Abstract
In addition to monoclonal antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9), vaccines against PCSK9 and smaller molecule inhibitors as well as RNA inhibitors of PCSK9 production have been created. The monoclonal antibodies against PCSK9 and the PCSK9 RNA inhibitors can reduce low-density lipoproteins (LDLs) by over 50%, non-high-density lipoprotein (HDL) cholesterol and triglycerides, and increasing HDL. Although effective in several homozygous familial hypercholesterolemia patient types, PCSK9 inhibitors does not work in all patient types. Outcome trials show no effects on mortality but do show reductions in atherosclerotic events such as myocardial infarctions, strokes, and need for coronary revascularization. PCSK9 inhibitors have a very attractive safety profile with no significant elevations in measures of muscle or liver damage. The current and more advanced experimental agents all require subcutaneous dosing, and injection site reactions are among the most common adverse events. Therapy for the Food and Drug Administration (FDA) approved agents is markedly expensive, and this is the primary barrier to utilization. However, it is possible to identify patients with a number needed to treat to prevent an atherosclerotic event low enough to render it cost-effective and one such factor is whether or not you require a 50% reduction in LDL in order to achieve your LDL goal.
Introduction
In 2015, evolocumab and alirocumab became Food and Drug Administration approved drugs in the new proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor class. 1 –3 Using monoclonal antibody technology and leveraging strong epidemiologic evidence of potential benefit from inhibiting PCSK9, the much anticipated drugs were released with a premium price tag of $12 000 to $15 000 per year. 4 Since that time the clinical impact of the PCSK9 inhibitors and its potential cost-effectiveness has come into greater focus. The only investigational PCSK9 inhibitor in advanced phase III clinical trials had its development abandoned in 2017. 5,6 However, there are some new investigational approaches to block PCSK9, and some agents in these subclasses are starting human trials with promising initial results.
This review will discuss the mechanism of action for FDA-approved and experimental PCSK9 inhibitors and critically evaluate their efficacy, safety, and place in therapy for general use and then specifically in the treatment of autosomal recessive and dominant hypercholesterolemia.
Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors Mechanism of Action
Figure 1 displays low-density lipoproteins (LDLs) function and recycling, mechanism of PCSK9 action, and approaches to impede PCSK9 function either by suppressing the amount of PCSK9 or by blocking its activity. 1,7 –14 PCSK9 is endogenously created to maintain LDL receptor density equilibrium in normal participants. 7,8 The enzyme is synthesized in the nucleus of hepatocytes and undergoes activating autocleavage of the N-terminal in the endoplasmic reticulum before being secreted. After secretion, PCSK9 binds to expressed LDL receptors. 7,8 PCSK9 stabilizes the LDL receptor/LDL complex and prevents the LDL receptor from being released from the endocytosed vesicle causing lysosomal destruction of the LDL receptor. 1,7,8 In a normal patient, an LDL receptor normally recycles as many as 150 times and continues to remove LDL every time it is reexpressed on the cell surface. 7,8 As such, there is an inverse relationship between the level of PCSK9 in the blood and the number of functional LDL receptors. 1
Pictorial representation of LDL + LDL receptor interactions and disposition with and without PCSK9. 1,7 –14 This figure displays the degradation of LDL without and then with the presence of PCSK9. It then shows current and investigational modalities to impede PCSK9 concentration of function. LDL indicates low-density lipoprotein; mAB, monoclonal antibody; PCSK9, proprotein convertase subtilisin kexin-9; RNA, ribonucleic acid.
