Evinacumab-dgnb (Evkeeza)

Number: 0989

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses evinacumab-dgnb (Evkeeza) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

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, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

Note: Site of Care Utilization Management Policy applies for commercial plans.  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 members 5 years of age and older for the treatment of homozygous familial hypercholesterolemia (HoFH) when both of the following criteria are met:

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

      1. Variant in two low-density lipoprotein receptor (LDLR) alleles; or
      2. Presence of homozygous or compound heterozygous variants in apolipoprotein B (APOB) or proprotein covertase subtilisin-kexin type 9 (PCSK9); or
      3. Member has compound heterozygosity or homozygosity for variants in the gene encoding low-density lipoprotein receptor adaptor protein 1 (LDLRAP1); or
      4. An untreated LDL-C of greater than 400 mg/dL and either of the following:
         
         
         1. Presence of cutaneous or tendinous xanthomas before the age of 10 years; or
         2. An untreated LDL-C level of greater than or equal to 190 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 treated LDL-C of greater than or equal to 100 mg/dL (or greater than or equal to 70 mg/dL with clinical atherosclerotic cardiovascular disease [ASCVD]; and
      2. Member meets one of the following:
         

         1. Member is 10 years of age or older and meets both of the following:

            1. Member is receiving stable treatment with at least 3 lipid-lowering therapies (e.g., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] directed therapy) at the maximally tolerated dose; and
            2. Member will continue to receive concomitant lipid-lowering therapy at the maximally tolerated dose; or

         2. Member is 7 years of age to less than 10 years of age, and meets either of the following:

            1. Member is receiving stable treatment with at least one lipid-lowering therapy (e.g., statins, LDL apheresis) at the maximally tolerated dose and will continue to receive concomitant lipid-lowering therapy at the maximally tolerated dose; or
            2. Member has an intolerance or contraindication to other lipid-lowering therapies; or

         3. Member is 5 years of age to less than 7 years of age.

   Aetna considers all other indications as experimental, investigational, or unproven.  

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 meets one of the following:
      
      
      1. Member is 10 years of age or older and is currently receiving concomitant lipid-lowering therapy at the maximally tolerated dose; or
      2. Member is 7 years of age to less than 10 years of age and meets either of the following:
         
         
         1. Member is currently receiving concomitant lipid-lowering therapy at the maximally tolerated dose; or
         2. Member has an intolerance or contraindication to other lipid lowering therapies; or

      3. Member is 5 years of age to less than 7 years of age; and

   3. The member is receiving benefit from therapy. Benefit is defined as either of the following:

      1. LDL-C is now at goal; or
      2. Member has had at least 30% reduction of LDL-C from baseline.

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, 2023b

Experimental, Investigational, or Unproven

Aetna considers evinacumab as experimental, investigational, or unproven for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Treatment of chylomicronemia
• Treatment of hypertriglyceridemia
• Treatment of lipodystrophies.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
81401	Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, *2, *3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation a
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) ABCD1 (ATP-binding cassette, sub-family D [ALD], member 1) (eg, adrenoleukodystrophy), full gene sequence ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), full gene sequence ACTA2 (actin, alpha 2, smooth muscle, aorta) (eg, thoracic aortic aneurysms and aortic dissections), full gene sequence ACTC1 (actin, alpha, cardiac muscle 1)(eg, familial hypertrophic cardiomyopathy), full gene sequence ANKRD1 (ankyrin repeat domain 1) (eg, dilated cardiomyopathy), full gene sequence APTX (aprataxin) (eg, ataxia with oculomotor apraxia 1), full gene sequence ARSA (arylsulfatase A) (eg, arylsulfatase A deficiency), full gene sequence BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (eg, maple syrup urine disease, type 1A), full gene sequence BCS1L (BCS1-like [S. cerevisiae]) (eg, Leigh syndrome, mitochondrial complex III deficiency, GRACILE syndrome), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), duplication/deletion analysis CASQ2 (calsequestrin 2 [cardiac muscle]) (eg, catecholaminergic polymorphic ventricular tachycardia), full gene sequence CASR (calcium-sensing receptor) (eg, hypocalcemia), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), duplication/deletion analysis CHRNA4 (cholinergic receptor, nicotinic, alpha 4) (eg, nocturnal frontal lobe epilepsy), full gene sequence CHRNB2 (cholinergic receptor, nicotinic, beta 2 [neuronal])(eg, nocturnal frontal lobe epilepsy), full gene sequence COX10 (COX10 homolog, cytochrome c oxidase assembly protein) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence COX15 (CO
81406	Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), f
81407	Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), full gene sequence AGL (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) (eg, glycogen storage disease type III), full gene sequence AHI1 (Abelson helper integration site 1) (eg, Joubert syndrome), full gene sequence APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B) full gene sequence ASPM (asp [abnormal spindle] homolog, microcephaly associated [Drosophila]) (eg, primary microcephaly), full gene sequence CHD7 (chromodomain helicase DNA binding protein 7) (eg, CHARGE syndrome), full gene sequence COL4A4 (collagen, type IV, alpha 4) (eg, Alport syndrome), full gene sequence COL4A5 (collagen, type IV, alpha 5) (eg, Alport syndrome), duplication/deletion analysis COL6A1 (collagen, type VI, alpha 1) (eg, collagen type VI-related disorders), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), full gene sequence COL6A3 (collagen, type VI, alpha 3) (eg, collagen type VI-related disorders), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), full gene sequence KDM5C (lysine [K]-specific demethylase 5C) (eg, X-linked mental retardation), full gene sequence KIAA0196 (KIAA0196) (eg, spastic paraplegia), full gene sequence L1CAM (L1 cell adhesion molecule) (eg, MASA syndrome, X-linked hydrocephaly), full gene sequence LAMB2 (laminin, beta 2 [laminin S]) (eg, Pierson syndrome), full gene sequence MYBPC3 (myosin binding protein C, cardiac) (eg, familial hypertrophic cardiomyopathy), full gene sequence MYH6 (myosin, heavy chain 6, cardiac muscle, alpha)
82465	Cholesterol, serum or whole blood, total
83721	Lipoprotein, direct measurement; LDL cholesterol
96365 – 96368	Intravenous infusion, for therapy, prophylaxis
HCPCS codes covered if selection criteria are met:
J1305	Injection, evinacumab-dgnb, 5mg
Other HCPCS codes related to the CPB:
G9664	Patients who are currently statin therapy users or received an order (prescription) for statin therapy
ICD-10 codes covered if selection criteria are met:
E78.01	Familial hypercholesterolemia
ICD-10 codes not covered if selection criteria are met:
E78.1	Pure hyperglyceridemia
E78.3	Hyperchylomicronemia
E88.1	Lipodystrophy

