Coverage Policy Manual
Policy #: 2021027
Category: Pharmacy
Initiated: April 2021
Last Review: September 2024
  Evinacumab-dgnb (e.g., Evkeeza)
Description:
Evinacumab-dgnb is an ANGPTL3 (angiopoietin-like 3) inhibitor. ANGPTL3 is a protein that plays a key role in lipid metabolism by inhibiting lipoprotein lipase, which is the main enzyme involved in hydrolysis of triglyceride-rich lipoproteins, resulting in increased triglycerides and other lipids. Scientists found that individuals whose ANGPTL3 gene did not function properly had significantly lower levels of blood lipids.
 
Approximately 1 in 300,000 people have the rare genetic disorder homozygous familial hypercholesterolemia (HoFH) which occurs when an individual inherits two FH genes from their parents, one from each parent. Normally, extra LDL (low density lipoprotein) cholesterol is removed by the liver via LDL receptors. HoFH causes the loss of function of the LDL receptors resulting in high LDL levels. Individuals with HoFH have LDL cholesterol levels over 400 mg/dL. This level is often much higher at birth. Additional signs/symptoms of HoFH include: xanthelasmas (yellowish deposits of cholesterol underneath the skin, usually found on or near the eyelids), xanthomas (yellowish-colored skin lesions containing cholesterol and fats), and corneal arcus (cholesterol deposits in the outer edge of cornea). HoFH can lead to heart disease and heart attack at a young age. To lower cholesterol, multiple lipid lowering medications and LDL apheresis may be administered. However, some individuals with this condition are still unable to reach guideline recommended LDL cholesterol levels. Evinacumab-dgnb reduces LDL, high-density lipoprotein (HDL), and triglycerides. It is indicated as an adjunct to LDL cholesterol lowering therapies for the treatment of adults and pediatric individuals, aged 12 years and older, with HoFH (Evkeeza, 2021).
 
Evinacumab-dgnb does not carry a black box warning. However, adverse reactions, including nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea, could occur. Serious hypersensitivity reactions including anaphylaxis are also possible. This medication can also result in fetal harm when administered to pregnant women (Evkeeza, 2021).
 
Regulatory Status
 
Evinacumab-dgnb (e.g., Evkeeza) was approved by the U.S. Food and Drug Administration (FDA) on February 11, 2021 as an adjunct to other LDL cholesterol lowering therapies to treat adult and pediatric individuals 12 years of age and older with homozygous familial hypercholesterolemia (HoFH).
 
Limitations of Use:
    • The safety and effectiveness of Evinacumab-dgnb have not been established in individuals with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH) (Evkeeza, 2021).
    • The effects of Evinacumab-dgnb on cardiovascular morbidity and mortality have not been determined (Evkeeza, 2021).  
 
On March 21, 2023, the U.S. Food and Drug Administration (FDA) expanded the indication for evinacumab-dgnb (e.g., Evkeeza), as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of individuals with homozygous familial hypercholesterolemia (HoFH), previously limited to adult and pediatric individuals, aged 12 years and older, to now also include pediatric individuals aged 5 to 11 years with HoFH.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective April 21, 2021, Prior Approval is required for Evinacumab-dgnb (e.g., Evkeeza).
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective October 4, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW may be approved for 3 months:
 
Evinacumab-dgnb (e.g., Evkeeza) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
FAMILIAL HYPERCHOLESTEROLEMIA
 