Genetic polymorphisms can result in “gain of function” (N157K and D374Y polymorphisms) where LDL receptors are broken down prematurely or “loss of function” (C679X, R46L, Y142X polymorphisms) where LDL receptors have a longer survival time. 9 –11 The relationship between loss of function polymorphisms and lower LDL and cardiovascular disease was suggested in several evaluations. 10 In one large observational study, 2.6% of the 3363 African American participants and 3.2% of the 9524 Caucasian participants had loss of function polymorphisms resulting in LDLs that were 28% and 15% lower than those without loss of function polymorphisms. Importantly, they also had lower hazard ratios (HRs) for cardiovascular disease (African American: HR 0.11, 95% confidence interval [CI: 0.02-0.81]; Caucasian: HR 0.50, 95% CI [0.32-0.79]) than those without loss of function polymorphisms, respectively. 11
This means that PCSK9 inhibitors can mimic the loss of function scenario preserving LDL receptor recycling to the hepatocyte surface. 1 The most studied PCSK9 inhibitors are the fully human whole monoclonal antibodies alirocumab, evolocumab, and bococizumab. 1 –3,7 These PCSK9 monoclonal antibodies require subcutaneous administration and the inhibition is dose-dependent. The antibodies are distributed through the circulation and eliminated at low concentrations by binding to their target and at higher concentrations through a proteolytic pathway. 1
Investigational approaches to diminish PCSK9’s effects are 3-fold: using a smaller molecule like an adnectin-based protein instead of a monoclonal antibody to inhibit PCSK9, using messenger RNA gene silencing to reduce endogenous PCSK9 production, or provide a vaccination against PCSK9, so the body produces long-lasting immune system action against PCSK9. 12 Data on lipid effects in humans are available for the adnectin-based and messenger RNA approaches, but they are not far enough along to assess their impact on clinical outcomes. 13,14 The vaccination approach and efficacy of other small molecule PCSK9 inhibitors (including orally administered inhibitors) are still being investigated solely in animals. 12
Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitor Efficacy and Safety
The known impact of PCSK9 inhibitors on lipid, cardiovascular event, and safety data from select clinical trials are summarized in Table 1. 6,13,15 –17 To date, the monoclonal antibody PCSK9 inhibitors evolocumab, alirocumab, and bococizumab have been extensively studied in phase III clinical trials for lipid, clinical outcome, and safety effects. 6,13,15 –18 However, the data specifically in homozygous familial hypercholesterolemia (FH) are quite limited. 1
The RNA interference PCSK9 inhibitor inclisarin has phase II data on lipoprotein modulation and safety, and the small molecule PCSK9 inhibitor BMS-962474 only has available data on LDL reduction. 13,14
Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors Lipid Impact in Homozygous FH
In many heterozygous forms of FH (where only one allele has a genetic polymorphism), the receptor function is impaired by up to 50% and LDL levels can be elevated 2 to 3 times above normal. In homozygous forms, which can be true homozygous disease (where both alleles have the same genetic polymorphism) or compound heterozygous, where there are 2 or more different genetic polymorphisms negatively impacting LDL receptor function in the same individual, LDL receptor function is reduced 70% to 97% and LDL concentrations are elevated 4 to 8 times above normal. 19 –21 Heterozygous FH occurs in 1 in 250 to 300 people worldwide, while homozygous FH occurs in 1 in a million people. 7,21
The Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities (TESLA) Part B trial (n = 50 patients, average age 31 years) was a randomized, double-blind, placebo-controlled phase III trial that evaluated the impact of PCSK9 monoclonal antibodies specifically in patients with autosomal dominant or recessive homozygous FH. 22 Patients were on lipid-lowering therapy but not lipid apheresis and were randomized to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Overall, 45% of patients had true double allele homozygous FH, and 47% had compound heterozygous FH. One patient had a homozygous familial Apolipoprotein B (ApoB) disorder, another had an autosomal recessive disorder, and one had both a homozygous ApoB and heterozygous FH disorder. 22
