Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS; and Thomas J. Cook, PhD, RPh
Whether aiming for a percentage reduction or for specific numerical targets, reducing low-density lipoprotein cholesterol (LDL-C) is a core component of lipid management in the prevention of cardiovascular disease (CVD) and related sequelae. 1-3
The steps of the cholesterol cycle provide numerous potential targets for pharmacologic intervention to reduce LDL-C. The primary mechanisms of action of current standard lipid-lowering therapies focus on specific steps of the cholesterol cycle: statins inhibit hydroxymethyl glutaryl coenzyme A reductase, which decreases cholesterol synthesis and upregulates LDL receptors (LDLRs); bile salt sequestrants bind bile acids in the distal gastrointestinal tract to reduce enterohepatic recycling; and ezetimibe inhibits intestinal cholesterol absorption. Research on other targets in the cholesterol cycle may yield promising pharmacologic agents to complement or supplant current lipid-lowering strategies.2,3
Many patients with hypercholesterolemia do not respond sufficiently to standard lipid-lowering therapies. They may not tolerate the adverse effects (AEs) of statins or they may have familial hypercholesterolemia (FH) that limits the effectiveness of lipid-lowering therapies. For these patients, alternative pharmacologic approaches may be necessary to lower LDL-C to help avoid cardiovascular (CV) events. Guidance on such alternative approaches is described in the 2016 report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. The report provides a detailed decision pathway for the use of nonstatin therapies in treating 4 patient groups.1
PCSK9 Inhibitors: Alirocumab and Evolocumab
Mechanism of Action
A novel target in the cholesterol cycle is the protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), which plays a major role in the uptake of LDL-C into hepatocytes (Figure4)
Individuals with loss-of-function mutations in PCSK9 have reduced levels of LDL-C and are protected from CVD.5,6
LDL-C, through its apolipoprotein B100 carrier protein, binds to LDLRs on the cell surface of hepatocytes, after which PCSK9 binds to LDLR on the hepatocyte surface. Cellular uptake of this complex occurs via endocytosis. Bound PCSK9 then directs the resulting endocytic vesicle to the lysosome for degradation. Lysosomal degradation of the LDLR decreases the concentration of receptors, which are responsible for clearing LDL-C from the bloodstream. When PCSK9 binding is inhibited, however, LDLRs avoid lysosomal degradation and are recycled to the cell surface to bind more LDL-C particles.7
This recycling of LDLRs, prompted by the lack of bound PCSK9, leads to an increased clearance of LDL-C from the plasma, thus reducing LDL-C levels.7,8
One efficient mechanism for inhibiting PCSK9 binding is to use monoclonal antibodies (mAbs) that target PCSK9 (Figure4
). Recently approved PCSK9 inhibitors, alirocumab and evolocumab, bind to free PCSK9 in the plasma, thus preventing PCSK9 binding to LDLRs9,10
LDLRs and PCSK9 are also linked at the transcription level. Regulation of LDLR and PCSK9 expression occurs via the sterol regulatory element-binding protein-2 (SREBP-2) such that induction of SREBP-2 leads to increased production of LDLRs and PCSK9.11
Statins have been reported to increase PCSK9 levels12
while also reducing LDL-C levels.13,14
This apparently dichotomous scenario led researchers to postulate that the LDL-C–lowering effects of statins could be enhanced by inhibiting PCSK9,11
a hypothesis that came to fruition with the approvals of alirocumab and evolocumab, the current PCSK9 inhibitors on the market in the United States.
Alirocumab is a human mAb of the immunoglobulin G1
) isotype that is manufactured in Chinese hamster ovary (CHO) cells.15
Evolocumab, also manufactured in CHO cells, is a human mAb of the IgG2
Both alirocumab and evolocumab bind PCSK9 with high affinity at subnanomolar and nanomolar ranges for alirocumab and evolocumab, respectively.17,18
The binding of the antibodies to free PCSK9 in the plasma prevents PCSK9 binding to the LDLR, leading to reductions in plasma LDL-C through the mechanism described above.