1. Individual is 5 years of age or older (Evkeeza, 2023); AND
2. Individual has a diagnosis of homozygous familial hypercholesterolemia (HoFH) confirmed by either of the following (Raal, 2020):
a. Presence of two mutant alleles at the LDLR, apoB, PCSK9 or ARH adaptor protein (LDLRAP1) gene locus; OR
b. Presence of the following:
i. Untreated LDL-C greater than or equal to 500 mg/dL; OR
ii. Treated LDL-C greater than or equal to 300 mg/dL; AND one of the following:
1. Cutaneous or tendonous xanthoma before age of 10 years; OR
2. Untreated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents (greater than 250 mg/dL); AND
3. Individual has an LDL-C of greater than 100 despite optimal compliance for 90 days of all of the following (“a”, “b”, and “c”):
a. High intensity statin at the maximum tolerated dose (high intensity statin is defined as atorvastatin 40 mg or higher OR rosuvastatin 20 mg or higher) OR one of the following (AHA/ACC, 2018):
i. Individual is unable to tolerate at least two statins (with at least one started at the lowest starting daily dose) demonstrated by adverse effects associated with statin therapy that resolve or improve with dose reduction or discontinuation (NLA, 2022); OR
ii. Individual has statin associated rhabdomyolysis or immune-medicated necrotizing myopathy (IMNM) after a trial of one statin; OR
iii. Individual has documented anaphylactic reactions to two high intensity statins; OR
iv. Individual has a contraindication for statin therapy including but not limited to active liver disease, unexplained persistent elevation of hepatic transaminases or pregnancy; AND
b. Ezetimibe (AHA/ACC, 2018) OR individual has a documented contraindication or intolerance to ezetimibe; AND
c. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor therapy OR one of the following (AHA/ACC, 2018):
i. Individual has a documented contraindication or intolerance to ALL PCSK9 inhibitor therapies [i.e., evolocumab (e.g., Repatha) and alirocumab (e.g., Praluent)]; OR
ii. Documentation that individual has two LDL-receptor negative alleles (NLA, 2017); AND
4. Individual remains on other traditional low-density lipoprotein-cholesterol (LDL-C) lowering therapies (e.g., maximally tolerated statins, ezetimibe) in combination with Evkeeza if no contraindication or intolerance is documented; AND
5. None of the below exclusion criteria exist:
a. No concurrent use of lipid apheresis; AND
b. No concurrent use of lomitapide; AND
6. Evinacumab-dgnb (e.g., Evkeeza) is prescribed by a physician with expertise in lipid management of individuals with familial hypercholesterolemia. (Raal, 2020); AND
7. Must be dosed in accordance with FDA label.
 
CONTINUED APPROVAL for up to 12 months:
 
1. The individual is compliant with use of evinacumab; AND
2. There is evidence of significant reduction in LDL-cholesterol from baseline value on maximal medical therapy; AND
3. Individual remains on other traditional low-density lipoprotein-cholesterol (LDL-C) lowering therapies (e.g., maximally tolerated statins, ezetimibe) in combination with Evkeeza (if no contraindication or intolerance is documented as outlined in the initial criteria); AND
4. None of the below exclusion criteria exist:
a. No concurrent use of lipid apheresis; AND
b. No concurrent use of lomitapide
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of evinacumab-dgnb is 15 mg/kg administered by IV infusion once monthly (every 4 weeks).
 
Evinacumab-dgnb is available as 345 mg/2.3 mL (150 mg/mL) and 1,200 mg/8 mL (150 mg/mL) solution in single-dose vials.
 
Evinacumab-dgnb should be administered as an intravenous infusion by a healthcare professional.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Evinacumab-dgnb (e.g., Evkeeza) for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of evinacumab-dgnb for any indication or circumstance not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 1, 2022 to October 2, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of evinacumab-dgnb meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
    • Individual is 12 years of age or older (Raal, 2020; FDA, 2021) AND
    • Individual has a diagnosis of homozygous familial hypercholesterolemia (HoFH) confirmed by either of the following:
 
      • Genetic confirmation as below (Raal, 2020):
        • two known pathogenic (homozygous or compound heterozygous) variant LDLR alleles, OR
        • two known pathogenic (homozygous or compound heterozygous) variant alleles in APOB or PCSK9, OR
        • two known pathogenic (homozygous or compound heterozygous) variant alleles in LDLRAP1
 
OR
 
      • Clinical confirmation (Raal, 2020):
An untreated LDL-C > 500 mg/dL with either
            • Cutaneous or tendon xanthoma before age 10 years OR
            • Documentation of total cholesterol > than 250 mg/dL in both parents,
 
