PDF: ALPACA
(2025)Objective
To assess the safety and efficacy of lepodisiran, an extended-duration small interfering RNA (siRNA) targeting hepatic synthesis of lipoprotein(a), in reducing serum lipoprotein(a) concentrations in adults with elevated Lp(a) levels.
Study Summary
• Lepodisiran 400 mg produced a placebo-adjusted Lp(a) reduction of 93.9% (day 60-180) and 94.8% (day 30-360) with two doses given 6 months apart
• Dose-dependent reductions: 16 mg → -40.8%, 96 mg → -75.2%, pooled 400 mg → -93.9% (primary endpoint, day 60-180)
• Apolipoprotein B concentrations also decreased in a dose-dependent manner, with maximal reductions of 15.5% at day 240 in the 400 mg group
• Serious adverse events occurred in 35 participants (11%), none deemed related to lepodisiran or placebo
• Injection-site reactions were mild, transient, and dose-dependent, occurring in 0-12% of lepodisiran recipients
• Dose-dependent reductions: 16 mg → -40.8%, 96 mg → -75.2%, pooled 400 mg → -93.9% (primary endpoint, day 60-180)
• Apolipoprotein B concentrations also decreased in a dose-dependent manner, with maximal reductions of 15.5% at day 240 in the 400 mg group
• Serious adverse events occurred in 35 participants (11%), none deemed related to lepodisiran or placebo
• Injection-site reactions were mild, transient, and dose-dependent, occurring in 0-12% of lepodisiran recipients
Intervention
Lepodisiran (siRNA targeting hepatic apolipoprotein(a) mRNA) administered as subcutaneous injection at doses of 16 mg, 96 mg, or 400 mg versus placebo
Inclusion Criteria
Adults ≥40 years with serum Lp(a) ≥175 nmol/L; stable doses of lipid-modifying drugs (statins, PCSK9 inhibitors, etc.) for ≥4 weeks before screening
Study Design
Arms: 5 arms in 1:2:2:2:2 ratio — (1) Placebo at baseline and day 180; (2) Lepodisiran 16 mg at baseline and day 180; (3) Lepodisiran 96 mg at baseline and day 180; (4) Lepodisiran 400 mg at baseline, placebo at day 180; (5) Lepodisiran 400 mg at baseline and day 180
Patients per Arm: Placebo: 69; Lepodisiran 16 mg: 36; Lepodisiran 96 mg: 74; Lepodisiran 400 mg-Placebo: 72; Lepodisiran 400 mg-400 mg: 69
Outcome
• Primary: Placebo-adjusted time-averaged percent change in Lp(a) from day 60-180 was -40.8% (16 mg), -75.2% (96 mg), and -93.9% (pooled 400 mg)
• Secondary: Time-averaged Lp(a) reduction from day 30-360 was -41.2% (16 mg), -77.2% (96 mg), -94.8% (400 mg x2)
• Secondary: Apolipoprotein B reduction was dose-dependent, maximal -15.5% at day 240 in the 400 mg x2 group
• Safety: No serious adverse events related to lepodisiran; injection-site reactions in up to 12% (mild, transient)
• Secondary: Time-averaged Lp(a) reduction from day 30-360 was -41.2% (16 mg), -77.2% (96 mg), -94.8% (400 mg x2)
• Secondary: Apolipoprotein B reduction was dose-dependent, maximal -15.5% at day 240 in the 400 mg x2 group
• Safety: No serious adverse events related to lepodisiran; injection-site reactions in up to 12% (mild, transient)
Bottom Line
Lepodisiran resulted in substantial and durable reductions in serum lipoprotein(a) levels up to 540 days, with a favorable safety profile.
Major Points
- ALPACA (phase 2) demonstrated that lepodisiran, a GalNAc-conjugated siRNA targeting hepatic apolipoprotein(a) mRNA, reduces Lp(a) by up to 94.8% — the most potent Lp(a)-lowering agent tested to date. Published NEJM 2025.
