**2. Mechanism of action**

The proprotein convertase subtilisin/kexin-9 (PCSK9) is a serine protease, which has been found to be integral in the regulation of LDL-C plasma concentrations. The LDL receptors (LDL-R) present on hepatocytes are responsible for binding circulating LDL-C and removing them from plasma. In the absence of PCKS9, the LDL-C/LDL-R complex enters hepatocytes within the endosome and dissociates into LDL-C and LDL-R as a result of the acidic pH present in the endosome. The LDL-R is then recycled back to the hepatocyte surface, making it available to bind more LDL-C, thereby lowering the serum LDL-C concentration. In the presence of PCSK9, however, the LDL-C/LDL-R complex does not dissociate within the endosome, and the entire complex is marked for lysosomal degradation. Without LDL-R recycling, less LDL-C is removed from circulation, resulting in higher LDL-C plasma concentrations [8].

The clinical implications of PCSK9 have been demonstrated in both loss of function and gain of function mutations. A gain of function mutation was first discovered in two French families with familial hypercholesterolemia that was not associated with LDLR or APOB mutations [9]. The mutated allele created an overexpression of PCSK9, and subsequently elevated plasma LDL-C levels, with sequelae of significant hypercholesterolemia including tendinous xanthomas and risk of premature ASCVD in the fourth and fifth decade. While gain of mutation functions have been discovered in other cohorts in Utah, Norway and the United Kingdom, familial hypercholesterolemia secondary to PCKS9 gain of function mutations is uniquely rare [8]. However, this discovery provided insight to PCSK9 activity, and that overexpression of this protein results in excessive LDL-C in vivo. This discovery also provided the third locus for autosomal dominant familial

**157**

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

hypercholesterolemia inheritance, adding to the already known LDL-R and APOB

Conversely, loss of function mutations of PCKS9 have been shown to significantly reduce circulating LDL levels, which sparked interest in accumulating data on how this translated to reduced ASCVD risk. One study discovered that loss of function mutations in one population was present in 2.3% of black patients, and 3.2% of white patients. The loss of PCKS9 function resulted in a 28 percent mean reduction of LDL, and an 88 percent reduction in ASCVD risk in the black population, and a 15 percent mean reduction in LDL and a 47 percent reduction in ASCVD risk in the white populations [10]. This review also supported the idea that loss of PCSK9 function would not impact viability, as both populations in this review had intact reproductive or neurologic function. This was further corroborated in PSCK9 knockout mice, in which no PCKS9 function resulted in exceedingly low LDL-C levels [11, 12]. These findings suggest that PCKS9 function is not vital for life, and complete inhibition of this proteinase would be well tolerated in humans, further sparking the search to create a mechanism in which we could inhibit PCKS9

Currently, two monoclonal against PCSK9 are available: alirocumab and evolocumab, which bind with a 1: 1 ratio to circulating PCSK9. Once the antibody binds to PCSK9, PCSK9 is unable to attach to LDL receptors which in turn inhibits the receptors' degradation. This leads to an increased expression of LDL receptors on hepatocytes, leading subsequently to rapid clearance of LDL particles [13].

The Food and Drug Administration (FDA) has approved alirocumab and evolocumab as "an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous Familial Hypercholesterolemia (FH) or clinical ASCVD who require additional lowering of LDL-C." Evolocumab is also indicated for treatment of homozygous FH and, based on the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, "to reduce the risk of myocardial infarction (MI), stroke, and coronary revascular-

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

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

Trials involving PCKS9 inhibitors have included patients that were both tolerant and intolerant to statin therapy, providing information on their safety profile.

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

mutations [9].

function pharmaceutically.

**3. Approved indication**

ization in adults with established CVD."

approximately 55–60% with the 150 mg dose.

increase in HDL cholesterol by 5–10% has been noted as well.

**4. Dosing and adverse effects**

**5. Adverse reactions**

hypercholesterolemia inheritance, adding to the already known LDL-R and APOB mutations [9].

Conversely, loss of function mutations of PCKS9 have been shown to significantly reduce circulating LDL levels, which sparked interest in accumulating data on how this translated to reduced ASCVD risk. One study discovered that loss of function mutations in one population was present in 2.3% of black patients, and 3.2% of white patients. The loss of PCKS9 function resulted in a 28 percent mean reduction of LDL, and an 88 percent reduction in ASCVD risk in the black population, and a 15 percent mean reduction in LDL and a 47 percent reduction in ASCVD risk in the white populations [10]. This review also supported the idea that loss of PCSK9 function would not impact viability, as both populations in this review had intact reproductive or neurologic function. This was further corroborated in PSCK9 knockout mice, in which no PCKS9 function resulted in exceedingly low LDL-C levels [11, 12]. These findings suggest that PCKS9 function is not vital for life, and complete inhibition of this proteinase would be well tolerated in humans, further sparking the search to create a mechanism in which we could inhibit PCKS9 function pharmaceutically.

Currently, two monoclonal against PCSK9 are available: alirocumab and evolocumab, which bind with a 1: 1 ratio to circulating PCSK9. Once the antibody binds to PCSK9, PCSK9 is unable to attach to LDL receptors which in turn inhibits the receptors' degradation. This leads to an increased expression of LDL receptors on hepatocytes, leading subsequently to rapid clearance of LDL particles [13].
