Evinacumab-dgnb (Evkeeza)

Number: 0989

Policy

Note: Requires Precertification  

Precertification of evinacumab-dgnb (Evkeeza) is required of all Aetna participating providers and members in applicable plan designs. For precertification of evinacumab-dgnb (Evkeeza), call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies.  For information on site of service for evinacumab-dgnb (Evkeeza), see Utilization Management Policy on Site of Care for Specialty Drug Infusions

  1. Criteria for Initial Approval

    Aetna considers evinacumab-dgnb (Evkeeza) medically necessary for treatment of homozygous familial hypercholesterolemia (HoFH) when all of the following criteria are met:

    1. Member has a documented diagnosis of homozygous familial hypercholesterolemia confirmed by any of the following criteria:

      1. Functional mutation or mutations in both low-density lipoprotein (LDL) receptor alleles; or
      2. Presence of homozygous or compound heterozygous mutations in apolipoprotein B (APOB) or PCSK9; or
      3. Member is double heterozygous (i.e., mutations on different genes [e.g., LDLR/PCSK9]) or homozygous for LDL receptor adaptor protein 1 (LDLRAP1) mutations; or
      4. History of an untreated total cholesterol level of greater than 500 mg/dL and either of the following:

        1. Presence of cutaneous or tendinous xanthomas before the age of 10 years; or
        2. An untreated total cholesterol level of more than 250 mg/dL in both parents; and
    2. Prior to initiation of treatment with the requested medication, both of the following criteria are/were met:

      1. Member has a current LDL-C level of at least 70 mg/dL; and
      2. Member is receiving stable treatment with at least 3 lipid-lowering therapies (e.g., statins, ezetimibe, PCSK9 inhibitors) at the maximum tolerated dose; and
    3. Member will continue to receive concomitant lipid-lowering therapy; and
    4. Member is 12 years of age or older.

    Aetna considers all other indications as experimental and investigational.

  2. Continuation of Therapy

    Aetna considers continuation of evinacumab-dgnb (Evkeeza) therapy medically necessary for members (including new members) who meet all of the following criteria:

    1. Member meets all initial authorization criteria; and
    2. Member has achieved or maintained an LDL-C reduction (i.e., LDL-C is now at goal or 40% reduction of LDL-C from baseline); and
    3. Member is currently receiving concomitant lipid-lowering therapy.

Dosage and Administration

Evinacumab-dgnb is available as Evkeeza which is supplied as 345 mg/2.3 mL (150 mg/mL) and 1,200 mg/8 mL (150 mg/mL) solution in single-dose vials for intravenous (IV) infusion.

Homozygous familial hypercholesterolemia (HoFH)

The recommended dose of Evkeeza is 15 mg/kg administered by IV infusion over 60 minutes once monthly (every 4 weeks).

Source: Regenron, 2021a

Background

U.S. Food and Drug Administratin (FDA)-Approved Indications

  • Evkeeza is indicated as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and pediatric patients, aged 12 years and older, with homozygous familial hypercholesterolemia (HoFH).
  • Limitations of Use:

    • The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH).
    • The effects of Evkeeza on cardiovascular morbidity and mortality have not been determined.

Evinacumab-dgnb is available as Evkeeza (Regeneron Pharmaceuticals, Inc.). Evkeeza is an angiopoietin-like (ANGPTL3) inhibitor. Evinacumab-dgnb is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3, which is a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). Evinacumab-dgnb inhibition of ANGPTL3 leads to reduction in LDL-C, HDL-C, and triglycerides (TG). Evinacumab-dgnb reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting very low-density lipoprotein (VLDL) processing and clearance upstream of LDL formation. Evinacumab-dgnb blockade of ANGPTL3 lowers TG and HDL-C by rescuing LPL and EL activities, respectively (Regeneron, 2021a).  

Evinacumab-dgnb (Evkeeza) carries the following warnings and precautions:

  • Serous hypersensitivity reaction. In clinical trials, 1 (1%) evinacumab-treated patient experienced anaphylaxis versus 0 (0%) patients who received placebo. 
  • Embryo-fetal toxicity. Administration of evinacumab to rabbits during organogenesis caused increases in fetal malformations at doses below the human exposure. The Precribing Information recommends to advise patients who may become pregnant of the risk to a fetus and to use effective contraception during treatment with evinacumab-dgnb, and for at least 5 months following the last treatment dose.

The most common adverse reactions (5% or more) include nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea.

Homozygous Familial Hypercholesterolemia 

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition in which a person has a significantly elevated low-density lipoprotein cholesterol (LDL-C), typically greater than 400mg/dL, which increases the risk of early onset atherosclerotic disease (severe vascular disease including coronary artery disease (CAD) and aortic stenosis).  HoFH is usually identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL-C. Vascular events can be seen in the teenage years, and without aggressive treatment, mortality is common before age 30 (NORD, 2020).