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Background

U.S. Food and Drug Administration (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 5 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 high-density lipoprotein-cholesterol (HDL-C) by rescuing LPL and EL activities, respectively (Regeneron, 2023b).  

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 Prescribing 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, nausea, and fatigue.

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, 2023b).

In March 2023, the FDA extended the approval of Evkeeza as an adjunct to other lipid-lowering therapies to treat children aged 5 to 11 years old with HoFH. FDA approval was based on a multicenter, single-arm, open-label, phase 3 trial that evaluated the efficacy of Evkeeza in pediatric patients (n=14) aged 5 to 11 years old with HoFH and who had an average LDL-C level of 264 mg/dL. Patients were administered 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. The primary efficacy endpoint was percent change in calculated LDL-C from baseline to week 24. With the addition of Evkeeza, these pediatric patients were able to reduce their LDL-C by 48% at week 24 on average, meeting the trial’s primary endpoint. Significant reductions were also observed in other key secondary endpoints including levels of apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C) and total cholesterol. The safety profile observed in pediatric patients was consistent with the safety profile observed in adults, with the additional adverse reaction of fatigue (Regeneron, 2023a, 2023b, 2023c).

The European Atherosclerosis Society (EAS) 2023 Consensus Statement includes an update to the criterion for clinical diagnosis of homozygous familial hypercholesterolemia (HoFH). In 2014, the EAS consensus statement recommended that the LDL-C diagnostic criterion be greater than 500 mg/dL for untreated patients or greater than 300 mg/dL for patients treated with conventional therapy, as well as evidence of cutaneous or tendon xanthomas before the age of 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents. However, the panel noted there were confirmed HoFH cases in which LDL-C was less than 500 mg/dL. Thus, given the genetic complexity of HoFH and variability in LDL-C levels and clinical phenotype, the panel lowered the LDL-C recommendation to greater than 400 mg/dL. The EAS guideline now uses 400 mg/dL as cut off for starting evaluation for family history and genetic testing for HoFH.

Evinacumab Plus Lipoprotein Apheresis for the Treatment of Homozygous Familial Hypercholesterolemia

Duell et al (2022) noted that patients with homozygous FH have severe hypercholesterolemia from birth and if untreated may experience very early onset of CAD in childhood or young adulthood with an aggressive course resulting in early death.  Early initiation of aggressive LDL-C lowering is the mainstay of treatment, which requires the use of a multi-drug treatment regimen, often in combination with lipoprotein apheresis. However, LDL-C goal achievement is often unattainable due to the severity of baseline hypercholesterolemia and hypo-responsiveness to many LDL-C-lowering medications.  Evinacumab, a monoclonal antibody that sequesters angiopoietin-like 3 protein and lowers LDL-C by an average of 49 % in patients with homozygous FH, was approved by the FDA in February 2021 and is a major advance in treatment of these high-risk patients.  In this report, these researchers described the complementary role of evinacumab in combination with lipoprotein apheresis in 2 patients with homozygous FH.  The authors stated that although neither of these 2 patients was able to discontinue treatment with lipoprotein apheresis after initiating treatment with evinacumab, both achieved marked improvements in their lipid profile results that are likely to be clinically beneficial.  The preliminary findings need to be validated by well-designed studies.

