Inclisiran
PCSK9 inhibitor — siRNA therapy · “The twice-yearly injection”
The Clinical Case
Male, 69 yo. High CV risk. LDL 3.1 mmol/L despite maximum statin + ezetimibe. Was prescribed a PCSK9 monoclonal antibody but stopped after 3 months due to poor adherence with fortnightly injections. Lipid clinic switches him to an RNA-based therapy that silences PCSK9 mRNA production in hepatocytes — given as SC injections just twice a year, with no drug-drug interactions and consistent effect between doses.
The Answer
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Clinical Pearl
Mechanism: siRNA — silences PCSK9 mRNA in hepatocytes via GalNAc-conjugate targeting the asialoglycoprotein receptor; intracellular action
All Hints
Mechanism: siRNA — silences PCSK9 mRNA in hepatocytes via GalNAc-conjugate targeting the asialoglycoprotein receptor; intracellular action
Dosing: 284 mg SC at day 1, month 3, then every 6 months — 2 injections per year; transforms adherence vs biweekly mAbs
Sustained effect: mRNA silencing maintains consistent LDL↓ ~50%; no peak-trough variability between clinic visits
No interactions: Intracellular mechanism — no CYP450 interactions, no plasma protein displacement; unique PK profile
Outcomes: ORION-4 (~15,000 pts) CV outcomes trial; ESC "guidelines": recommended alongside mAbs for PCSK9 pathway inhibition
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