The patient’s disease burden was severe with 43% having coronary artery disease, 25% undergoing coronary artery bypass surgery, 14% having aortic valve replacement, and 8% having cerebrovascular or peripheral vascular disease. 22 Every patient was receiving a statin, 94% was receiving high-intensity statin therapy, and 92% were receiving adjunctive ezetimibe, but the baseline LDL was still 165.6 mg/dL. At the end of 12 weeks, the mean difference (MD) in LDL between groups was −30.9% (95% CI: −43.9% to −18.0%). One patient entered the study in error with single allele heterozygous FH only and had a much more robust LDL reduction of 55.7%. Those with compound heterozygous FH had a greater MD from placebo if they had a defective polymorphism on each allele (MD: −46.9%; 95% CI: −68.0% to −25.7%) than if they had one defective and one receptor negative allele (MD: −24.5%; 95% CI: −41.6% to −7.3%). The patient with LDL receptor negative mutations in both alleles and the patient with autosomal recessive homozygous hypercholesterolemia did not respond to evocolumab, with their LDL concentrations rising over the 12 weeks. The impact of evolocumab in homozygous ApoB patients cannot be discerned because both of the patients with this genetic polymorphism were randomized to the placebo group. 22
Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitor Lipid Lowering Effects in the General Hypercholesterolemic Population
A meta-analysis of 35 randomized, controlled trials (n = 45 539 patients, mean age 61.0 ± 2.8 years, mean baseline LDL 106 ± 22 mg/dL) by Karatasakis et al compared PCSK9 monoclonal antibodies with either placebo or active control. 18 Many of these trials had baseline lipid therapy with statins in the active and comparator groups. Potent lipid modification was achieved including reductions in LDL (MD: −54.8%; 95% CI: −58.3 to −51.3), total cholesterol (MD: −35.0; 95% CI: −37.5 to −32.4), and Lp(a) (MD: −26.5; 95% CI: −28.9 to −24.0), while high-density lipoproteins (HDLs) was increased (MD: +6.9; 95% CI: +6.10 to +7.60). The reductions in LDL were greater in placebo-controlled trials (MD: −60.9%; 95% CI: −63.2% to −58.6%) than when ezetimibe (MD: −31.3; 95% CI: −34.8 to −27.8) was the comparator. 18
These reductions are closely aligned with the reductions in Table 1 derived from major clinical trials of evolocumab and alirocumab. 15 –17 The ODYSSEY-DM trial was recently published and was not included in this meta-analysis so it requires special mention. 23 In ODYSSEY-DM, participants with type 2 (n = 441) or type 1 diabetes mellitus (n = 76) and an LDL level ≥70 mg/dL were randomized 2:1 to subcutaneous alirocumab or placebo every 2 weeks for 24 weeks. Alirocumab-treated participants received 75 mg every 2 weeks, with a blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥70 mg/dL. Alirocumab reduced LDL cholesterol from baseline to week 24 by 49.0% and 47.8% versus placebo in participants with type 2 and type 1 diabetes, respectively (both P < .001 for both comparisons). Significant reductions were observed in total cholesterol (−27.6% and −29.2% vs placebo; P < .001) and in non-HDL cholesterol (−38.7% and 42.7% vs placebo; P < .001). Although reductions in triglycerides and increases in HDL were seen, they were unable to show significant improvements except for HDL raising in type 2 diabetics versus placebo (+4.4%; P < .01). 23
Abbreviations: ADE, adverse event; CHD, coronary heart disease; CVD, cardiovascular disease; FDA, Food and Drug Administration; HDLs, high-density lipoproteins; LDLs, low-density lipoproteins; MACE, major adverse cardiac events; MI, myocardial infarction; PCSK9, proprotein convertase subtilisin-kexin type 9; TC, total cholesterol; Tris, triglycerides.