Other Indications

Atherosclerotic Cardiovascular Disease

Gaine et al (2022) noted that the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on optimizing cardiovascular health and appropriate pharmacotherapy, a mainstay of which is lowering of LDL-C.  In general, statin therapy remains the 1st-line approach.  Advances in technology and understanding of lipid metabolism have facilitated the development of several novel therapeutic targets and medications within the past 10 years.  These investigators focused on medications recently approved by the FDA for the reduction of LDL-C and ASCVD risk, as well as new therapies in the pipeline.  Novel lipid therapies aim to lower risk of ASCVD by targeting reduction of atherogenic compounds, such as LDL, lipoprotein(a) (Lp(a)), and triglyceride-rich lipoproteins.  Evolocumab and alirocumab, monoclonal antibody proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, which lower LDL-C by approximately 60 %, have emerged as important therapies for use in patients with ASCVD as well as FH.  Bempedoic acid, an ATP citrate lyase inhibitor, is an oral medication recently approved that can lower LDL-C by approximately 18 % alone and 38 % when combined with ezetimibe.  Inclisiran, a small-interfering RNA (siRNA) molecule, which inhibits the translation of PCSK9, is the most recently FDA-approved LDL-C lowering medication; and can reduce LDL-C by approximately 50 % with twice-yearly subcutaneous dosing.  The cardiovascular (CV) outcome trials for bempedoic acid and inclisiran are still on-going.  Evinacumab, a monoclonal antibody which targets angiopoietin-like protein 3 (ANGPTL3), has been approved for use in patients with HoFH.  SiRNAs and anti-sense oligonucleotides (ASO) facilitating selective inhibition of the production of targeted proteins including Lp(a) and ANGLPTL3 are active areas of clinical investigation. 

Using a Monte Carlo simulation model, Gu et al (2022) estimated the number and proportion of very-high risk patients with ASCVD who would be able to achieve LDL-C of less than 70 mg/dL with various lipid-lowering therapies (LLTs), including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, and evinacumab.  With current therapeutic options for lowering LDL-C, including statin, ezetimibe, bempedoic acid, and PCSK9 inhibitors, it was estimated that most very-high risk patients with ASCVD (99.1 %) were able to achieve the LDL-C goal of less than 70 mg/dL.  Nevertheless, approximately 88,715 patients in the U.S. were estimated to be unable to achieve the LDL-C goal following current available LLTs, thus, remaining at elevated risk for recurrent CV events.  The authors concluded that evinacumab may be useful in addressing such unmet needs effectively, as the majority of those not at goal following PCSK9 inhibitors could achieve the goal of less than 70 mg/dL after taking evinacumab.

Chylomicronemia

Shamsudeen and Hegele (2022) stated that primary chylomicronemia is characterized by pathological accumulation of chylomicrons in the plasma causing severe hypertriglyceridemia, typically greater than 10 mmol/L (greater than 875 mg/dL).  Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies.  The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life (QOL).  New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis.  Antagonists of apolipoprotein (apo) C-III, such as the ASO volanesorsen, significantly reduce triglyceride levels in chylomicronemia.  However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia.  Newer apo C-III antagonists, namely, the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and siRNA ARO-APOC3, appeared to show effectiveness with less risk of thrombocytopenia.  Potential use of antagonists of ANGPTL3 such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined.  The authors concluded that emerging pharmacotherapies for chylomicronemia show promise, especially apo C-III antagonists; however, these treatments are still investigational.  These investigators stated that further investigation of the safety and effectiveness of these emerging pharmacotherapies in patients with both rare FCS and more common multi-factorial chylomicronemia is needed.

Hypertriglyceridemia

Ruscica and co-workers (2020) stated that among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of ANGPTL3 and ANGPTL4 in regulating the activity of LPL, antagonizing the hydrolysis of TG. Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants.  In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia.  In humans, loss-of-function mutations of ANGPTL3 were associated with a marked reduction of plasma levels of VLDL, LDL and HDL.  Carriers of loss-of-function mutations of ANGPTL4 showed instead lower TG-rich lipoproteins and a modest but significant increase of HDL.  The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets was proven by the development of monoclonal antibodies or antisense oligonucleotides.  Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induced activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects.  Inhibition of both targets also partially reduced LDL-C, independent of the LDL receptor.  Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX.  The authors concluded that genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias; and conclusive data of phase-II and phase-III clinical trials are still needed to define their safety and effectiveness profile. 

