PCSK9 Inhibitors

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in the regulation of the low-density lipoprotein (LDL) receptor, the primary method of removing LDL particles from the blood. Currently approved PCSK9 inhibitors include the PCSK9 monoclonal antibodies (mAbs) alirocumab and evolocumab, and the small interfering RNA (siRNA) molecule inclisiran. PCSK9 inhibitors block the activity of PCSK9 and substantially lower low-density lipoprotein cholesterol (LDL-C) with or without background statin therapy in a wide range of patients, including those with familial hypercholesterolemia. Large atherosclerotic cardiovascular disease (ASCVD) outcomes trials have demonstrated reductions in major cardiovascular (CV) events for alirocumab or evolocumab added to background high- or moderate-intensity statin therapy in patients with clinical ASCVD. To date, both PCSK9 mAbs have had a good safety profile in clinical trials with up to 4 years of follow-up.

Monoclonal antibody manufacturing is a high-tech endeavor, markedly increasing costs over the small molecule drugs that can be taken orally as pills. The initial average wholesale pricing of the PCSK9 mAbs has resulted in limited uptake in the United States. However, recent price reductions may make the PCSK9 mAbs more accessible for patients likely to benefit from further LDL-C lowering to reduce ASCVD risk. The presence of high-risk patient characteristics may further improve the cost-effectiveness for these drugs.

Clinical Highlight I

• Maximize statin therapy to reduce ASCVD risk and increase the efficacy of the PCSK9 inhibitor.
• Consider adding a PCSK9 inhibitor in patients with clinical ASCVD who achieve <50% LDL-C reduction on maximally-tolerated LDL-C-lowering therapy (statin and ezetimibe for very high risk ASCVD; statin for non-very high risk ASCVD) and whose LDL-C level is ≥55 mg/dL (for very high risk ASCVD) or ≥70 mg/dL (for non-very high risk ASCVD).
• Consider adding a PCSK9 inhibitor in patients with familial hypercholesterolemia who achieve <50% LDL-C reduction on maximally-tolerated statin therapy and whose LDL-C level is ≥100 mg/dL.
• Consider adding a PCSK9 inhibitor in patients with clinical ASCVD or familial hypercholesterolemia who cannot tolerate statin therapy.
• Do not down-titrate the statin if LDL-C levels are low on a PCSK9 inhibitor; if LDL-C levels are <15 mg/dL on two or more occasions more than 2 to 3 months apart, it is acceptable to continue to observe.

Appropriate Uses

In the United States, the Food and Drug Administration (FDA) has approved alirocumab to reduce the risk of myocardial infarction (MI), stroke and unstable angina requiring hospitalization in patients with established CV disease. Evolocumab is approved to reduce the risk of MI, stroke, revascularization in patients with established CV disease. Both PCSK9 mAbs are approved as an adjunct to diet, with or without other LDL-C lowering medications, for LDL-C lowering in adult patient with primary hyperlipidemia, including those with heterozygous familial hypercholesterolemia (HeFH). Furthermore, both are also approved, in combination with other LDL-C lowering medications, for LDL-C lowering in adult patients with homozygous familial hypercholesterolemia (HoFH). Evolocumab is additionally approved, in combination with other LDL-C lowering medications, for LDL-C lowering in children with HoFH aged 10 years and older, and also as an adjunct to diet and other LDL-C lowering medications in children with HeFH aged 10 years and older. Inclisiran is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD who require additional lowering of LDL-C.

The 2018 multi-society cholesterol guideline contains several recommendations on the use of PCSK9 inhibitors, which in 2018 included only the two mAbs:

• For secondary prevention in patients with clinical ASCVD, following a clinician-patient discussion about the net benefit, addition of a PCSK9 inhibitor to a maximally-tolerated LDL-C-lowering therapy is reasonable (class of recommendation [COR] IIa) for patients with very high risk ASCVD whose LDL-C levels are ≥70 mg/dL; the maximally tolerated LDL-C-lowering therapy should (COR I) include ezetimibe and a statin before addition of a PCSK9 mAb is considered
• For primary prevention, addition of a PCSK9 may be considered (COR IIb) in patients 30-75 years of age with FH (baseline LDL-C ≥190 mg/dL) and an LDL-C level of ≥100 mg/dL while on maximally tolerated statin and ezetimibe therapy and in patients 40-75 years of age with a baseline LDL-C level of ≥220 mg/dL whose LDL-C level on a maximally tolerated statin and ezetimibe regimen is ≥130 mg/dL.

