What are the considerations for using Protein Kinase 9 (PK9) inhibitors in disease treatment?

PCSK9 Inhibitors in Disease Treatment

PCSK9 inhibitors are recommended for patients with atherosclerotic cardiovascular disease (ASCVD) or at very high cardiovascular risk who have not achieved target LDL-C levels despite maximally tolerated statin therapy and ezetimibe. 1

Mechanism and Efficacy

• PCSK9 inhibitors are monoclonal antibodies (evolocumab, alirocumab) that prevent degradation of LDL receptors, allowing for continued recycling of these receptors to the hepatocyte surface and resulting in significant LDL-C reduction 1, 2
• These agents reduce LDL-C by 50-65%, with mean LDL-C levels of approximately 0.9 mmol/L (35 mg/dL) achievable when added to maximal statin therapy 1
• Beyond LDL-C reduction, PCSK9 inhibitors improve other lipid parameters, including Lp(a) which is reduced by up to 25% 1

Clinical Indications

Secondary Prevention (Patients with ASCVD)

• In patients with clinical ASCVD who are judged to be at very high risk and are on maximally tolerated LDL-C lowering therapy with LDL-C ≥70 mg/dL (≥1.8 mmol/L), adding a PCSK9 inhibitor is reasonable 1
• The 2019 ESC/EAS guidelines recommend PCSK9 inhibitors for very high-risk patients who do not achieve their LDL-C goal on maximum tolerated statin dose and ezetimibe 1
• For patients with ASCVD, PCSK9 inhibitors should be considered after optimizing statin therapy and adding ezetimibe 1

Primary Prevention

• For primary prevention in patients with familial hypercholesterolemia (FH) and LDL-C ≥100 mg/dL while taking maximum tolerated statins and ezetimibe, PCSK9 inhibitors may be considered 1
• PCSK9 inhibitors have shown particular benefit in FH patients, allowing a substantial proportion to achieve LDL-C <1.8 mmol/L (<70 mg/dL) for the first time 1

Special Populations

• In patients with homozygous FH on maximal lipid-lowering therapy, evolocumab 420 mg every 4 weeks reduced LDL-C by approximately 30%, with efficacy related to the degree of residual LDL receptor activity 1
• For statin-intolerant patients, PCSK9 inhibitors are well accepted with muscle-related adverse events comparable to those seen with ezetimibe 1

Dosing and Administration

• Alirocumab 150 mg biweekly and evolocumab 140 mg biweekly or 420 mg every 4 weeks have comparable LDL-lowering efficacy 1
• PCSK9 inhibitors are administered by subcutaneous injection once every two or four weeks, depending on the specific agent and dosing regimen 2, 3

Safety Profile

• PCSK9 inhibitors appear well tolerated in trials up to 78 weeks in duration 1
• Common side effects include injection site reactions, which are relatively infrequent and mild 1, 2
• A small, non-significant increase in neurocognitive events has been reported for alirocumab and evolocumab 1
• No excess adverse events have emerged in patients with very low LDL-C levels (<0.65 mmol/L or <25 mg/dL) over 78 weeks of treatment 1

Cardiovascular Outcomes

• Preliminary data suggest that PCSK9 inhibitors reduce cardiovascular events over 1 to 1.5 years 1
• The FOURIER trial demonstrated that the addition of evolocumab to statin therapy significantly reduced cardiovascular morbidity and mortality in patients with prevalent atherosclerotic CVD 1
• A meta-analysis of phase 2 and 3 trials found reduced total mortality with alirocumab and evolocumab in trials ranging from 12 to 78 weeks 1

Treatment Algorithm and Considerations

1. First-line therapy: High-intensity statin therapy to achieve >50% reduction in LDL-C 1
2. Second-line therapy: If LDL-C goal is not achieved after 4-6 weeks with maximally tolerated statin dose, add ezetimibe 1
3. Third-line therapy: Consider PCSK9 inhibitor if LDL-C remains elevated despite maximally tolerated statin plus ezetimibe 1

Practical Considerations and Challenges

• Cost-effectiveness remains a concern, with PCSK9 inhibitors having a relatively high cost compared to traditional lipid-lowering therapies 1
• Real-world adherence data shows that approximately one-third of patients filled PCSK9 inhibitor prescriptions for ≤60 days, indicating potential adherence challenges 4
• Despite guidelines recommending combination with statins, real-world data indicates that only about one-third of patients on PCSK9 inhibitors have evidence of concurrent statin therapy 4
• Statin intolerance alone is not an indication for PCSK9 inhibitor treatment; patients must still meet criteria for high cardiovascular risk and elevated LDL-C despite alternative lipid-lowering therapies 3

Emerging PCSK9 Inhibition Strategies

• Beyond monoclonal antibodies, other PCSK9 inhibition strategies are under development, including small interfering RNA molecules and small molecule inhibitors 2, 5
• Rare cases of non-response to PCSK9 inhibitor monotherapy have been reported, particularly in patients with specific LDL receptor abnormalities, suggesting that combination therapy may be necessary in some cases 6