Efficacy, Safety, and Tolerability
Alirocumab and evolocumab were approved in 2015 as adjunct therapies, in addition to diet and maximally tolerated statin therapy.19,20
They share indications for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or with clinical atherosclerotic cardiovascular disease (ASCVD) where additional lowering of LDL-C is necessary beyond maximally tolerated statin therapy and diet.19,20
Evolocumab has an added indication for treatment in adults with homozygous familial hypercholesterolemia (HoFH).20
Patients with HeFH inherit a pathogenic variant in 1 of 3 key genes that are involved in lipoprotein metabolism: APOB, LDLR,
HoFH is more rare than HeFH, with a prevalence rate of about 1 in 1 million births compared with up to 1 in 200 individuals with HeFH.21
Both approved PCSK9 inhibitors have been studied in numerous randomized, controlled clinical trials with patient populations that include HeFH, established CVD, and/or statin intolerance while evolocumab has been studied in patients with HoFH as well. Several robust meta-analyses also provide excellent guidance in analyzing the safety and efficacy of the PCSK9 inhibitors.23-25
In their meta-analysis, Navarese et al reviewed 24 phase 2 and 3 randomized, controlled trials with more than 10,000 subjects. Combined analyses of primary clinical endpoints and secondary safety endpoints were reported for alirocumab and evolocumab. The summary analysis of efficacy endpoints, primarily a reduction in LDL-C, was also reported as combined results of the 2 PCSK9 inhibitors, justified by additional analyses on the type of and dose of PCSK9 inhibitor. The authors’ primary conclusions were that treatment with PCSK9 inhibitors, either alirocumab or evolocumab, resulted in a significant reduction in LDL-C with PCSK9 antibody treatment compared with no anti-PCSK9 treatment (47.49%; 95% CI, 25.35%-69.64%; P
<.001); a significant difference in all-cause mortality (0.31% vs 0.53%, respectively; OR, 0.45; 95% CI, 0.23-0.86; P
= .015); and a significant difference in myocardial infarction (MI) (0.58% vs 1.00%; OR, 0.49; 95% CI, 0.26-0.93; P
= .030), with no increase in serious AEs compared with controls.24
Zhang et al evaluated 25 randomized, controlled trials in their meta-analysis of alirocumab and evolocumab, and reported separate analyses for each. In the primary efficacy outcome of reduction of LCL-C at 12 weeks of follow-up, at a dosage of 420 mg monthly, evolocumab versus placebo significantly reduced LDL-C levels by 54.6% (95% CI, 50.5%-58.7%); at 140 mg biweekly, LDL-C was reduced by 60.4% compared with placebo (95% CI, 52.0%-68.8%). Further, compared with ezetimibe, evolocumab significantly reduced LDL-C at dosages of 420 mg monthly (36.3%; 95% CI, 33.9%-38.8%) or 140 mg biweekly (38.2%; 95% CI, 34.5%-41.5%).
Alirocumab also significantly reduced LDL-C, with the greatest reduction seen with biweekly dosing. Compared with placebo, 150-mg to 300-mg monthly dosages of alirocumab reduced LDL-C by 32.2% (95% CI, 15.6%-48.7%), while a biweekly dosage of 50 to 150 mg of alirocumab reduced LDL-C by 52.6% (95% CI, 47.0%-58.2%). Compared with ezetimibe, biweekly dosages of 50- to 150-mg dosages of alirocumab reduced LDL-C by 29.9% (95% CI, 26.9%-32.9%).