The above recommendations were updated and supplemented in the 2022 American College of Cardiology (ACC) Expert Consensus Decision Pathway (ECDP) on the use of nonstatins, which was released to provide interim guidance to clinicians and patients on the appropriate use of novel nonstatins (including inclisiran) until a new set of guidelines can be published. The 2022 ACC ECDP recommends (without providing a COR):

• For secondary prevention in patients with very high risk (Table 8-2) clinical ASCVD, consider adding a PCSK9 mAb (and/or ezetimibe) to maximally tolerated statin therapy if the patient achieves <50% LDL-C reduction and their LDL-C level is ≥55 mg/dL; may also consider inclisiran as a second-line option in this patient group
• For secondary prevention in patients with clinical ASCVD not at very high risk, consider adding a PCSK9 mAb to maximally-tolerated statin and ezetimibe therapy if the patient achieves <50% LDL-C reduction and their LDL-C level is ≥70 mg/dL; may also consider inclisiran as a third-line option in this patient group
• For primary prevention in patients with primary hypercholesterolemia (LDL-C ≥190 mg/dL), consider adding a PCSK9 mAb (and/or ezetimibe) to maximally-tolerated statin therapy if the patient achieves <50% LDL-C reduction and their LDL-C level is ≥100 mg/dL; may also consider inclisiran as a second-line option in this patient group.

In patients with clinical ASCVD or primary hypercholesterolemia (LDL-C ≥190 mg/dL) who are unable to tolerate at least two statin therapies with one attempt at the lowest FDA-approved dose and trial of alternate dosing regimens, a PCSK9 mAb (with or without ezetimibe) may be considered for first-line therapy and inclisiran may be considered for second-line therapy.

PCSK9 Discovery

Gain-of-function mutations in PCSK9 were first described in 2003 in a French family with autosomal dominant familial hypercholesterolemia and premature ASCVD. Loss-of-function PCSK9 mutations were described shortly thereafter. Individuals heterozygous for PCSK9 loss-of-function mutations have markedly reduced ASCVD risk due to lifetime exposure to moderately lower than average LDL-C levels (mean LDL-C was 100 mg/dL in one study with an 88% reduction in coronary artery disease (CAD) risk).

Drug development was rapid, with anti-PCSK9 monoclonal antibodies in phase 1 and 2 trials by 2010. Phase 3 efficacy and safety studies were reported in 2014, and the first CV outcomes trial, FOURIER, was reported in 2017, with the second, ODYSSEY OUTCOMES, reported shortly thereafter in 2018. In 2020, reports from three phase 3 trials (ORION 9, ORION 10 and ORION 11) led to the approval of inclisiran, an siRNA targeting the PCSK9 mRNA. Mechanism of Action.

In the absence of PCSK9, when an LDL receptor/LDL particle complex forms on the cell surface, the complex is internalized via endocytosis (Figure 23-1). The LDL particle is degraded in the lysosome, releasing cholesterol for storage or other cellular activities. The LDL receptor then returns to the cell surface and can be recycled up to 150 times (Panel A).

PCSK9 is primarily synthesized in the liver but is also found in the intestine and kidney. It is secreted into the circulation, where it can irreversibly bind the LDL receptor/LDL particle complex on the outside of the cell. The PCSK9/LDL receptor/LDL particle complex is then internalized via endocytosis. In this case, the entire complex is degraded in the lysosome, thus preventing recycling of the LDL receptor (Panel B).

Intracellular cholesterol levels, via steroid receptor binding protein (SREBP)-2, regulate transcription of both PCSK9 and the LDL receptor. Statins inhibit the rate limiting step in cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, thereby reducing intracellular cholesterol levels. Consequently, statins increase the synthesis of both PCSK9 and LDL receptors, tempering statin efficacy as the dose is increased (Panel C). This is also why the efficacy of PCSK9 inhibitors is enhanced when used in the setting of background statin therapy: the PCSK9 inhibitor blocks the higher level of PCSK9 present in statin-treated patients, restoring LDL receptor recycling (Panel D).

PCSK9 Monoclonal Antibodies

The inactivation site for PCSK9 does not have suitable clefts for binding a small molecule that will inactivate it. Large molecule biologic therapy has proven a more successful approach since mAbs can effectively bind the catalytic domain of the PCSK9 molecule to impair its function. mAbs are large, complex proteins requiring subcutaneous administration using an autoinjector pen or device. mAbs have a long serum half-life and are highly specific to their target, limiting off-target adverse effects. They do not penetrate the blood-brain barrier and are eliminated via the reticuloendothelial system.

mAbs are highly specific antibodies produced by a single clone of cells or cell lines. Although the initial generation of therapeutic mAbs was in mice, humanized or fully human antibodies have now been engineered to have a human constant region. An increasing proportion of human sequence in the antibody reduces immunogenicity. The approved PCSK9 inhibitors alirocumab and evolocumab are fully human antibodies.

Figure 23-2 illustrates the pharmacodynamics of PCSK9 mAb administration. After subcutaneous injection, the level of the PCSK9 mAb rapidly rises in the blood. Blood levels of circulating PCSK9 mAbs fall as they bind PCSK9. LDL receptors can then freely recirculate to the surface to continue removing LDL particles, and blood LDL-C levels fall. Once PCSK9 mAbs are consumed, PCSK9 levels begin to rise. PCSK9 is again available to bind the LDL receptor/LDL particle complex, resulting in the irreversible degradation of LDL receptors and increasing blood LDL-C levels. “Saw-toothing” of blood LDL-C levels can occur as PCSK9 mAbs are administered and consumed. This can be avoided either by administering the PCSK9 mAbs more frequently (1 dose every 2 weeks) or at higher doses so PCSK9 mAbs are not completely consumed before the next dose (as for evolocumab given in a 3-fold higher dose every 4 weeks).

