Lipid-efficacy RCT · JAMA 2024
ALPACA (zerlasiran phase 2) trial
Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial.
The bottom line
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.
Primary lipid endpoint metUS status: Investigational
At a glance
- Medicine
- Zerlasiran (siRNA targeting hepatic apolipoprotein(a) synthesis): 450 mg every 24 weeks for 2 doses (n=45), 300 mg every 16 weeks for 3 doses (n=42), or 300 mg every 24 weeks for 2 doses (n=44)
- Compared with
- Placebo (pooled: subcutaneous placebo every 16 weeks for 3 doses, n=23, or every 24 weeks for 2 doses, n=24)
- People
- 178
- Who took part
- Patients with stable atherosclerotic cardiovascular disease (ASCVD) and serum lipoprotein(a) concentrations ≥125 nmol/L, enrolled at 26 sites in Europe and South Africa; mean age 63.7 years, 25.8% female, median baseline Lp(a) 213 (177-282) nmol/L
- Design
- Multicenter, randomized, placebo-controlled, phase 2 trial
- Follow-up
- Primary outcome at 36 weeks; follow-up to 60 weeks
- Main question
- Time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks
Main result
Least-squares mean time-averaged percent change in Lp(a) vs pooled placebo: -85.6% (95% CI, -90.9% to -80.3%) for 450 mg q24wk, -82.8% (95% CI, -88.2% to -77.4%) for 300 mg q16wk, and -81.3% (95% CI, -86.7% to -76.0%) for 300 mg q24wk
Effect on LDL cholesterol
Not reported (trial measured lipoprotein(a), not LDL-C)
Other results
Median (IQR) percent change in lipoprotein(a) concentration at week 36 was -94.5% (-97.3% to -84.2%) for the 450 mg every 24 weeks group, -96.4% (-97.7% to -92.3%) for the 300 mg every 16 weeks group, and -90.0% (-93.7% to -81.3%) for the 300 mg every 24 weeks group.
Safety
The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.
In the trial's own words
“Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was -85.6% (95% CI, -90.9% to -80.3%), -82.8% (95% CI, -88.2% to -77.4%), and -81.3% (95% CI, -86.7% to -76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively.”
Quoted from the abstract of JAMA 2024, checked word for word against PubMed. PubMed 39556769 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Olpasiran, lepodisiran and zerlasiran
Common questions
What did the ALPACA (zerlasiran phase 2) trial find?
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.
Who was in ALPACA (zerlasiran phase 2)?
178 people. Patients with stable atherosclerotic cardiovascular disease (ASCVD) and serum lipoprotein(a) concentrations ≥125 nmol/L, enrolled at 26 sites in Europe and South Africa; mean age 63.7 years, 25.8% female, median baseline Lp(a) 213 (177-282) nmol/L.
What was ALPACA (zerlasiran phase 2)'s main result?
Least-squares mean time-averaged percent change in Lp(a) vs pooled placebo: -85.6% (95% CI, -90.9% to -80.3%) for 450 mg q24wk, -82.8% (95% CI, -88.2% to -77.4%) for 300 mg q16wk, and -81.3% (95% CI, -86.7% to -76.0%) for 300 mg q24wk
How much did LDL cholesterol change in ALPACA (zerlasiran phase 2)?
Not reported (trial measured lipoprotein(a), not LDL-C)
Related trials
- ALPACA (2025)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.
- 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.
- 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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