**4. Dosing and adverse effects**

Alirocumab in the doses of either 75 mg or 150 mg could either be given subcutaneously every 2 weeks, or as a monthly 300 mg subcutaneous injection. LCL-C levels decrease around 45% from the 75 mg dose, and LCL-C levels decrease approximately 55–60% with the 150 mg dose.

Evolocumab also could be either given in a dose of 140 mg subcutaneous injections every 2 weeks, or as a 420 mg subcutaneous injection monthly. Both doses lower LDL-C approximately 55–60%. Besides lowering LDL, both alirocumab and evolocumab achieve mild lowering of triglycerides by 10–15% range. A modest increase in HDL cholesterol by 5–10% has been noted as well.

## **5. Adverse reactions**

Trials involving PCKS9 inhibitors have included patients that were both tolerant and intolerant to statin therapy, providing information on their safety profile. Serious adverse reactions attributed directly to drug injection have been rarely reported, with <10% of patients requiring drug discontinuation during separate study trials [14, 15].

With both available PCKS9i injectable solutions, the most reported adverse effect has been injection site reaction, which occurs in approximately >5% of patients, including injection site allergic reactions. Additional adverse reactions that have been reported by both study data and real-world use databases include upper respiratory infections, nasopharyngitis, myalgias, back pain and neurocognitive events including memory impairment and confusion [14, 15].

In regard to myalgia and muscle symptoms, evolocumab was studied head to head against ezetimibe in the GAUSS-3 trial [14]. This trial examined patient who were intolerant to statins due to muscle symptoms, and randomly assigned patients to either evolocumab or ezetimibe. In this trial population, drug discontinuation due to muscle symptoms occurred in 6.8% of ezetimibe patients and 0.7% of evolocumab patients. However, more patients in the evolucumab arm, 2.8% had elevations in CK levels, compared to 1.4% of patients in the ezetimibe arm.

The only absolute contraindication to PCKS9 inhibitor use is a history of hypersensitivity reaction to prior PCKS9 injections, with limited data available to determine whether allergenic cross-reactivity exists between the two available PCKS9 formulations.

### **6. Available scientific evidence**

The FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) tested clinical outcomes when evolocumab was added to maximum statin therapy in ASCVD patients [16]. A total of 27,564 patients were randomized to either evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. Patients who were treated with evolocumab had close to 60% LCL-C lowering. After a follow up period of 24 months, the combined endpoint of cardiovascular mortality, myocardial infarction, stroke, hospitalization related to angina, or revascularization was seen in 9.8% of patients in the evolocumab group compared to 11.3% in the placebo group.

The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) evaluated outcomes in patients treated with alirocumab after acute coronary syndrome who were already on maximally tolerated statins [17]. A total of 18,924 patients were randomized to either alirocumab or placebo. The composite endpoint of CV death, nonfatal myocardial infarction, fatal and nonfatal stroke, or hospitalization due to angina occurred less the alirocumab arm compared to placebo (9.5% Vs. 11.1%, p = 0.003).

The GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial was designed to study the effect of using PCSK9 inhibition on atherosclerotic plaque burden and regression [18]. Over a period of 18 months a total of 968 patients with ASCVD were treated with either evolocumab or placebo. LDL-C levels were significantly lower in the evolocumab group compared to the placebo group. Atheroma volume was assessed using intravascular ultrasound, which demonstrated larger reduction in the evolocumab group compared to placebo.

The ODYSSEY ALTERNATIVE trial assessed the performance of alirocumab against ezetimibe and atorvastatin in patients with statin associated skeletal muscle effects [19]. Patients were randomized in a 2:2:1 fashion to either alirocumab 75 mg subcutaneously Q2W, ezetimibe 10 mg daily, or atorvastatin 20 mg daily.

**159**

this surveillance period.

*Utility and Appropriate Use of PCSK9 Inhibitors in the Current Era*

Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe; % decrease was 45% vs. 14.6%, difference 30.4, p < 0.0001. Muscle-related side effects were lower in the alirocumab arm (32.5%) compared with the ezetimibe (41.1%, p = 0.096) and atorvastatin arms (46%, p = 0.042). Alirocumab was found to be superior to ezetimibe in lowering LDL-C levels and achieving target levels in patients with statin intolerance, with a lower risk of muscle-related side effects. The GAUSS-2 (Global Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial assessed primarily the safety of evolocumab in patients with statin-associated muscle side effects [20]. It was a double-blind study in which patients were randomized to either evolocumab or ezetimibe. Superior efficacy and no muscle-related adverse events requiring discontinuation was seen in

Based on the results from multiple large scale clinical outcome trials of PCSK9i, this class of LDL-C lowering agents has been recommended as appropriate secondline agents, or as an alternative therapy in cases of significant statin intolerance, for patients with established ASCVD and suboptimal LDL levels. As evidence supporting their efficacy and safety continues to mount, use of PCSK9i is likely to keep