Inclisiran, the chemically synthesized PCSK9 RNA inhibitor, was studied in a 180-day randomized, double-blind, placebo-controlled phase II dose ranging study called the ORION-1 trial. When single doses of inclisiran 200, 300, or 500 mg were given subcutaneously, LDLs at 180 days were reduced in a dose-related fashion from 27.9% to 41.9% (P < .001 vs placebo for all doses). 13 When inclisiran doses of 100, 200, or 300 mg were given subcutaneously at baseline and again at day 90 (total doses over 90 days of 200, 400, and 600 mg), the LDL reductions at day 180 were reduced in a dose-related fashion from 35.5% to 52.6% (P < .001 vs placebo for all doses). Total cholesterol and non-HDL cholesterol also followed a dose-related lowering effect ranging from −17.6% to −23.7% and −25.1% to 35.2% with single dosing and −22.4% to −33.2% and −31.7% to −46.0% with double dosing, respectively (P < .001 vs placebo for all regimens). 13
There is one phase II trial assessing the impact of adnectin-based protein inhibition of PCSK9 function on LDL. It is only available in abstract form, and the results had to be estimated from the graphs. 14 In this dose ranging study, BMS-962474 was given either subcutaneously at doses from 0.03, 0.1, or 0.3mg/kg or intravenously at 0.3 mg/kg, and the LDL effects over 42 days were assessed. No LDL reductions were seen with subcutaneous doses of 0.03 mg/kg. The maximum decreases in LDL in the subcutaneous 0.1 mg/kg group were ∼25% and occurred between 6 and14 days. The 0.3 mg/kg groups achieved maximal LDL reductions of ∼35% (intravenous) to 40% (subcutaneous) between 12 and 14 days. The LDL reductions were only in the 10% to 20% range for the drug regardless of the dosing after day 30. 14
Clinical Outcomes and Safety
The aforementioned meta-analysis by Karatasakis et al included data from 35 clinical trials including the ODYSSEY Long-Term, OSLER 1 and 2, and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trials, which are by far the largest trials and whose results are displayed individually in Table 1. 15 –18 It does not contain data on bococizumab or nonmonoclonal antibody PCSK9 inhibitors.
In the ODYSSEY Long-Term trial,
15
2341 patients at high risk of cardiovascular events, who had LDL concentrations of 70 mg/dL or more and were receiving maximum tolerated statins (with or without other lipid-lowering therapy), were randomized to receive alirocumab 150 mg or placebo subcutaneous injection every other week for 78 weeks. Over 99% of patients were already receiving statins and 47% received high-intensity statins. Twenty-eight percent were already receiving adjunctive lipid-lowering therapy.
15
The OSLER investigators combined the results of 2 open label, randomized trials of 4465 patients who were enrolled after completing 1 of the 12 phase 2 or 3 trials of subcutaneous evolocumab (140 mg every 2 weeks or 420 mg every 4 weeks) plus standard therapy versus standard therapy alone for a median of 11.1 months.
16
The FOURIER trial was by far the largest and most important clinical trial conducted on PCSK9 inhibitors to date and drives many of the outcomes in the meta-analysis.
17
In this multicenter, multinational trial, 27 525 patients (mean: 63 years, 81.1% previous myocardial infarction [MI], 19.4% previous stroke, 13.2% peripheral artery disease, 69.3% high-intensity statin, 30.4% moderate-intensity statin) with a baseline LDL of
In the meta-analysis, overall mortality (odds ratio [OR]: 0.71; 95% CI: 0.47-1.09), cardiovascular mortality (OR: 1.01; 95% CI: 0.85-1.19), unstable angina (OR: 0.97; 95% CI: 0.81-1.16)], or heart failure exacerbation (OR: 0.98; 95% CI: 0.86-1.13) were not changed by the addition of PCSK9 inhibitor therapy. 18 A meta-regression found that there was a significant relationship between increasing baseline LDL and the reduction in overall mortality (y = 2.229–[0.024 × baseline LDL]; P = .038 for association]. This suggests that when PCSK9 inhibitor therapy is used in patients with a baseline LDL (with or without statins) of around 100 mg/dL, there are no mortality benefits, but that these benefits may be manifested when used at higher baseline LDLs in the 120 to 150 mg/dL range. If this holds true in future trials where mortality is a prespecified primary outcome, this would help ameliorate its cost-effectiveness problem. Aside from FOURIER, the remaining trials of evolocumab and alirocumab have very wide CIs for total mortality which straddled favoring PCSK9 inhibitors or favoring control suggesting that this single variable meta-regression may or may not hold true when future large trials are completed. 18