Safety results, in the form of common AEs for evolocumab and alirocumab, did not show significant differences compared with placebo or ezetimibe, except for 2 parameters for alirocumab. Treatment with alirocumab resulted in an increased rate of injection-site reactions (RR, 1.48; 95% CI, 1.05-2.09) compared with placebo. Also, alirocumab exhibited an overall significantly lower rate of death compared with placebo (RR, 0.43; 95% CI, 0.19-0.96).25
Through the Drug Effectiveness Review Project (DERP),26
McDonagh et al produced a systematic review of 17 clinical studies of evolocumab or alirocumab.23
These included 7 studies for alirocumab10,27-32
and 10 for evolocumab.33-42
The clinical studies were evaluated for quality using methods developed through DERP43
and with respect to strength of evidence, based on the guidance from the Agency for Healthcare Research and Quality (AHRQ).44
In the absence of clinical trials that directly compare alirocumab and evolocumab in a face-to-face, controlled manner, this type of systematic review may provide a valuable guidepost for evaluating the efficacy of the 2 PCSK9 inhibitors.
The clinical studies evaluated by McDonagh et al were stratified based on the characteristics of the patient populations (eg, HeFH or HoFH with high CV risk, patients with varied CV risk). Based on the AHRQ’s strength-of-evidence criteria, alirocumab performed best in studies of patients at high CV risk, leading to greater reductions in LDL-C levels and more patients reaching defined goals for LDL-C (ie, <70 mg/dL). In patients with HeFH, most of whom were concurrently taking a statin and ezetimibe, the strength of evidence for a greater reduction in LDL-C was higher for evolocumab at either 140 mg biweekly or 420 mg monthly compared with placebo. Evolocumab in patients with HoFH concurrently taking a statin and ezetimibe was determined to significantly reduce LDL-C.23
To date, alirocumab has not been studied in patients with HoFH, which is reflected in the approved indications.15
The analysis of AE data concluded that no differences in safety were observed for either PCSK9 inhibitor compared with placebo, with the possible exception of injection-site reactions. Overall, the review by McDonagh et al concluded that “moderate to large” reductions in LDL-C were evident when a PCSK9 mAb is used in conjunction with statin therapy with or without ezetimibe. The authors caution that long-term benefits and risks of the PCSK9 inhibitors are generally unknown at this time.23
The reviews of PCSK9 inhibitor efficacy and safety studies provide evidence that alirocumab and evolocumab are effective at reducing LDL-C levels in at-risk populations. Although no direct comparison study is available, the meta-analyses seem to show that the compounds are almost comparable in their efficacy and safety. One major difference is that only evolocumab has shown efficacy in patients with HoFH. From the multiple studies, the results show that PCSK9 inhibitors may reduce LDL-C levels by at least 47% composite, compared with placebo (range: 23%-71%).24,25
No major concerns are evident with respect to AEs.
CV outcomes trials for PCSK9 inhibitors, which are longer in duration, add to the body of literature to evaluate safety and efficacy. The FOURIER trial enrolled 27,564 patients with established ASCVD on moderate- to-high-intensity statin therapy and added evolocumab at 140 mg every other week or 420 mg monthly, or placebo. The median duration of follow-up was 2.2 years, and there was a 15% reduction in the primary composite outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization with evolocumab compared with placebo (HR, 0.85; 95% CI, 0.79-0.92; P
The authors estimate that 74 patients would need to be treated with evolocumab for 2 years to prevent 1 CV death, MI, or stroke. There was no significant difference in CV death or death from any cause between evolocumab and placebo. Adverse events were similar between groups, including new-onset diabetes and neurocognitive events. Injection-site reactions were more common with evolocumab than with placebo (2.1% vs 1.6%).45
The ODYSSEY Outcomes trial, expected to be completed in December 2017, is evaluating alirocumab versus placebo on the occurrence of major adverse CV events in 18,000 patients who recently experienced an acute coronary syndrome.46
Dosage and Administration
The pharmacokinetics (PK) and pharmacodynamics (PD) of alirocumab and evolocumab guide their dosing requirements. As with many therapeutic antibodies, the PK and PD of alirocumab and evolocumab appear to be subject to the effects of target-mediated drug disposition (TMDD).47,48