The pharmacokinetics of PCSK9 mAbs are not affected by age, sex, race, or renal or hepatic impairment in the populations studied.

PCSK9 Inhibiting siRNA

Small interfering RNAs are short, double-stranded RNA molecules that mediate silencing of target genes by guiding sequence-dependent slicing of their target mRNAs. Inclisiran is a chemically synthesized siRNA directed against the PCSK9 mRNA, conjugated with a triantennary N-Acetylgalactosamine (GalNAc) moiety on the sense strand. Specific binding of the GalNAc ligand to asialoglycoprotein receptors (ASGPR) enables targeted uptake of inclisiran into hepatocytes. Following uptake into hepatocytes, the antisense strand of inclisiran (which specifically corresponds to human PCSK9 mRNA) is integrated into the RNA-induced silencing complex, directing the catalytic breakdown of the PCSK9 mRNA and thus preventing PCSK9 protein translation. This leads to LDL-C receptor recycling and expression on the hepatocyte cell surface, which enhances LDL-C uptake, thus reducing LDL-C levels in blood.

The pharmacokinetics of inclisiran are not significantly affected by age, body weight, gender, race, or creatinine clearance. In patients with mild, moderate, or severe renal impairment, an increase of ~2.3 to 3.3-fold in C_max and ~1.6 to 2.3-fold in AUC was reported. In patients with mild and moderate hepatic impairment, a C_max increase of ~1.1 to 2.1-fold and an AUC increase of ~1.3 to 2.0-fold (compared to patients with normal hepatic function) was reported. The decreases in LDL-C across the groups of inclisiran-treated patients with normal hepatic function and mild hepatic impairment were comparable despite the increased plasma inclisiran exposures. Baseline PCSK9 levels and LDL-C reductions in individuals with moderate hepatic impairment were lower than those seen in patients with normal hepatic function. Patients with severe hepatic impairment have not been examined in relation to inclisiran.

ASCVD and Mortality Outcomes

CV outcomes trials for both alirocumab and evolocumab have shown a reduction in major CV and ASCVD events when added to high- or moderate-intensity statin therapy in ASCVD patients.

Alirocumab

ODYSSEY OUTCOMES randomized 18,924 patients with an ACS within the prior 1 to 12 months and LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL or apoB ≥80 mg/dL to alirocumab or placebo. Patients were required to be on high- (89%) or moderate-intensity statin therapy at the time of randomization. Alirocumab 75 mg to 150 mg was dosed according to protocol-specified dosing algorithms to target an LDL-C level of 25 to 50 mg/dL. Alirocumab was also down-titrated if LDL-C levels consistently fell below 15 mg/dL.

Median follow-up was 2.8 years. At 4 months, LDL-C was 40 mg/dL in the alirocumab group and 93 mg/dL in the placebo group. LDL-C rose gradually in both alirocumab and placebo groups over the course of the trial (Figure 23-3).

Alirocumab reduced the primary endpoint of major CV events (coronary death, MI, stroke, or hospitalization for unstable angina) by 15% (95% CI 7-22%, P <0.001) (Figure 23-4). Greater relative risk reduction occurred among patients with LDL-C ≥100 mg/dL at baseline than in those with lower levels. Similar risk reductions occurred in other prespecified subgroups. The hazard ratio for the main secondary endpoint of all-cause mortality was 0.85 (95% CI 0.73-0.98; Figure 23-5), a non-significant difference with alirocumab as per pre-specified method to control for type 1 error.

Evolocumab

FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) randomized 27,564 patients with ASCVD and LDL-C levels ≥70 mg/dL or non-HDL-C levels ≥100 mg/dL to evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. Patients were required to be on high- (69%) or moderate-intensity statin therapy.

Median follow-up was 2.2 years. LDL-C levels were reduced by 59%, from a median baseline value of 92 mg/dL to 30 mg/dL at 48 weeks (Figure 23-6). Efficacy was sustained over the 3 years of the trial.

Evolocumab reduced the primary endpoint of major CV events (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) by 15% (95% CI 8-21%, P <0.001). Risk reductions were consistent across prespecified subgroups. The key secondary endpoint (CV death, MI, or stroke) was reduced by 20% (95% CI 12-27%, P <0.001) (Figure 23-7). Total mortality was not reduced (HR 1.04; 95% CI 0.91-1.19).

Inclisiran

The approval of inclisiran was based on phase 3 trials (ORION-9, ORION-10 and ORION-11) that were designed to assess its LDL cholesterol-lowering efficacy (see the LDL-C Lowering Efficacy section below). These trials were not powered for cardiovascular outcomes and the effect of inclisiran on cardiovascular morbidity and mortality is still being tested in ORION-4, an ongoing cardiovascular outcomes trial in ~15,000 patients. Nevertheless, ORION-9, -10 and -11 did include prespecified exploratory cardiovascular endpoints, including cardiac death and any signs or symptoms of cardiac arrest, nonfatal myocardial infarction, or nonfatal stroke.

