Clinical Trials of PCSK9 Inhibitors

proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL-C levels by regulating the LDL receptors on cell membrane. These proteins bind to LDL receptors and allow their recycling via internalization and lysosomal breakdown. The PSCK9 inhibitors are antibodies that bind to PCSK9 proteins and prevent internalization and break down of LDL receptors, therefore, allowing binding and removal of LDL from the blood.

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SPIRE 1 and 2 Trials – Bococizumab

In total, 4 clinical trials have been published. These include SPIRE 1 and SPIRE 2 trials and later on ODYSSEY outcomes and FOURIER trials. The SPIRE 1 trial included patients with either ACS hx or risk factors low-risk LDL-C cutoffs (LDL-C ≥ 70 and < 100 or Non-HDL-C > 100 and < 130). The SPIRE 2 population was similar but had a high-risk lipid profile (LDL-C ≥ 100 and Non-HDL-C ≥ 130). The PCSK9 inhibitor used in SPIRE 1 and 2 was Bococizumab and the trial was published in 2017. Take a look at the visual abstract of the SPIRE1 trial below.

SPIRE1 Bococizumab clinical trial

In the higher-risk, longer-duration trial (SPIRE 2), the patients included had a baseline LDL cholesterol level of ≥100 mg/dl and the median follow-up was 12 months. The SPIRE 2 trial has 10,621 patients in total who were randomized to receive Bococizumab (N=5312) or placebo (N=5309). Major cardiovascular events occurred in 179 and 224 patients, respectively (HR, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The authors concluded that adverse cardiovascular events were reduced with Bococizumab versus placebo in the SPIRE-2 trial, but not in the SPIRE-1 trial. SPIRE 2 visual abstract:

SPIRE 2 clinical trial

ODYSSEY Outcomes Trial -Alirocumab

Alirocumab is a 100% humanized monoclonal antibody in comparison to bococizumab which is a partially murine monoclonal antibody. This was deemed as one of the factors leading to different and more favorable results for Alirocumab. The ODYSSEY Outcomes trial (evaluation of cardiovascular outcomes with Alirocumab after an ACS) was a randomized, double-blind, placebo-controlled trial. The objective of this trial was to compare the safety and efficacy of alirocumab compared with placebo among patients with recent acute coronary syndrome (ACS) already on intensive or maximum-tolerated statin therapy. In total, 18,924 patients (>40 years) with ACS history within the past 1-12 months, on maximum-tolerated statin therapy with inadequate control of lipids were randomized to receive alirocumab q2 weeks SC (n = 9,462) or placebo (n = 9,462). The primary outcome of major CV events occurred in 9.5% of patients receiving alirocumab compared to 11.1% in the placebo group (HR 0.85, 95% CI 0.78-0.93, p < 0.001). The authors concluded that the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received a placebo in patients who had previous ACS and who were receiving high-intensity statin therapy. Check out the visual abstract:

ODYSSEY Outcomes trial visual abstract

FOURIER trial – Evolocumab

Evolocumab is another humanized monoclonal antibody that showed significant benefits in terms of lowering LDL-C and improving outcomes in patients with cardiovascular disease. FOURIER trial (Evolocumab and clinical outcomes in patients with cardiovascular disease) was a multicenter, randomized, double-blind, clinical trial that aimed to assess if PCSK9 inhibitor evolocumab reduce major CV events in patients with atherosclerotic disease and LDL >70 despite statins. The trial was one of the largest PCSK9 inhibitor trial to date. 27,564 patients with atherosclerotic disease and on statin therapy were randomized. Primary outcome of CV death, MI, stroke, hospitalization for UA, coronary revascularization occured in 9.8% of patients receiving evolocumab compared to 11.3% in placebo (HR 0.85, 95% CI 0.79-0.92, p<0.001). Using PCSK9 inhibitors, the LDL-C was successfully reduced to < 30 mg/dl in the trial population which in turn demonstrated significant cardiovascular protection and benefits. Check out the visual abstract of FOURIER trial:

FOURIER trial

PCSK9 Inhibitors Guidelines Recommendations

Based on the above mentioned trials, the 2018 AHA/ACC cholesterol guidelines recommended adding PCSK9 inhibitors in patients with very high ASCVD risk only.

  1. PCSK9 inhibitor should be considered after patient is already on maximal statin therapy and ezetimibe. (Class I)
  2. If LDL-C > 70 mg/dl or non-HDL-C > 100 mg/dl despite being on maximal lipid lowering therapy, PCSK9 inhibitors addition is reasonable. (Class IIa)
  3. In terms of primary prevention, Familial hypercholesterolemia is an FDA-approved indication for both PCSK9 inhibitors. Other than that use of these medications for primary prevention is not well studied.