The ACC/AHA multi-society Cholesterol Clinical Practical Guidelines released

in late 2018 give a class I recommendation for PSCK9i in patients with clinical ASCVD and very high risk (VHR) for future ASCVD events who are on maximally tolerated statin therapy and ezetimibe [6]. There is also a class IIa recommendation for VHR patients with ASCVD taking maximally tolerated statin therapy and ezetimibe with LDL-C ≥ 70 mg/dL (≥1.8 mmol/L) or a non-HDL-C level ≥ 100 mg/ dL (≥2.6 mmol/L) to consider PCSK9i. Criteria to be considered VHR include major ASCVD events such as acute coronary syndrome within the past 12 months, history of myocardial infarction, history of embolic stroke, and symptomatic peripheral arterial disease, as well as high-risk conditions such as age ≥ 65 years old, heterozygous familial hypercholesterolemia, history of primary coronary artery bypass surgery or percutaneous coronary intervention, diabetes mellitus, hypertension, chronic kidney disease stage III or worse, ongoing tobacco use, persistent elevated LDL-C ≥ 100 mg/dL (≥2.6 mmol/L) despite maximally tolerated statin therapy and ezetimibe, and history of congestive heart failure. Regarding primary prevention, patients with heterozygous familial hypercholesterolemia aged 30 to 75 years old with an LDL-C ≥ 100 mg/dL (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy and patients aged 40 to 75 years old with a baseline LDL-C ≥ 220 mg/dL (≥5.7 mmol/L) and have an on-treatment LDL-C ≥ 130 mg/dL (≥3.4 mmol/L) while taking maximally tolerated statin and ezetimibe, the addition

Despite strong multi-societal recommendations, uptake rates for PCSK9i have lagged. A study looked at electronic health record data to characterize use of PCSK9i, in addition to standard therapies [21]. Data were obtained from 18 health systems within the National Patient-Centered Clinical Research Network using a common data model. Out of more than 17.5 million adults, 3.6 million met study criteria. Approximately half of patients had been prescribed lipid-lowering medication but <1% were prescribed PCSK9i. A trend towards increased PCSK9i prescription over time was seen for patients with ASCVD but not for those with dyslipidemia. PCSK9i, which effectively lower LDL cholesterol, had low use during

*DOI: http://dx.doi.org/10.5772/intechopen.95238*

patients treated with evolocumab.

expanding in the current ASCVD population.

of a PCSK9i is given a class IIb recommendation.

**7. Appropriate use**

Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe; % decrease was 45% vs. 14.6%, difference 30.4, p < 0.0001. Muscle-related side effects were lower in the alirocumab arm (32.5%) compared with the ezetimibe (41.1%, p = 0.096) and atorvastatin arms (46%, p = 0.042). Alirocumab was found to be superior to ezetimibe in lowering LDL-C levels and achieving target levels in patients with statin intolerance, with a lower risk of muscle-related side effects.

The GAUSS-2 (Global Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial assessed primarily the safety of evolocumab in patients with statin-associated muscle side effects [20]. It was a double-blind study in which patients were randomized to either evolocumab or ezetimibe. Superior efficacy and no muscle-related adverse events requiring discontinuation was seen in patients treated with evolocumab.

### **7. Appropriate use**

*Management of Dyslipidemia*

study trials [14, 15].

formulations.

Vs. 11.1%, p = 0.003).

compared to placebo.

**6. Available scientific evidence**

Serious adverse reactions attributed directly to drug injection have been rarely reported, with <10% of patients requiring drug discontinuation during separate

events including memory impairment and confusion [14, 15].

With both available PCKS9i injectable solutions, the most reported adverse effect has been injection site reaction, which occurs in approximately >5% of patients, including injection site allergic reactions. Additional adverse reactions that have been reported by both study data and real-world use databases include upper respiratory infections, nasopharyngitis, myalgias, back pain and neurocognitive

In regard to myalgia and muscle symptoms, evolocumab was studied head to head against ezetimibe in the GAUSS-3 trial [14]. This trial examined patient who were intolerant to statins due to muscle symptoms, and randomly assigned patients to either evolocumab or ezetimibe. In this trial population, drug discontinuation due to muscle symptoms occurred in 6.8% of ezetimibe patients and 0.7% of evolocumab patients. However, more patients in the evolucumab arm, 2.8% had elevations in CK levels, compared to 1.4% of patients in the ezetimibe arm.

