Alirocumab
Details
Alirocumab (brand: Praluent; Regeneron/Sanofi) is a fully human monoclonal IgG1 antibody targeting PCSK9. Subcutaneous administration; FDA-approved for hypercholesterolaemia, HeFH, and ASCVD risk reduction.
Key Facts
Dosing
- Titrated regimen (standard): start 75 mg Q2 weeks → increase to 150 mg Q2W if LDL-C ≥70 mg/dL at 4 weeks; yields ~45–50% LDL-C reduction on average sources/pcsk9-inhibitors-nrc-2018 (very high)
- Fixed maximum dose: 150 mg Q2W → ~60% LDL-C reduction (comparable to evolocumab at maximum dose)
- Alternative regimen: 300 mg Q4 weeks → ~55–60% LDL-C reduction (Phase III ODYSSEY CHOICE I)
LDL-C Effects
- HeFH (heterozygous): 40–60% LDL-C reduction (ODYSSEY FH I/FH II; n=735; 78 weeks)
- HoFH: highly genotype-dependent; ranges from 7% LDL-C increase to 64% decrease sources/pcsk9-inhibitors-nrc-2018 (very high)
- Also reduces: Lp(a) ~25%, ApoB ~50%, TG ~15%; no effect on CRP
- Fully human → no neutralizing antibody development
ODYSSEY Outcomes Cardiovascular Outcome Trial
- Design: n=18,924; 1–12 months after ACS hospitalisation; LDL-C ≥70 mg/dL on high-intensity statin (89%); median follow-up 2.8 years
- Dosing in trial: titrated to achieve LDL-C 25–50 mg/dL; stopped if persistently <15 mg/dL (protocol-mediated down-titration)
- LDL-C effect: baseline 87 mg/dL; −57% at 4 weeks; attenuated to −36% at end of study due to down-titration sources/pcsk9-inhibitors-nrc-2018 (very high)
- Primary endpoint (CHD death/MI/ischaemic stroke/UA hosp): HR 0.85 (95% CI 0.78–0.93; P=0.003) — 15% RRR
- Individual components directionally consistent, including CHD death
- All-cause mortality: HR 0.85 (95% CI 0.73–0.98; nominal 15% reduction) — not statistically significant after hierarchical testing (tested after CHD death [NS] and CV death [NS])
- Safety: comparable to FOURIER — no excess DM, cataracts, myalgias, neurocognitive events; injection-site reactions ~0.6%/year excess (higher than FOURIER, likely due to alirocumab being slightly less fully human in manufacturing characteristics)
Subgroup Notes (ODYSSEY Outcomes)
- Non-monotonic baseline LDL-C subgroup pattern: patients with lower baseline LDL-C appeared to have less benefit — but this was confounded by protocol-mediated dose reduction in those patients (lower LDL-C → dose down-titrated → less LDL-C lowering → attenuated clinical benefit)
- This is a pharmacological/trial-design explanation, not evidence that lower LDL-C patients derive less benefit sources/pcsk9-inhibitors-nrc-2018 (very high)
Contradictions / Open Questions
- Nominal all-cause mortality reduction (HR 0.85) did not reach statistical significance due to hierarchical testing; whether longer follow-up would establish mortality benefit remains unresolved (FOURIER also showed no CV death reduction at 2.2 years)
- No head-to-head RCT vs evolocumab; minor pharmacological differences (IgG1 vs IgG2 isotype) but no evidence of clinically meaningful differential efficacy
Connections
- Related to concepts/PCSK9-Inhibitors — class overview
- Related to entities/Evolocumab — companion PCSK9 mAb
- Related to concepts/Familial-Hypercholesterolemia — HeFH/HoFH use
- Related to concepts/Dyslipidemia-Management — position in treatment algorithm
Sources
- sources/pcsk9-inhibitors-nrc-2018 (very high)