AND
 
    • The member is on maximal therapy consisting of a) maximal tolerated dose of a high-intensity statin (e.g. rosuvastatin or atorvastatin) + b) ezetimibe + c) PCSK9 inhibitor with evidence of optimal compliance for 90 days with an LDL > 100 mg/dl on treatment. (Raal, 2020) AND
    • None of the below exclusion criteria exist:
        • No concurrent use of lipid apheresis AND
        • No concurrent use of lomitapide AND
    • Equal or below a maximum dosage of 15 mg/ kg (based on a confirmed weight with estimate of lean body mass) administered no more often than every 4 weeks IV when prescribed by a physician with expertise in lipid management of individuals with familial hypercholesterolemia. (Raal, 2020)
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Concurrent review:
 
Initial treatment requests may be approved for 3 months.
 
Continuation of therapy following the 3-month initial treatment meets primary coverage criteria when all of the following apply:
 
    • The member is compliant with use of evinacumab AND
    • There is evidence of significant reduction in LDL-cholesterol from baseline value on maximal medical therapy AND
    • The member remains on maximal medical therapy (as defined above) AND
    • None of the below exclusion criteria exist:
      • No concurrent use of lipid apheresis AND
      • No concurrent use of lomitapide
 
Annual review is required for continued treatment.
 
Dosage and Administration
 
The recommended dose of evinacumab-dgnb is 15 mg/kg administered by IV infusion once monthly (every 4 weeks).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of evinacumab-dgnb does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not listed above or if the above criteria are not met.
 
For members with contracts without primary coverage criteria, the use of evinacumab-dgnb for any indication not listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective April 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of evinacumab-dgnb (Evkeeza) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when ALL of the following criteria are met:
 
    • Individual is 12 years of age or older AND
    • Individual has a diagnosis of homozygous familial hypercholesterolemia (HoFH) confirmed by either of the following:
 
      • Genetic confirmation as below:
        • two known pathogenic (homozygous or compound heterozygous) variant LDLR alleles, OR
        • two known pathogenic (homozygous or compound heterozygous) variant alleles in APOB or PCSK9, OR
        • two known pathogenic (homozygous or compound heterozygous) variant alleles in LDLRAP1
 
OR
 
      • Clinical confirmation:
An untreated LDL-C > 500 mg/dL with either
            • Cutaneous or tendon xanthoma before age 10 years OR
            • Documentation of total cholesterol > than 250 mg/dL in both parents,
 
AND
 
    • The member is on maximal therapy consisting of a) maximal tolerated dose of a high-intensity statin (e.g. rosuvastatin or atorvastatin) + b) ezetimibe + c) PCSK9 inhibitor with evidence of optimal compliance for 90 days with an LDL > 100 mg/dl on treatment. AND
    • None of the below exclusion criteria exist:
        • No concurrent use of lipid apheresis AND
        • No concurrent use of lomitapide AND
    • Equal or below a maximum dosage of 15 mg/ kg (based on a confirmed weight with estimate of lean body mass) administered no more often than every 4 weeks IV when prescribed by a physician with expertise in lipid management of individuals with familial hypercholesterolemia.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Concurrent review:
 
Initial treatment requests may be approved for 3 months.
 
Continuation of therapy following the 3-month initial treatment meets primary coverage criteria when all of the following apply:
 
    • The member is compliant with use of evinacumab AND
    • There is evidence of significant reduction in LDL-cholesterol from baseline value on maximal medical therapy AND
    • The member remains on maximal medical therapy (as defined above) AND
    • None of the below exclusion criteria exist:
      • No concurrent use of lipid apheresis AND
      • No concurrent use of lomitapide
 
Annual review is required for continued treatment.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of evinacumab-dgnb (Evkeeza) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not listed above or if the above criteria are not met.
 
For members with contracts without primary coverage criteria, the use of evinacumab-dgnb (Evkeeza) for any indication not listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
A phase 2, proof-of-concept study (NCT02265952) demonstrated that evinacumab, a fully human monoclonal antibody to ANGPTL3, reduced LDL-C (low density lipoprotein- cholesterol) levels in 9 patients with genotypically confirmed homozygous familial hypercholesterolemia (Banerjee, 2019). The results suggest that evinacumab is effective in lowering LDL-C in patients with homozygous familial hypercholesterolemia, and the inhibition of ANGPTL3 in humans lowers LDL-C in a mechanism independent of the LDL receptor.
 