Prespecified exploratory cardiovascular events occurred in 58 patients (7.4%) in the inclisiran group and 79 (10.2%) patients in the placebo group in ORION-10 and 63 patients (7.8%) in the inclisiran group and 83 (10.3%) patients in the placebo group in ORION-11. In ORION-9, prespecified exploratory cardiovascular events occurred at a similar rate in the inclisiran group (10 patients; 4.1%) and in the placebo group (10 patients; 4.2%).

LDL-C Lowering Efficacy

Alirocumab and evolocumab have different approaches to dosing, while inclisiran acts via a different mechanism of action, resulting in somewhat differing efficacies, as described below.

Alirocumab

Depending on the dosing strategy used, alirocumab added to background statin therapy reduces LDL-C by 43 to 58% compared to placebo. In most efficacy trials, the starting dose for alirocumab was 75 mg every 2 weeks, uptitrated to 150 mg every 2 weeks if LDL-C remained ≥70 mg/dL after 8 weeks of treatment. Patients with HeFH experienced similar reduction in LDL-C as ASCVD patients without HeFH. Alirocumab 150 mg every 2 weeks as the starting dose reduced LDL-C by 58% compared to placebo at 24 weeks, with continued sustained LDL-C lowering efficacy of 52% over 78 weeks of follow-up (Figure 23-8).

Alirocumab can also be given as 300 mg every 4 weeks. Compared to placebo, alirocumab 300 mg every 4 weeks reduced LDL-C by 54%.

In the CV outcomes trial, ODYSSEY OUTCOMES, alirocumab 75 mg to 150 mg was dosed according to protocol-specified dosing algorithms to target an LDL-C level of 25 to 50 mg/dL. Alirocumab was also down-titrated if LDL-C levels consistently fell below 15 mg/dL. At 1 year, LDL-C was reduced by 50%, from 96 mg/dL in the placebo group to 48 mg/dL in the alirocumab group.

As monotherapy, alirocumab 75 mg every 2 weeks reduced LDL-C by about 50%. In comparison to ezetimibe, alirocumab 75 mg every 2 weeks (up-titrated to 150 mg every 2 weeks if LDL-C remained ≥70 mg/dL) reduced LDL-C an additional 30% in high-risk patients treated with maximally tolerated statin therapy.

Evolocumab

Evolocumab can be administered as 140 mg every 2 weeks or as 420 mg once monthly, with average LDL-C lowering efficacy of 47% to 71% when added to background statin therapy in patients with and without HeFH after 12 to 52 weeks of treatment. Evolocumab lowers LDL-C about 55% as monotherapy.

In comparison to ezetimibe, evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks reduced LDL-C by an additional 34% to 44% in statin intolerant patients and 37% to 45% in patients treated with moderate- or high-intensity statins.

Inclisiran

The recommended dosage of inclisiran is 284 mg/1.5 mL (189 mg/mL) administered as a single subcutaneous injection initially, followed by another after three months, and then every six months (all at the same dose). This dosing schedule was used in the three pivotal clinical trials of inclisiran LDL-C lowering efficacy, described below.

ORION-10 randomized 1561 patients with ASCVD and LDL-C ≥70 mg/dL to inclisiran or placebo. Patients were required to be on stable doses of background lipid-lowering therapies for at least 30 days before screening. Patients receiving treatment with monoclonal antibodies directed toward PCSK9 within 90 days before screening were excluded. The patients received either 284 mg of inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, day 270 and day 450.

At day 510, LDL-C levels were reduced by 52.3% (95% confidence interval [CI], 48.8 to 55.7), with time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) (P <0.001 for all comparisons vs placebo) after day 90 and up to day 540. The percentage change and absolute change in LDL-C levels over time are shown in Figure 23-9.

ORION-11 enrolled 1617 patients with ASCVD or ASCVD risk equivalent (type 2 diabetes, familial hypercholesterolemia, or a 10-year risk of a cardiovascular event of ≥20% as assessed by the Framingham Risk Score for Cardiovascular Disease or equivalent) and LDL-C levels ≥70 mg/dL for ASCVD patients or ≥100 mg/dL for patients with an ASCVD risk equivalent, and randomized them to inclisiran or placebo. Patients were required to be on stable doses of background lipid-lowering therapies for at least 30 days before screening. Patients receiving treatment with monoclonal antibodies directed toward PCSK9 within 90 days before screening were excluded. Subcutaneous injections were administered on day 1, day 90, day 270 and day 450 with either 284 mg of inclisiran or placebo.

At day 510, LDL-C levels were reduced by 49.9% (95% CI, 46.6 to 53.1), with corresponding time-adjusted reductions of 49.2% (95% CI, 46.8 to 51.6) (P <0.001 for all comparisons vs placebo). The percentage change and absolute change in LDL-C levels over time are shown in Figure 23-9.