Toroghi and colleagues (2021) noted that a model to quantitatively characterize the effect of evinacumab (an investigational monoclonal antibody against ANGPTL3 on lipid trafficking) is needed.  A quantitative systems pharmacology (QSP) approach was developed to predict the transient responses of different TG-rich lipoprotein particles in response to evinacumab administration.  A previously published hepatic lipid model was modified to address specific queries relevant to the mechanism of evinacumab and its effect on lipid metabolism.  Modifications included the addition of intermediate-density lipoprotein and LDL compartments to address the modulation of LPL activity by evinacumab, ANGPTL3 biosynthesis and clearance, and a target-mediated drug disposition model.  A sensitivity analysis guided the creation of virtual patients (VPs).  The drug-free QSP model was found to agree well with clinical data published with the initial hepatic liver model over simulations ranging from 20 to 365 days in duration.  The QSP model, including the interaction between LPL and ANGPTL3, was validated against clinical data for total evinacumab, total ANGPTL3, and TG concentrations as well as inhibition of apolipoprotein CIII.  Free ANGPTL3 concentration and LPL activity were also modeled.  A total of 7 VPs were created; the lipid levels of the VPs were found to match the range of responses observed in evinacumab clinical trial data.  The QSP model results agreed with clinical data for various subjects and was shown to characterize known TG physiology and drug effects in a range of patient populations with varying levels of TGs, enabling hypothesis-testing of evinacumab effects on lipid metabolism.  

These researchers stated that although evinacumab is known to affect lipid metabolism by inhibiting ANGPTL3, with changes in plasma lipid concentrations mirroring the lipid phenotype observed in individuals with ANGPTL3 LOF variants, the detailed mechanism by which evinacumab modifies lipid metabolism is yet to be elucidated.  The QSP modeling platform provided a unique tool to allow different hypotheses to be tested.  For example, the model could be used to give reasonable estimates of LDL‐C, and with additional calibration and mechanisms could address fat accumulation in the liver, as occurs in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).  Furthermore, the model could be extended to represent cholesterol in TRL particles; thus, enabling the effects of statins to be modeled, allowing the investigation of combination therapies with statins or, for example, with ApoCIII inhibitors.  These investigators noted that further investigations are in progress to examine the drug effect on LDL‐C and TC as well as the differential effects of ANGPTL3 on LPL as it affects, for example, chylomicrons and VLDL/IDL/LDL TG metabolism. 

Surma and associates (2023) noted that angiopoietin-like proteins (ANGPTL) are involved in the regulation of numerous physiological and biochemical processes.  ANGPTL3, 4 and 8, which are involved in the regulation of lipoprotein metabolism, are especially important.  ANGPTL3, 4 and 8 have been shown to regulate TG availability depending on the nutritional status of the body.  Furthermore, a deficiency of these proteins has been found to cause hypolipidemia.  Increases in ANGPTL3, 4 and 8 appeared to be associated with cardiovascular risk.  Animal studies indicated that the use of ANGPTL3 (evinacumab) inhibitors significantly reduced plasma TC, TG and LDL concentrations.  The use of evinacumab in clinical trials also led to the normalization of plasma lipid concentrations in patients with atherogenic dyslipidemia and HoFH.  The authors concluded that the findings of these studies indicated that evinacumab may in the future be used in the treatment of lipid disorders, especially those with hypertriglyceridemia.

Lipodystrophies

Shamsudeen and Hegele (2022) stated that lipodystrophies are a group of rare, heterogeneous disorders characterized by a lack or maldistribution of adipose tissue.  Treatment focusses on the management of complications, including hypertriglyceridemia, which can be severe.  Patients are pre-disposed to early atherosclerotic cardiovascular disease and acute pancreatitis.  These investigators reviewed the recent advances in the treatment of lipodystrophies, with a particular focus on the treatment of hypertriglyceridemia in familial partial lipodystrophy (FPLD).  Treatment of dyslipidemia in FPLD requires management of secondary exacerbating factors, especially insulin resistance and diabetes, together with modification of atherosclerotic cardiovascular disease risk factors.  Furthermore, specific lipid-lowering therapies are usually needed, starting with statins and fibrates.  Several emerging treatments for hypertriglyceridemia include apo C-III antagonists (volanesorsen, AKCEA-APOCIII-LRx and ARO-APOC3) and angiopoietin-like 3 antagonists (evinacumab, vupanorsen and ARO-ANG3); efficacy observed in clinical trials of these agents in non-lipodystrophic patients with severe hypertriglyceridemia suggested that they may also be helpful in lipodystrophy.  The authors concluded that emerging therapies for dyslipidemia show promise in advancing the care of patients with lipodystrophy; however, these treatments are not yet approved for use in lipodystrophy.  These researchers stated that further study of their safety and effectiveness in this patient population is needed.

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