A phase 3, randomized, placebo-controlled, parallel-group trial (NCT03399786) was conducted on patients with HoFH (Raal, 2020). This trial (Elipse HoFH trial) was conducted at 30 sites in 11 countries. 43 patients received evinacumab and 22 received placebo. One member in the placebo group was given evinacumab in error at week 20. Therefore, they were included in the evinacumab group. The majority of trial patients received a statin (94%). At week 24, 47.1% reduction in LDL from baseline was noted in the evinacumab group compared to a 1.9% increase in placebo group. Evinacumab-dgnb (Evkeeza) is the first FDA-approved treatment that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3).
The above represent surrogate makers of effectiveness.  Continued approval of this product will depend on the proof of meaningful net health outcomes (e.g. improvement in deaths or a composite cardiovascular outcome) in ongoing studies.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023.
 
October 2023 Update
Trial R1500-CL-17100 (NCT04233918; Trial 3) was a multicenter, three-part, single-arm, open label trial in pediatric patients aged 5 to 11 years with HoFH. Part B of this trial evaluated the efficacy of EVKEEZA 15 mg/kg given intravenously every 4 weeks as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, lomitapide, and lipoprotein apheresis) for 24 weeks in 14 patients with HoFH.
 
In Part B, the mean LDL-C at baseline was 264 mg/dL. At baseline, 86% of patients were on statins, 93% on ezetimibe, 14% on lomitapide, and 50% were receiving lipoprotein apheresis. The mean age at baseline was 9 years (range 5 to 11); 57% females; 0% Hispanic; 57% White, 14% Asian, 7% Black or African American, 7% American Indian or Alaska Native, and 14% other races. Mean body weight was 40 kg. Body mass index (BMI) was 20 kg/m2. Endpoint Results The primary efficacy endpoint was percent change in calculated LDL-C from baseline to Week 24. At Week 24, the mean percent change in calculated LDL-C from baseline was −48% (95% confidence interval: −69% to −28%). HDL-C and TG reductions observed in this trial were similar to changes seen in Trial 1. At Week 24, the reduction in LDL-C with EVKEEZA was similar across baseline characteristics, including age, sex, limited LDLR activity, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, and lomitapide). (FDA, 2023)
 
2024 Update
Results from long-term safety and efficacy trial NCT03399786 have been published in July 2024. In this open-label, single-arm, Phase 3 trial, individuals aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. A total of 116 individuals (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Individuals were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.
 
CPT/HCPCS:
C9079Injection, evinacumab-dgnb, 5 mg
J1305Injection, evinacumab-dgnb, 5mg
J3490Unclassified drugs
J3590Unclassified biologics
References: Banerjee, P., Chan, K. C., Tarabocchia, M., Benito-Vicente, A., Alves, A. C., Uribe, K. B., Bourbon, M., Skiba, P. J., Pordy, R., Gipe, D. A., Gaudet, D., & Martin, C.(2019) Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activity. Arteriosclerosis, thrombosis, and vascular biology, 39(11), 2248–2260. https://doi.org/10.1161/ATVBAHA.119.313051

Evkeeza (evinacumab-dgnb) [prescribing information]. Tarrytown, NY. Regeneron Pharmaceuticals, Inc. 2021.

Grundy SM, Stone NJ, Bailey AL, et al.(2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/APhA/ASPC/NLA/ PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285–350.

Orringer CE, Jacobson TA, Saseen JJ, et. al.(2017) Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association (NLA). ). J Clin Lipidol. 2017 Jul-Aug;11(4):880-890.

Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D;(2020) ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947.

U.S. Food and Drug Administration (FDA).(2021) Evkeeza. Prescribing Information. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf.Last accessed August 17, 2021.

U.S. Food and Drug Administration (FDA).(2023) Evkeeza. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761181s001lbl.pdf. Last accessed September 8, 2023.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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