Both alirocumab and evolocumab have been evaluated in patients with

HeFH.

176–178 All patients in these studies were on maximally tolerated doses of

statins. In the combined studies evaluating alirocumab, patients had an average

baseline LDL-C of 141 mg/dL. Patients were treated for 12 weeks with alirocumab

75 mg every 2 weeks or placebo. At the end of the treatment period, the mean LDL-C

reduction observed with alirocumab was 48%. As with other studies with

alirocumab, if additional LDL-C lowering was needed patients were given an

additional 12 weeks of therapy with an increased dose of 150 mg every 2 weeks.

Following an additional 12 weeks of treatment, the mean LDL-C reduction from

baseline was 54% (p < 0.0001). Almost half (42%) of the study population received

the higher dose. Evolocumab was evaluated in the patient population in the

RUTHERFORD-2 trial.

178 Patients were randomized to receive 140 mg every 2

weeks of evolocumab, or 420 mg once monthly or placebo. The mean baseline LDLC was 156 mg/dL with 76% on high-intensity statin therapy. Following 12 weeks of

therapy, evolocumab reduced baseline LDL-C by 61% with twice-weekly dosing and

62% with monthly dosing (p < 0.0001).

Evolocumab has been studied in patients with HoFH in the Trial Evaluating

PCSK9 Antibody in Subjects with LDLReceptor Abnormalities (TESLA- Part B).

179

This was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial

in 49 patients. Patients received 420 mg monthly of evolocumab or placebo. The

mean LDL-C at baseline was 349 mg/dL. All patients were on either atorvastatin or

rosuvastatin with 92% also being on ezetimibe. Following 12 weeks of treatment

with evolocumab, the mean decrease in LDL-C from baseline was 31% (p < 0.0001).

PHARMACOKINETICS/PHARMACODYNAMICS

Alirocumab and evolocumab are both human monoclonal IGg2 antibodies and

therefore must be administered via subcutaneous injection to exert an effect.

Maximum suppression of PCSK9 occurs in approximately 4 hours with evolocumab

and 4 to 8 hours with alirocumab. Maximum serum concentrations reached in 3 to 4

days with evolocumab and 3 to 7 days with alirocumab. The volume of distribution

for both agents is small; therefore, these agents are expected to stay in the

extracellular space. Alirocumab is eliminated through degradation to small peptides

and amino acids while evolocumab is cleared based on its concentration. At low

concentrations it is cleared primarily thru saturable binding to PCSK9 and at higher

concentrations it is eliminated via a

p. 130

p. 131

non-saturable proteolytic pathway. The half-life of alirocumab is 17 to 20 days and

11 to 17 days for evolocumab.

ADVERSE EFFECTS

The most common adverse effects reported in the 52 weeks study with evolocumab

were nasopharyngitis, upper respiratory tract infection, influenza, back pain, and

injection site reactions. However, the difference in the incidence compared to

placebo is relatively small. The most common injection site reactions were erythema,

pain, and bruising. The most common adverse effect leading to discontinuation was

myalgia that occurred in 0.3% of evolocumab patients and 0% in those receiving

placebo. In pooled studies the types of adverse effects reported were relatively

similar. Allergic reactions occurred in 5.1% of evolocumab-treated patients and

4.6% in those treated with placebo. Neurocognitive events were reported in less than

0.2% of patients. Hypersensitivity reactions such as rash and urticaria were also

reported in 1% and 0.4%, respectively, with cases resulting in discontinuation of

therapy. The adverse reactions reported with alirocumab were nasopharyngitis,

injection site reactions, influenza, and urinary tract infection. The main adverse

effects associated with discontinuation were allergic reactions (0.6% vs. 0.2% for

placebo) and elevated liver enzymes (0.3% vs. <0.1% for placebo). Injection site

reactions were similar to those reported with evolocumab. Neurocognitive events

were reported in 0.8% of patients treated with alirocumab compared to 0.7% for

placebo. Hypersensitivity reactions also occurred with alirocumab. However,

hypersensitivity vasculitis as well as hypersensitivity reactions requiring

hospitalizations were reported with alirocumab but not with evolocumab.

Neutralizing antibodies were detected in 1.2% of patients treated with alirocumab,

and no cases were reported in patients taking evolocumab. However, the long-term

consequences from developing neutralizing antibodies are currently unknown.

PLACE IN THERAPY

Both alirocumab and evolocumab are indicated as an adjunct to diet and maximally

tolerated statin therapy in patients with HeFH or clinical ASCVD, who require

additional reductions in LDL-C. These agents should be considered as either add-on

therapy to patients already on statin therapy who need additional LDL-C lowering, or

in patients who are deemed statin intolerant.

100 Evolocumab is also indicated for use

in combination with other lipid-lowering therapies including LDL apheresis in

patients with HoFH who require additional lowering in LDL-C. Alirocumab is

administered as a dose of 75 mg every 2 weeks and may be increased in 4 to 8 weeks

to 150 mg every 2 weeks if additional LDL-C lowering is required. Evolocumab is

dosed at 140 mg every 2 weeks or 420 mg once monthly for HeFH and those with

primary hypercholesterolemia with clinical ASCVD. In patients with HoFH, the dose

is 420 mg once monthly. Alirocumab has only been studied in patients over the age of

18, while evolocumab may be used in the adolescent population with HoFH aged 13

to 17. Neither agent requires a dose adjustment in patients with mild to moderate

renal insufficiency. No data are available for patients with CrCl < 30 mL/minute.

Since these proteins do not rely upon the kidneys as a method of excretion, they can

likely be used in patients with low CrCl, including those undergoing hemodialysis.

However, the PCSK9 inhibitors have not been studied in this patient population.

Additionally, since they are large molecules, it is unlikely they would be removed by

hemodialysis. No dose adjustment is necessary in patients with hepatic impairment.

CLINICAL PEARLS

Allow evolocumab injections to warm at room temperature for at least 30 minutes

prior to use and alirocumab 30 to 40 minutes prior to use.

Do not warm evolocumab by any other means than setting at room temperature (e.g.,

rolling between hands).

If you miss a dose of evolocumab and the time to next dose is greater than 7 days,

administer the dose. If less than 7 days, hold the dose and get back on usual

schedule.

Evolocumab and alirocumab may be injected into the thigh, abdomen, or upper arm.

Evolocumab can remain at room temperature but expires in 30 days.

Alirocumab should not be left unrefrigerated for greater than 24 hours.

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A full list of references for this chapter can be found at

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