Importantly, in this meta-analysis myocardial infarction (OR: 0.72; 95% CI: 0.64-0.81), stroke (OR: 0.80; 95% CI: 0.67-0.96), and coronary revascularization (OR: 0.78; 95% CI: 0.71-0.86) were significantly reduced. 18
The Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) 1 and 2 trials were very large phase III trials assessing the impact of bococizumab on cardiovascular events and are included in Table 1. 6 In these trials, a total of 27 438 patients (62.9 years, 92.9% statin use) received subcutaneous bococizumab 150 mg every 2 weeks or matching placebo. The trials were stopped early (7 months follow-up in SPIRE 1 and 12 months in SPIRE 2) after the sponsor realized that the development of bococizumab antibodies were reducing its ability to reduce LDL over time. Over half of the participants had bococizumab antibodies and 29% had neutralizing antibodies that dramatically attenuated the LDL reductions seen at 14 weeks. This decision impacted the ability to show significant reductions in cardiovascular events with the use of bococizumab. Even so, the promising results in SPIRE 2 which was conducted in a higher risk population with higher baseline LDL levels and had a longer duration of follow-up than SPIRE 1 show that PCSK9 inhibitor therapy with inhibitors other than evolocumab and alirocumab can still impact cardiovascular events. 6
Safety Outcomes
In the meta-analysis by Karatasakis et al, PCSK9 inhibitor therapy was not associated with adverse effects ascribed to statins including creatine kinase elevations (OR: 0.84; 95% CI: 0.70-1.01), myalgia (OR: 0.95; 95% CI: 0.75-1.20), AST or ALT increases (OR: 0.96; 95% CI: 0.82-1.12), or diabetes mellitus (OR: 1.05; 95% CI: 0.95-1.17). 18 Although identified as a potential issue in previous clinical trials with PCSK9 inhibitors, neurocognitive adverse events (OR: 1.12; 95% CI: 0.88-1.42) were not significantly elevated which was driven by the results of the FOURIER trial. 17,18 The meta-analysis did not assess for injection site reactions which are more clearly more common with evolocumab and alirocumab than with oral cholesterol reducing agents. Although injection site reactions were not included, overall serious adverse events were not more common with PCSK9 inhibitors than with control therapy (OR: 0.99; 95% CI: 0.95-1.05). 18
In the combined SPIRE 1 and 2 trial results, bococizumab significantly increased the risk of discontinuing therapy due to an adverse drug reaction (incidence rate [IR]: 1.49; 95% CI: 1.33-1.68), any adverse event (IR: 1.14; 95% CI: 1.11-1.18), and injection site reactions (IR: 8.33; 95% CI: 6.99-9.92). 6 It is thought that the antibodies against bococizumab led to the elevated risk of injection site reactions. 6
The safety of alirocumab versus placebo in the aforementioned ODYSSEY-DM trial, which was not included in the meta-analysis, was affirmed in the diabetic population with similar rates of any adverse events (64.5% vs 64.1%) or treatment-emergent adverse events (9.0% vs 9.4%). 23
Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors Place in Therapy
Evolocumab is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease; as an adjunct to diet, alone or in combination with other lipid-lowering therapies for treatment of adults with primary hyperlipidemia (including heterozygous FH) to reduce LDL; and as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) in patients with homozygous FH, who require additional lowering of LDL. 2
Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL. 3 The package labeling specifies that the effect of alirocumab on cardiovascular morbidity and mortality has not been adequately determined, but the ODYSSEY Outcomes trial is ongoing even as alirocumab itself is unable to be sold. 3,24 This phase III multicenter, randomized, double-blind, placebo-controlled trial will involve more than 18 000 patients from 57 countries. 24 Patients who experienced a heart attack or unstable angina requiring hospitalization within a year and are unable to control their LDL cholesterol despite receiving maximally tolerated statins are eligible. Patients are being randomized to receive either alirocumab 75 mg subcutaneously every 2 weeks or placebo. Patients can have their dose increased to 150 mg subcutaneously every 2 weeks at week 8 if their LDL remains above 50 mg/dL. Results are anticipated in 2018 at the earliest but are not yet available. 24
