
- Main question
- Time-averaged percent change from baseline in serum lipoprotein(a) concentration (placebo-adjusted) from day 60 to day 180
Main result
Placebo-adjusted time-averaged percent change from baseline in serum Lp(a) from day 60 to day 180 was -40.8 percentage points (95% CI, -55.8 to -20.6) in the 16-mg group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups
Effect on LDL cholesterol
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Other results
The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively
Safety
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.
In the trial's own words
“The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups.”
Quoted from the abstract of N Engl J Med 2025, checked word for word against PubMed. PubMed 40162643 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Olpasiran, lepodisiran and zerlasiran
Common questions
What did the ALPACA trial find?
Lepodisiran produced large, dose-dependent and durable reductions in serum lipoprotein(a) with generally mild injection-site reactions, but this trial did not assess cardiovascular outcomes.
Who was in ALPACA?
320 people. Participants with elevated lipoprotein(a); median baseline Lp(a) concentration 253.9 nmol per liter.
What was ALPACA's main result?
Placebo-adjusted time-averaged percent change from baseline in serum Lp(a) from day 60 to day 180 was -40.8 percentage points (95% CI, -55.8 to -20.6) in the 16-mg group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups
How much did LDL cholesterol change in ALPACA?
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Related trials
- KRAKEN (2025)Oral muvalaplin produced large, dose-dependent reductions in lipoprotein(a) over 12 weeks with no safety or tolerability concerns, though whether this translates into fewer cardiovascular events is still unknown.
- ALPACA (zerlasiran phase 2) (2024)In patients with established atherosclerotic cardiovascular disease and very high Lp(a), zerlasiran safely lowered Lp(a) levels by more than 80% on average over 36 weeks compared with placebo.
- OCEAN(a)-DOSE (2022)Olpasiran markedly and dose-dependently lowered lipoprotein(a) levels in patients with established atherosclerotic cardiovascular disease and elevated Lp(a), with similar overall adverse event rates to placebo, but whether this translates into reduced cardiovascular events remains to be determined.
- Pelacarsen phase 2 (2020)In patients with cardiovascular disease and elevated Lp(a), the antisense drug APO(a)-LRx (pelacarsen) lowered Lp(a) levels in a dose-dependent manner, with no significant safety signals versus placebo, though cardiovascular outcomes were not assessed in this trial.
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