HoFH is caused when a person inherits two copies of the familial hypercholesterolemia (FH)-causing genes, one from each parent. Research suggests individuals with FH that have variants in different genes (LDLR, APOB, PCSK9) or of different types of DNA changes may have different individual risks. However, due to a wide enough variation among those data sets, it can be difficult to provide personalized risk information by one’s genotype (NORD, 2020).  

de Ferranti (2020) states that pediatrics diagnosed with homozygous FH based on phenotype (i.e., untreated LDL-C 500 mg/dL or greater) or genetic testing, should be managed by a pediatric lipid specialist and a pediatric cardiologist. Management of children and adolescents with HoFH has included a combination of statin, ezetimibe, anti-PCSK9 therapy, lomitapide and/or LDL apheresis. Among experts, there are differences in opinion regarding the target LDL-C goal. Values between less than 50 mg/dL and 135 mg/dL have been articulated. "However, values at the low end of this range may be difficult if not impossible to achieve even with multiple cholesterol-lowering drugs. This is due to the fact that they usually depend on the presence of the LDL receptor, which is absent or nearly absent" in patients with HoFH (Rosenson and Durrington, 2020).

Rosenson and Durrington (2020) state that all adult patients with HoFH should receive care from a lipid expert. Adults with HoFH, who have untreated LDL-C values greater than 500 mg/dL, are at very high risk of developing potentially lethal atherosclerotic cardiovascular disease at a very young age. The treatment approach for this population is with intensive LDL-C lowering. In addition to a high-dose statin (atorvastatin 80 mg daily or rosuvastatin 40 mg daily), most homozygous patients will require additional therapies such as ezetimibe, a PCSK9 inhibitor, or potentially LDL-C apheresis.

In February 2021, the U.S. FDA approved Evkeeza (evinacumab-dgnb) as an adjunct to other LDL-C lowering therapies to treat adult and pediatric patients aged 12 years and older with HoFH. FDA approval is based on results from the ELIPSE-HoFH (NCT03399786) trial, which was a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of evinacumab compared to placebo in 65 patients with HoFH. 

Raal et. al. (2020) state that loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease, and that evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. In the ELIPSE-HoFH trial, the investigators randomly assigned, in a 2:1 ratio, 65 patients with diagnosis of HoFH who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight; n=43) every 4 weeks or placebo (n=22). The diagnosis of HoFH was determined by genetic testing or by the presence of the following clinical criteria: history of an untreated total cholesterol (TC) greater than 500 mg/dL and either xanthoma before 10 years of age or evidence of TC greater than 250 mg/dL in both parents. In this trial, 40% (26 of 65) patients had limited LDL receptor (LDLR) function, defined by either less than 15% receptor function by in vitro assays or by genetic variants likely to result in minimal to no LDLR function by mutation analysis. Patients were required to be on other lipid-lowering therapies, including maximally tolerated statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis. The mean baseline LDL-C level in the two groups was 255 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. The primary outcome was the percent change from baseline in the LDL-C level at week 24. The investigators found that the at week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL-C level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; p<0.001); the between-group least-squares mean absolute difference in the LDL-C level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; p<0.001). The LDL-C level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. After the 24 week double-blind treatment period, 64 of 65 patients entered a 24-week open-label extension period in which all patients received evinacumab 15 mg/kg IV every 4 weeks. After 24 weeks of open-label evinacumab treatment (Week 24 to Week 48), the observed LDL-C reduction from baseline was similar in patients who crossed over from placebo to evinacumab, and was maintained in patients who remained on evinacumab for 48 weeks (Raal et. al., 2020; Regeneron, 2021a).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB:

96365 – 96368 Intravenous infusion, for therapy, prophylaxis

HCPCS codes covered if selection criteria are met:

C9079 Injection, evinacumab-dgnb, 5 mg

ICD-10 codes covered if selection criteria are met:

E78.01 Familial hypercholesterolemia

The above policy is based on the following references:

  1. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146-2157.
  2. de Ferranti SD. Familial hypercholesterolemia in children. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2020.
  3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC guideline on the management of blood cholesterol: Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. November 10, 2018.
  4. National Organization for Rare Disorders (NORD). Familial hypercholesterolemia. Rare Disease Database. Danbury, CT; 2020. Available at: https://rarediseases.org/rare-diseases/familial-hypercholesterolemia/. Accessed March 1, 2021.
  5. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383:711-20.
  6. Regeneron Pharmaceuticals, Inc. Evkeeza (evinacumab-dgnb) injection, for intravenous use. Prescribing Information. Tarrytown, NY: Regeneron; revised February 2021a.
  7. Regeneron Pharmaceuticals, Inc. FDA approves first-in-class Evkeeza (evinacumab-dgnb) for patients with ultra-rare inherited form of high cholesterol. PRNewswire. Tarrytown, NY: Regeneron; February 11, 2021b. 
  8. Rosenson RS, Durrington P. Familial hypercholesterolemia in adults: Treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2020.