Some characteristics of mAbs that are sensitive to TMDD include more rapid, nonlinear elimination at low doses with subsequent linear clearance at higher doses when the target is saturated.47
Gibbs et al developed a TMDD model using phase 1 study data to describe the PK and PD of evolocumab. The model, which included nonlinear evolocumab elimination mediated by PCSK9, satisfactorily predicted that 140 mg once every 2 weeks or 420 mg once every month (ie, the recommended dosages) would produce similar results in reduction of LDL-C levels.48
Using data from more than 2800 subjects, Djebli et al constructed a population-based, TMDD PK model for alirocumab as well as PCSK9.47
Because both alirocumab and evolocumab are approved for use in addition to maximally tolerated statin therapy, a concern regarding co-administration of mAbs and statins is the potential PK/PD drug interaction based on the effects of statins on PCSK9. Statins can raise PCSK9 levels49,50
and co-administration may increase the clearance of the PCSK9 mAb inhibitors. Similar concerns regarding co-administration of alirocumab and ezetimibe or fenofibrate were studied in healthy subjects with LCL-C levels >130 mg/dL. Co-administration led to increased clearance of alirocumab and a reduction in the duration of efficacy in LDL-C levels. The study authors, however, concluded that the observed effects would not prohibit the recommended dosing of alirocumab (ie, every 4 weeks) in individuals concurrently taking ezetimibe or fenofibrate.51
Both alirocumab and evolocumab are administered subcutaneously (SC). The recommended starting dose of alirocumab is 75 mg SC biweekly, (ie, once every 2 weeks) with up to a maximum 150 mg SC biweekly.15
Evolocumab dosing recommendations differ based on patient populations. For patients with HoFH, the recommended dose is 420 mg SC once per month; for other patients, including those with HeFH, the recommended dose is either 140 mg biweekly or 420 mg monthly.16
provides an overview of available products for alirocumab and evolocumab with storage recommendations.
With the variety of dosage forms available for each drug (Table15,16
), patients will require counseling on storage, administration, and disposal of the drug products. For alirocumab, the different strengths in each type of dosage form availability should require diligence in pharmacy dispensing to reduce medication errors. The manufacturers provide detailed videos and patient instructions on appropriate administration technique for the various dosage forms as a resource on their respective websites. One differentiating aspect between the 2 drugs is their stability. For alirocumab, the package insert advises against using the product if it has been stored at room temperature for more than 24 hours.15
Evolocumab can be stored for up to 30 days at room temperature.16
Investigational PCSK9 Inhibitors
Another mAb, bococizumab, reached phase 3 trials before its manufacturer discontinued development in November 2016. The decision was made based on unanticipated attenuation of LDL-C lowering over time, as well as a higher level of immunogenicity and rate of injection-site reactions compared with the other PCSK9 inhibitors.52
Pharmaceutical manufacturers are actively investigating other approaches, such as small interference RNA gene therapy, anti-PCSK9 vaccines, and small-molecule inhibition of PCSK9 binding or PCSK9 expression. Many of these investigational agents are in early stage development.
Recently, Ray et al reported on the results of the phase 2 ORION-1 Trial of the Small interfering RNA (siRNA) compound, inclisiran. The study was conducted in patients with elevated LDL-C levels who were at high risk for CVD. Of the 501 subjects who were randomized, 73% received statin therapy and 31%, ezetimibe. Regimens of a single-dose (200, 300, or 500 mg) or double-dose (100, 200, or 300 mg) were tested against placebo in a double-blind fashion. At the 180-day mark, substantial and statistically significant reductions in LDL-C were observed for all inclisiran treatment groups, with the greatest reduction in the 300-mg double-dose regimen (52.6%; 95% CI, 48.1%-57.1%).53
Although preliminary in scope, the positive results show promise for the siRNA approach directed at PCSK9.
PCSK9 Inhibitors Economic Concerns in the Managed Care Setting
Regarding the reduction of LDL-C, the efficacy of the PCSK9 inhibitors seems reasonably well established as described above. Similarly, the agents appear to be well tolerated with limited AEs in short-term studies. Whereas long-term safety and efficacy results remain to be collected and evaluated, cost must still be addressed, particularly in the managed care setting.