ORION-9 enrolled 482 patients with heterozygous familial hypercholesterolemia (HeFH). A total of 90% of the patients were on a background statin regimen (including 75% on high-intensity statins) and more than 50% were also receiving ezetimibe. The patients were required to have an LDL-C level of ≥100 mg/dL despite receiving a maximally tolerated dose of statin therapy, with or without ezetimibe. Inclisiran sodium (300 mg; corresponding to 284 mg inclisiran) or a matching placebo were administered on days 1, 90, 270 and 450.

At day 510, LDL-C levels were reduced by 39.7% (95% CI, -43.7 to -35.7) in the inclisiran group and increased by 8.2% (95% CI, 4.3 to 12.2) in the placebo group. The time-averaged change in LDL-C level after day 90 and up to day 540 was -38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and 6.2% (95% CI, 3.3 to 9.2) in the placebo group. Among the patients with ASCVD in the inclisiran group, 38 of 59 (64%) had an LDL cholesterol level of less than 70 mg per deciliter. The percentage change and absolute change in LDL-C levels over time are shown in Figure 23-10.

PCSK9 mAb Subgroup Efficacy

The PCSK9 mAbs evaluated to date appear to be similarly efficacious across most subgroups of patients, including those with HeFH, diabetes, or Asian ancestry and for intensity or type of back-ground lipid-lowering therapy.

In the ODYSSEY OUTCOMES trial, patients with LDL-C ≥100 mg/dL at randomization had a greater relative and absolute risk reduction in major CV events, CAD events and mortality. These results are consistent with a meta-analysis of LDL-C lowering trials (e.g., statins, PCSK9 mAbs and ezetimibe) which found greater relative risk reductions in total morality, CV mortality, major CV events, MI and revascularizations when baseline LDL-C levels were ≥100 mg/dL in the trial.

Patients Who Cannot Tolerate Statins

PCSK9 mAbs were not approved by the FDA specifically for use in patients who cannot tolerate statins, however, both PCSK9 mAbs are well tolerated in this group of patients. Alirocumab and evolocumab used in patients with statin-associated side effects (SASE) have similar LDL-C lowering efficacy (45% to 55% LDL-C reduction) as when used as monotherapy in patients without a history of SASE.

LDL-C lowering is somewhat less in the absence of PCSK9 upregulation due to statin therapy. Patients should therefore be encouraged to take some dose of statin to enhance the efficacy of the PCSK9 mAb.

Homozygous FH

Alirocumab reduced LDL-C by 36% in adult patients with HoFH, compared to the placebo. Homozygous FH was diagnosed either by genetic testing or by clinical diagnosis (a history of an untreated total cholesterol concentration above 500 mg/dL, combined with xanthoma before 10 years of age or a history of total cholesterol >250 mg in both parents).

In the TESLA trial, evolocumab reduced LDL-C by 31% compared to placebo in adult patients with HoFH, depending on the level of residual LDL receptor function. The diagnosis of homozygous FH in this trial was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C >500 mg/dL together with either xanthoma before age 10 years or evidence of heterozygous FH in both parents. Another trial tested the LDL-C lowering efficacy of evolocumab in pediatric patients with HoFH aged 10 to 17 years. At week 80, the median percent reduction in LDL-C levels from baseline was 14%. The confirmation of HoFH diagnosis was made by genetic testing.

Heterozygous FH

In ODESSEY HIGH FH, which enrolled adult patients with HeFH, alirocumab treatment resulted in a 43% reduction in LDL-C levels at week 24 (compared to 7% with placebo; P <.0001). The diagnosis of HeFH was made by genetic testing or clinical criteria.

In RUTHERFORD-2, evolocumab treatment resulted in significant lowering of the LDL-C levels from baseline by week 12 (61% at the 140 mg every 2 weeks and 60% at the 420 mg once monthly dosage; P <.0001 for both). The diagnosis of HeFH was established by Simon Broome criteria. The LDL-C lowering efficacy of evolocumab was also tested in pediatric patients with HeFH aged 10 to 17, in the HAUSER-RCT trial. At week 24, evolocumab treatment resulted in a 38% reduction from baseline in LDL-C levels. The diagnosis of HeFH was established through either the Simon Broome or the Dutch Lipid Clinic Network criteria, or genetic testing.

In ORION-9, inclisiran significantly lowered LDL-C levels in adult patients with HeFH, reaching a reduction of 39.7% in the treated group (vs an elevation of 8.2% with the placebo). The diagnosis of familial hypercholesterolemia was based on genetic confirmation or established phenotypic Simon Broome criteria.

Effects on Other Lipids and Lipoproteins

PCSK9 mAbs have additional effects on other lipids and lipoproteins. The most striking is the 25% to 35% reduction in lipoprotein (a) [Lp(a)] levels, although the mechanism has yet to be elucidated (Figure 23-11). Evidence is emerging from the PCSK9 mAb CV outcomes trials that Lp(a) lowering may further reduce ASCVD events beyond that expected from the magnitude of LDL-C lowering. Inclisiran also reduced Lp(a) levels by 17.2% from baseline.