In patients without homozygous FH, PCSK9 inhibitors are primarily competing against ezetimibe for the adjunctive agent of first resort when maximally tolerated statins are insufficient. 1,2,18 Although ezetimibe has strong clinical trial data to suggest event reductions over and above a statin alone based on the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, other adjunctive options like niacin and bile acid sequestrants have either not been studied in large trials with statins or have not been shown to provide additional benefits over statins alone. 1,25 –28
Ezetimibe has an edge over PCSK9 monoclonal antibodies based on a longer time on the US market, strong safety profile, oral availability, and markedly lower cost. 1,25 However, ezetimibe can only reduce LDL by an additional 20% instead of approximately 50% with the PCSK9 inhibitors. 1,25
Additional LDL lowering is strongly linked to fewer major cardiovascular events. In a meta-analysis of 27 statin trials, the Cholesterol Treatment Trialists (CTT) found a linear relationship where every 39 mg/dL reduction in LDL yields a 22% reduction in major cardiovascular events over 5 years of therapy. 29 Applying data from the IMPROVE IT, ODYSSEY Long Term, and OSLER 1 and 2 trials to the aforementioned CTT data set does not change the relationship between LDL reduction and major cardiovascular events after 5 years of therapy or the magnitude of that reduction. 30 The FOURIER investigators also content that their 2-year major cardiovascular event results are also in line with the projected benefits from the CTT data set. 17 This suggests that it is more of a function of the LDL that you achieve that determines the degree of cardiovascular benefit, not what therapy you utilize but whether this relationship extends beyond statins, ezetimibe, and PCSK9 inhibitors to other lipid-lowering therapies such as bile acid sequestrants has not been proven. Niacin should not be considered an adjunctive agent solely for the lowering of LDL or the raising of HDL given the lackluster results of its clinical trials. 26,27
In an analysis, the cost-effectiveness of the PCSK9 inhibitors were estimated and directly related to the Number needed to treat (NNT) to reduce an event using the CTT relationship. 8 If the NNT on PCSK9 inhibitor therapy is 30 to 50, 15 to 29, or 10 to 14, therapy would cost ∼$300 000, ∼$280 000, or ∼$150 000 per quality-adjusted life year (QALY) at $14 000 per year. 30 The cost/QALY willingness to pay limit in the United States has not been firmly set, but <$50 000/QALY, <$100 000/QALY, and <$150 000/QALY have been proposed as reasonable. Another important consideration is the level of discounting or rebating that a health plan negotiates. Using a NNT of ∼25, a PCSK9 inhibitor discount of 50% is needed to achieve the $150 000/QALY level, and a 77% reduction is needed to truly be considered cost-effective at $50 000/QALY. Assuming that a health plan is getting a 50% discount, the LDL reduction from baseline is 50%, and the NNT is 30 or less, PCSK9 inhibitor therapy will be <$150 000/QALY for very high-risk patients with baseline LDLs >100 mg/dL and for high-risk patients with baseline LDLs >130 mg/dL but would be cost prohibitive in moderate risk patients even at a baseline LDL of 190 mg/dL. 30
Unlike in clinical trials, only about a third of patients are treated with high-intensity statin therapy and even less achieve global LDL goals, necessitating adjunctive therapy. 31 This is also the case in patients with FH. 32 If a patient is already on the maximum statin therapy they can tolerate and requires a 20% reduction to achieve their LDL goal, then ezetimibe is clearly the drug of choice. If they require more than a 50% reduction then a PCSK9 inhibitor would be the dominant evidence-based choice and based on the degree of baseline risk and the discounts provided, it could be cost-effective. 30 It is the patient who requires a reduction above 20% but below 50% that poses a dilemma. Is it better to use ezetimibe plus a bile acid sequestrant assuming that the benefits will be provided as per the CTT relationship between LDL and cardiovascular events will be seen or to use a PCSK9 inhibitor which will be unlikely to be cost-effective by any measure but has proven event reductions for this magnitude of LDL reduction? 30