It is important to recognize that some of the other high-cost medications that appeared on the market recently for other conditions, such as hepatitis C or cancer, typically have a short duration of therapy, while the PCSK9 inhibitors are intended as lifelong therapy. The annual cost of treatment with alirocumab or evolocumab has been estimated at $14,000 to $15,000.54
Statins and other lipid-lowering therapies, while carrying a much lower annual cost, may not be adequate for some patient populations based on lack of tolerance, lack of sufficient PD response, and/or a genetic profile that does not respond to standard therapies.
Cost-benefit analyses of the use of PCSK9 inhibitors can help guide cost-management issues in the managed care setting.54-57
Conclusions of these analyses vary likely due to different model assumptions and inputs. Analyses by Arrieta et al and Kazi et al conclude that the current annual price of the PCSK9 inhibitors should be lowered to the range of $4250 to $4536 to be cost-effective.54,55
On the other hand, Toth et al and Gandra et al suggest that the pricing of evolocumab is justified under certain conditions by the value provided by the drug, particularly with respect to the potential reduction in CVD events.56,57
The Institute for Clinical and Economic Review has begun a New Evidence Update to its 2015 review of the comparative clinical effectiveness and value of PCSK9 inhibitors and will include a value-based price benchmark for evolocumab based on the FOURIER study.58
Prior authorization can be used as a mechanism to ensure that expensive medications are limited to patients most likely to derive benefit. Criteria must be put in place to ensure any PCSK9 inhibitor is being prescribed for an FDA-approved indication and to confirm that the patient has HeFH, HoFH, or clinical ASCVD rather than being used in patients with lower CV risk. Additional criteria may include patients who are receiving maximally tolerated statin therapy with or without addition of ezetimibe and whose lipids remain uncontrolled. Because statin therapy remains the mainstay of therapy for CV risk reduction, payers may request documentation of intolerance to multiple statins, including the dose and duration of therapy, before approving a PCSK9 inhibitor.
Baum et al examined approval rates for a PCSK9 inhibitor among Medicare and commercially insured patients in the IMS Formulary Impact analyzer database from July 26, 2015, to July 15, 2016. With more than 44,000 new prescriptions for PCSK9 inhibitors over the study period, the overall approval rate was 57% for Medicare patients and 30% for commercially insured patients. After approval, 60.3% of Medicare patients and 74.4% of commercial patients went on to fill the prescription.59
The lack of consensus around the value of PCSK9 inhibitors has led to some interesting contractual approaches to gaining formulary access. Amgen recently announced a value-based contract agreement with Harvard Pilgrim Health Care, where Amgen agreed to provide additional discounts if evolocumab fails to meet certain LDL-C reduction levels. If a patient has an MI while on evolocumab, the payer is eligible for a full rebate from Amgen for the cost of the medication. These value-based contracts may allow for improved access to high-cost medications that payers are reluctant to cover because of their cost.60,61
It is imperative that payers are good stewards of healthcare dollars. They need to explore the potential cost savings of reducing ASCVD events as additional clinical trial data become available compared with the cost of long-term use of PCSK9 inhibitors. The 2016 American College of Cardiology expert consensus decision pathway on the role of nonstatin therapies for LDL-C lowering can provide guidance on when it may be reasonable to consider therapy.1
Maximum tolerated statin therapy should remain the mainstay therapy for ASCVD reduction. Therefore, before starting a PCSK9 inhibitor, patients and clinicians should employ shared decision making regarding potential benefits for ASCVD risk reduction, AEs, cost, and patient willingness to use an injectable medication.
The advent of effective PCSK9 inhibitors offers new opportunities for the management of hypercholesterolemia, particularly in patients experiencing statin intolerance, as well as patients with HeFH or HoFH. Cost considerations will continue to be a major factor in the use of this relatively new drug class. Such economic factors could shift when other PCSK9 inhibitors are approved, either new types of inhibitors (eg, siRNA, vaccines, or orally administered drugs) or possible biosimilars. The long-term efficacy and safety evaluation of PCSK9 inhibitors must be studied more intently regarding its cost-benefit analysis in order to establish the role of this drug class in the management of hypercholesterolemia.