As would be expected from the reduction in LDL-C, non–high-density lipoprotein cholesterol (non–HDL-C) is also reduced by 50% to 65%, apolipoprotein B by 45% to 55% for alirocumab 150 mg every 2 weeks or evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks. PSCK-9 mAbs can modestly raise HDL-C by 4% to 7% and lower triglycerides by 10% to 15% (Figure 23-12). A reduction in LDL-C and non–HDL-C and an increase in HDL-C were also reported with inclisiran treatment.

Dosing

Alirocumab

• 75 mg subcutaneously once every 2 weeks. If additional LDL-C lowering is needed, increase to 150 mg every 2 weeks.
• Alternatively, for patients preferring less frequent dosing, 300 mg once every 4 weeks (monthly).

Evolocumab

• In patients with clinical ASCVD or primary hyperlipidemia (including HeFH) 140 mg subcutaneously once every 2 weeks, or 420 mg once monthly in the abdomen, thigh, or upper arm.
• In homozygous FH patients, 420 mg once monthly.
• The 420 mg dose can be administered over 9 minutes using the single use on-body infusor with a prefilled cartridge, or by giving three consecutive 140-mg injections within 30 minutes using the single use prefilled autoinjector or single use prefilled syringe.

Inclisiran

• 284 mg subcutaneously, as a single injection initially, again at 3 months and then every 6 months in the abdomen, thigh, or upper arm.

See the manufacturer’s package insert for managing missed doses and administration and storage instructions. The manufacturers’ websites provide patient instructional resources for self-injection.

Contraindications

Patients with a history of serious hypersensitivity to the PCSK9 mAb. There are no contraindications for inclisiran.

Safety

Warnings and Precautions

Allergic hypersensitivity reactions (pruritus, rash, urticaria) including some serious events (hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization) have been reported for alirocumab. Angiodema, rash and urticarial have been reported for evolocumab. If signs or symptoms of serious allergic reactions occur, discontinue PCSK9 mAb treatment, treat according to the standard of care and monitor until signs and symptoms resolve. No specific warnings and precautions are listed in the package insert for inclisiran.

Adverse Reactions

The most commonly occurring adverse reactions for alirocumab were nasopharyngitis, injection site reactions and influenza, which occurred in ≥5% of patients and occurred more frequently in the alirocumab than placebo group. For evolocumab, nasopharyngitis, upper respiratory infections, influenza, back pain and injection site reactions were the most commonly occurring (≥5%) adverse events in the primary hyperlipidemia trials. Diabetes mellitus, nasopharyngitis and upper respiratory infections were the most commonly occurring (≥5%) in FOURIER.

For inclisiran, the most commonly occurring adverse reactions, reported in ≥3% of patients in ORION-9, -10 and -11 and occurring more commonly with inclisiran than with placebo included injection site reactions, arthralgia, urinary tract infections, diarrhea, bronchitis, extremity pain and dyspnea.

Pregnancy and Nursing Mothers

PCSK9 mAbs

Pregnancy exposure registries are available for both PCSK9 mAbs. Refer to the manufacturer’s package insert.

No data are available regarding the risk of PCSK9 mAbs in pregnancy or nursing mothers. PCSK9 mAbs are IgG antibodies and are able to cross the placenta. Monkey studies suggest PCSK9 mAbs may immunosuppress infant monkeys. The FDA’s experience with monoclonal antibodies in humans suggests they do not cross the placenta in the first trimester but are likely to cross the placenta in the second and third trimesters. The benefits and risks of PCSK9 mAbs to the mother and the risks to the fetus should be considered before prescribing a PCSK9 mAbs to a woman who may become pregnant. In the US population, major birth defects are estimated to occur in 2% to 4% of pregnancies and miscarriages in 15% to 20% of pregnancies.

There are no data on PCSK9 mAbs in human milk or the effects on breastfed infants. Human IgG is present in human milk, but published data suggest maternal IgG does not enter the infant circulation in substantial amounts. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the PCSK9 mAb and any potential adverse effects on the breastfed infant from the PCSK9 mAb or from the underlying maternal condition.

PCSK9 siRNA

Based on its mechanism of action, inclisiran may harm developing fetuses when administered to individuals who are pregnant. Hyperlipidemia therapy is not typically required during pregnancy. Therefore, treatment should be discontinued as soon as pregnancy is recognized. There are no available data on the use of inclisiran in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no information on the presence of inclisiran in human milk, the effects on the breastfed infant, or the effects on milk production.

No unfavorable developmental effects were seen in rats or rabbits during organogenesis following subcutaneous administration of inclisiran at dosages up to 5 to 10 times the maximum recommended human dose (MRHD) based on a body surface area (BSA) comparison. Inclisiran was present in the milk of lactating rats in all dose groups. Rats given inclisiran from organogenesis through lactation at 5 times the MRHD based on BSA comparison did not produce offspring with adverse developmental outcomes.

Allergic Reactions

Rash and urticaria have occurred slightly more commonly with PCSK9 mAbs compared to placebo. Serious allergic reactions have been reported (hyper­sensitivity vasculitis or hypersensitivity requiring hospitalization). If signs or symptoms of serious allergic reactions occur, discontinue the PCSK9 mAb, treat according to the standard of care and monitor until signs and symptoms resolve.