The only absolute contraindication to PCKS9 inhibitor use is a history of hypersensitivity reaction to prior PCKS9 injections, with limited data available to determine whether allergenic cross-reactivity exists between the two available PCKS9

The FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) tested clinical outcomes when evolocumab was added to maximum statin therapy in ASCVD patients [16]. A total of 27,564 patients were randomized to either evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. Patients who were treated with evolocumab had close to 60% LCL-C lowering. After a follow up period of 24 months, the combined endpoint of cardiovascular mortality, myocardial infarction, stroke, hospitalization related to angina, or revascularization was seen in 9.8% of patients

The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) evaluated outcomes in patients treated with alirocumab after acute coronary syndrome who were already on maximally tolerated statins [17]. A total of 18,924 patients were randomized to either alirocumab or placebo. The composite endpoint of CV death, nonfatal myocardial infarction, fatal and nonfatal stroke, or hospitalization due to angina occurred less the alirocumab arm compared to placebo (9.5%

The GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial was designed to study the effect of using PCSK9 inhibition on atherosclerotic plaque burden and regression [18]. Over a period of 18 months a total of 968 patients with ASCVD were treated with either evolocumab or placebo. LDL-C levels were significantly lower in the evolocumab group compared to the placebo group. Atheroma volume was assessed using intravascular ultrasound, which demonstrated larger reduction in the evolocumab group

The ODYSSEY ALTERNATIVE trial assessed the performance of alirocumab against ezetimibe and atorvastatin in patients with statin associated skeletal muscle effects [19]. Patients were randomized in a 2:2:1 fashion to either alirocumab 75 mg subcutaneously Q2W, ezetimibe 10 mg daily, or atorvastatin 20 mg daily.

in the evolocumab group compared to 11.3% in the placebo group.

**158**

Based on the results from multiple large scale clinical outcome trials of PCSK9i, this class of LDL-C lowering agents has been recommended as appropriate secondline agents, or as an alternative therapy in cases of significant statin intolerance, for patients with established ASCVD and suboptimal LDL levels. As evidence supporting their efficacy and safety continues to mount, use of PCSK9i is likely to keep expanding in the current ASCVD population.

The ACC/AHA multi-society Cholesterol Clinical Practical Guidelines released in late 2018 give a class I recommendation for PSCK9i in patients with clinical ASCVD and very high risk (VHR) for future ASCVD events who are on maximally tolerated statin therapy and ezetimibe [6]. There is also a class IIa recommendation for VHR patients with ASCVD taking maximally tolerated statin therapy and ezetimibe with LDL-C ≥ 70 mg/dL (≥1.8 mmol/L) or a non-HDL-C level ≥ 100 mg/ dL (≥2.6 mmol/L) to consider PCSK9i. Criteria to be considered VHR include major ASCVD events such as acute coronary syndrome within the past 12 months, history of myocardial infarction, history of embolic stroke, and symptomatic peripheral arterial disease, as well as high-risk conditions such as age ≥ 65 years old, heterozygous familial hypercholesterolemia, history of primary coronary artery bypass surgery or percutaneous coronary intervention, diabetes mellitus, hypertension, chronic kidney disease stage III or worse, ongoing tobacco use, persistent elevated LDL-C ≥ 100 mg/dL (≥2.6 mmol/L) despite maximally tolerated statin therapy and ezetimibe, and history of congestive heart failure. Regarding primary prevention, patients with heterozygous familial hypercholesterolemia aged 30 to 75 years old with an LDL-C ≥ 100 mg/dL (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy and patients aged 40 to 75 years old with a baseline LDL-C ≥ 220 mg/dL (≥5.7 mmol/L) and have an on-treatment LDL-C ≥ 130 mg/dL (≥3.4 mmol/L) while taking maximally tolerated statin and ezetimibe, the addition of a PCSK9i is given a class IIb recommendation.

Despite strong multi-societal recommendations, uptake rates for PCSK9i have lagged. A study looked at electronic health record data to characterize use of PCSK9i, in addition to standard therapies [21]. Data were obtained from 18 health systems within the National Patient-Centered Clinical Research Network using a common data model. Out of more than 17.5 million adults, 3.6 million met study criteria. Approximately half of patients had been prescribed lipid-lowering medication but <1% were prescribed PCSK9i. A trend towards increased PCSK9i prescription over time was seen for patients with ASCVD but not for those with dyslipidemia. PCSK9i, which effectively lower LDL cholesterol, had low use during this surveillance period.

Cost, or perceived expense, has been another barrier limiting patient access to PCSK9i use. High co-pays have been shown to lower access to PCSK9i, despite Medicare and other third-party payer coverage for PCSK9i [22]. Cost-effective analyses are essential in navigating which scenarios are prudent for treatment. Prior to October 2018, most cost-effectiveness studies concluded that PCSK9i were not cost-effective with the accepted threshold of \$100,000 per quality-adjusted life-year (QALY) gained and cost of treatment estimated around \$14,000 a year [23, 24]. However, in October 2018, the list price of evolocumab was decreased by 60% to \$5850 in the United States, in an effort to lower copays and improve patient access. This dropped the ratios below the threshold of \$50,000 per QALY gained and meeting accepted cost-effectiveness benchmarks [25]. Reducing cost can improve access to PCSK9i, however, prior authorization requirements, lack of insurance approval, and unfamiliarity amongst healthcare providers with this relatively new class of drug remain problematic.
