PCSK9 Inhibitor Examples
The two PCSK9 inhibitors currently approved in Canada and the United States are alirocumab and evolocumab, both administered as subcutaneous injections. 1, 2
Available PCSK9 Inhibitors
First-Generation Monoclonal Antibodies (Currently Approved)
Alirocumab:
- Dosing: 75 mg or 150 mg subcutaneously every 2 weeks, or 300 mg monthly 2
- LDL-C reduction: 50-60% from baseline 2
- Approved for familial hypercholesterolemia and ASCVD patients requiring additional LDL-C lowering beyond maximally tolerated statin therapy 1
Evolocumab:
- Dosing: 140 mg subcutaneously every 2 weeks or 420 mg monthly 1, 3
- LDL-C reduction: 53.6-59% 2, 3
- Same indications as alirocumab 1
Second-Generation RNA-Based Therapy (Approved)
Inclisiran:
- Small-interfering RNA (siRNA) that targets PCSK9 4
- LDL-C reduction: approximately 18% 5
- Administered less frequently than monoclonal antibodies 4
Third-Generation Agents (In Development)
Oral PCSK9 Inhibitors:
- MK-0616 (Enlicitide decanoate): Oral small molecule showing up to 66% LDL-C reduction with good safety profile; outcome trials underway 6
- AZD0780: Oral agent demonstrating 50.7% LDL-C reduction at highest dose (30 mg) when added to statin therapy 7
Other Novel Agents:
- Lerodalcibep: Fusion protein under development 4
- Bococizumab: Development terminated due to attenuation of LDL-C lowering effect from antidrug antibodies 2
Clinical Context
Both approved monoclonal antibodies (alirocumab and evolocumab) have demonstrated cardiovascular benefit in major outcome trials. The FOURIER trial with evolocumab showed 15% relative risk reduction in cardiovascular events 1, 3, while the ODYSSEY OUTCOMES trial with alirocumab demonstrated similar 15% reduction in the primary endpoint 2. These agents are well-tolerated, with injection site reactions being the most common adverse effect 1.
The emerging oral PCSK9 inhibitors may offer improved convenience and adherence compared to injectable formulations, though they require completion of cardiovascular outcome trials before widespread clinical adoption 6, 7.