From the respective manufacturer’s package insert:

Alirocumab

Allergic reactions were reported more frequently in patients treated with alirocumab than in those treated with placebo (8.6% vs 7.8%). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with alirocumab (0.6% vs 0.2%). Serious allergic reactions, such as hypersensitivity, nummular eczema and hypersensitivity vasculitis were reported in patients using alirocumab in controlled clinical trials.

Evolocumab

Allergic reactions occurred in 5.1% and 4.7% of evolocumab-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% vs 0.5% for evolocumab and placebo, respectively), eczema (0.4% vs 0.2%), erythema (0.4% vs 0.2%) and urticaria (0.4% vs 0.1%).

Injection Site Reactions

Local injection site reactions occur slightly more frequently with alirocumab and inclisiran than placebo. Rates are similar for evolocumab and placebo. Most common injection site reactions are erythema, pain and bruising, usually mild and are transient. Patients rarely discontinued PCSK9 inhibitors due to injection site reactions.

From the respective manufacturer’s package insert:

Alirocumab

In a pool of placebo-controlled trials evaluating alirocumab 75 mg and/or 150 mg administered every 2 weeks (Q2W), one local injection site reactions including erythema/ redness, itching, swelling and pain/tenderness was reported more frequently in patients treated with alirocumab (7.2% vs 5.1% for alirocumab and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% vs 0.4% for alirocumab and placebo, respectively). Patients receiving alirocumab had a greater number of injection site reactions, had more reports of associated symptoms and had reactions of longer average duration than patients receiving placebo.

In a 48-week placebo-controlled trial evaluating alirocumab 300 mg every 4 weeks (Q4W) and 75 mg Q2W, in which all patients received an injection of drug or placebo every 2 weeks to maintain the blind, local injection site reactions were reported more frequently in patients treated with alirocumab 300 mg Q4W as compared to those receiving alirocumab 75 mg Q2W or placebo (16.6%, 9.6% and 7.9%, respectively). Three patients (0.7%) treated with alirocumab 300 mg Q4W discontinued treatment due to local injection site reactions vs no patients (0%) in the other two treatment groups.

In ODYSSEY OUTCOMES, local injection site reactions were reported in 3.8% of patients treated with alirocumab vs 2.1% patients treated with placebo and led to permanent discontinuation in 26 patients (0.3%) vs 3 patients (<0.1%), respectively.

Evolocumab

Injection site reactions occurred in 3.2% and 3.0% of evolocumab-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in evolocumab-treated patients and placebo-treated patients were 0.1% and 0%, respectively.

Inclisiran

In clinical trials of inclisiran, the reported incidence of injection site reactions was 1.8% with placebo and 8.2% with inclisiran. Injection site reactions led to discontinuation in 0.2% of patients treated with inclisiran and 0% of those who received placebo.

Muscle Symptoms

Muscle symptoms occurred at similar rates in the PCSK9 mAb and placebo groups in the CV outcomes trials. In randomized, double-blind trials performed in patients with SASE, rates of musculoskeletal complaints in PCSK9-treated patients occurred at a lower rate than in ezetimibe or atorvastatin-treated patients (Figure 23-13). Muscle symptoms in these studies did not necessarily lead to treatment discontinuation.

Interestingly, in a 24-week trial of alirocumab in patients with documented intolerance to two or more statins, during the blinded, placebo run-in phase of the trial, half of run-in failures reported musculoskeletal complaints. During the trial, 55% had no musculoskeletal complaints on atorvastatin 20 mg, and during the open-label extension where all patients received alirocumab, only 5% had muscle complaints leading to alirocumab discontinuation. This reveals the large role that psychological factors play in adverse events reported during cholesterol treatment, and the need to emphasize with patients the importance of continuing statin therapy, which enhances the efficacy of the PCSK9 mAb. Similar findings were reported for evolocumab in the GAUSS3 trial in patients reporting intolerance to two or statins.

Hepatic Transaminases

PCSK9 inhibitors have minimal effects on hepatic transaminase levels.

In the primary hyperlipidemia alirocumab trials, liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of alirocumab-treated patients treated and 1.8% of placebo-treated patients treated with placebo; treatment discontinuation occurred in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than three times the upper limit of normal occurred in 1.7% of alirocumab-treated patients and 1.4% of placebo-treated patients.

Immunogenicity

Like all therapeutic proteins, PCSK9 mAbs have the potential for immunogenicity. Antibody detection is highly dependent on the sensitivity and specificity of the assay and positivity may be influenced by several factors including sample handling, timing of sample collection, assay methodology, concomitant medications and comorbid conditions. Antibodies to alirocumab and evolocumab do occur (persistent antibodies 0.7% for alirocumab vs 0.4% for placebo; 0.3% evolocumab, but neutralizing antibodies are uncommon (<1% for alirocumab vs placebo; none for evolocumab). Loss of efficacy has been observed with neutralizing antibodies to alirocumab. Patients who developed antibodies to alirocumab had more frequent injection site reactions. Assays for anti-alirocumab/evolocumab antibodies are not available to practitioners.