In the subset of patients with homozygous autosomal dominant hypercholesterolemia (including homozygous FH), statins and ezetimibe should be used as initial baseline therapy. 1,19,20 If needed to achieve greater LDL reduction, evolocumab is primarily competing against lipoprotein apheresis for third-line therapy, and it is difficult to suggest that one is clearly superior to the other given the available evidence with a few exceptions. 1,19,20 In patients homozygous for LDL receptor negative FH or autosomal recessive hypercholesterolemia, PCSK9 monoclonal antibodies do not reduce LDL, and lipoprotein apheresis is a superior option. 22 People with homozygous ApoB autosomal dominant disease should also preferentially receive lipoprotein apheresis over PCSK9 monoclonal antibodies because that population was only studied in the placebo group of TESLA-B. 22 Lipoprotein apheresis is inconvenient for patients and is also very expensive, but it has been used for many years and reduces LDL levels by 60% to 64%. 19 There are many pieces of evidence suggesting plasma apheresis can regress xanthomas and reduce the burden of fatal and nonfatal coronary ischemic events in patients with homozygous FH, but the small sample sizes and limited follow-up durations make determining its impact on cardiovascular events very difficult. 19 Similarly, the TESLA-B trial only made up a very small portion of the PCSK9 inhibitor meta-analysis, so its impact on cardiovascular events in this population is unknown. 18 Both PCSK9 monoclonal antibodies and lipid apheresis offer many safety advantages over mipomersen and lomitapide therapy. 1,28 Finally, the TESLA-B trial specifically excluded patients on lipoprotein apheresis from entering the trial, so the impact of the 4 therapy regimen (statins, ezetimibe, PCSK9 inhibitor, and lipoprotein apheresis) on LDL levels is unknown even though this eventuality is included in the indication for evolocumab. 22
In a late-breaking clinical trial session at the American College of Cardiology Meeting in March 2018, the ODYSSEY Outcomes trial results were presented. Patients (n = 18 924) on high-intensity statins (or documented intolerance to higher dose statins) with a recent acute coronary syndrome (within 1-12 months) were randomized to alirocumab 75 to 150 mg subcutaneously (to keep the LDL between 25 and 50 mg/dL) every 2 weeks or placebo (n = 9462). After 48 months of follow-up, major adverse cardiac events (the primary endpoint) were 9.5% for alirocumab versus 11.1% for placebo (HR: 0.85; 95% CI: 0.78-0.93) driven by significant reductions in MI (P = .006), ischemic stroke (P = .01), and unstable angina (P = .02). A secondary endpoint of note is all cause mortality which was 3.5% in the alirocumab group and 4.1% in the placebo group (P = .026) marking the first time that an adjunctive therapy to a statin has reduced this endpoint. On the concerning side, there was a higher occurrence of neutralizing drug antibodies among those using alirocumab which may impede prolonged LDL lowering with the product but was not much of a concern over the 48 months of the current trial. 33
Conclusions
The available evidence evaluating the PCSK9 monoclonal antibodies alirocumab, evolocumab, and bococizumab supports their use in effectively lowering LDL by >50% in pooled populations. Bococizumab’s phase III clinical trial was halted after it was clear that the development of antibococizumab antibodies attenuates long-term LDL suppression and greater injection site reactions. Evolocumab works well in many patients with homozygous FH but do not work in patients with homozygous FH who cannot produce an LDL receptor or patients with autosomal recessive hypercholesterolemia. The most promising investigational PCSK9 inhibiting agent is inclisiran, which works through a novel RNA pathway to suppress PCSK production. FDA approved and investigational PCSK9 inhibitors are relatively safe compared to placebo and ezetimibe, even when used adjunctively with statins. Ezetimibe and plasma apheresis are the primary competitors for PCSK9 inhibitors in general use and use in homozygous FH, respectively. Even with the PCSK9 inhibitors very high yearly cost, it can still be cost-effective in patients in the number needed to treat to prevent one cardiovascular event is sufficiently low.
Footnotes
Authors’ Note
I attest that this article is written solely for this journal and I am the sole author without conflicts of interest germane to this topic area. I transmit, convey, and give copyright to Sage unless the article is ultimately not accepted.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