- Mechanism: siRNA silences APOA1 gene expression in hepatocytes via RISC-mediated mRNA degradation. GalNAc conjugation enables liver-specific uptake via asialoglycoprotein receptors. Two subcutaneous injections provide >1 year of sustained suppression.
- 400 mg dose (×2 injections at baseline + day 180) achieved time-averaged Lp(a) reduction of -93.9% (95% CI -95.1 to -92.5) — virtually eliminating Lp(a) from circulation.
- Remarkably durable effect: single 400 mg dose still showed ~80% reduction at day 360 (6 months after injection). This ultra-long duration differentiates lepodisiran from monthly antisense oligonucleotide (pelacarsen) and antibody (olpasiran) approaches.
- 95% of high-dose patients achieved Lp(a) <125 nmol/L (the threshold associated with cardiovascular risk) — suggesting near-complete population coverage at optimal dosing.
- Favorable safety profile: no serious drug-related adverse events. Mild injection-site reactions in ≤12% (dose-dependent). ALT >3× ULN in 3% — all resolved. No liver toxicity signal.
- Part of the 'Lp(a)-lowering race' alongside pelacarsen (ASO, Novartis/Ionis, HORIZON CVOT ongoing), olpasiran (siRNA, Amgen, OCEAN(a)-OUTCOMES ongoing), and muvalaplin (oral, Eli Lilly). Lepodisiran is the Eli Lilly entry.
- Phase 3 cardiovascular outcomes trial ACCLAIM-Lp(a) is now underway — will test whether Lp(a) reduction translates to fewer MACE events. This is the 'Lp(a) hypothesis' — the most important unanswered question in lipidology.
- Apolipoprotein B was also reduced by up to 15.5% — suggesting some downstream effect on LDL metabolism, which could provide additional cardiovascular benefit.
- 320 patients across 66 centers in 10 countries — well-powered for a phase 2 biomarker trial. Dose-response relationship was clear and consistent across all ethnic subgroups.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled phase 2 trial
- Randomization
- Yes
- Blinding
- Double-blind (participants and investigators)
- Sample Size
- 320
- Follow-up
- 540 days
- Centers
- 66
- Countries
- Argentina, China, Denmark, Germany, Japan, Mexico, Netherlands, Romania, Spain, USA
Primary Outcome
Definition: Time-averaged % change in serum Lp(a) from day 60–180 (placebo-adjusted)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0% | -93.9% (400 mg pooled) | - (-95.1 to -92.5) | - |
Limitations & Criticisms
- Phase 2 surrogate endpoint trial — reduced Lp(a) is NOT a validated surrogate for cardiovascular events. The 'Lp(a) hypothesis' remains unproven until ACCLAIM-Lp(a) or similar CVOT reports results.
- Only 2 doses administered (baseline + day 180) — long-term safety of chronic siRNA-mediated gene silencing in hepatocytes is unknown. Repeated exposure could cause cumulative liver effects.
- Few Black participants (highest Lp(a) prevalence and risk) — a critical limitation since the population that stands to benefit most is underrepresented.
- No cardiovascular outcomes — cannot determine if the dramatic Lp(a) reduction translates to fewer heart attacks, strokes, or deaths. The leap from biomarker to outcome is not guaranteed (cf. CETP inhibitors).
- Short follow-up (540 days) — insufficient to detect long-term safety signals such as hepatotoxicity, immune responses to repeated siRNA, or effects on wound healing (Lp(a) may play a role in tissue repair).
- The 3% ALT >3× ULN rate in lepodisiran recipients warrants monitoring — liver-targeted siRNA therapies (inclisiran, fitusiran) have shown hepatotoxicity signals with longer use.
- Exclusion of women of childbearing potential limits generalizability — reproductive-age women with high Lp(a) represent an important clinical population.
- No head-to-head comparison with pelacarsen (ASO) or olpasiran (competing siRNA) — relative efficacy, durability, and safety across Lp(a)-lowering modalities is unknown.
- Industry-sponsored (Eli Lilly, the lepodisiran developer) — potential for publication bias and favorable trial design choices.
Citation
N Engl J Med 2025; DOI:10.1056/NEJMoa2415818