As with all oligonucleotides, inclisiran carries the potential for immunogenicity. A persistent anti-drug antibody response was identified in 31 (1.7%) inclisiran-treated individuals with a baseline negative sample. The pharmacological profile, clinical response, or safety of inclisiran were not shown to be affected by the presence of anti-drug binding antibodies; however, the long-term effects of continuing inclisiran treatment in the presence of anti-drug binding antibodies are unknown.

Neurocognitive Events

Neurocognitive events have been reported uncommonly in patients receiving alirocumab and evolocumab. A substudy of FOURIER, EBBINGHAUS, formally tested neurocognitive function and found no differences in the evolocumab and placebo groups.

Diabetes

Genetic data suggest lower PCSK9 and LDL-C levels are associated with slightly higher risk of diabetes mellitus over a lifetime.

In the ODYSSEY OUTCOMES trial, new-onset diabetes was reported in 9.6% of alirocumab-treated patients and 10.1% of placebo-treated patients.

In the FOURIER CV outcomes trial, new-onset diabetes was reported in 8.1% of evolocumab-treated patients and 7.7% of placebo-treated patients.

Pediatric Use

Evolocumab has been evaluated in pediatric patients aged 10 years and above with HeFH and HoFH (see above). The safety profile appears similar to adults. The use of evolocumab has not been evaluated in pediatric patients without HeFH or HoFH, or those younger than 10 years.

The safety and effectiveness of alirocumab and inclisiran have not been established in pediatric patients.

Geriatric Use

There appear to be no differences in PCSK9 mAb or siRNA efficacy or safety in patients ≥65 years or ≥75 years.

Renal Impairment

No dose adjustment is needed in patients with mild to moderate renal impairment. No data are available on alirocumab or evolocumab use in patients with severe renal impairment, while no dose adjustments are necessary with inclisiran.

Hepatic Impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment. No data are available for patients with severe hepatic impairment.

Low LDL-C Levels

PCSK9 mAb-treated patients often experience LDL-C levels <25 mg/dL and some experience LDL-C levels <15 mg/dL, especially at the maximum dosing. Theoretical concerns have been raised regarding the long-term exposure to very low LDL-C levels. Hemorrhagic stroke, neurologic and neurocognitive dysfunction, cancer and reproductive problems are potential concerns. The identification of PCSK9 loss-of-function homozygotes who have had lifetime LDL-C levels of 14-16 mg/dL and are healthy, high-functioning individuals with children offers some reassurance. The results of long-term follow-up of the CV outcomes trials will be informative for determining whether pharmacologically induced very low LDL-C levels may have adverse effects in older adults, many of whom may have other comorbidities.

LDL-C calculated from the Friedewald equation becomes increasingly inaccurate when compared to more direct measures when LDL-C levels are <70 mg/dL. In a pooled analysis of 14 alirocumab trials, in PCSK9 mAb-treated patients with calculated LDL-C <25 or <15 mg/dL, the calculated and beta-quantification LDL-C levels were not excessively discordant if the low level was present on two consecutive occasions. No excess of adverse events was reported in patients with LDL-C <25 or <15 mg/dL for periods of up to 3 years in the CV outcomes trials. Fat soluble vitamin and hormone levels were considered normal in the low LDL-C patients. Observational analyses of the PCKS9 trials suggest new-onset diabetes may be more common in patients whose LDL-C levels are <25 mg/dL on PCSK9 mAb therapy, but this may be related to the lower baseline LDL-C in this group, who had more diabetes risk factors at baseline.

Management of LDL-C <25 or <15 mg/Dl

A reasonable approach would be to recheck the fasting LDL-C in 2 to 3 months. Intercurrent illness may depress LDL-C levels, as can excessive thyroid replacement. Note that “saw-toothing” may occur as the antibody is consumed (Figure 23-2), so reassessment of the fasting LDL-C levels should be done just prior to the next dose. If on recheck, LDL-C is <15 mg/Dl then a direct LDL-C can be obtained to confirm the low level.

Do not adjust the dose of statin. Since there is no indication at this time that low LDL-C is harmful, the patient can continue the same dosage regimen with regular monitoring. If the low LDL-C is of significant concern to the patient, the dose of the PCSK9 mAb can be reduced (if available) or the dosage interval could be increased by 1 to 2 weeks. Again, note that saw-toothing could occur as the antibody is consumed, so recheck the fasting LDL-C levels just prior to the next dose.

Drug-Drug Interactions

Because of their highly specific targeting of PCSK9, PCSK9 mAbs have few, if any, drug interactions. They do not interact with the cytochrome P450 system or other metabolic or transport pathways, nor do they affect the QT interval.

No formal clinical drug interaction studies have been performed for PCSK9 siRNA inclisiran. Since no components of inclisiran are substrates, inhibitors, or inducers of cytochrome P450 enzymes or transporters, it is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes or transporters.

Statins

PCSK9 mAb efficacy may be increased in statin-treated patients due to the upregulation of PCSK9 in response to lower intracellular cholesterol levels after statin therapy.